Edge Hill University
Cholesterol Metabolism: A Review of How Ageing Disrupts the Biological Mechanisms Responsible for its RegulationA. E. Morgan a, K. M. Mooney b, S. J. Wilkinson a, N. A. Pickles c, and M. T. Mc Auley aa Department of Chemical Engineering, University of Chester, Thornton Science Park, Chester, CH2 4NUb Faculty of Health and Social Care, Edge Hill University, Ormskirk, Lancashire, L39 4QPc Department of Biological Sciences, University of Chester, Parkgate Road, Chester, CH1 4BJAbstractCholesterol plays a vital role in the human body as a precursor of steroid hormones and bile acids, in addition to providing structure to cell membranes. Whole body cholesterol metabolism is maintained by a highly coordinated balancing act between cholesterol ingestion, synthesis, absorption, and excretion. The aim of this review is to discuss how ageing interacts with these processes. Firstly, we will present an overview of cholesterol metabolism. Following this, we discuss how the biological mechanisms which underpin cholesterol metabolism are effected by ageing. Included in this discussion are lipoprotein dynamics, cholesterol absorption/synthesis and the enterohepatic circulation/synthesis of bile acids. Moreover, we discuss the role of oxidative stress in the pathological progression of atherosclerosis and also discuss how cholesterol biosynthesis is effected by both the mammalian target of rapamycin and sirtuin pathways. Next, we examine how diet and alterations to the gut microbiome can be used to mitigate the impact ageing has on cholesterol metabolism. We conclude by discussing how mathematical models of cholesterol metabolism can be used to identify therapeutic interventions. KeywordsCholesterol, ageing, longevity, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), microbiome1.0 Introduction An intriguing feature of ageing, is that it is often accompanied by the dysregulation of whole body cholesterol metabolism ADDIN EN.CITE <EndNote><Cite><Author>Mc Auley</Author><Year>2014</Year><RecNum>143</RecNum><DisplayText>(Mc Auley and Mooney, 2014)</DisplayText><record><rec-number>143</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">143</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mc Auley, Mark T.</author><author>Mooney, Kathleen M.</author></authors></contributors><titles><title>Lipid metabolism and hormonal interactions: impact on cardiovascular disease and healthy aging</title><secondary-title>Expert Review of Endocrinology & Metabolism</secondary-title></titles><pages>357-367</pages><volume>9</volume><number>4</number><dates><year>2014</year><pub-dates><date>2014/07/01</date></pub-dates></dates><publisher>Taylor & Francis</publisher><isbn>1744-6651</isbn><urls><related-urls><url>;(Mc Auley and Mooney, 2014). A clinical manifestation of this process is an age-related rise in the plasma levels of low density lipoprotein cholesterol (LDL-C) ADDIN EN.CITE <EndNote><Cite><Author>Abbott</Author><Year>1983</Year><RecNum>181</RecNum><DisplayText>(Abbott et al., 1983)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abbott, R D</author><author>Garrison, R J</author><author>Wilson, P W</author><author>Epstein, F H</author><author>Castelli, W P</author><author>Feinleib, M</author><author>LaRue, C</author></authors></contributors><titles><title>Joint distribution of lipoprotein cholesterol classes. The Framingham study</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>260-72</pages><volume>3</volume><number>3</number><dates><year>1983</year><pub-dates><date>May 1, 1983</date></pub-dates></dates><urls><related-urls><url>;(Abbott et al., 1983). This rise in LDL-C has a significant impact on cardiovascular disease (CVD) risk, due to the association elevated plasma LDL-C has with the mechanisms which underpin atherosclerotic plaque formation ADDIN EN.CITE <EndNote><Cite><Author>Gould</Author><Year>2007</Year><RecNum>79</RecNum><DisplayText>(Gould et al., 2007)</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gould, A. Lawrence</author><author>Davies, Glenn M.</author><author>Alemao, Evo</author><author>Yin, Donald D.</author><author>Cook, John R.</author></authors></contributors><titles><title>Cholesterol reduction yields clinical benefits: meta-analysis including recent trials</title><secondary-title>Clinical Therapeutics</secondary-title></titles><pages>778-794</pages><volume>29</volume><number>5</number><keywords><keyword>cholesterol</keyword><keyword>coronary disease</keyword><keyword>3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors</keyword><keyword>hypercholesterolemia</keyword><keyword>meta-analysis</keyword></keywords><dates><year>2007</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0149-2918</isbn><urls><related-urls><url>;(Gould et al., 2007). Conversely, prospective studies have shown that high density lipoprotein (HDL) levels diminish with age ADDIN EN.CITE <EndNote><Cite><Author>Wilson</Author><Year>1994</Year><RecNum>37</RecNum><DisplayText>(Wilson et al., 1994)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">37</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wilson, P. W.</author><author>Anderson, K. M.</author><author>Harris, T.</author><author>Kannel, W. B.</author><author>Castelli, W. P.</author></authors></contributors><auth-address>Framingham Heart Study, Massachusetts.</auth-address><titles><title>Determinants of change in total cholesterol and HDL-C with age: the Framingham Study</title><secondary-title>J Gerontol</secondary-title></titles><periodical><full-title>J Gerontol</full-title><abbr-1>Journal of gerontology</abbr-1></periodical><pages>M252-7</pages><volume>49</volume><number>6</number><edition>1994/11/01</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aging/ metabolism</keyword><keyword>Alcohol Drinking</keyword><keyword>Body Mass Index</keyword><keyword>Cholesterol/ blood</keyword><keyword>Cholesterol, HDL/ blood</keyword><keyword>Cohort Studies</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Diuretics/therapeutic use</keyword><keyword>Estrogens/therapeutic use</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Sex Factors</keyword><keyword>Smoking</keyword></keywords><dates><year>1994</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-1422 (Print)
0022-1422 (Linking)</isbn><accession-num>7963277</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wilson et al., 1994). This is clinically significant, as HDLs are central to reverse cholesterol transport (RCT) ADDIN EN.CITE <EndNote><Cite><Author>Groen</Author><Year>2004</Year><RecNum>269</RecNum><DisplayText>(Groen et al., 2004)</DisplayText><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Groen, A. K.</author><author>Oude Elferink, R. P.</author><author>Verkade, H. J.</author><author>Kuipers, F.</author></authors></contributors><auth-address>AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands. A.K.groen@amc.uva.nl</auth-address><titles><title>The ins and outs of reverse cholesterol transport</title><secondary-title>Ann Med</secondary-title><alt-title>Annals of medicine</alt-title></titles><periodical><full-title>Ann Med</full-title><abbr-1>Annals of medicine</abbr-1></periodical><alt-periodical><full-title>Ann Med</full-title><abbr-1>Annals of medicine</abbr-1></alt-periodical><pages>135-45</pages><volume>36</volume><number>2</number><edition>2004/05/04</edition><keywords><keyword>ATP-Binding Cassette Transporters/metabolism</keyword><keyword>Animals</keyword><keyword>Bile/metabolism</keyword><keyword>Biological Transport</keyword><keyword>Cholesterol/*metabolism</keyword><keyword>Humans</keyword><keyword>Intestinal Absorption</keyword><keyword>Liver/metabolism</keyword></keywords><dates><year>2004</year></dates><isbn>0785-3890 (Print)
0785-3890</isbn><accession-num>15119833</accession-num><urls></urls><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(Groen et al., 2004). This process, which results in the trafficking of HDL-C, or the so-called ‘good cholesterol’ to the liver for subsequent removal via the intestine, represents the only way of eliminating excess cholesterol from peripheral tissue. There is a plethora of epidemiological evidence supporting an inverse relationship between HDL -C levels and CVD risk, and evidence has consistently shown that HDL-C levels are correlated with longevity in several population groups ADDIN EN.CITE <EndNote><Cite><Author>Ferrara</Author><Year>1997</Year><RecNum>180</RecNum><DisplayText>(Ferrara et al., 1997)</DisplayText><record><rec-number>180</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">180</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferrara, A.</author><author>Barrett-Connor, E.</author><author>Shan, J.</author></authors></contributors><auth-address>Department of Family and Preventive Medicine, University of California, San Diego, School of Medicine, La Jolla 92093-0607, USA.</auth-address><titles><title>Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984-1994</title><secondary-title>Circulation</secondary-title></titles><pages>37-43</pages><volume>96</volume><number>1</number><edition>1997/07/01</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/ physiology</keyword><keyword>Alcohol Drinking/adverse effects</keyword><keyword>Body Weight/physiology</keyword><keyword>California/epidemiology</keyword><keyword>Cholesterol/ blood</keyword><keyword>Cholesterol, HDL/ blood/drug effects</keyword><keyword>Cholesterol, LDL/ blood/drug effects</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Estrogen Replacement Therapy</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Linear Models</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Reference Values</keyword><keyword>Smoking/adverse effects</keyword><keyword>Thyroid Hormones/pharmacology</keyword></keywords><dates><year>1997</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0009-7322 (Print)
0009-7322 (Linking)</isbn><accession-num>9236414</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ferrara et al., 1997). It is therefore not surprising, that a healthy ageing phenotype has regularly been associated with the fine tuning of cholesterol metabolism, within certain cohorts of individuals who possess particular genetic variants in tandem with exceptional longevity ADDIN EN.CITE <EndNote><Cite><Author>Milman</Author><Year>2014</Year><RecNum>225</RecNum><DisplayText>(Milman et al., 2014)</DisplayText><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Milman, Sofiya</author><author>Atzmon, Gil</author><author>Crandall, Jill</author><author>Barzilai, Nir</author></authors></contributors><titles><title>Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity</title><secondary-title>Current vascular pharmacology</secondary-title></titles><pages>690-697</pages><volume>12</volume><number>5</number><dates><year>2014</year></dates><isbn>1570-1611
1875-6212</isbn><accession-num>PMC4087084</accession-num><urls><related-urls><url>;(Milman et al., 2014). For example, a three-fold increase in the prevalence of homozygosity for the favourable I405V polymorphism, a mutation in the cholesteryl ester transfer protein (CETP), a key enzyme involved in RCT has been observed in those exhibiting exceptional longevity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJ6aWxhaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA (Barzilai et al., 2003; Kulanuwat et al., 2015). Many key mechanisms involved in cholesterol metabolism are affected by ageing (Figure 1). For instance, ageing has been associated with a decline in the hepatic expression of cholesterol 7-alpha-hydroxylase (CYP7AI), a key regulator of bile acid synthesis, thus resulting in a decreased cholesterol demand for conversion to bile acids PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXJ0b2xvdHRpPC9BdXRob3I+PFllYXI+MjAwNzwvWWVh
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Tm90ZT5=
ADDIN EN.CITE.DATA (Bertolotti et al., 2007). Furthermore, there is a decline in hepatic LDL receptors (LDLr) with age, leading to a reduction in LDL-C clearance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYXI8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Duan et al., 2006). In addition, there is a decline in the predominant bacterial populations that play a role in the enterohepatic circulation of bile acids ADDIN EN.CITE <EndNote><Cite><Author>Hopkins</Author><Year>2002</Year><RecNum>44</RecNum><DisplayText>(Hopkins and Macfarlane, 2002)</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hopkins, M. J.</author><author>Macfarlane, G. T.</author></authors></contributors><auth-address>MRC Microbiology and Gut Biology Group, University of Dundee Medical School. m.j.hopkins@dundee.ac.uk</auth-address><titles><title>Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection</title><secondary-title>J Med Microbiol</secondary-title></titles><pages>448-54</pages><volume>51</volume><number>5</number><edition>2002/05/07</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Bacteroides/isolation & purification</keyword><keyword>Bifidobacterium/isolation & purification</keyword><keyword>Clostridium/isolation & purification</keyword><keyword>Clostridium Infections/ microbiology</keyword><keyword>Clostridium difficile/isolation & purification</keyword><keyword>Diarrhea/ microbiology</keyword><keyword>Enterobacteriaceae/isolation & purification</keyword><keyword>Enterococcus/isolation & purification</keyword><keyword>Eubacterium/isolation & purification</keyword><keyword>Feces/ microbiology</keyword><keyword>Humans</keyword><keyword>Lactobacillus/isolation & purification</keyword><keyword>Prevotella/isolation & purification</keyword></keywords><dates><year>2002</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-2615 (Print)
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ADDIN EN.CITE.DATA (Tao et al., 2013). These recent findings suggest that it is not one mechanism that is the central driver of cholesterol dysregulation with age, but rather a number of mechanisms interacting with one another to disrupt cholesterol metabolism. Therefore, it is important to view cholesterol metabolism and its relationship with ageing in an integrated way. In this review we will 1) discuss in depth how ageing impacts cholesterol metabolism, 2) discuss a number of the genes involved in cholesterol metabolism which have been implicated with longevity, 3) discuss the role of oxidative stress in disrupting cholesterol metabolism, 4) describe the role of caloric restriction (CR) in modulating cholesterol metabolism, 5) describe recent evidence that demonstrates the role mTOR and sirtuins play in cholesterol biosynthesis, 6) provide an overview of diet and its impact on cholesterol metabolism, 7) discuss the interactions between cholesterol metabolism and the gut microbiome, 8) propose therapeutic strategies based around the gut microbiome which could help to prevent the dysregulation of cholesterol metabolism with age, and lastly we will provide an overview of mathematical models that have been used to gain an increased insight into the dynamics of cholesterol metabolism.2.0 Overview of Cholesterol MetabolismCholesterol plays a vital role in the human body, as it is an essential component of all cell membranes. In addition, it is the precursor of steroid hormones, which control a range of physiological functions. Cholesterol is also the precursor to bile acids, which are necessary for the intestinal absorption of cholesterol, fats and lipophilic vitamins. Cholesterol can be obtained from the diet as well as being endogenously synthesised, the latter being the main source in humans ADDIN EN.CITE <EndNote><Cite><Author>Gylling</Author><Year>2004</Year><RecNum>54</RecNum><DisplayText>(Gylling, 2004)</DisplayText><record><rec-number>54</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">54</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gylling, H.</author></authors></contributors><titles><title>Cholesterol metabolism and its implications for therapeutic interventions in patients with hypercholesterolaemia</title><secondary-title>International Journal of Clinical Practice</secondary-title></titles><pages>859-866</pages><volume>58</volume><number>9</number><keywords><keyword>Cholesterol absorption</keyword><keyword>cholesterol synthesis</keyword><keyword>therapy</keyword><keyword>cardiovascular diseases</keyword></keywords><dates><year>2004</year></dates><publisher>Blackwell Science Ltd</publisher><isbn>1742-1241</isbn><urls><related-urls><url>;(Gylling, 2004). A subtle balancing act between ingestion, absorption, synthesis and excretion maintains whole body cholesterol metabolism (Figure 1). Briefly, 1) the average daily intake of cholesterol is 304 and 213mg/day, for males and females respectively, living in the UK ADDIN EN.CITE <EndNote><Cite><Author>Henderson</Author><Year>2003</Year><RecNum>48</RecNum><DisplayText>(Henderson et al., 2003)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">48</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Henderson, L.</author><author>Gregory, J.</author><author>Irving, K</author><author>Swan, G.</author></authors></contributors><titles><title>The National Diet & Nutrition Survey: adults aged 19 to 64 years</title></titles><volume>2</volume><dates><year>2003</year></dates><pub-location>Office for National Statistics</pub-location><urls><related-urls><url>;(Henderson et al., 2003). Of this, 85-90% is free cholesterol while 10-15% is in the esterified form ADDIN EN.CITE <EndNote><Cite><Author>Iqbal</Author><Year>2009</Year><RecNum>49</RecNum><DisplayText>(Iqbal and Hussain, 2009)</DisplayText><record><rec-number>49</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">49</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iqbal, Jahangir</author><author>Hussain, M. Mahmood</author></authors></contributors><titles><title>Intestinal lipid absorption</title><secondary-title>American Journal of Physiology - Endocrinology and Metabolism</secondary-title></titles><pages>E1183-E1194</pages><volume>296</volume><number>6</number><dates><year>2009</year><pub-dates><date>01/21
11/07/received
01/19/accepted</date></pub-dates></dates><publisher>American Physiological Society</publisher><isbn>0193-1849
1522-1555</isbn><accession-num>PMC2692399</accession-num><urls><related-urls><url>;(Iqbal and Hussain, 2009). Ingested cholesterol then enters the small intestine, where absorption occurs ADDIN EN.CITE <EndNote><Cite><Author>Tancharoenrat</Author><Year>2014</Year><RecNum>59</RecNum><DisplayText>(Tancharoenrat et al., 2014)</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tancharoenrat, P.</author><author>Ravindran, V.</author><author>Zaefarian, F.</author><author>Ravindran, G.</author></authors></contributors><titles><title>Digestion of fat and fatty acids along the gastrointestinal tract of broiler chickens</title><secondary-title>Poultry Science</secondary-title></titles><pages>371-379</pages><volume>93</volume><number>2</number><dates><year>2014</year><pub-dates><date>February 1, 2014</date></pub-dates></dates><urls><related-urls><url>;(Tancharoenrat et al., 2014). 2) Cholesterol in the free form is more readily incorporated into a bile acid micelle for absorption. Therefore, cholesterol ester hydrolase (CEH) converts the esterified cholesterol into free cholesterol, which can then be incorporated into a bile acid micelle ADDIN EN.CITE <EndNote><Cite><Author>Ikeda</Author><Year>2002</Year><RecNum>50</RecNum><DisplayText>(Ikeda et al., 2002)</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ikeda, Ikuo</author><author>Matsuoka, Ryosuke</author><author>Hamada, Tadateru</author><author>Mitsui, Kosuke</author><author>Imabayashi, Sachiko</author><author>Uchino, Akira</author><author>Sato, Masao</author><author>Kuwano, Eiichi</author><author>Itamura, Tomoaki</author><author>Yamada, Koji</author><author>Tanaka, Kazunari</author><author>Imaizumi, Katsumi</author></authors></contributors><titles><title>Cholesterol esterase accelerates intestinal cholesterol absorption</title><secondary-title>Biochimica et Biophysica Acta (BBA) - General Subjects</secondary-title></titles><pages>34-44</pages><volume>1571</volume><number>1</number><keywords><keyword>Cholesterol esterase</keyword><keyword>Caco-2 cells</keyword><keyword>Cholesterol absorption</keyword><keyword>Phosphatidylcholine</keyword><keyword>Phospholipase A2</keyword></keywords><dates><year>2002</year><pub-dates><date>5/10/</date></pub-dates></dates><isbn>0304-4165</isbn><urls><related-urls><url>(02)00204-0</electronic-resource-num></record></Cite></EndNote>(Ikeda et al., 2002). This enables NPC1L1 to absorb the cholesterol by clathrin-mediated endocytosis ADDIN EN.CITE <EndNote><Cite><Author>Betters</Author><Year>2010</Year><RecNum>56</RecNum><DisplayText>(Betters and Yu, 2010)</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Betters, Jenna L.</author><author>Yu, Liqing</author></authors></contributors><titles><title>NPC1L1 and cholesterol transport</title><secondary-title>FEBS Letters</secondary-title></titles><pages>2740-2747</pages><volume>584</volume><number>13</number><keywords><keyword>Ezetimibe</keyword><keyword>Intestinal cholesterol absorption</keyword><keyword>Hypercholesterolemia</keyword><keyword>ABCG5/ABCG8</keyword></keywords><dates><year>2010</year><pub-dates><date>7/2/</date></pub-dates></dates><isbn>0014-5793</isbn><urls><related-urls><url>;(Betters and Yu, 2010). Upon entry to the enterocyte, acetyl CoA acetyltransferase 2 (ACAT2) converts the cholesterol into the esterified form in order to maintain the concentration gradient ADDIN EN.CITE <EndNote><Cite><Author>Chang</Author><Year>2009</Year><RecNum>58</RecNum><DisplayText>(Chang et al., 2009)</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chang, Ta-Yuan</author><author>Li, Bo-Liang</author><author>Chang, Catherine C. Y.</author><author>Urano, Yasuomi</author></authors></contributors><titles><title>Acyl-coenzyme A:cholesterol acyltransferases</title><secondary-title>American Journal of Physiology - Endocrinology and Metabolism</secondary-title></titles><pages>E1-E9</pages><volume>297</volume><number>1</number><dates><year>2009</year><pub-dates><date>01/13
11/12/received
01/12/accepted</date></pub-dates></dates><publisher>American Physiological Society</publisher><isbn>0193-1849
1522-1555</isbn><accession-num>PMC2711667</accession-num><urls><related-urls><url>;(Chang et al., 2009). Microsomal triglyceride transfer protein (MTP) then shuttles the esterified cholesterol with apo B-48, while triacylglycerol and phospholipids are also incorporated to form a chylomicron ADDIN EN.CITE <EndNote><Cite><Author>Jamil</Author><Year>1995</Year><RecNum>57</RecNum><DisplayText>(Jamil et al., 1995)</DisplayText><record><rec-number>57</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">57</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jamil, Haris</author><author>Dickson, John K.</author><author>Chu, Ching-Hsuen</author><author>Lago, Michael W.</author><author>Rinehart, J. Kent</author><author>Biller, Scott A.</author><author>Gregg, Richard E.</author><author>Wetterau, John R.</author></authors></contributors><titles><title>Microsomal Triglyceride Transfer Protein: SPECIFICITY OF LIPID BINDING AND TRANSPORT</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><pages>6549-6554</pages><volume>270</volume><number>12</number><dates><year>1995</year><pub-dates><date>March 24, 1995</date></pub-dates></dates><urls><related-urls><url>;(Jamil et al., 1995). 3) The chylomicron is then exported to the lymphatic system via exocytosis, and enters the blood stream, where it can deliver fatty acids to the tissues before being removed by hepatic remnant receptors and degraded in the liver ADDIN EN.CITE <EndNote><Cite><Author>Cooper</Author><Year>1997</Year><RecNum>53</RecNum><DisplayText>(Cooper, 1997)</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cooper, A. D.</author></authors></contributors><auth-address>Research Institute, Palo Alto Medical Foundation, CA 94301, USA.</auth-address><titles><title>Hepatic uptake of chylomicron remnants</title><secondary-title>J Lipid Res</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>2173-92</pages><volume>38</volume><number>11</number><edition>1997/12/10</edition><keywords><keyword>Animals</keyword><keyword>Apolipoproteins/metabolism</keyword><keyword>Chylomicrons/ metabolism</keyword><keyword>Humans</keyword><keyword>Lipase/metabolism</keyword><keyword>Liver/anatomy & histology/ metabolism</keyword><keyword>Models, Biological</keyword><keyword>Phospholipases/metabolism</keyword><keyword>Proteoglycans/metabolism</keyword><keyword>Receptors, LDL/metabolism</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-2275 (Print)
0022-2275 (Linking)</isbn><accession-num>9392416</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Cooper, 1997). 4) Cholesterol is also synthesised endogenously in all nucleated cells in the body, including the hepatocytes and enterocytes from acetyl CoA ADDIN EN.CITE <EndNote><Cite><Author>Bloch</Author><Year>1965</Year><RecNum>68</RecNum><DisplayText>(Bloch, 1965)</DisplayText><record><rec-number>68</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">68</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bloch, Konrad</author></authors></contributors><titles><title>The Biological Synthesis of Cholesterol</title><secondary-title>Science</secondary-title></titles><pages>19-28</pages><volume>150</volume><number>3692</number><dates><year>1965</year><pub-dates><date>October 1, 1965</date></pub-dates></dates><urls><related-urls><url>;(Bloch, 1965). 5) From the hepatic cholesterol pool, very low density lipoprotein cholesterol (VLDL-C) is formed, to enable the transport of endogenously synthesised triacylglycerol to the tissues. Partial hydrolysis of VLDL-C by lipoprotein lipase (LPL) forms the LDL-C precursor, intermediate density lipoprotein cholesterol (IDL-C). IDL-C is further hydrolysed by hepatic lipase to form LDL-C ADDIN EN.CITE <EndNote><Cite><Author>Havel</Author><Year>1984</Year><RecNum>69</RecNum><DisplayText>(Havel, 1984)</DisplayText><record><rec-number>69</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">69</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Havel, R. J.</author></authors></contributors><titles><title>The formation of LDL: mechanisms and regulation</title><secondary-title>J Lipid Res</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>1570-6</pages><volume>25</volume><number>13</number><edition>1984/12/15</edition><keywords><keyword>Animals</keyword><keyword>Apolipoprotein B-100</keyword><keyword>Apolipoproteins B/metabolism</keyword><keyword>Humans</keyword><keyword>Hyperlipoproteinemia Type II/metabolism</keyword><keyword>Lipoproteins, LDL/ biosynthesis</keyword><keyword>Lipoproteins, VLDL/metabolism</keyword><keyword>Liver/metabolism</keyword><keyword>Receptors, LDL/metabolism</keyword></keywords><dates><year>1984</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>0022-2275 (Print)
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ADDIN EN.CITE.DATA (Veniant et al., 1998). In addition, LDL-C can also be absorbed by receptor independent means ADDIN EN.CITE <EndNote><Cite><Author>Spady</Author><Year>1985</Year><RecNum>65</RecNum><DisplayText>(Spady et al., 1985)</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Spady, D. K.</author><author>Turley, S. D.</author><author>Dietschy, J. M.</author></authors></contributors><titles><title>Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><pages>1113-22</pages><volume>76</volume><number>3</number><edition>1985/09/01</edition><keywords><keyword>Animals</keyword><keyword>Biological Transport, Active</keyword><keyword>Cholesterol, LDL/metabolism</keyword><keyword>Dexamethasone/pharmacology</keyword><keyword>Endocrine Glands/metabolism</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Lipoproteins, LDL/ metabolism</keyword><keyword>Liver/metabolism</keyword><keyword>Metabolic Clearance Rate/drug effects</keyword><keyword>Methylation</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword><keyword>Receptors, Cell Surface/analysis/drug effects/ metabolism</keyword><keyword>Receptors, Lipoprotein</keyword><keyword>Sucrose/metabolism</keyword></keywords><dates><year>1985</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0021-9738 (Print)
0021-9738 (Linking)</isbn><accession-num>2995447</accession-num><urls></urls><custom2>PMC424002</custom2><electronic-resource-num>10.1172/jci112066</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Spady et al., 1985). 7) Accumulation of LDL-C can develop into atherosclerosis the major clinical manifestation of CVD ADDIN EN.CITE <EndNote><Cite><Author>Baigent</Author><Year>2010</Year><RecNum>67</RecNum><DisplayText>(Baigent et al., 2010)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baigent, C.</author><author>Blackwell, L.</author><author>Emberson, J.</author><author>Holland, L. E.</author><author>Reith, C.</author><author>Bhala, N.</author><author>Peto, R.</author><author>Barnes, E. H.</author><author>Keech, A.</author><author>Simes, J.</author><author>Collins, R.</author></authors></contributors><auth-address>Clinical Trial Service Unit and Epidemiological Studies Unit(CTSU), Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.</auth-address><titles><title>Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials</title><secondary-title>Lancet</secondary-title></titles><pages>1670-81</pages><volume>376</volume><number>9753</number><edition>2010/11/12</edition><keywords><keyword>Cholesterol, LDL/ blood</keyword><keyword>Coronary Disease/mortality/prevention & control</keyword><keyword>Humans</keyword><keyword>Hydroxymethylglutaryl-CoA Reductase Inhibitors/ administration & dosage/adverse</keyword><keyword>effects</keyword><keyword>Myocardial Infarction/prevention & control</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Stroke/prevention & control</keyword></keywords><dates><year>2010</year><pub-dates><date>Nov 13</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>21067804</accession-num><urls></urls><custom2>PMC2988224</custom2><electronic-resource-num>10.1016/s0140-6736(10)61350-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Baigent et al., 2010). 8) Cholesterol can be removed from the tissues by HDL in RCT, via receptors including ATP-binding cassette subfamily A member 1 (ABCA1), and scavenger receptor class B member 1 (SRB1), or independently. CETP then acts to facilitate the 1:1 exchange of cholesterol from HDL-C for triacylglycerol from VLDL-C and LDL-C ADDIN EN.CITE <EndNote><Cite><Author>Ohashi</Author><Year>2005</Year><RecNum>66</RecNum><DisplayText>(Ohashi et al., 2005)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ohashi, R.</author><author>Mu, H.</author><author>Wang, X.</author><author>Yao, Q.</author><author>Chen, C.</author></authors></contributors><auth-address>Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston 77030, USA.</auth-address><titles><title>Reverse cholesterol transport and cholesterol efflux in atherosclerosis</title><secondary-title>QJM</secondary-title></titles><pages>845-56</pages><volume>98</volume><number>12</number><edition>2005/11/01</edition><keywords><keyword>ATP Binding Cassette Transporter 1</keyword><keyword>ATP-Binding Cassette Transporters/genetics</keyword><keyword>Animals</keyword><keyword>Atherosclerosis/ etiology/genetics</keyword><keyword>Biological Transport/genetics/physiology</keyword><keyword>Cholesterol/ metabolism</keyword><keyword>Humans</keyword><keyword>Life Style</keyword><keyword>Lipoproteins, HDL/metabolism</keyword><keyword>Mice</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1460-2725 (Print)
1460-2393 (Linking)</isbn><accession-num>16258026</accession-num><urls></urls><electronic-resource-num>10.1093/qjmed/hci136</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ohashi et al., 2005). 9) Cholesterol can be removed from the body by two mechanisms, as cholesterol can be removed directly via the ATP-binding cassette subfamily G5/G8 (ABCG5/G8) receptor and effluxed to the gall bladder ADDIN EN.CITE <EndNote><Cite><Author>Repa</Author><Year>2002</Year><RecNum>61</RecNum><DisplayText>(Repa et al., 2002)</DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Repa, Joyce J.</author><author>Berge, Knut E.</author><author>Pomajzl, Chris</author><author>Richardson, James A.</author><author>Hobbs, Helen</author><author>Mangelsdorf, David J.</author></authors></contributors><titles><title>Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors α and β</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><pages>18793-18800</pages><volume>277</volume><number>21</number><dates><year>2002</year><pub-dates><date>May 24, 2002</date></pub-dates></dates><urls><related-urls><url>;(Repa et al., 2002) or alternatively, cholesterol can be converted to bile acids for faecal excretion. Bile acids are usually conjugated to glycine or taurine (3:1) before being effluxed to the gallbladder by receptors, including bile salt export pumps (BSEP) ADDIN EN.CITE <EndNote><Cite><Author>Soroka</Author><Year>2014</Year><RecNum>52</RecNum><DisplayText>(Soroka and Boyer, 2014)</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soroka, C. J.</author><author>Boyer, J. L.</author></authors></contributors><auth-address>Yale University School of Medicine, Department of Internal Medicine, New Haven, CT 06520, United States. Electronic address: carol.soroka@yale.edu.
Yale University School of Medicine, Department of Internal Medicine, New Haven, CT 06520, United States. Electronic address: james.boyer@yale.edu.</auth-address><titles><title>Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations</title><secondary-title>Mol Aspects Med</secondary-title></titles><pages>3-14</pages><volume>37</volume><edition>2013/05/21</edition><keywords><keyword>ATP-Binding Cassette Transporters/ biosynthesis/ genetics/metabolism</keyword><keyword>Bile Acids and Salts/metabolism</keyword><keyword>Biliary Tract/metabolism/pathology</keyword><keyword>Cholestasis, Intrahepatic/ genetics/pathology</keyword><keyword>Female</keyword><keyword>Hepatocytes/metabolism</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Pregnancy</keyword><keyword>ATP-binding cassette transporter</keyword><keyword>Bile salt secretion</keyword><keyword>Cholestasis</keyword></keywords><dates><year>2014</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1872-9452 (Electronic)
0098-2997 (Linking)</isbn><accession-num>23685087</accession-num><urls></urls><custom2>PMC3784619</custom2><custom6>Nihms481143</custom6><electronic-resource-num>10.1016/j.mam.2013.05.001</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Soroka and Boyer, 2014) for release into the small intestine postprandially in response to cholecystokinin (CKK) ADDIN EN.CITE <EndNote><Cite><Author>Marciani</Author><Year>2013</Year><RecNum>51</RecNum><DisplayText>(Marciani et al., 2013)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marciani, L.</author><author>Cox, E. F.</author><author>Hoad, C. L.</author><author>Totman, J. J.</author><author>Costigan, C.</author><author>Singh, G.</author><author>Shepherd, V.</author><author>Chalkley, L.</author><author>Robinson, M.</author><author>Ison, R.</author><author>Gowland, P. A.</author><author>Spiller, R. C.</author></authors></contributors><auth-address>Nottingham Digestive Diseases Centre and NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham, UK.</auth-address><titles><title>Effects of various food ingredients on gall bladder emptying</title><secondary-title>Eur J Clin Nutr</secondary-title></titles><pages>1182-7</pages><volume>67</volume><number>11</number><edition>2013/09/21</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Cholecystokinin/ metabolism</keyword><keyword>Diet</keyword><keyword>Dietary Fats/ pharmacology</keyword><keyword>Female</keyword><keyword>Food</keyword><keyword>Gallbladder/ drug effects/physiology</keyword><keyword>Gallbladder Emptying/ drug effects</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Postprandial Period</keyword><keyword>Single-Blind Method</keyword><keyword>Young Adult</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1476-5640 (Electronic)
0954-3007 (Linking)</isbn><accession-num>24045793</accession-num><urls></urls><custom2>PMC3898429</custom2><electronic-resource-num>10.1038/ejcn.2013.168</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Marciani et al., 2013). 10) On average, 500mg/day of both cholesterol and bile acids are excreted ADDIN EN.CITE <EndNote><Cite><Author>Lu</Author><Year>2010</Year><RecNum>60</RecNum><DisplayText>(Lu et al., 2010)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lu, Y.</author><author>Feskens, E. J.</author><author>Boer, J. M.</author><author>Muller, M.</author></authors></contributors><auth-address>Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands. kevin.lu@wur.nl</auth-address><titles><title>The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>14-27</pages><volume>210</volume><number>1</number><edition>2009/11/26</edition><keywords><keyword>ATP-Binding Cassette Transporters/genetics</keyword><keyword>Bile Acids and Salts/biosynthesis</keyword><keyword>Cholesterol/blood/ metabolism</keyword><keyword>Cholesterol 7-alpha-Hydroxylase/genetics</keyword><keyword>Enterohepatic Circulation/physiology</keyword><keyword>Genetic Variation</keyword><keyword>Hepatocyte Nuclear Factor 4/genetics</keyword><keyword>Lipoproteins</keyword><keyword>Membrane Proteins/genetics</keyword><keyword>Orphan Nuclear Receptors/genetics</keyword></keywords><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>1879-1484 (Electronic)
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ADDIN EN.CITE.DATA (Batta et al., 1999; Gérard, 2014). Conjugated bile acids are deconjugated by bacterial modification ADDIN EN.CITE <EndNote><Cite><Author>Joyce</Author><Year>2014</Year><RecNum>125</RecNum><DisplayText>(Joyce et al., 2014)</DisplayText><record><rec-number>125</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joyce, Susan A.</author><author>MacSharry, John</author><author>Casey, Patrick G.</author><author>Kinsella, Michael</author><author>Murphy, Eileen F.</author><author>Shanahan, Fergus</author><author>Hill, Colin</author><author>Gahan, Cormac G. M.</author></authors></contributors><titles><title>Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut</title><secondary-title>Proceedings of the National Academy of Sciences</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences</full-title></periodical><pages>7421-7426</pages><volume>111</volume><number>20</number><dates><year>2014</year><pub-dates><date>May 20, 2014</date></pub-dates></dates><urls><related-urls><url>;(Joyce et al., 2014). Bacterial species such as Lactobacillus and Bifidobacterium produce bile acid hydrolase (BSH) in order to remove the associated amino acid ADDIN EN.CITE <EndNote><Cite><Author>Oner</Author><Year>2014</Year><RecNum>62</RecNum><DisplayText>(Oner et al., 2014)</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oner, O.</author><author>Aslim, B.</author><author>Aydas, S. B.</author></authors></contributors><auth-address>Gazi University Faculty of Science, Department of Biology, Biotechnology Laboratory, Ankara, Turkey.</auth-address><titles><title>Mechanisms of cholesterol-lowering effects of lactobacilli and bifidobacteria strains as potential probiotics with their bsh gene analysis</title><secondary-title>J Mol Microbiol Biotechnol</secondary-title></titles><pages>12-8</pages><volume>24</volume><number>1</number><edition>2013/10/26</edition><keywords><keyword>Amidohydrolases/ metabolism</keyword><keyword>Anticholesteremic Agents/ pharmacology</keyword><keyword>Bifidobacterium/drug effects/ enzymology/growth & development</keyword><keyword>Cholesterol/ metabolism</keyword><keyword>Cholic Acid/metabolism</keyword><keyword>Humans</keyword><keyword>Lactobacillus plantarum/drug effects/ enzymology/growth & development</keyword><keyword>Microbial Viability/drug effects</keyword><keyword>Probiotics/ pharmacology</keyword></keywords><dates><year>2014</year></dates><isbn>1660-2412 (Electronic)
1464-1801 (Linking)</isbn><accession-num>24158048</accession-num><urls></urls><electronic-resource-num>10.1159/000354316</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Oner et al., 2014). There are several survival-promoting motives for bacteria to respond in this way; these include providing a nutrition source and bile acid detoxification ADDIN EN.CITE <EndNote><Cite><Author>Begley</Author><Year>2006</Year><RecNum>45</RecNum><DisplayText>(Begley et al., 2006)</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Begley, Máire</author><author>Hill, Colin</author><author>Gahan, Cormac G. M.</author></authors></contributors><titles><title>Bile Salt Hydrolase Activity in Probiotics</title><secondary-title>Applied and Environmental Microbiology</secondary-title></titles><pages>1729-1738</pages><volume>72</volume><number>3</number><dates><year>2006</year></dates><publisher>American Society for Microbiology</publisher><isbn>0099-2240
1098-5336</isbn><accession-num>PMC1393245</accession-num><urls><related-urls><url>;(Begley et al., 2006). This modulation of bile acid circulation indicates that the gut microbiome also plays an important role in maintaining cholesterol metabolism. Collectively the mechanisms we have discussed coordinate together to maintain whole body cholesterol balance and age-related changes to such mechanisms have important implications for health. 3.0 Impact of Ageing on Cholesterol Metabolism3.1 Lipoprotein Dynamics and AgeingIt is well established that LDL-C levels rise with age ADDIN EN.CITE <EndNote><Cite><Author>Abbott</Author><Year>1983</Year><RecNum>181</RecNum><DisplayText>(Abbott et al., 1983)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abbott, R D</author><author>Garrison, R J</author><author>Wilson, P W</author><author>Epstein, F H</author><author>Castelli, W P</author><author>Feinleib, M</author><author>LaRue, C</author></authors></contributors><titles><title>Joint distribution of lipoprotein cholesterol classes. The Framingham study</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>260-72</pages><volume>3</volume><number>3</number><dates><year>1983</year><pub-dates><date>May 1, 1983</date></pub-dates></dates><urls><related-urls><url>;(Abbott et al., 1983). Evidence from the Framingham Study demonstrates LDL-C steadily rises from 97.08 and 100.44mg/dL in 15-19 year olds, to 132.25 and 156.91mg/dL in 75-79 year olds in males and females, respectively ADDIN EN.CITE <EndNote><Cite><Author>Abbott</Author><Year>1983</Year><RecNum>181</RecNum><DisplayText>(Abbott et al., 1983)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abbott, R D</author><author>Garrison, R J</author><author>Wilson, P W</author><author>Epstein, F H</author><author>Castelli, W P</author><author>Feinleib, M</author><author>LaRue, C</author></authors></contributors><titles><title>Joint distribution of lipoprotein cholesterol classes. The Framingham study</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>260-72</pages><volume>3</volume><number>3</number><dates><year>1983</year><pub-dates><date>May 1, 1983</date></pub-dates></dates><urls><related-urls><url>;(Abbott et al., 1983). An increase in LDL-C is correlated with an increased risk of CVD; every 1mmol/L of LDL-C is associated with a 28% increased risk of coronary heart disease (CHD)-mortality ADDIN EN.CITE <EndNote><Cite><Author>Gould</Author><Year>2007</Year><RecNum>79</RecNum><DisplayText>(Gould et al., 2007)</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gould, A. Lawrence</author><author>Davies, Glenn M.</author><author>Alemao, Evo</author><author>Yin, Donald D.</author><author>Cook, John R.</author></authors></contributors><titles><title>Cholesterol reduction yields clinical benefits: meta-analysis including recent trials</title><secondary-title>Clinical Therapeutics</secondary-title></titles><pages>778-794</pages><volume>29</volume><number>5</number><keywords><keyword>cholesterol</keyword><keyword>coronary disease</keyword><keyword>3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors</keyword><keyword>hypercholesterolemia</keyword><keyword>meta-analysis</keyword></keywords><dates><year>2007</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0149-2918</isbn><urls><related-urls><url>;(Gould et al., 2007). Paradoxically, this is not always the case, as higher levels of LDL-C was associated with a lower risk of all causes of mortality in a Chinese cohort of 935 ≥80 year old males and females. In this cohort each 1mmol/L increase in LDL-C reflected a 19% decrease in mortality ADDIN EN.CITE <EndNote><Cite><Author>Lv</Author><Year>2015</Year><RecNum>21</RecNum><DisplayText>(Lv et al., 2015)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lv, Yue-Bin</author><author>Yin, Zhao-Xue</author><author>Chei, Choy-Lye</author><author>Qian, Han-Zhu</author><author>Kraus, Virginia Byers</author><author>Zhang, Juan</author><author>Brasher, Melanie Sereny</author><author>Shi, Xiao-Ming</author><author>Matchar, David Bruce</author><author>Zeng, Yi</author></authors></contributors><titles><title>Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: Data from the Chinese Longitudinal Healthy Longevity Survey</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>137-142</pages><volume>239</volume><number>1</number><keywords><keyword>LDL-C</keyword><keyword>Mortality</keyword><keyword>Oldest old</keyword><keyword>Epidemiology</keyword><keyword>China</keyword></keywords><dates><year>2015</year><pub-dates><date>3//</date></pub-dates></dates><isbn>0021-9150</isbn><urls><related-urls><url>;(Lv et al., 2015). Furthermore, abnormally high LDL-C (≥3.37mmol) resulted in a 40% reduction in mortality risk. Participants that survived the three year survey-based study were also found to have a higher prevalence (39.0% vs. 27.7%) of central obesity ADDIN EN.CITE <EndNote><Cite><Author>Lv</Author><Year>2015</Year><RecNum>21</RecNum><DisplayText>(Lv et al., 2015)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lv, Yue-Bin</author><author>Yin, Zhao-Xue</author><author>Chei, Choy-Lye</author><author>Qian, Han-Zhu</author><author>Kraus, Virginia Byers</author><author>Zhang, Juan</author><author>Brasher, Melanie Sereny</author><author>Shi, Xiao-Ming</author><author>Matchar, David Bruce</author><author>Zeng, Yi</author></authors></contributors><titles><title>Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: Data from the Chinese Longitudinal Healthy Longevity Survey</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>137-142</pages><volume>239</volume><number>1</number><keywords><keyword>LDL-C</keyword><keyword>Mortality</keyword><keyword>Oldest old</keyword><keyword>Epidemiology</keyword><keyword>China</keyword></keywords><dates><year>2015</year><pub-dates><date>3//</date></pub-dates></dates><isbn>0021-9150</isbn><urls><related-urls><url>;(Lv et al., 2015). This phenomenon in the oldest old could be explained by several factors. Firstly, it is possible that individuals susceptible to the effects of increased LDL-C levels had already died before the age of 80 years, and are consequently not included in studies of the oldest old. It has also been suggested increased LDL-C enhances the immune response to pathogens PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXN3YXM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Veniant et al., 1998). From the hepatic pool, cholesterol can be directly effluxed to the small intestine for excretion, or first be converted to bile acids. This process occurs in order to maintain the levels of circulating cholesterol, by counteracting the synthesis and ingestion of cholesterol. Deficiency in LDLr results in severe hypercholesterolaemia (type II), as cholesterol cannot be removed from the plasma and into the liver for excretion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3dhbGE8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Hasan et al., 2014; Kowala et al., 2000). Murine models have shown LDLr deficiency increases the residence time of LDL-C and VLDL-C by decreasing the clearance rate ADDIN EN.CITE <EndNote><Cite><Author>Ishibashi</Author><Year>1993</Year><RecNum>83</RecNum><DisplayText>(Ishibashi et al., 1993)</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ishibashi, S.</author><author>Brown, M. S.</author><author>Goldstein, J. L.</author><author>Gerard, R. D.</author><author>Hammer, R. E.</author><author>Herz, J.</author></authors></contributors><titles><title>Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><pages>883-893</pages><volume>92</volume><number>2</number><dates><year>1993</year></dates><isbn>0021-9738</isbn><accession-num>PMC294927</accession-num><urls><related-urls><url>;(Ishibashi et al., 1993). For example, Ishibashi et al. (1993) demonstrated LDLr deficiency increased the half-life of 125I-LDL and 125I-VLDL by 2.5- and 30-fold respectively, while the half-life of 125I-HDL was unaffected. Furthermore, LDLr deficiency induced a 2-fold increase in total cholesterol, a 7- and 9-fold increase in IDL-C, and LDL-C respectively, in addition to a modest 1.3-fold rise in HDL-C ADDIN EN.CITE <EndNote><Cite><Author>Ishibashi</Author><Year>1993</Year><RecNum>83</RecNum><DisplayText>(Ishibashi et al., 1993)</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ishibashi, S.</author><author>Brown, M. S.</author><author>Goldstein, J. L.</author><author>Gerard, R. D.</author><author>Hammer, R. E.</author><author>Herz, J.</author></authors></contributors><titles><title>Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><pages>883-893</pages><volume>92</volume><number>2</number><dates><year>1993</year></dates><isbn>0021-9738</isbn><accession-num>PMC294927</accession-num><urls><related-urls><url>;(Ishibashi et al., 1993). In humans the number of hepatic LDLr decrease with age, thus reducing the rate of LDL-C clearance, and augmenting LDL-C residence time PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYXI8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Millar et al., 1995). This age-related decline in LDLr is possibly a contributing factor to LDL-C accumulation. It is likely there are several factors influencing the decline in LDLr with age, the primary factor being the decline in the rate of bile acid synthesis, as discussed in section 3.2. Briefly, a decline in bile acid synthesis, results in a decline in cholesterol utilisation from the hepatic pool. Thus, less cholesterol is required to maintain the hepatic pool, resulting in down regulation of LDLr and plasma cholesterol accumulation. More recently, proprotein convertase subtilisin kexin-9 (PSCK9) has also been associated with LDLr degradation. PCSK9, regulated by SREBP-2, acts by binding to the epidermal growth factor like repeat A domain of LDLr leading to receptor degradation. Levels of PCSK9 have been shown to rise with age, and may account for the age-related reduction in LDLr and LDL-C clearance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWJ1YzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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AG==
ADDIN EN.CITE.DATA (Cui et al., 2010; Dubuc et al., 2010).HDL-C levels are also affected by the ageing process ADDIN EN.CITE <EndNote><Cite><Author>Wilson</Author><Year>1994</Year><RecNum>183</RecNum><DisplayText>(Wilson et al., 1994)</DisplayText><record><rec-number>183</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">183</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wilson, P. W.</author><author>Anderson, K. M.</author><author>Harris, T.</author><author>Kannel, W. B.</author><author>Castelli, W. P.</author></authors></contributors><auth-address>Framingham Heart Study, Massachusetts.</auth-address><titles><title>Determinants of change in total cholesterol and HDL-C with age: the Framingham Study</title><secondary-title>J Gerontol</secondary-title></titles><periodical><full-title>J Gerontol</full-title><abbr-1>Journal of gerontology</abbr-1></periodical><pages>M252-7</pages><volume>49</volume><number>6</number><edition>1994/11/01</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aging/ metabolism</keyword><keyword>Alcohol Drinking</keyword><keyword>Body Mass Index</keyword><keyword>Cholesterol/ blood</keyword><keyword>Cholesterol, HDL/ blood</keyword><keyword>Cohort Studies</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Diuretics/therapeutic use</keyword><keyword>Estrogens/therapeutic use</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Sex Factors</keyword><keyword>Smoking</keyword></keywords><dates><year>1994</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-1422 (Print)
0022-1422 (Linking)</isbn><accession-num>7963277</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wilson et al., 1994). Typically, HDL-C is observed to decrease by 1% per year ADDIN EN.CITE <EndNote><Cite><Author>Ferrara</Author><Year>1997</Year><RecNum>180</RecNum><DisplayText>(Ferrara et al., 1997)</DisplayText><record><rec-number>180</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">180</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferrara, A.</author><author>Barrett-Connor, E.</author><author>Shan, J.</author></authors></contributors><auth-address>Department of Family and Preventive Medicine, University of California, San Diego, School of Medicine, La Jolla 92093-0607, USA.</auth-address><titles><title>Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984-1994</title><secondary-title>Circulation</secondary-title></titles><pages>37-43</pages><volume>96</volume><number>1</number><edition>1997/07/01</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/ physiology</keyword><keyword>Alcohol Drinking/adverse effects</keyword><keyword>Body Weight/physiology</keyword><keyword>California/epidemiology</keyword><keyword>Cholesterol/ blood</keyword><keyword>Cholesterol, HDL/ blood/drug effects</keyword><keyword>Cholesterol, LDL/ blood/drug effects</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Estrogen Replacement Therapy</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Linear Models</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Reference Values</keyword><keyword>Smoking/adverse effects</keyword><keyword>Thyroid Hormones/pharmacology</keyword></keywords><dates><year>1997</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0009-7322 (Print)
0009-7322 (Linking)</isbn><accession-num>9236414</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ferrara et al., 1997). The age-related decline of the atheroprotective HDL-C is linked with the pathogenesis of CVD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29uZXk8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Cooney et al., 2009). For instance, a favourable HDL-C profile is often observed in the offspring of centenarians ADDIN EN.CITE <EndNote><Cite><Author>Barzilai</Author><Year>2001</Year><RecNum>213</RecNum><DisplayText>(Barzilai et al., 2001)</DisplayText><record><rec-number>213</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">213</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barzilai, N.</author><author>Gabriely, I.</author><author>Gabriely, M.</author><author>Iankowitz, N.</author><author>Sorkin, J. D.</author></authors></contributors><auth-address>Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.</auth-address><titles><title>Offspring of centenarians have a favorable lipid profile</title><secondary-title>J Am Geriatr Soc</secondary-title></titles><pages>76-9</pages><volume>49</volume><number>1</number><edition>2001/02/24</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Cardiovascular Diseases/blood/ epidemiology/genetics</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Jews</keyword><keyword>Lipoproteins/ blood/genetics</keyword><keyword>Longevity</keyword><keyword>Male</keyword><keyword>Phenotype</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2001</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0002-8614 (Print)
0002-8614 (Linking)</isbn><accession-num>11207846</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Barzilai et al., 2001). Due to the lack of controls, to compare the lipoprotein protein of long lived individuals with age-matched controls, offspring studies are utilised. By using this approach, inherited elevated HDL-C levels can be observed ADDIN EN.CITE <EndNote><Cite><Author>Barzilai</Author><Year>2001</Year><RecNum>213</RecNum><DisplayText>(Barzilai et al., 2001)</DisplayText><record><rec-number>213</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">213</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barzilai, N.</author><author>Gabriely, I.</author><author>Gabriely, M.</author><author>Iankowitz, N.</author><author>Sorkin, J. D.</author></authors></contributors><auth-address>Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.</auth-address><titles><title>Offspring of centenarians have a favorable lipid profile</title><secondary-title>J Am Geriatr Soc</secondary-title></titles><pages>76-9</pages><volume>49</volume><number>1</number><edition>2001/02/24</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Cardiovascular Diseases/blood/ epidemiology/genetics</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Jews</keyword><keyword>Lipoproteins/ blood/genetics</keyword><keyword>Longevity</keyword><keyword>Male</keyword><keyword>Phenotype</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2001</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0002-8614 (Print)
0002-8614 (Linking)</isbn><accession-num>11207846</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Barzilai et al., 2001). Therefore, increased levels of HDL-C have been highlighted as a potential mechanism conferring exceptional longevity. This is substantiated by evidence detailing individuals with familial hyperalphalipoproteinaemia, whereby the production rate of apo A-I is markedly increased. These individuals display increased HDL-C levels, and exhibit reduced rates of CHD, which may play a role in promoting exceptional longevity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWRlcjwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Rader et al., 1993).3.2 Cholesterol Absorption and the Synthesis and Enterohepatic Circulation of Bile AcidsCholesterol from both the diet and bile is absorbed in the small intestine ADDIN EN.CITE <EndNote><Cite><Author>Repa</Author><Year>2002</Year><RecNum>61</RecNum><DisplayText>(Repa et al., 2002; Tancharoenrat et al., 2014)</DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Repa, Joyce J.</author><author>Berge, Knut E.</author><author>Pomajzl, Chris</author><author>Richardson, James A.</author><author>Hobbs, Helen</author><author>Mangelsdorf, David J.</author></authors></contributors><titles><title>Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors α and β</title><secondary-title>Journal of Biological Chemistry</secondary-title></titles><pages>18793-18800</pages><volume>277</volume><number>21</number><dates><year>2002</year><pub-dates><date>May 24, 2002</date></pub-dates></dates><urls><related-urls><url> app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tancharoenrat, P.</author><author>Ravindran, V.</author><author>Zaefarian, F.</author><author>Ravindran, G.</author></authors></contributors><titles><title>Digestion of fat and fatty acids along the gastrointestinal tract of broiler chickens</title><secondary-title>Poultry Science</secondary-title></titles><pages>371-379</pages><volume>93</volume><number>2</number><dates><year>2014</year><pub-dates><date>February 1, 2014</date></pub-dates></dates><urls><related-urls><url>;(Repa et al., 2002; Tancharoenrat et al., 2014). Cholesterol absorption is regulated by two receptors on the apical membrane, NPC1L1 and ABCG5/G8. NPC1L1 is predominantly located in the jejunum, although this is found the length of the small intestine, and is responsible for the absorption of sterols from the intestinal lumen into the enterocytes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5lPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Duan et al., 2006). These findings are intriguing, as it has long been suggested that an increase in cholesterol absorption is an important factor in the rise in LDL-C which accompanies ageing ADDIN EN.CITE <EndNote><Cite><Author>Hollander</Author><Year>1979</Year><RecNum>215</RecNum><DisplayText>(Hollander and Morgan, 1979)</DisplayText><record><rec-number>215</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">215</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hollander, D.</author><author>Morgan, D.</author></authors></contributors><titles><title>Increase in cholesterol intestinal absorption with aging in the rat</title><secondary-title>Exp Gerontol</secondary-title></titles><pages>201-4</pages><volume>14</volume><number>4</number><edition>1979/01/01</edition><keywords><keyword>Aging</keyword><keyword>Animals</keyword><keyword>Cholesterol/ metabolism</keyword><keyword>Intestinal Absorption</keyword><keyword>Intestine, Small/metabolism</keyword><keyword>Male</keyword><keyword>Rats</keyword></keywords><dates><year>1979</year></dates><isbn>0531-5565 (Print)
0531-5565 (Linking)</isbn><accession-num>477764</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Hollander and Morgan, 1979).Bile acid synthesis declines with age in humans PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FaW5hcnNzb248L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFy
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ADDIN EN.CITE.DATA (Bertolotti et al., 2007). This in turn reduces cholesterol utilisation, which is accompanied by a rise in plasma cholesterol ADDIN EN.CITE <EndNote><Cite><Author>Uchida</Author><Year>1996</Year><RecNum>130</RecNum><DisplayText>(Uchida et al., 1996)</DisplayText><record><rec-number>130</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Uchida, K.</author><author>Satoh, T.</author><author>Chikai, T.</author><author>Takase, H.</author><author>Nomura, Y.</author><author>Nakao, H.</author><author>Takeuchi, N.</author></authors></contributors><auth-address>Strategic Information Unit, Shionogi & Co., Ltd., Tokyo, Japan.</auth-address><titles><title>Influence of cholesterol feeding on bile acid metabolism in young and aged germ-free rats</title><secondary-title>Jpn J Pharmacol</secondary-title></titles><pages>113-8</pages><volume>71</volume><number>2</number><edition>1996/06/01</edition><keywords><keyword>Aging</keyword><keyword>Animals</keyword><keyword>Bile Acids and Salts/ metabolism</keyword><keyword>Chenodeoxycholic Acid/metabolism</keyword><keyword>Cholesterol/analysis</keyword><keyword>Cholesterol, Dietary/ administration & dosage</keyword><keyword>Cholic Acid</keyword><keyword>Cholic Acids/metabolism</keyword><keyword>Feces/ chemistry</keyword><keyword>Germ-Free Life/ physiology</keyword><keyword>Intestine, Large/ metabolism</keyword><keyword>Intestine, Small/ metabolism</keyword><keyword>Liver/metabolism</keyword><keyword>Male</keyword><keyword>Rats</keyword></keywords><dates><year>1996</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0021-5198 (Print)
0021-5198 (Linking)</isbn><accession-num>8835637</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Uchida et al., 1996). Significantly, it has been estimated that with every 10 years, there is a decrease of 60mg/day in cholesterol converted to bile acids ADDIN EN.CITE <EndNote><Cite><Author>Bertolotti</Author><Year>1993</Year><RecNum>84</RecNum><DisplayText>(Bertolotti et al., 1993)</DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bertolotti, M.</author><author>Abate, N.</author><author>Bertolotti, S.</author><author>Loria, P.</author><author>Concari, M.</author><author>Messora, R.</author><author>Carubbi, F.</author><author>Pinetti, A.</author><author>Carulli, N.</author></authors></contributors><auth-address>Istituto di Patologia Medica, Universita di Modena, Italy.</auth-address><titles><title>Effect of aging on cholesterol 7 alpha-hydroxylation in humans</title><secondary-title>J Lipid Res</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>1001-7</pages><volume>34</volume><number>6</number><edition>1993/06/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/ metabolism</keyword><keyword>Bile Acids and Salts/metabolism</keyword><keyword>Cholesterol 7-alpha-Hydroxylase/ metabolism</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lipids/blood</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1993</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0022-2275 (Print)
0022-2275 (Linking)</isbn><accession-num>8354947</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Bertolotti et al., 1993). Thus, a decline in bile acid synthesis is another factor which could contribute to the dysregulation of whole body cholesterol metabolism with age. In rodents a mechanistic explanation for the decline in CYP7AI activity has been postulated. It is suggested the reduction in its activity is in part, due to neuroendocrine dysfunction which causes an age dependent decrease in growth hormone, which is known to act pleiotropically on lipoprotein metabolism ADDIN EN.CITE <EndNote><Cite><Author>Parini</Author><Year>1999</Year><RecNum>88</RecNum><DisplayText>(Parini et al., 1999)</DisplayText><record><rec-number>88</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">88</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parini, P.</author><author>Angelin, B.</author><author>Rudling, M.</author></authors></contributors><auth-address>Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden.</auth-address><titles><title>Cholesterol and lipoprotein metabolism in aging: reversal of hypercholesterolemia by growth hormone treatment in old rats</title><secondary-title>Arterioscler Thromb Vasc Biol</secondary-title></titles><pages>832-9</pages><volume>19</volume><number>4</number><edition>1999/04/09</edition><keywords><keyword>Aging/ metabolism</keyword><keyword>Animals</keyword><keyword>Cholesterol/blood/ metabolism</keyword><keyword>Human Growth Hormone/ therapeutic use</keyword><keyword>Hypercholesterolemia/ drug therapy</keyword><keyword>Infusion Pumps, Implantable</keyword><keyword>Lipoproteins/blood/ metabolism</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Receptors, LDL/biosynthesis/genetics</keyword></keywords><dates><year>1999</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1079-5642 (Print)
1079-5642 (Linking)</isbn><accession-num>10195906</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Parini et al., 1999). Synthesised bile acids are effluxed from the liver primarily by BSEP, and stored in the gall bladder, with BSEP expression remaining fairly consistent with age in mice ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>2012</Year><RecNum>100</RecNum><DisplayText>(Fu et al., 2012)</DisplayText><record><rec-number>100</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">100</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, Zidong Donna</author><author>Csanaky, Iván L.</author><author>Klaassen, Curtis D.</author></authors></contributors><titles><title>Gender-Divergent Profile of Bile Acid Homeostasis during Aging of Mice</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e32551</pages><volume>7</volume><number>3</number><dates><year>2012</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Fu et al., 2012). Following release into the small intestine postprandially, bile acids aid in the absorption of dietary lipids, and undergo bacterial modification before being reabsorbed or excreted. Therefore, any age related alterations to these processes will have consequences for whole body cholesterol metabolism. Digestive microflora play a vital role in the enterohepatic circulation of bile acids, by modifying bile acids and influencing feedback mechanisms. For example, conventionally grown mice have a 71% reduction in the size of their bile acid pool compared to germ free mice. Furthermore, these conventionally grown mice excrete over 4 times the amount of bile acids ADDIN EN.CITE <EndNote><Cite><Author>Sayin</Author><Year>2013</Year><RecNum>96</RecNum><DisplayText>(Sayin et al., 2013)</DisplayText><record><rec-number>96</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">96</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sayin, Sama?I</author><author>Wahlstr?m, Annika</author><author>Felin, Jenny</author><author>J?ntti, Sirkku</author><author>Marschall, Hanns-Ulrich</author><author>Bamberg, Krister</author><author>Angelin, Bo</author><author>Hy?tyl?inen, Tuulia</author><author>Ore?i?, Matej</author><author>B?ckhed, Fredrik</author></authors></contributors><titles><title>Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist</title><secondary-title>Cell Metabolism</secondary-title></titles><periodical><full-title>Cell Metab</full-title><abbr-1>Cell metabolism</abbr-1></periodical><pages>225-235</pages><volume>17</volume><number>2</number><dates><year>2013</year><pub-dates><date>2/5/</date></pub-dates></dates><isbn>1550-4131</isbn><urls><related-urls><url>;(Sayin et al., 2013). This emphasises the comprehensive role of the gut microbiota in regulating enterohepatic circulation. It is therefore logical changes to the gut microbiota with age will have an impact on overall cholesterol metabolism. Within the digestive tract, bile acids are metabolised by the digestive microbiota and converted to secondary bile acids. Deconjugation of primary bile acids by bacterial BSH is essential for this conversion to secondary bile acids. Deconjugated bile acids are more readily excreted than conjugated bile acids, as they are less readily reabsorbed by the apical sodium dependent bile acid transporter (ASBT) ADDIN EN.CITE <EndNote><Cite><Author>Dawson</Author><Year>2011</Year><RecNum>131</RecNum><DisplayText>(Dawson, 2011)</DisplayText><record><rec-number>131</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">131</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dawson, Paul A.</author></authors></contributors><titles><title>Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition</title><secondary-title>Handbook of experimental pharmacology</secondary-title></titles><periodical><full-title>Handb Exp Pharmacol</full-title><abbr-1>Handbook of experimental pharmacology</abbr-1></periodical><pages>169-203</pages><number>201</number><dates><year>2011</year></dates><isbn>0171-2004</isbn><accession-num>PMC3249407</accession-num><urls><related-urls><url>;(Dawson, 2011). The excreted bile acids need to be replenished from the conversion of cholesterol ADDIN EN.CITE <EndNote><Cite><Author>Joyce</Author><Year>2014</Year><RecNum>125</RecNum><DisplayText>(Joyce et al., 2014)</DisplayText><record><rec-number>125</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joyce, Susan A.</author><author>MacSharry, John</author><author>Casey, Patrick G.</author><author>Kinsella, Michael</author><author>Murphy, Eileen F.</author><author>Shanahan, Fergus</author><author>Hill, Colin</author><author>Gahan, Cormac G. M.</author></authors></contributors><titles><title>Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut</title><secondary-title>Proceedings of the National Academy of Sciences</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences</full-title></periodical><pages>7421-7426</pages><volume>111</volume><number>20</number><dates><year>2014</year><pub-dates><date>May 20, 2014</date></pub-dates></dates><urls><related-urls><url>;(Joyce et al., 2014). With age, the rise in LDL-C can in part be explained by the decline in BSH+ species, such as Lactobacillus and Bifidobacterium species ADDIN EN.CITE <EndNote><Cite><Author>Hopkins</Author><Year>2002</Year><RecNum>44</RecNum><DisplayText>(Hopkins and Macfarlane, 2002)</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hopkins, M. J.</author><author>Macfarlane, G. T.</author></authors></contributors><auth-address>MRC Microbiology and Gut Biology Group, University of Dundee Medical School. m.j.hopkins@dundee.ac.uk</auth-address><titles><title>Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection</title><secondary-title>J Med Microbiol</secondary-title></titles><pages>448-54</pages><volume>51</volume><number>5</number><edition>2002/05/07</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Bacteroides/isolation & purification</keyword><keyword>Bifidobacterium/isolation & purification</keyword><keyword>Clostridium/isolation & purification</keyword><keyword>Clostridium Infections/ microbiology</keyword><keyword>Clostridium difficile/isolation & purification</keyword><keyword>Diarrhea/ microbiology</keyword><keyword>Enterobacteriaceae/isolation & purification</keyword><keyword>Enterococcus/isolation & purification</keyword><keyword>Eubacterium/isolation & purification</keyword><keyword>Feces/ microbiology</keyword><keyword>Humans</keyword><keyword>Lactobacillus/isolation & purification</keyword><keyword>Prevotella/isolation & purification</keyword></keywords><dates><year>2002</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-2615 (Print)
0022-2615 (Linking)</isbn><accession-num>11990498</accession-num><urls></urls><electronic-resource-num>10.1099/0022-1317-51-5-448</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Hopkins and Macfarlane, 2002). A decline in BSH results in fewer bile acids being deconjugated, and thus more are reabsorbed, and fewer are excreted. This results in a decline in the need for bile acid synthesis, and thus cholesterol utilisation is reduced ADDIN EN.CITE <EndNote><Cite><Author>Joyce</Author><Year>2014</Year><RecNum>125</RecNum><DisplayText>(Joyce et al., 2014)</DisplayText><record><rec-number>125</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joyce, Susan A.</author><author>MacSharry, John</author><author>Casey, Patrick G.</author><author>Kinsella, Michael</author><author>Murphy, Eileen F.</author><author>Shanahan, Fergus</author><author>Hill, Colin</author><author>Gahan, Cormac G. M.</author></authors></contributors><titles><title>Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut</title><secondary-title>Proceedings of the National Academy of Sciences</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences</full-title></periodical><pages>7421-7426</pages><volume>111</volume><number>20</number><dates><year>2014</year><pub-dates><date>May 20, 2014</date></pub-dates></dates><urls><related-urls><url>;(Joyce et al., 2014). One way to combat this decline in BSH is via the administration of probiotic strains ADDIN EN.CITE <EndNote><Cite><Author>Al-Sheraji</Author><Year>2012</Year><RecNum>94</RecNum><DisplayText>(Al-Sheraji et al., 2012)</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Al-Sheraji, S. H.</author><author>Ismail, A.</author><author>Manap, M. Y.</author><author>Mustafa, S.</author><author>Yusof, R. M.</author><author>Hassan, F. A.</author></authors></contributors><auth-address>Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.</auth-address><titles><title>Hypocholesterolaemic effect of yoghurt containing Bifidobacterium pseudocatenulatum G4 or Bifidobacterium longum BB536</title><secondary-title>Food Chem</secondary-title></titles><pages>356-61</pages><volume>135</volume><number>2</number><edition>2012/08/08</edition><keywords><keyword>Animals</keyword><keyword>Anticholesteremic Agents/ metabolism</keyword><keyword>Bifidobacterium/ metabolism</keyword><keyword>Cholesterol/blood/metabolism</keyword><keyword>Humans</keyword><keyword>Hypercholesterolemia/ diet therapy/metabolism/microbiology</keyword><keyword>Male</keyword><keyword>Probiotics/metabolism/ therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Yogurt/analysis/ microbiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Nov 15</date></pub-dates></dates><isbn>0308-8146 (Print)
0308-8146 (Linking)</isbn><accession-num>22868099</accession-num><urls></urls><electronic-resource-num>10.1016/j.foodchem.2012.04.120</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Al-Sheraji et al., 2012). However, caution is needed when suggesting this strategy as a therapeutic intervention for the treatment of hypercholesterolaemia, as increased concentrations of secondary bile acids can increase inflammation and cancer risk in the colon ADDIN EN.CITE <EndNote><Cite><Author>Salemans</Author><Year>1993</Year><RecNum>97</RecNum><DisplayText>(Salemans et al., 1993)</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salemans, J. M.</author><author>Nagengast, F. M.</author><author>Tangerman, A.</author><author>van Schaik, A.</author><author>Hopman, W. P.</author><author>de Haan, A. F.</author><author>Jansen, J. B.</author></authors></contributors><auth-address>Department of Medicine, University Hospital Nijmegen, The Netherlands.</auth-address><titles><title>Effect of ageing on postprandial conjugated and unconjugated serum bile acid levels in healthy subjects</title><secondary-title>Eur J Clin Invest</secondary-title></titles><pages>192-8</pages><volume>23</volume><number>3</number><edition>1993/03/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/ blood/physiology</keyword><keyword>Bile Acids and Salts/ blood/metabolism</keyword><keyword>Chenodeoxycholic Acid/blood</keyword><keyword>Cholic Acid</keyword><keyword>Cholic Acids/blood</keyword><keyword>Colorectal Neoplasms/etiology</keyword><keyword>Deoxycholic Acid/blood</keyword><keyword>Eating/physiology</keyword><keyword>Fasting/physiology</keyword><keyword>Female</keyword><keyword>Gastrointestinal Transit</keyword><keyword>Humans</keyword><keyword>Intestinal Absorption</keyword><keyword>Jejunum/metabolism/microbiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1993</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0014-2972 (Print)
0014-2972 (Linking)</isbn><accession-num>8477795</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Salemans et al., 1993). This is emphasized in older individuals, where intestinal transit time is elevated, and reabsorption of conjugated bile acids is decreased, thus increasing the exposure of the intestinal mucosa to bile acids ADDIN EN.CITE <EndNote><Cite><Author>Salemans</Author><Year>1993</Year><RecNum>97</RecNum><DisplayText>(Salemans et al., 1993)</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salemans, J. M.</author><author>Nagengast, F. M.</author><author>Tangerman, A.</author><author>van Schaik, A.</author><author>Hopman, W. P.</author><author>de Haan, A. F.</author><author>Jansen, J. B.</author></authors></contributors><auth-address>Department of Medicine, University Hospital Nijmegen, The Netherlands.</auth-address><titles><title>Effect of ageing on postprandial conjugated and unconjugated serum bile acid levels in healthy subjects</title><secondary-title>Eur J Clin Invest</secondary-title></titles><pages>192-8</pages><volume>23</volume><number>3</number><edition>1993/03/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/ blood/physiology</keyword><keyword>Bile Acids and Salts/ blood/metabolism</keyword><keyword>Chenodeoxycholic Acid/blood</keyword><keyword>Cholic Acid</keyword><keyword>Cholic Acids/blood</keyword><keyword>Colorectal Neoplasms/etiology</keyword><keyword>Deoxycholic Acid/blood</keyword><keyword>Eating/physiology</keyword><keyword>Fasting/physiology</keyword><keyword>Female</keyword><keyword>Gastrointestinal Transit</keyword><keyword>Humans</keyword><keyword>Intestinal Absorption</keyword><keyword>Jejunum/metabolism/microbiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1993</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0014-2972 (Print)
0014-2972 (Linking)</isbn><accession-num>8477795</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Salemans et al., 1993). This elevated exposure time results in the promotion of colorectal cancer in the elderly ADDIN EN.CITE <EndNote><Cite><Author>Ajouz</Author><Year>2014</Year><RecNum>99</RecNum><DisplayText>(Ajouz et al., 2014)</DisplayText><record><rec-number>99</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">99</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ajouz, Hana</author><author>Mukherji, Deborah</author><author>Shamseddine, Ali</author></authors></contributors><titles><title>Secondary bile acids: an underrecognized cause of colon cancer</title><secondary-title>World Journal of Surgical Oncology</secondary-title></titles><pages>164-164</pages><volume>12</volume><dates><year>2014</year><pub-dates><date>05/24
08/06/received
05/09/accepted</date></pub-dates></dates><publisher>BioMed Central</publisher><isbn>1477-7819</isbn><accession-num>PMC4041630</accession-num><urls><related-urls><url>;(Ajouz et al., 2014).4.0 Impact of Genetic Variation on Cholesterol Metabolism and Healthy AgeingThere are several key genes involved in cholesterol metabolism; mutations to these genes can impact on plasma cholesterol levels; the response to pharmaceutical intervention; and the pathogenesis of age-related disease. In this section we will discuss several of the key genetic polymorphisms responsible for the dysfunction of cholesterol metabolism, as well as those promoting exceptional longevity. Asselbergs et al. (2012) describe 122 single nucleotide polymorphisms (SNPs) which could account for ~9.9% of the variance in HDL-C levels. Furthermore, 104 SNPs could explain ~9.5% of the variance in LDL-C, 142 SNPs could explain 10.3% of variance in total cholesterol, while 110 SNPs could explain 8.0% of the variance associated with triglyceride levels PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc3NlbGJlcmdzPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh
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ADDIN EN.CITE.DATA (Asselbergs et al., 2012). In addition, genetic factors can also influence the lipoprotein response to extrinsic factors, such as pharmaceutical intervention or diet. For example, in response to increases in dietary cholesterol, individuals can be categorised as either a hypo-responder, where plasma total cholesterol increases <0.05mmol/L, or as hyper-responders, where there is an increase of ≥0.06mmol/L per each additional 100mg dietary cholesterol, respectively ADDIN EN.CITE <EndNote><Cite><Author>Herron</Author><Year>2003</Year><RecNum>89</RecNum><DisplayText>(Herron et al., 2003)</DisplayText><record><rec-number>89</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">89</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herron, K. L.</author><author>Vega-Lopez, S.</author><author>Conde, K.</author><author>Ramjiganesh, T.</author><author>Shachter, N. S.</author><author>Fernandez, M. L.</author></authors></contributors><auth-address>Department of Nutritional Sciences, University of Connecticut, Storrs 06269, USA. kristin.herron@uconn.edu</auth-address><titles><title>Men classified as hypo- or hyperresponders to dietary cholesterol feeding exhibit differences in lipoprotein metabolism</title><secondary-title>J Nutr</secondary-title></titles><pages>1036-42</pages><volume>133</volume><number>4</number><edition>2003/04/04</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Cholesterol/ blood</keyword><keyword>Cholesterol, Dietary/ administration & dosage</keyword><keyword>Cross-Over Studies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2003</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-3166 (Print)
0022-3166 (Linking)</isbn><accession-num>12672915</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Herron et al., 2003). Likewise, Herron et al. (2003) demonstrated ingestion of ~640mg/day resulted in a 30% increase in LDL-C and an 8% increase in HDL-C in individuals classified as hyper-responders, whereas LDL-C and HDL-C were unaffected in individuals classed as hypo-responders. Thus, it is not surprising that previously Bosner et al. (1999) demonstrated cholesterol absorption varies from 29.0 to 80.1% in healthy subjects aged between 17 and 80 years of age. Ethnicity also plays a role in this variation, with African-Americans on average absorbing larger amounts of cholesterol than Caucasians or those from Asian descent (63.4% vs. 56.2%). Although, dietary intake, rather than absorption efficiency, appeared to be the dominant factor in cholesterol absorption ADDIN EN.CITE <EndNote><Cite><Author>Bosner</Author><Year>1999</Year><RecNum>151</RecNum><DisplayText>(Bosner et al., 1999)</DisplayText><record><rec-number>151</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bosner, Matthew S.</author><author>Lange, Louis G.</author><author>Stenson, William F.</author><author>Ostlund, Richard E.</author></authors></contributors><titles><title>Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>302-308</pages><volume>40</volume><number>2</number><dates><year>1999</year><pub-dates><date>February 1, 1999</date></pub-dates></dates><urls><related-urls><url>;(Bosner et al., 1999). In addition, the response to pharmaceutical intervention, such as the administration of cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors is highly variable PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW1vbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Barber et al., 2010; Simon et al., 2005). For example, the presence of at least 1 minor allele at g.-18C resulted in a 15% improved reduction in LDL-C in response to ezetimibe + statin therapy ADDIN EN.CITE <EndNote><Cite><Author>Simon</Author><Year>2005</Year><RecNum>91</RecNum><DisplayText>(Simon et al., 2005)</DisplayText><record><rec-number>91</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">91</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simon, Jason S.</author><author>Karnoub, Maha C.</author><author>Devlin, David J.</author><author>Arreaza, Maria G.</author><author>Qiu, Ping</author><author>Monks, Stephanie A.</author><author>Severino, Michael E.</author><author>Deutsch, Paul</author><author>Palmisano, Joanne</author><author>Sachs, Alan B.</author><author>Bayne, Marvin L.</author><author>Plump, Andrew S.</author><author>Schadt, Eric E.</author></authors></contributors><titles><title>Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment</title><secondary-title>Genomics</secondary-title></titles><pages>648-656</pages><volume>86</volume><number>6</number><keywords><keyword>Target of ezetimibe</keyword><keyword>NPC1L1</keyword><keyword>Drug response</keyword><keyword>Genetic association</keyword><keyword>Clinical trial</keyword><keyword>Cholesterol</keyword></keywords><dates><year>2005</year><pub-dates><date>12//</date></pub-dates></dates><isbn>0888-7543</isbn><urls><related-urls><url>;(Simon et al., 2005). 4.1 Cholesteryl Ester Transfer ProteinMutations to the gene encoding for the CETP enzyme can influence CETP activity and size PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DZWZhbHU8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Cefalu et al., 2009). This affects both the amount of esterified cholesterol transported from HDL to LDL and VLDL, as well as lipoprotein size and number ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2002</Year><RecNum>146</RecNum><DisplayText>(Wang et al., 2002)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, J.</author><author>Qiang, H.</author><author>Chen, D.</author><author>Zhang, C.</author><author>Zhuang, Y.</author></authors></contributors><auth-address>Department of Biochemistry, Jinling Hospital, Clinical School of Medical College, Nanjing University, 305#, East Zhong Shan Road, Nanjing 210002, PR China. wangjj@</auth-address><titles><title>CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease</title><secondary-title>Clin Chim Acta</secondary-title></titles><pages>85-90</pages><volume>322</volume><number>1-2</number><edition>2002/07/10</edition><keywords><keyword>Aged</keyword><keyword>Carrier Proteins/ genetics</keyword><keyword>Cholesterol Ester Transfer Proteins</keyword><keyword>Coronary Disease/ genetics/ metabolism</keyword><keyword>DNA Mutational Analysis</keyword><keyword>Female</keyword><keyword>Gene Frequency</keyword><keyword>Glycoproteins</keyword><keyword>Humans</keyword><keyword>Lipoproteins, LDL/ chemistry</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mutation/ genetics</keyword><keyword>Particle Size</keyword><keyword>Polymerase Chain Reaction</keyword><keyword>Polymorphism, Restriction Fragment Length</keyword></keywords><dates><year>2002</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0009-8981 (Print)
0009-8981 (Linking)</isbn><accession-num>12104085</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wang et al., 2002). There are several mutations within the CETP gene that have been discovered. Of these polymorphisms, several have been associated with lower CETP levels, reduced risk of CVD, and increased longevity. Murine models transfected with CETP undergo extensive lipid profile remodelling resulting in an increased risk for CVD ADDIN EN.CITE <EndNote><Cite><Author>Westerterp</Author><Year>2006</Year><RecNum>150</RecNum><DisplayText>(Westerterp et al., 2006)</DisplayText><record><rec-number>150</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">150</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Westerterp, Marit</author><author>van der Hoogt, Caroline C.</author><author>de Haan, Willeke</author><author>Offerman, Erik H.</author><author>Dallinga-Thie, Geesje M.</author><author>Jukema, J. Wouter</author><author>Havekes, Louis M.</author><author>Rensen, Patrick C.N.</author></authors></contributors><titles><title>Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>2552-2559</pages><volume>26</volume><number>11</number><dates><year>2006</year><pub-dates><date>November 1, 2006</date></pub-dates></dates><urls><related-urls><url>;(Westerterp et al., 2006). Therefore, any mutation resulting in decreased CETP, is thought to reduce CVD risk and increase life-span. For example, homozygosity for the common I405V polymorphism is associated exceptional longevity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJ6aWxhaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA (Barzilai et al., 2006; Barzilai et al., 2003). It is likely that larger LDL molecules are less readily able to penetrate the arterial tissue, and therefore result in a decreased risk for atherosclerosis pathogenesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJ6aWxhaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA (Barzilai et al., 2003). Homozygosity for the I405V polymorphism is therefore regarded as a protective phenotype for healthy ageing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJ6aWxhaTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+
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ADDIN EN.CITE.DATA (Atzmon et al., 2005; Barzilai et al., 2006). The D442G mutation has also been described as an atheroprotective genotype, as the D442G mutation has been shown to increase LDL-C particle size, and HDL-C levels ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2002</Year><RecNum>146</RecNum><DisplayText>(Wang et al., 2002)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, J.</author><author>Qiang, H.</author><author>Chen, D.</author><author>Zhang, C.</author><author>Zhuang, Y.</author></authors></contributors><auth-address>Department of Biochemistry, Jinling Hospital, Clinical School of Medical College, Nanjing University, 305#, East Zhong Shan Road, Nanjing 210002, PR China. wangjj@</auth-address><titles><title>CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease</title><secondary-title>Clin Chim Acta</secondary-title></titles><pages>85-90</pages><volume>322</volume><number>1-2</number><edition>2002/07/10</edition><keywords><keyword>Aged</keyword><keyword>Carrier Proteins/ genetics</keyword><keyword>Cholesterol Ester Transfer Proteins</keyword><keyword>Coronary Disease/ genetics/ metabolism</keyword><keyword>DNA Mutational Analysis</keyword><keyword>Female</keyword><keyword>Gene Frequency</keyword><keyword>Glycoproteins</keyword><keyword>Humans</keyword><keyword>Lipoproteins, LDL/ chemistry</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mutation/ genetics</keyword><keyword>Particle Size</keyword><keyword>Polymerase Chain Reaction</keyword><keyword>Polymorphism, Restriction Fragment Length</keyword></keywords><dates><year>2002</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0009-8981 (Print)
0009-8981 (Linking)</isbn><accession-num>12104085</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wang et al., 2002), in addition to decreasing the risk for CVD mortality ADDIN EN.CITE <EndNote><Cite><Author>Koropatnick</Author><Year>2008</Year><RecNum>148</RecNum><DisplayText>(Koropatnick et al., 2008)</DisplayText><record><rec-number>148</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">148</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koropatnick, T. A.</author><author>Kimbell, J.</author><author>Chen, R.</author><author>Grove, J. S.</author><author>Donlon, T. A.</author><author>Masaki, K. H.</author><author>Rodriguez, B. L.</author><author>Willcox, B. J.</author><author>Yano, K.</author><author>Curb, J. D.</author></authors></contributors><auth-address>Pacific Health Research Institute, 846 South Hotel St., Suite 301, Honolulu, Hawaii 96813, USA.</auth-address><titles><title>A prospective study of high-density lipoprotein cholesterol, cholesteryl ester transfer protein gene variants, and healthy aging in very old Japanese-american men</title><secondary-title>J Gerontol A Biol Sci Med Sci</secondary-title></titles><periodical><full-title>J Gerontol A Biol Sci Med Sci</full-title><abbr-1>The journals of gerontology. Series A, Biological sciences and medical sciences</abbr-1></periodical><pages>1235-40</pages><volume>63</volume><number>11</number><edition>2008/11/29</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Cardiovascular Diseases/mortality</keyword><keyword>Cholesterol Ester Transfer Proteins/ genetics</keyword><keyword>Hawaii</keyword><keyword>Humans</keyword><keyword>Japan/ethnology</keyword><keyword>Lipoproteins, HDL/ blood</keyword><keyword>Longevity/ physiology</keyword><keyword>Male</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1079-5006 (Print)
1079-5006 (Linking)</isbn><accession-num>19038839</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Koropatnick et al., 2008). However, Zhong et al. (1996) demonstrated an increase in HDL-C associated with this genotype, was correlated with an increase in CHD risk ADDIN EN.CITE <EndNote><Cite><Author>Zhong</Author><Year>1996</Year><RecNum>147</RecNum><DisplayText>(Zhong et al., 1996)</DisplayText><record><rec-number>147</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">147</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhong, S.</author><author>Sharp, D. S.</author><author>Grove, J. S.</author><author>Bruce, C.</author><author>Yano, K.</author><author>Curb, J. D.</author><author>Tall, A. R.</author></authors></contributors><auth-address>Department of Medicine, Columbia University, New York 10032, USA.</auth-address><titles><title>Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><pages>2917-23</pages><volume>97</volume><number>12</number><edition>1996/06/15</edition><keywords><keyword>Aged</keyword><keyword>Asian Americans</keyword><keyword>Carrier Proteins/ genetics/physiology</keyword><keyword>Cholesterol Ester Transfer Proteins</keyword><keyword>Cholesterol Esters/ metabolism</keyword><keyword>Cholesterol, HDL/ blood</keyword><keyword>Coronary Disease/blood/ etiology</keyword><keyword>Glycoproteins</keyword><keyword>Humans</keyword><keyword>Japan/ethnology</keyword><keyword>Male</keyword><keyword>Mutation</keyword></keywords><dates><year>1996</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0021-9738 (Print)
0021-9738 (Linking)</isbn><accession-num>8675707</accession-num><urls></urls><custom2>PMC507389</custom2><electronic-resource-num>10.1172/jci118751</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Zhong et al., 1996). Alternatively, Hirano et al. (1997) demonstrated that a G to A mutation in intron 14, which induced a rise in HDL-C exhibited a U-shaped curve of the incidence risk of ischemic change ADDIN EN.CITE <EndNote><Cite><Author>Hirano</Author><Year>1997</Year><RecNum>149</RecNum><DisplayText>(Hirano et al., 1997)</DisplayText><record><rec-number>149</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">149</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hirano, K.</author><author>Yamashita, S.</author><author>Nakajima, N.</author><author>Arai, T.</author><author>Maruyama, T.</author><author>Yoshida, Y.</author><author>Ishigami, M.</author><author>Sakai, N.</author><author>Kameda-Takemura, K.</author><author>Matsuzawa, Y.</author></authors></contributors><auth-address>Second Department of Internal Medicine, Osaka University Medical School, Japan.</auth-address><titles><title>Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity</title><secondary-title>Arterioscler Thromb Vasc Biol</secondary-title></titles><pages>1053-9</pages><volume>17</volume><number>6</number><edition>1997/06/01</edition><keywords><keyword>Aged</keyword><keyword>Carrier Proteins/ genetics</keyword><keyword>Cholesterol Ester Transfer Proteins</keyword><keyword>Female</keyword><keyword>Glycoproteins</keyword><keyword>Humans</keyword><keyword>Japan</keyword><keyword>Lipid Metabolism, Inborn Errors/epidemiology/ physiopathology</keyword><keyword>Lipoproteins, HDL/ blood</keyword><keyword>Longevity</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1079-5642 (Print)
1079-5642 (Linking)</isbn><accession-num>9194754</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Hirano et al., 1997). Moreover, Agerholm-Laren et al. (2000) demonstrated the A373P/R451Q genotype resulted in a decrease in HDL-C in both males and females from the Danish general population. Homozygosity for the mutation resulted in the effect being more pronounced than in heterozygotes, with HDL-C levels of 1.19 and 1.38mmol/L in males and females respectively compared to 1.26 and 1.62mmol/L. Non-carrier males and females had HDL levels of 1.4 and 1.74mmol/L, respectively. Although this CETP genotype induced reduced HDL-C levels, they were not associated with ischemic heart disease (IHD). Furthermore, when the authors adjusted for a group of risk factors in addition to HDL-C, the mutation resulted in a 36% reduction in risk of IHD ADDIN EN.CITE <EndNote><Cite><Author>Agerholm-Larsen</Author><Year>2000</Year><RecNum>144</RecNum><DisplayText>(Agerholm-Larsen et al., 2000)</DisplayText><record><rec-number>144</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">144</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agerholm-Larsen, Birgit</author><author>Tybj?rg-Hansen, Anne</author><author>Schnohr, Peter</author><author>Steffensen, Rolf</author><author>Nordestgaard, B?rge G.</author></authors></contributors><titles><title>Common Cholesteryl Ester Transfer Protein Mutations, Decreased HDL Cholesterol, and Possible Decreased Risk of Ischemic Heart Disease: The Copenhagen City Heart Study</title><secondary-title>Circulation</secondary-title></titles><pages>2197-2203</pages><volume>102</volume><number>18</number><dates><year>2000</year><pub-dates><date>October 31, 2000</date></pub-dates></dates><urls><related-urls><url>;(Agerholm-Larsen et al., 2000).4.2 Niemann-Pick C1-Like 1 Intestinal absorption of cholesterol varies significantly from person to person. In healthy individuals, cholesterol absorption can range from 29.0-80.1% ADDIN EN.CITE <EndNote><Cite><Author>Bosner</Author><Year>1999</Year><RecNum>151</RecNum><DisplayText>(Bosner et al., 1999)</DisplayText><record><rec-number>151</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bosner, Matthew S.</author><author>Lange, Louis G.</author><author>Stenson, William F.</author><author>Ostlund, Richard E.</author></authors></contributors><titles><title>Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>302-308</pages><volume>40</volume><number>2</number><dates><year>1999</year><pub-dates><date>February 1, 1999</date></pub-dates></dates><urls><related-urls><url>;(Bosner et al., 1999). This is due, in part to the genetic variation in the genes encoding for the NPC1L1 receptor, which is responsible for the clathrin-mediated endocytosis of cholesterol from the digestive tract. Cohen et al. (2006) discovered 20 polymorphisms within individuals classified as hypo-absorbers, compared to only 5 for the hyper-absorber category. Of the 20 mutations conferring a low cholesterol absorption efficiency, 18 were observed in African-Americans. This reflected the findings that these hypo-absorber phenotypes were more prevalent in African Americans (6.2%) than white (1.8%) or Hispanic (1.7%) populations. These hypo-absorber phenotypes conferred an average 8.6% reduction in LDL-C ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>2006</Year><RecNum>154</RecNum><DisplayText>(Cohen et al., 2006)</DisplayText><record><rec-number>154</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">154</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cohen, J. C.</author><author>Pertsemlidis, A.</author><author>Fahmi, S.</author><author>Esmail, S.</author><author>Vega, G. L.</author><author>Grundy, S. M.</author><author>Hobbs, H. H.</author></authors></contributors><auth-address>Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052, USA. jonathan.cohen@utsouthwestern.edu</auth-address><titles><title>Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><pages>1810-5</pages><volume>103</volume><number>6</number><edition>2006/02/02</edition><keywords><keyword>Absorption</keyword><keyword>Adult</keyword><keyword>Ethnic Groups/genetics</keyword><keyword>Female</keyword><keyword>Genetic Variation/ genetics</keyword><keyword>Haplotypes</keyword><keyword>Humans</keyword><keyword>Lipoproteins, LDL/ blood</keyword><keyword>Male</keyword><keyword>Membrane Proteins/ genetics/ metabolism</keyword><keyword>Middle Aged</keyword><keyword>Proteins/ genetics/ metabolism</keyword><keyword>Sterols/ metabolism/pharmacokinetics</keyword><keyword>Texas</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb 7</date></pub-dates></dates><isbn>0027-8424 (Print)
0027-8424 (Linking)</isbn><accession-num>16449388</accession-num><urls></urls><custom2>PMC1413637</custom2><electronic-resource-num>10.1073/pnas.0508483103</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Cohen et al., 2006). In individuals with autosomal dominant hypercholesterolaemia, lacking LDLr or apo B mutations, NPC1L1 mutations may play a role in the hypercholesterolaemic phenotype displayed. For example, it has been shown that the -133A>G polymorphism, significantly increases NPC1L1 promoter activity ADDIN EN.CITE <EndNote><Cite><Author>Martín</Author><Year>2010</Year><RecNum>155</RecNum><DisplayText>(Martín et al., 2010)</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martín, B.</author><author>Solanas-Barca, M.</author><author>García-Otín, ? L.</author><author>Pampín, S.</author><author>Cofán, M.</author><author>Ros, E.</author><author>Rodríguez-Rey, J. C.</author><author>Pocoví, M.</author><author>Civeira, F.</author></authors></contributors><titles><title>An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia</title><secondary-title>Nutrition, Metabolism and Cardiovascular Diseases</secondary-title></titles><pages>236-242</pages><volume>20</volume><number>4</number><keywords><keyword>Familial hypercholesterolemia</keyword><keyword>Polymorphisms</keyword><keyword>Cholesterol intestinal absorption</keyword></keywords><dates><year>2010</year><pub-dates><date>5//</date></pub-dates></dates><isbn>0939-4753</isbn><urls><related-urls><url>;(Martín et al., 2010). More recently, NPC1L1 SNPs have been linked with CVD. For instance, Polisecki et al. (2010) demonstrated that homozygous carriers for the minor alleles at -18A>C, L272L, V1296V or U3_28650A>G exhibited a 2-8% increase in LDL-C, while the risk of developing a fatal or nonfatal CHD event escalated by 50-67% ADDIN EN.CITE <EndNote><Cite><Author>Polisecki</Author><Year>2010</Year><RecNum>159</RecNum><DisplayText>(Polisecki et al., 2010)</DisplayText><record><rec-number>159</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Polisecki, Eliana</author><author>Peter, Inga</author><author>Simon, Jason S.</author><author>Hegele, Robert A.</author><author>Robertson, Michele</author><author>Ford, Ian</author><author>Shepherd, James</author><author>Packard, Christopher</author><author>Jukema, J. Wouter</author><author>de Craen, Anton J. M.</author><author>Westendorp, Rudi G. J.</author><author>Buckley, Brendan M.</author><author>Schaefer, Ernst J.</author><author>on behalf of the Prospective Study of Pravastatin in the Elderly at Risk, Investigators</author></authors></contributors><titles><title>Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>1201-1207</pages><volume>51</volume><number>5</number><dates><year>2010</year><pub-dates><date>09/09/received
09/14/revised</date></pub-dates></dates><publisher>The American Society for Biochemistry and Molecular Biology</publisher><isbn>0022-2275
1539-7262</isbn><accession-num>PMC2853447</accession-num><urls><related-urls><url>;(Polisecki et al., 2010). Muendlein et al. (2015) determined that 24 variants, particularly rs55837134 were associated with future cardiovascular events. Homozygosity for the rare rs55837134 variant was associated with a 3-fold increase in cardiovascular event incidence, compared with carriers homozygous for the common allele ADDIN EN.CITE <EndNote><Cite><Author>Muendlein</Author><Year>2015</Year><RecNum>158</RecNum><DisplayText>(Muendlein et al., 2015)</DisplayText><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Muendlein, Axel</author><author>Leiherer, Andreas</author><author>Saely, Christoph H.</author><author>Rein, Philipp</author><author>Zanolin, Daniela</author><author>Kinz, Elena</author><author>Brandtner, Eva-Maria</author><author>Fraunberger, Peter</author><author>Drexel, Heinz</author></authors></contributors><titles><title>Common single nucleotide polymorphisms at the NPC1L1 gene locus significantly predict cardiovascular risk in coronary patients</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>340-345</pages><volume>242</volume><number>1</number><keywords><keyword>Coronary artery disease</keyword><keyword>Cardiovascular risk</keyword><keyword>Cholesterol</keyword><keyword>Single nucleotide polymorphisms</keyword><keyword>NPC1L1</keyword></keywords><dates><year>2015</year><pub-dates><date>9//</date></pub-dates></dates><isbn>0021-9150</isbn><urls><related-urls><url>;(Muendlein et al., 2015). In contrast, Stitziel et al. (2014) demonstrated that the presence of 1 of 15 NPC1L1 inactivating mutations, as observed in 1/650 individuals, corresponded to a 12mg/dL decline in LDL-C, and a 53% reduction in cardiovascular event risk ADDIN EN.CITE <EndNote><Cite><Author>Stitziel</Author><Year>2014</Year><RecNum>157</RecNum><DisplayText>(Stitziel et al., 2014)</DisplayText><record><rec-number>157</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stitziel, Nathan O</author><author>Won, Hong-Hee</author><author>Morrison, Alanna C</author><author>Peloso, Gina M</author><author>Do, Ron</author><author>Lange, Leslie A</author><author>Fontanillas, Pierre</author><author>Gupta, Namrata</author><author>Duga, Stefano</author><author>Goel, Anuj</author></authors></contributors><titles><title>Inactivating mutations in NPC1L1 and protection from coronary heart disease</title><secondary-title>The New England journal of medicine</secondary-title></titles><pages>2072-2082</pages><volume>371</volume><number>22</number><dates><year>2014</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>(Stitziel et al., 2014). In addition to affecting baseline lipoprotein characteristics, mutations to the NPC1L1 gene also influence the lipoprotein profile response to therapeutic intervention. For example, Simon et al. (2005) demonstrated that individuals homozygous for the common allele g.-18C>A exhibited a 24.2% decline in LDL-C from baseline levels with ezetimibe treatment, compared with 27.8% for individuals heterozygous for the minor allele. Thus, heterozygosity for the minor allele represented a 15% increased response to ezetimibe treatment ADDIN EN.CITE <EndNote><Cite><Author>Simon</Author><Year>2005</Year><RecNum>91</RecNum><DisplayText>(Simon et al., 2005)</DisplayText><record><rec-number>91</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">91</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simon, Jason S.</author><author>Karnoub, Maha C.</author><author>Devlin, David J.</author><author>Arreaza, Maria G.</author><author>Qiu, Ping</author><author>Monks, Stephanie A.</author><author>Severino, Michael E.</author><author>Deutsch, Paul</author><author>Palmisano, Joanne</author><author>Sachs, Alan B.</author><author>Bayne, Marvin L.</author><author>Plump, Andrew S.</author><author>Schadt, Eric E.</author></authors></contributors><titles><title>Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment</title><secondary-title>Genomics</secondary-title></titles><pages>648-656</pages><volume>86</volume><number>6</number><keywords><keyword>Target of ezetimibe</keyword><keyword>NPC1L1</keyword><keyword>Drug response</keyword><keyword>Genetic association</keyword><keyword>Clinical trial</keyword><keyword>Cholesterol</keyword></keywords><dates><year>2005</year><pub-dates><date>12//</date></pub-dates></dates><isbn>0888-7543</isbn><urls><related-urls><url>;(Simon et al., 2005). In addition to NPC1L1 mutations leading to an altered response to the NPC1L1 inhibitor ezetimibe, statin treatment efficiency is also affected. Polisecki et al. (2010) demonstrated the -133A>G SNP influenced the LDL-C response to Pravastatin treatment. Males homozygous for the minor -133A>G allele had the greatest decline in LDL-C with pravastatin treatment, while females with the major -133A>G allele exhibited the greatest response to treatment ADDIN EN.CITE <EndNote><Cite><Author>Polisecki</Author><Year>2010</Year><RecNum>159</RecNum><DisplayText>(Polisecki et al., 2010)</DisplayText><record><rec-number>159</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Polisecki, Eliana</author><author>Peter, Inga</author><author>Simon, Jason S.</author><author>Hegele, Robert A.</author><author>Robertson, Michele</author><author>Ford, Ian</author><author>Shepherd, James</author><author>Packard, Christopher</author><author>Jukema, J. Wouter</author><author>de Craen, Anton J. M.</author><author>Westendorp, Rudi G. J.</author><author>Buckley, Brendan M.</author><author>Schaefer, Ernst J.</author><author>on behalf of the Prospective Study of Pravastatin in the Elderly at Risk, Investigators</author></authors></contributors><titles><title>Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>1201-1207</pages><volume>51</volume><number>5</number><dates><year>2010</year><pub-dates><date>09/09/received
09/14/revised</date></pub-dates></dates><publisher>The American Society for Biochemistry and Molecular Biology</publisher><isbn>0022-2275
1539-7262</isbn><accession-num>PMC2853447</accession-num><urls><related-urls><url>;(Polisecki et al., 2010).4.3 Apolipoprotein EApo E is present on chylomicrons, VLDL, IDL, and HDL and acts as a ligand for hepatic LDLr and LRP to enable lipoprotein uptake. There are three major alleles associated with the APOE gene. These are, ?2, ?3, and ?4, which have a population frequency of 6.9, 76.2 and 16.9%, respectively in a Belgian cohort ADDIN EN.CITE <EndNote><Cite><Author>Engelborghs</Author><Year>2003</Year><RecNum>161</RecNum><DisplayText>(Engelborghs et al., 2003)</DisplayText><record><rec-number>161</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">161</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Engelborghs, S.</author><author>Dermaut, B.</author><author>Goeman, J.</author><author>Saerens, J.</author><author>Marien, P.</author><author>Pickut, B.</author><author>Van den Broeck, M.</author><author>Serneels, S.</author><author>Cruts, M.</author><author>Van Broeckhoven, C.</author><author>De Deyn, P. P.</author></authors></contributors><titles><title>Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects</title><secondary-title>Journal of Neurology, Neurosurgery, and Psychiatry</secondary-title></titles><pages>1148-1151</pages><volume>74</volume><number>8</number><dates><year>2003</year></dates><publisher>BMJ Group</publisher><isbn>0022-3050
1468-330X</isbn><accession-num>PMC1738626</accession-num><urls><related-urls><url>;(Engelborghs et al., 2003). The ?3 allele is most commonly observed, and is considered as the ‘neutral’ apo E genotype. Along with ?2, ?3 preferentially binds to HDL-C, while the ?4 allele has a preference for VLDL-C ADDIN EN.CITE <EndNote><Cite><Author>Dong</Author><Year>1996</Year><RecNum>167</RecNum><DisplayText>(Dong and Weisgraber, 1996)</DisplayText><record><rec-number>167</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dong, L. M.</author><author>Weisgraber, K. H.</author></authors></contributors><auth-address>Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.</auth-address><titles><title>Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins</title><secondary-title>J Biol Chem</secondary-title></titles><pages>19053-7</pages><volume>271</volume><number>32</number><edition>1996/08/09</edition><keywords><keyword>Apolipoprotein E4</keyword><keyword>Apolipoproteins E/genetics/ metabolism</keyword><keyword>Arginine/ metabolism</keyword><keyword>Glutamic Acid/ metabolism</keyword><keyword>Humans</keyword><keyword>Lipoproteins, VLDL/ metabolism</keyword><keyword>Mutagenesis, Site-Directed</keyword><keyword>Protein Binding</keyword><keyword>Sequence Deletion</keyword></keywords><dates><year>1996</year><pub-dates><date>Aug 9</date></pub-dates></dates><isbn>0021-9258 (Print)
0021-9258 (Linking)</isbn><accession-num>8702576</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Dong and Weisgraber, 1996). The presence of the ?4 allele confers a 15 and 25% decline in plasma apo E in males and females, respectively, compared to those with the ?3 allele. This decline in apo E is associated with a 2 and 5% increase in LDL-C in males and females, respectively. In comparison, those with the ?2 allele exhibit a 27 and 32% increase in apo E, which is associated with a 10% decrease in LDL-C levels ADDIN EN.CITE <EndNote><Cite><Author>Larson</Author><Year>2000</Year><RecNum>162</RecNum><DisplayText>(Larson et al., 2000)</DisplayText><record><rec-number>162</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">162</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larson, Ilona A.</author><author>Ordovas, Jose M.</author><author>DeLuca, Carl</author><author>Barnard, James R.</author><author>Feussner, Giso</author><author>Schaefer, Ernst J.</author></authors></contributors><titles><title>Association of apolipoprotein (Apo)E genotype with plasma apo E levels</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>327-335</pages><volume>148</volume><number>2</number><keywords><keyword>Apolipoprotein (apo)</keyword><keyword>Lipoprotein</keyword><keyword>Apo E genotype</keyword></keywords><dates><year>2000</year><pub-dates><date>2/1/</date></pub-dates></dates><isbn>0021-9150</isbn><urls><related-urls><url>(99)00280-4</electronic-resource-num></record></Cite></EndNote>(Larson et al., 2000). The presence of an ?4 allele is considered a risk factor for the development of many conditions including atherosclerosis ADDIN EN.CITE <EndNote><Cite><Author>Zende</Author><Year>2013</Year><RecNum>172</RecNum><DisplayText>(Zende et al., 2013)</DisplayText><record><rec-number>172</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zende, P. D.</author><author>Bankar, M. P.</author><author>Kamble, P. S.</author><author>Momin, A. A.</author></authors></contributors><auth-address>Assistant Professor, Department of Biochemistry, Institute of Medical Sciences & Research , Mayani, Tal- Khatav, District- Satara, Maharashtra, India .</auth-address><titles><title>Apolipoprotein e gene polymorphism and its effect on plasma lipids in arteriosclerosis</title><secondary-title>J Clin Diagn Res</secondary-title></titles><pages>2149-52</pages><volume>7</volume><number>10</number><edition>2013/12/04</edition><keywords><keyword>Apolipoprotein E</keyword><keyword>Arteriosclerosis</keyword><keyword>Cerebrovascular Stroke</keyword><keyword>Coronary artery disease</keyword><keyword>Hyperlipidemia</keyword><keyword>Myocardial infarction</keyword></keywords><dates><year>2013</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>2249-782X (Print)
0973-709X (Linking)</isbn><accession-num>24298461</accession-num><urls></urls><custom2>PMC3843439</custom2><electronic-resource-num>10.7860/jcdr/2013/6195.3455</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Zende et al., 2013), Alzheimer’s Disease ADDIN EN.CITE <EndNote><Cite><Author>Rhinn</Author><Year>2013</Year><RecNum>171</RecNum><DisplayText>(Rhinn et al., 2013)</DisplayText><record><rec-number>171</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rhinn, Herve</author><author>Fujita, Ryousuke</author><author>Qiang, Liang</author><author>Cheng, Rong</author><author>Lee, Joseph H.</author><author>Abeliovich, Asa</author></authors></contributors><titles><title>Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>45-50</pages><volume>500</volume><number>7460</number><dates><year>2013</year><pub-dates><date>08/01/print</date></pub-dates></dates><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><isbn>0028-0836</isbn><work-type>Article</work-type><urls><related-urls><url>;(Rhinn et al., 2013), and multiple sclerosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3Jha292YTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA (Horakova et al., 2010), in addition to accelerating telomere shortening ADDIN EN.CITE <EndNote><Cite><Author>Wikgren</Author><Year>2012</Year><RecNum>164</RecNum><DisplayText>(Wikgren et al., 2012)</DisplayText><record><rec-number>164</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wikgren, M.</author><author>Karlsson, T.</author><author>Nilbrink, T.</author><author>Nordfjall, K.</author><author>Hultdin, J.</author><author>Sleegers, K.</author><author>Van Broeckhoven, C.</author><author>Nyberg, L.</author><author>Roos, G.</author><author>Nilsson, L. G.</author><author>Adolfsson, R.</author><author>Norrback, K. F.</author></authors></contributors><auth-address>Division of Psychiatry, Department of Clinical Sciences, Umea University, SE-901 87 Umea, Sweden. mikael.wikgren@psychiat.umu.se</auth-address><titles><title>APOE epsilon4 is associated with longer telomeres, and longer telomeres among epsilon4 carriers predicts worse episodic memory</title><secondary-title>Neurobiol Aging</secondary-title></titles><pages>335-44</pages><volume>33</volume><number>2</number><edition>2010/04/17</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Apolipoprotein E4/ genetics/ metabolism</keyword><keyword>Biological Markers/metabolism</keyword><keyword>Brain/ physiopathology</keyword><keyword>Female</keyword><keyword>Heterozygote</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Memory, Episodic</keyword><keyword>Middle Aged</keyword><keyword>Statistics as Topic</keyword><keyword>Telomere/ genetics</keyword><keyword>Telomere Shortening/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1558-1497 (Electronic)
0197-4580 (Linking)</isbn><accession-num>20395015</accession-num><urls></urls><electronic-resource-num>10.1016/j.neurobiolaging.2010.03.004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wikgren et al., 2012). On the other hand, this allele has been associated with a higher vitamin D status ADDIN EN.CITE <EndNote><Cite><Author>Huebbe</Author><Year>2011</Year><RecNum>173</RecNum><DisplayText>(Huebbe et al., 2011)</DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huebbe, P.</author><author>Nebel, A.</author><author>Siegert, S.</author><author>Moehring, J.</author><author>Boesch-Saadatmandi, C.</author><author>Most, E.</author><author>Pallauf, J.</author><author>Egert, S.</author><author>Muller, M. J.</author><author>Schreiber, S.</author><author>Nothlings, U.</author><author>Rimbach, G.</author></authors></contributors><auth-address>Institute of Human Nutrition and Food Science, Christian-Albrechts-University, Kiel, Germany.</auth-address><titles><title>APOE epsilon4 is associated with higher vitamin D levels in targeted replacement mice and humans</title><secondary-title>FASEB J</secondary-title></titles><pages>3262-70</pages><volume>25</volume><number>9</number><edition>2011/06/11</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Alleles</keyword><keyword>Animals</keyword><keyword>Apolipoprotein E4/genetics/ metabolism</keyword><keyword>Calcium/metabolism</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Middle Aged</keyword><keyword>Vitamin D/ blood</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1530-6860 (Electronic)
0892-6638 (Linking)</isbn><accession-num>21659554</accession-num><urls></urls><electronic-resource-num>10.1096/fj.11-180935</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Huebbe et al., 2011), and has been identified as a possible protective genotype against macular degeneration ADDIN EN.CITE <EndNote><Cite><Author>Kovacs</Author><Year>2007</Year><RecNum>174</RecNum><DisplayText>(Kovacs et al., 2007)</DisplayText><record><rec-number>174</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">174</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacs, K. A.</author><author>Pamer, Z.</author><author>Kovacs, A.</author><author>Fekete, S.</author><author>Miseta, A.</author><author>Kovacs, B.</author><author>Kovacs, G. L.</author></authors></contributors><auth-address>Department of Ophthalmology, University of Pecs, Pecs.</auth-address><titles><title>Association of apolipoprotein E polymorphism with age-related macular degeneration and Alzheimer's disease in south-western Hungary</title><secondary-title>Ideggyogy Sz</secondary-title></titles><pages>169-72</pages><volume>60</volume><number>3-4</number><edition>2007/04/25</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alzheimer Disease/blood/ epidemiology/ genetics</keyword><keyword>Apolipoprotein E2/genetics</keyword><keyword>Apolipoprotein E4/genetics</keyword><keyword>Apolipoproteins E/ genetics</keyword><keyword>Cholesterol/blood</keyword><keyword>Cholesterol, HDL/blood</keyword><keyword>Female</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Hungary/epidemiology</keyword><keyword>Macular Degeneration/blood/ epidemiology/ genetics</keyword><keyword>Male</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Triglycerides/blood</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar 30</date></pub-dates></dates><isbn>0019-1442 (Print)
0019-1442 (Linking)</isbn><accession-num>17451062</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kovacs et al., 2007). The ?2 allele in contrast has been associated with an increased risk for the disease, or for its earlier onset ADDIN EN.CITE <EndNote><Cite><Author>Tikellis</Author><Year>2007</Year><RecNum>175</RecNum><DisplayText>(Tikellis et al., 2007)</DisplayText><record><rec-number>175</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">175</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tikellis, G.</author><author>Sun, C.</author><author>Gorin, M. B.</author><author>Klein, R.</author><author>Klein, B. E.</author><author>Larsen, E. K.</author><author>Siscovick, D. S.</author><author>Hubbard, L. D.</author><author>Wong, T. Y.</author></authors></contributors><auth-address>Centre for Eye Research Australia, University of Melbourne, Victoria, Australia.</auth-address><titles><title>Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study</title><secondary-title>Arch Ophthalmol</secondary-title></titles><pages>68-73</pages><volume>125</volume><number>1</number><edition>2007/01/11</edition><keywords><keyword>African Americans</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alleles</keyword><keyword>Apolipoprotein E2/ genetics</keyword><keyword>Apolipoprotein E3/ genetics</keyword><keyword>Apolipoprotein E4/ genetics</keyword><keyword>Cardiovascular Diseases/genetics</keyword><keyword>European Continental Ancestry Group</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Macular Degeneration/ genetics</keyword><keyword>Male</keyword><keyword>Odds Ratio</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0003-9950 (Print)
0003-9950 (Linking)</isbn><accession-num>17210854</accession-num><urls></urls><electronic-resource-num>10.1001/archopht.125.1.68</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Tikellis et al., 2007). Furthermore, homozygosity for the ?2 allele is found in 90% of individuals with hyperlipoproteinaemia type III ADDIN EN.CITE <EndNote><Cite><Author>Mahley</Author><Year>2000</Year><RecNum>169</RecNum><DisplayText>(Mahley and Rall, 2000)</DisplayText><record><rec-number>169</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">169</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahley, R. W.</author><author>Rall, S. C., Jr.</author></authors></contributors><auth-address>Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, California 94141-9100, USA. rmahley@gladstone.ucsf.edu</auth-address><titles><title>Apolipoprotein E: far more than a lipid transport protein</title><secondary-title>Annu Rev Genomics Hum Genet</secondary-title></titles><pages>507-37</pages><volume>1</volume><edition>2001/11/10</edition><keywords><keyword>Alleles</keyword><keyword>Animals</keyword><keyword>Apolipoproteins E/chemistry/ genetics/ metabolism</keyword><keyword>Arteriosclerosis/etiology/genetics</keyword><keyword>Biological Transport, Active</keyword><keyword>Communicable Diseases/etiology/genetics</keyword><keyword>Female</keyword><keyword>Heart Diseases/etiology/genetics</keyword><keyword>Humans</keyword><keyword>Hyperlipoproteinemia Type III/genetics/metabolism</keyword><keyword>Immunity/genetics</keyword><keyword>Lipid Metabolism</keyword><keyword>Lipoproteins/metabolism</keyword><keyword>Male</keyword><keyword>Models, Molecular</keyword><keyword>Neurobiology</keyword><keyword>Phenotype</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Protein Isoforms/chemistry/genetics/metabolism</keyword><keyword>Reproduction/genetics</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2000</year></dates><isbn>1527-8204 (Print)
1527-8204 (Linking)</isbn><accession-num>11701639</accession-num><urls></urls><electronic-resource-num>10.1146/annurev.genom.1.1.507</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Mahley and Rall, 2000). The ?2 isotope results in defective lipoprotein binding to LDLr, which in turn leads to incomplete catabolism of chylomicrons and VLDL-C, resulting in an accumulation of cholesterol rich lipoprotein remnants ADDIN EN.CITE <EndNote><Cite><Author>Phillips</Author><Year>2014</Year><RecNum>170</RecNum><DisplayText>(Phillips, 2014)</DisplayText><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillips, M. C.</author></authors></contributors><auth-address>Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 11-130 Translational Research Center, Philadelphia, PA, USA.</auth-address><titles><title>Apolipoprotein E isoforms and lipoprotein metabolism</title><secondary-title>IUBMB Life</secondary-title></titles><pages>616-23</pages><volume>66</volume><number>9</number><edition>2014/10/21</edition><keywords><keyword>Amino Acid Substitution/genetics</keyword><keyword>Apolipoproteins E/ genetics/ metabolism</keyword><keyword>Humans</keyword><keyword>Lipid Metabolism Disorders/genetics/ metabolism</keyword><keyword>Lipoproteins/ metabolism</keyword><keyword>Models, Molecular</keyword><keyword>Protein Binding</keyword><keyword>Protein Isoforms/genetics/ metabolism</keyword><keyword>apolipoprotein E</keyword><keyword>atherosclerosis</keyword><keyword>cholesterol</keyword><keyword>high density lipoprotein</keyword><keyword>lipoprotein metabolism</keyword><keyword>low density lipoprotein receptor</keyword><keyword>triglyceride</keyword><keyword>very low density lipoprotein</keyword></keywords><dates><year>2014</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1521-6551 (Electronic)
1521-6543 (Linking)</isbn><accession-num>25328986</accession-num><urls></urls><electronic-resource-num>10.1002/iub.1314</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Phillips, 2014). However, only 5% of ?2 homozygotes have this disease, and therefore there are other factors involved in the development of the disease ADDIN EN.CITE <EndNote><Cite><Author>de Beer</Author><Year>2002</Year><RecNum>168</RecNum><DisplayText>(de Beer et al., 2002)</DisplayText><record><rec-number>168</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">168</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Beer, Femke</author><author>Stalenhoef, Anton F.H.</author><author>Hoogerbrugge, Nicoline</author><author>Kastelein, John J.P.</author><author>Gevers Leuven, Jan A.</author><author>van Duijn, Cornelia M.</author><author>Havekes, Louis M.</author><author>Smelt, Augustinus H.M.</author></authors></contributors><titles><title>Expression of Type III Hyperlipoproteinemia in Apolipoprotein E2 (Arg158→Cys) Homozygotes Is Associated With Hyperinsulinemia</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>294-299</pages><volume>22</volume><number>2</number><dates><year>2002</year><pub-dates><date>February 1, 2002</date></pub-dates></dates><urls><related-urls><url>;(de Beer et al., 2002). With the exception of hyperlipoproteinaemia type III, this ?2 allele has been associated with a protective phenotype against CHD ADDIN EN.CITE <EndNote><Cite><Author>Bennet</Author><Year>2007</Year><RecNum>166</RecNum><DisplayText>(Bennet et al., 2007)</DisplayText><record><rec-number>166</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">166</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bennet, A. M.</author><author>Di Angelantonio, E.</author><author>Ye, Z.</author><author>Wensley, F.</author><author>Dahlin, A.</author><author>Ahlbom, A.</author><author>Keavney, B.</author><author>Collins, R.</author><author>Wiman, B.</author><author>de Faire, U.</author><author>Danesh, J.</author></authors></contributors><auth-address>Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.</auth-address><titles><title>Association of apolipoprotein E genotypes with lipid levels and coronary risk</title><secondary-title>JAMA</secondary-title></titles><pages>1300-11</pages><volume>298</volume><number>11</number><edition>2007/09/20</edition><keywords><keyword>Apolipoproteins E/ genetics</keyword><keyword>Cholesterol, LDL/blood</keyword><keyword>Coronary Disease/ epidemiology/genetics</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Lipids/ blood</keyword><keyword>Risk Assessment</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep 19</date></pub-dates></dates><isbn>1538-3598 (Electronic)
0098-7484 (Linking)</isbn><accession-num>17878422</accession-num><urls></urls><electronic-resource-num>10.1001/jama.298.11.1300</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Bennet et al., 2007). Furthermore, the ?2 allele is positively associated with exceptional longevity in Italian, Danish, US, and Japanese cohorts. In contrast, the presence of the ?4 allele reduced the chance of reaching exceptional longevity in Spanish, Italian, Danish, US and Japanese cohorts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJhdGFjaGVhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA (Garatachea et al., 2014; Schupf et al., 2013). 4.4 Lipoprotein and Hepatic Lipase Another enzyme that is effected by genetic mutation is LPL. LPL is primarily found on the endothelial wall of capillaries and is responsible for the hydrolysis of triacylglycerol in chylomicrons and VLDL into FFA and MAG ADDIN EN.CITE <EndNote><Cite><Author>Goldberg</Author><Year>2009</Year><RecNum>253</RecNum><DisplayText>(Goldberg et al., 2009)</DisplayText><record><rec-number>253</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">253</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goldberg, Ira J.</author><author>Eckel, Robert H.</author><author>Abumrad, Nada A.</author></authors></contributors><titles><title>Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><pages>S86-S90</pages><volume>50</volume><number>Supplement</number><dates><year>2009</year><pub-dates><date>April 1, 2009</date></pub-dates></dates><urls><related-urls><url>;(Goldberg et al., 2009). A common polymorphism in the LPL gene is S447X. In a cohort of middle-aged and elderly American subjects, 44.0 and 50.6% of males and females, respectively exhibited homozygosity for the common allele, while only 12.6 and 7.6% were homozygous for the rare allele ADDIN EN.CITE <EndNote><Cite><Author>Larson</Author><Year>1999</Year><RecNum>233</RecNum><DisplayText>(Larson et al., 1999)</DisplayText><record><rec-number>233</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">233</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larson, Ilona</author><author>Hoffmann, Michael M.</author><author>Ordovas, Jose M.</author><author>Schaefer, Ernst J.</author><author>M?rz, Winfried</author><author>Kreuzer, J?rg</author></authors></contributors><titles><title>The Lipoprotein Lipase HindIII Polymorphism: Association with Total Cholesterol and LDL-Cholesterol, but not with HDL and Triglycerides in 342 Females</title><secondary-title>Clinical Chemistry</secondary-title></titles><pages>963-968</pages><volume>45</volume><number>7</number><dates><year>1999</year><pub-dates><date>July 1, 1999</date></pub-dates></dates><urls><related-urls><url>;(Larson et al., 1999). Heterozygosity was displayed in 43.4 and 41.8% of males and females respectively. Females, but not males, exhibiting homozygosity for the rare allele had lower total cholesterol and LDL-C levels, when compared to heterozygotes and homozygotes for the common allele ADDIN EN.CITE <EndNote><Cite><Author>Larson</Author><Year>1999</Year><RecNum>233</RecNum><DisplayText>(Larson et al., 1999)</DisplayText><record><rec-number>233</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">233</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larson, Ilona</author><author>Hoffmann, Michael M.</author><author>Ordovas, Jose M.</author><author>Schaefer, Ernst J.</author><author>M?rz, Winfried</author><author>Kreuzer, J?rg</author></authors></contributors><titles><title>The Lipoprotein Lipase HindIII Polymorphism: Association with Total Cholesterol and LDL-Cholesterol, but not with HDL and Triglycerides in 342 Females</title><secondary-title>Clinical Chemistry</secondary-title></titles><pages>963-968</pages><volume>45</volume><number>7</number><dates><year>1999</year><pub-dates><date>July 1, 1999</date></pub-dates></dates><urls><related-urls><url>;(Larson et al., 1999). This alteration to cholesterol metabolism could play a role in the association of this genotype with age-related conditions such as hypertension, type 2 diabetes mellitus and coronary artery disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdcOxb3otQmFycmlvczwvQXV0aG9yPjxZZWFyPjIwMTI8
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ADDIN EN.CITE.DATA (Daoud et al., 2013; Mu?oz-Barrios et al., 2012). Hepatic lipase is responsible for the conversion of IDL to LDL, and can also be effected by genetic mutation. In contrast, the –C480T polymorphism in the hepatic lipase gene have been shown to elevate HDL-C levels. Homozygosity for the common allele was observed in 53.2% of control individuals, while 40.3% of these individuals were observed to be heterozygous. Homozygosity for the –C480T polymorphism was observed in 6.5% of healthy individuals, whereas, this was reduced to 4.7% for individuals with a paternal history of myocardial infarction before the age of 55 years, although this was not statistically significant ADDIN EN.CITE <EndNote><Cite><Author>Murtom?ki</Author><Year>1997</Year><RecNum>234</RecNum><DisplayText>(Murtom?ki et al., 1997)</DisplayText><record><rec-number>234</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">234</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murtom?ki, Sanna</author><author>Tahvanainen, Esa</author><author>Antikainen, Marjatta</author><author>Tiret, Laurence</author><author>Nicaud, Viviane</author><author>Jansen, Hans</author><author>Ehnholm, Christian</author><author>on behalf of the European Atherosclerosis Research Study Group</author></authors></contributors><titles><title>Hepatic Lipase Gene Polymorphisms Influence Plasma HDL Levels: Results From Finnish EARS Participants</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>1879-1884</pages><volume>17</volume><number>10</number><dates><year>1997</year><pub-dates><date>October 1, 1997</date></pub-dates></dates><urls><related-urls><url>;(Murtom?ki et al., 1997). Furthermore, McCaskie et al. (2006) found that although HDL-C levels were raised in an Australian population with this polymorphism, it was not associated with a decrease in CHD risk ADDIN EN.CITE <EndNote><Cite><Author>McCaskie</Author><Year>2006</Year><RecNum>235</RecNum><DisplayText>(McCaskie et al., 2006)</DisplayText><record><rec-number>235</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">235</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCaskie, P. A.</author><author>Cadby, G.</author><author>Hung, J.</author><author>McQuillan, B. M.</author><author>Chapman, C. M.</author><author>Carter, K. W.</author><author>Thompson, P. L.</author><author>Palmer, L. J.</author><author>Beilby, J. P.</author></authors></contributors><auth-address>Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, Western Australia. pmccask@cyllene.uwa.edu.au</auth-address><titles><title>The C-480T hepatic lipase polymorphism is associated with HDL-C but not with risk of coronary heart disease</title><secondary-title>Clin Genet</secondary-title></titles><pages>114-21</pages><volume>70</volume><number>2</number><edition>2006/08/02</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cholesterol, HDL/ genetics</keyword><keyword>Coronary Disease/etiology/ genetics</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lipase/ genetics</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Polymorphism, Single Nucleotide</keyword><keyword>Risk</keyword></keywords><dates><year>2006</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0009-9163 (Print)
0009-9163 (Linking)</isbn><accession-num>16879193</accession-num><urls></urls><electronic-resource-num>10.1111/j.1399-0004.2006.00659.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(McCaskie et al., 2006). In contrast, Fan et al. (2006) found that this polymorphism was associated with a lower coronary flow reserve, which is an early indicator of atherosclerosis ADDIN EN.CITE <EndNote><Cite><Author>Fan</Author><Year>2006</Year><RecNum>236</RecNum><DisplayText>(Fan et al., 2006)</DisplayText><record><rec-number>236</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">236</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fan, Yue-Mei</author><author>Laaksonen, Reijo</author><author>Janatuinen, Tuula</author><author>Vesalainen, Risto</author><author>Laine, Hanna</author><author>Raitakari, Olli T.</author><author>Nuutila, Pirjo</author><author>Knuuti, Juhani</author><author>Rontu, Riikka</author><author>Lehtim?ki, Terho</author></authors></contributors><titles><title>The influence of hepatic lipase C-480T polymorphism on coronary flow reserve in young men is independent of the plasma cholesterol level</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1></periodical><pages>391-397</pages><volume>188</volume><number>2</number><keywords><keyword>Coronary flow reserve</keyword><keyword>Hepatic lipase</keyword><keyword>Myocardial blood flow</keyword><keyword>Polymorphism</keyword><keyword>Positron emission tomography</keyword></keywords><dates><year>2006</year><pub-dates><date>10//</date></pub-dates></dates><isbn>0021-9150</isbn><urls><related-urls><url>;(Fan et al., 2006). 4.5 HMG CoA Reductase HMG CoA reductase is the enzyme responsible for the rate limiting step in cholesterol biosynthesis, and is therefore the main target for pharmaceutical intervention by statins ADDIN EN.CITE <EndNote><Cite><Author>Istvan</Author><Year>2001</Year><RecNum>254</RecNum><DisplayText>(Istvan and Deisenhofer, 2001)</DisplayText><record><rec-number>254</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Istvan, Eva S.</author><author>Deisenhofer, Johann</author></authors></contributors><titles><title>Structural Mechanism for Statin Inhibition of HMG-CoA Reductase</title><secondary-title>Science</secondary-title></titles><pages>1160-1164</pages><volume>292</volume><number>5519</number><dates><year>2001</year><pub-dates><date>May 11, 2001</date></pub-dates></dates><urls><related-urls><url>;(Istvan and Deisenhofer, 2001). Chasman et al. (2004) demonstrated that two genetic polymorphisms were not only able to influence the baseline characteristics of the lipoprotein profile, but also influence the efficacy of statin treatment. The presence of one copy of SNP 12 (rs17244841) induced an 18.9% reduction in LDL-C and 4.6% increase in HDL-C, compared with individuals homozygous for the major allele. Whereas, heterozygotes for SNP 29 (rs17238540), exhibited 18.9 and 2.4% reduction in LDL-C and HDL-C, respectively. The presence of one of the SNPs also resulted in the diminished efficacy for cholesterol lowering treatment by pravastatin. For individuals with either SNP, the total cholesterol and LDL-C lowering efficacy was reduced 22 and 19% respectively ADDIN EN.CITE <EndNote><Cite><Author>Chasman</Author><Year>2004</Year><RecNum>230</RecNum><DisplayText>(Chasman et al., 2004)</DisplayText><record><rec-number>230</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">230</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chasman, D. I.</author><author>Posada, D.</author><author>Subrahmanyan, L.</author><author>Cook, N. R.</author><author>Stanton,</author><author>Jr, V. P.</author><author>Ridker, P.</author></authors></contributors><titles><title>PHarmacogenetic study of statin therapy and cholesterol reduction</title><secondary-title>JAMA</secondary-title></titles><pages>2821-2827</pages><volume>291</volume><number>23</number><dates><year>2004</year></dates><isbn>0098-7484</isbn><urls><related-urls><url>;(Chasman et al., 2004). Thus, genetic polymorphisms in certain enzymes and receptor genes associated with cholesterol biosynthesis can provoke the dysregulation of cholesterol metabolism, lipoprotein profile, alter CVD risk, and the response of cholesterol metabolism to pharmaceutical intervention. 5.0 Oxidative Stress and Cholesterol Metabolism The free radical theory of ageing is underpinned by the belief, that the gradual accumulation of oxidative stress with time is responsible for the ageing process PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJtYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Harman, 1956, 2009). Reactive oxygen species (ROS) play a key role in the development of oxidative stress ADDIN EN.CITE <EndNote><Cite><Author>Kandola</Author><Year>2015</Year><RecNum>189</RecNum><DisplayText>(Kandola et al., 2015)</DisplayText><record><rec-number>189</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">189</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kandola, K.</author><author>Bowman, A.</author><author>Birch-Machin, M. A.</author></authors></contributors><auth-address>Dermatology, Medical School Newcastle University, Newcastle upon Tyne, NE24HH, U.K.</auth-address><titles><title>Oxidative stress - a key emerging impact factor in health, ageing, lifestyle and aesthetics</title><secondary-title>Int J Cosmet Sci</secondary-title></titles><pages>1-8</pages><volume>37 Suppl 2</volume><edition>2015/11/18</edition><keywords><keyword>genomics/proteomics/elisa/cell culture</keyword><keyword>hair growth/hair biology</keyword><keyword>skin physiology/structure</keyword></keywords><dates><year>2015</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1468-2494 (Electronic)
0142-5463 (Linking)</isbn><accession-num>26574299</accession-num><urls></urls><electronic-resource-num>10.1111/ics.12287</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>(Kandola et al., 2015). ROS are produced during mitochondrial oxidative phosphorylation, and by cells exposed to xenobiotics ADDIN EN.CITE <EndNote><Cite><Author>Berthiaume</Author><Year>2007</Year><RecNum>218</RecNum><DisplayText>(Berthiaume and Wallace, 2007)</DisplayText><record><rec-number>218</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">218</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Berthiaume, J. M.</author><author>Wallace, K. B.</author></authors></contributors><titles><title>Adriamycin-induced oxidative mitochondrial cardiotoxicity</title><secondary-title>Cell Biology and Toxicology</secondary-title><alt-title>Cell Biol Toxicol</alt-title></titles><pages>15-25</pages><volume>23</volume><number>1</number><keywords><keyword>Adriamycin</keyword><keyword>doxorubicin</keyword><keyword>mitochondria</keyword><keyword>reactive oxygen species</keyword><keyword>cardiac</keyword><keyword>mtDNA</keyword></keywords><dates><year>2007</year><pub-dates><date>2007/01/01</date></pub-dates></dates><publisher>Kluwer Academic Publishers</publisher><isbn>0742-2091</isbn><urls><related-urls><url>;(Berthiaume and Wallace, 2007), pathogen associated patterns (PAMPs) ADDIN EN.CITE <EndNote><Cite><Author>Tassi</Author><Year>2009</Year><RecNum>216</RecNum><DisplayText>(Tassi et al., 2009)</DisplayText><record><rec-number>216</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">216</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tassi, S.</author><author>Carta, S.</author><author>Vene, R.</author><author>Delfino, L.</author><author>Ciriolo, M. R.</author><author>Rubartelli, A.</author></authors></contributors><auth-address>Cell Biology Unit, National Cancer Research Institute, Genova, Italy.</auth-address><titles><title>Pathogen-induced interleukin-1beta processing and secretion is regulated by a biphasic redox response</title><secondary-title>J Immunol</secondary-title></titles><pages>1456-62</pages><volume>183</volume><number>2</number><edition>2009/06/30</edition><keywords><keyword>Bacterial Proteins/ pharmacology</keyword><keyword>Cells, Cultured</keyword><keyword>Cysteine/metabolism</keyword><keyword>Humans</keyword><keyword>Interleukin-1beta/metabolism/secretion</keyword><keyword>Monocytes/ metabolism</keyword><keyword>NADPH Oxidase/metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress</keyword><keyword>Polysaccharides, Bacterial/ pharmacology</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Thioredoxins/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul 15</date></pub-dates></dates><isbn>1550-6606 (Electronic)
0022-1767 (Linking)</isbn><accession-num>19561107</accession-num><urls></urls><electronic-resource-num>10.4049/jimmunol.0900578</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Tassi et al., 2009) or pro-inflammatory cytokines ADDIN EN.CITE <EndNote><Cite><Author>Yang</Author><Year>2007</Year><RecNum>217</RecNum><DisplayText>(Yang et al., 2007)</DisplayText><record><rec-number>217</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">217</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yang, Dongli</author><author>Elner, Susan G.</author><author>Bian, Zong-Mei</author><author>Till, Gerd O.</author><author>Petty, Howard R.</author><author>Elner, Victor M.</author></authors></contributors><titles><title>Pro-inflammatory Cytokines Increase Reactive Oxygen Species through Mitochondria and NADPH Oxidase in Cultured RPE Cells</title><secondary-title>Experimental eye research</secondary-title></titles><pages>462-472</pages><volume>85</volume><number>4</number><dates><year>2007</year><pub-dates><date>06/27</date></pub-dates></dates><isbn>0014-4835</isbn><accession-num>PMC2094037</accession-num><urls><related-urls><url>;(Yang et al., 2007). Despite the processed role ROS may play in the ageing process, ROS also have useful roles in processes such as phagocyte derived bactericidal and tumouricidal activity (Li et al., 2013; Vatansever et al., 2013), nitric oxide (NO) production (Shen et al., 2014), and in insulin signalling (Bashan et al., 2009). Atherosclerosis is suggested to be a condition mediated by ROS, LDL-C and intrinsic ageing ADDIN EN.CITE <EndNote><Cite><Author>Vogiatzi</Author><Year>2009</Year><RecNum>194</RecNum><DisplayText>(Vogiatzi et al., 2009)</DisplayText><record><rec-number>194</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">194</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vogiatzi, G.</author><author>Tousoulis, D.</author><author>Stefanadis, C.</author></authors></contributors><auth-address>1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Athens, Greece.</auth-address><titles><title>The role of oxidative stress in atherosclerosis</title><secondary-title>Hellenic J Cardiol</secondary-title></titles><pages>402-9</pages><volume>50</volume><number>5</number><edition>2009/09/22</edition><keywords><keyword>Antioxidants/ pharmacology/ therapeutic use</keyword><keyword>Atherosclerosis/drug therapy/enzymology/ physiopathology</keyword><keyword>Blood Vessels/metabolism</keyword><keyword>Humans</keyword><keyword>Nitric Oxide/metabolism</keyword><keyword>Oxidative Stress/ drug effects/ physiology</keyword><keyword>Reactive Oxygen Species/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><isbn>2241-5955 (Electronic)
1109-9666 (Linking)</isbn><accession-num>19767282</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Vogiatzi et al., 2009). Briefly, LDL-C migrate across damaged artery endothelium into the tunica intima, where an accumulation of LDL-C, immune cells, and proliferative smooth muscle cells occlude the artery lumen restricting blood flow ADDIN EN.CITE <EndNote><Cite><Author>Hansson</Author><Year>2011</Year><RecNum>204</RecNum><DisplayText>(Hansson and Hermansson, 2011)</DisplayText><record><rec-number>204</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">204</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hansson, Goran K.</author><author>Hermansson, Andreas</author></authors></contributors><titles><title>The immune system in atherosclerosis</title><secondary-title>Nat Immunol</secondary-title></titles><pages>204-212</pages><volume>12</volume><number>3</number><dates><year>2011</year><pub-dates><date>03//print</date></pub-dates></dates><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><isbn>1529-2908</isbn><work-type>10.1038/ni.2001</work-type><urls><related-urls><url>;(Hansson and Hermansson, 2011). This endothelial damage and dysfunction can be influenced by a variety of factors including smoking ADDIN EN.CITE <EndNote><Cite><Author>Ambrose</Author><Year>2004</Year><RecNum>201</RecNum><DisplayText>(Ambrose and Barua, 2004)</DisplayText><record><rec-number>201</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">201</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ambrose, John A.</author><author>Barua, Rajat S.</author></authors></contributors><titles><title>The pathophysiology of cigarette smoking and cardiovascular disease: An update</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><pages>1731-1737</pages><volume>43</volume><number>10</number><dates><year>2004</year><pub-dates><date>5/19/</date></pub-dates></dates><isbn>0735-1097</isbn><urls><related-urls><url>;(Ambrose and Barua, 2004), hypertension ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2005</Year><RecNum>202</RecNum><DisplayText>(Li and Chen, 2005)</DisplayText><record><rec-number>202</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">202</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, J. J.</author><author>Chen, J. L.</author></authors></contributors><auth-address>Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Science and Cardiovascular Institute, Peking Union Medical College, Beijing 100037, PR China. lijnjn@.cn</auth-address><titles><title>Inflammation may be a bridge connecting hypertension and atherosclerosis</title><secondary-title>Med Hypotheses</secondary-title></titles><pages>925-9</pages><volume>64</volume><number>5</number><edition>2005/03/23</edition><keywords><keyword>Arteriosclerosis/ complications/physiopathology</keyword><keyword>Humans</keyword><keyword>Hypertension/ complications/physiopathology</keyword><keyword>Inflammation/ complications/physiopathology</keyword><keyword>Reactive Oxygen Species</keyword></keywords><dates><year>2005</year></dates><isbn>0306-9877 (Print)
0306-9877 (Linking)</isbn><accession-num>15780486</accession-num><urls></urls><electronic-resource-num>10.1016/j.mehy.2004.10.016</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Li and Chen, 2005), hyperglycaemia ADDIN EN.CITE <EndNote><Cite><Author>Popov</Author><Year>2010</Year><RecNum>195</RecNum><DisplayText>(Popov, 2010)</DisplayText><record><rec-number>195</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">195</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Popov, Doina</author></authors></contributors><titles><title>Endothelial cell dysfunction in hyperglycemia: Phenotypic change, intracellular signaling modification, ultrastructural alteration, and potential clinical outcomes</title><secondary-title>International Journal of Diabetes Mellitus</secondary-title></titles><pages>189-195</pages><volume>2</volume><number>3</number><keywords><keyword>Quiescence</keyword><keyword>Inflammation</keyword><keyword>Proliferation</keyword><keyword>Apoptosis</keyword><keyword>Transcription factors</keyword><keyword>Signaling pathways</keyword></keywords><dates><year>2010</year><pub-dates><date>12//</date></pub-dates></dates><isbn>1877-5934</isbn><urls><related-urls><url>;(Popov, 2010), hyperlipidaemia ADDIN EN.CITE <EndNote><Cite><Author>Kerenyi</Author><Year>2006</Year><RecNum>198</RecNum><DisplayText>(Kerenyi et al., 2006)</DisplayText><record><rec-number>198</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">198</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kerenyi, L.</author><author>Mihalka, L.</author><author>Csiba, L.</author><author>Bacso, H.</author><author>Bereczki, D.</author></authors></contributors><auth-address>Department of Neurology, University of Debrecen, Medical and Health Science Center, Hungary.</auth-address><titles><title>Role of hyperlipidemia in atherosclerotic plaque formation in the internal carotid artery</title><secondary-title>J Clin Ultrasound</secondary-title></titles><pages>283-8</pages><volume>34</volume><number>6</number><edition>2006/06/22</edition><keywords><keyword>Aged</keyword><keyword>Atherosclerosis/etiology/ ultrasonography</keyword><keyword>Brain Ischemia/etiology</keyword><keyword>Carotid Artery, Internal</keyword><keyword>Carotid Stenosis/ etiology/ ultrasonography</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hyperlipidemias/ complications</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Retrospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Ultrasonography, Doppler</keyword></keywords><dates><year>2006</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>0091-2751 (Print)
0091-2751 (Linking)</isbn><accession-num>16788960</accession-num><urls></urls><electronic-resource-num>10.1002/jcu.20233</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kerenyi et al., 2006), ageing ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2012</Year><RecNum>206</RecNum><DisplayText>(Wang and Bennett, 2012)</DisplayText><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Julie C.</author><author>Bennett, Martin</author></authors></contributors><titles><title>Aging and Atherosclerosis: Mechanisms, Functional Consequences, and Potential Therapeutics for Cellular Senescence</title><secondary-title>Circulation Research</secondary-title></titles><pages>245-259</pages><volume>111</volume><number>2</number><dates><year>2012</year><pub-dates><date>July 6, 2012</date></pub-dates></dates><urls><related-urls><url>;(Wang and Bennett, 2012), infection ADDIN EN.CITE <EndNote><Cite><Author>Rosenfeld</Author><Year>2011</Year><RecNum>199</RecNum><DisplayText>(Rosenfeld and Campbell, 2011)</DisplayText><record><rec-number>199</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">199</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rosenfeld, M. E.</author><author>Campbell, L. A.</author></authors></contributors><auth-address>Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98109-4714, USA. ssmjm@u.washington.edu</auth-address><titles><title>Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis</title><secondary-title>Thromb Haemost</secondary-title></titles><pages>858-67</pages><volume>106</volume><number>5</number><edition>2011/10/21</edition><keywords><keyword>Animals</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Arteries/immunology/ microbiology/ virology</keyword><keyword>Atherosclerosis/drug therapy/immunology/ microbiology/ virology</keyword><keyword>Bacterial Infections/complications/drug therapy/immunology/ microbiology</keyword><keyword>Evidence-Based Medicine</keyword><keyword>Humans</keyword><keyword>Inflammation/drug therapy/immunology/ microbiology/ virology</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Treatment Failure</keyword><keyword>Virus Diseases/complications/drug therapy/immunology/ virology</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0340-6245 (Print)
0340-6245 (Linking)</isbn><accession-num>22012133</accession-num><urls></urls><electronic-resource-num>10.1160/th11-06-0392</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Rosenfeld and Campbell, 2011), and hyperhomocysteinaemia ADDIN EN.CITE <EndNote><Cite><Author>Guthikonda</Author><Year>2006</Year><RecNum>200</RecNum><DisplayText>(Guthikonda and Haynes, 2006)</DisplayText><record><rec-number>200</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">200</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Guthikonda, S.</author><author>Haynes, W. G.</author></authors></contributors><auth-address>Department of Cardiology, Bayor College of Medicine, Houston, TX 77584, USA. guthikon@bcm.tmc.edu</auth-address><titles><title>Homocysteine: role and implications in atherosclerosis</title><secondary-title>Curr Atheroscler Rep</secondary-title></titles><pages>100-6</pages><volume>8</volume><number>2</number><edition>2006/03/03</edition><keywords><keyword>Atherosclerosis/ blood/etiology</keyword><keyword>Biological Markers/blood</keyword><keyword>Disease Progression</keyword><keyword>Homocysteine/ blood</keyword><keyword>Humans</keyword><keyword>Hyperhomocysteinemia/blood/complications</keyword><keyword>Oxidative Stress</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1523-3804 (Print)
1523-3804 (Linking)</isbn><accession-num>16510043</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Guthikonda and Haynes, 2006). This damage results in increased ROS production, and a more permeable membrane in which LDL-C and immune cells can more freely migrate. Oxidation of LDL by ROS forms the cytotoxic and immunogenic oxLDL ADDIN EN.CITE <EndNote><Cite><Author>Mahmoudi</Author><Year>2011</Year><RecNum>203</RecNum><DisplayText>(Mahmoudi et al., 2011)</DisplayText><record><rec-number>203</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">203</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahmoudi, M. J.</author><author>Mahmoudi, M.</author><author>Siassi, F.</author><author>Shokri, F.</author><author>Eshraghian, M. R.</author><author>Zarnani, A. H.</author><author>Chahardoli, R.</author><author>Hedayat, M.</author><author>Khoshnoodi, J.</author><author>Nayeri, H.</author><author>Rezaei, N.</author><author>Saboor-Yaraghi, A. A.</author></authors></contributors><auth-address>Division of Cardiology, Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.</auth-address><titles><title>Lymphocyte cytotoxicity of oxLDL in patients with atherosclerosis</title><secondary-title>Iran J Immunol</secondary-title></titles><pages>27-33</pages><volume>8</volume><number>1</number><edition>2011/03/24</edition><keywords><keyword>Adult</keyword><keyword>Atherosclerosis/immunology/ physiopathology</keyword><keyword>Cell Proliferation/drug effects</keyword><keyword>Cell Survival/drug effects</keyword><keyword>Cells, Cultured</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Leukocytes, Mononuclear/ drug effects</keyword><keyword>Lipoproteins, LDL/ pharmacology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1735-1383 (Print)
1735-1383 (Linking)</isbn><accession-num>21427493</accession-num><urls></urls><electronic-resource-num>IJIv8i1A4</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Mahmoudi et al., 2011). Release of monocyte chemotactic protein-1 (MCP-1) by endothelial smooth muscle cells and macrophage that have already localised in the tunica intima, leads to the migration of monocytes across the endothelium where they differentiate into macrophage ADDIN EN.CITE <EndNote><Cite><Author>Dewald</Author><Year>2005</Year><RecNum>196</RecNum><DisplayText>(Dewald et al., 2005)</DisplayText><record><rec-number>196</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">196</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dewald, Oliver</author><author>Zymek, Pawel</author><author>Winkelmann, Kim</author><author>Koerting, Anna</author><author>Ren, Guofeng</author><author>Abou-Khamis, Tareq</author><author>Michael, Lloyd H.</author><author>Rollins, Barrett J.</author><author>Entman, Mark L.</author><author>Frangogiannis, Nikolaos G.</author></authors></contributors><titles><title>CCL2/Monocyte Chemoattractant Protein-1 Regulates Inflammatory Responses Critical to Healing Myocardial Infarcts</title><secondary-title>Circulation Research</secondary-title></titles><pages>881-889</pages><volume>96</volume><number>8</number><dates><year>2005</year><pub-dates><date>April 29, 2005</date></pub-dates></dates><urls><related-urls><url>;(Dewald et al., 2005). These macrophage then engulf oxLDL via scavenger receptors SR-A and CD36, forming lipid-laden foam cells ADDIN EN.CITE <EndNote><Cite><Author>Korporaal</Author><Year>2007</Year><RecNum>192</RecNum><DisplayText>(Korporaal et al., 2007)</DisplayText><record><rec-number>192</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">192</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Korporaal, Suzanne J.A.</author><author>Van Eck, Miranda</author><author>Adelmeijer, Jelle</author><author>Ijsseldijk, Martin</author><author>Out, Ruud</author><author>Lisman, Ton</author><author>Lenting, Peter J.</author><author>Van Berkel, Theo J.C.</author><author>Akkerman, Jan-Willem N.</author></authors></contributors><titles><title>Platelet Activation by Oxidized Low Density Lipoprotein Is Mediated by Cd36 and Scavenger Receptor-A</title><secondary-title>Arteriosclerosis, Thrombosis, and Vascular Biology</secondary-title></titles><pages>2476-2483</pages><volume>27</volume><number>11</number><dates><year>2007</year><pub-dates><date>November 1, 2007</date></pub-dates></dates><urls><related-urls><url>;(Korporaal et al., 2007). Meanwhile, T cells, mainly Th1, migrate across the endothelium and release pro-inflammatory cytokines such as IL-2, IL-12 and IFN-γ to intensify the immune response ADDIN EN.CITE <EndNote><Cite><Author>Baidya</Author><Year>2005</Year><RecNum>205</RecNum><DisplayText>(Baidya and Zeng, 2005)</DisplayText><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baidya, S.</author><author>Zeng, Q.</author></authors></contributors><titles><title>Helper T cells and atherosclerosis: the cytokine web</title><secondary-title>Postgraduate Medical Journal</secondary-title></titles><pages>746-752</pages><volume>81</volume><number>962</number><dates><year>2005</year></dates><publisher>BMJ Group</publisher><isbn>0032-5473
1469-0756</isbn><accession-num>PMC1743411</accession-num><urls><related-urls><url>;(Baidya and Zeng, 2005). Foam cells, macrophage, and T-cells then combine to form a fatty streak. The macrophage also secrete the pro-inflammatory cytokines TNFα, IL-1β, IL-6, and IL-12, in addition to the mitogen platelet derived growth factor (PDGF), which induces the proliferation of smooth muscle cells of the tunica media forming a cap for the plaque ADDIN EN.CITE <EndNote><Cite><Author>Ross</Author><Year>1990</Year><RecNum>184</RecNum><DisplayText>(Ross et al., 1990)</DisplayText><record><rec-number>184</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">184</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ross, R</author><author>Masuda, J</author><author>Raines, EW</author><author>Gown, AM</author><author>Katsuda, S</author><author>Sasahara, M</author><author>Malden, LT</author><author>Masuko, H</author><author>Sato, H</author></authors></contributors><titles><title>Localization of PDGF-B protein in macrophages in all phases of atherogenesis</title><secondary-title>Science</secondary-title></titles><pages>1009-1012</pages><volume>248</volume><number>4958</number><dates><year>1990</year><pub-dates><date>May 25, 1990</date></pub-dates></dates><urls><related-urls><url>;(Ross et al., 1990). This segregates the plaque from the blood, however the plaque cause the artery to harden and narrow, restricting blood flow. Subsequent instability in the plaque can result in it rupturing; which can block the supply of blood to the heart causing a myocardial infarction, or to the brain, triggering an ischaemic stroke ADDIN EN.CITE <EndNote><Cite><Author>Bentzon</Author><Year>2014</Year><RecNum>193</RecNum><DisplayText>(Bentzon et al., 2014)</DisplayText><record><rec-number>193</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">193</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bentzon, Jacob Fog</author><author>Otsuka, Fumiyuki</author><author>Virmani, Renu</author><author>Falk, Erling</author></authors></contributors><titles><title>Mechanisms of Plaque Formation and Rupture</title><secondary-title>Circulation Research</secondary-title></titles><pages>1852-1866</pages><volume>114</volume><number>12</number><dates><year>2014</year><pub-dates><date>June 6, 2014</date></pub-dates></dates><urls><related-urls><url>;(Bentzon et al., 2014). In addition to the effects of ROS on LDL, it has also been shown to interact with the atheroprotective particle HDL, it has been suggested HDL is oxidised during the pathogenesis of atherosclerosis, causing HDL to lose its protective properties and transform into a proinflammatory and proatherogenic mediator. These oxidised HDL, oxHDL, have been shown to promote smooth muscle cell proliferation and migration in a dose dependent manner, thus aiding in the progression of atherosclerosis pathogenesis ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2014</Year><RecNum>178</RecNum><DisplayText>(Wang et al., 2014)</DisplayText><record><rec-number>178</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">178</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Y.</author><author>Ji, L.</author><author>Jiang, R.</author><author>Zheng, L.</author><author>Liu, D.</author></authors></contributors><auth-address>Division of Cardiology, the Affiliated Zhongshan Hospital of Xiamen University, Xiamen Heart Center.</auth-address><titles><title>Oxidized high-density lipoprotein induces the proliferation and migration of vascular smooth muscle cells by promoting the production of ROS</title><secondary-title>J Atheroscler Thromb</secondary-title></titles><pages>204-16</pages><volume>21</volume><number>3</number><edition>2013/11/15</edition><keywords><keyword>Acetylcysteine/pharmacology</keyword><keyword>Animals</keyword><keyword>Cell Movement/drug effects</keyword><keyword>Cell Proliferation</keyword><keyword>Cells, Cultured</keyword><keyword>Lipoproteins, HDL/ metabolism</keyword><keyword>Male</keyword><keyword>Muscle, Smooth, Vascular/cytology/drug effects/ metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Reactive Oxygen Species/ metabolism</keyword></keywords><dates><year>2014</year></dates><isbn>1880-3873 (Electronic)
1340-3478 (Linking)</isbn><accession-num>24225481</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wang et al., 2014). Further to this, oxHDL, have also been shown to induce ROS production, upregulate the expression of the proinflammatory cytokine TNF-α, and upregulate the expression of prothrombotic cyclooxygenase-2 (COX-2) and plasminogen activator inhibitor-1 (PAI-1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb3VteWFyYW5pPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh
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ADDIN EN.CITE.DATA (Callegari et al., 2006; Norata et al., 2004; Soumyarani and Jayakumari, 2012). 6.0 Caloric RestrictionCR, a dietary regime defined by a 20-40% reduction of calories, which does not induce malnutrition ADDIN EN.CITE <EndNote><Cite><Author>Taormina</Author><Year>2014</Year><RecNum>224</RecNum><DisplayText>(Taormina and Mirisola, 2014)</DisplayText><record><rec-number>224</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">224</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Taormina, Giusi</author><author>Mirisola, Mario G.</author></authors></contributors><titles><title>Calorie Restriction in Mammals and Simple Model Organisms</title><secondary-title>BioMed Research International</secondary-title></titles><pages>10</pages><volume>2014</volume><dates><year>2014</year></dates><urls><related-urls><url>;(Taormina and Mirisola, 2014), has been demonstrated to extend life-span in a diverse range of organisms, however its effect on humans has not be fully established PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdWFyZW50ZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA (Barzilai et al., 2012; Guarente, 2013). CR has been associated with many metabolic effects linked to ageing and longevity. For example, CR has been associated with a reduction in the release of ROS from complex I of mitochondria within the cardiac tissue of rodents ADDIN EN.CITE <EndNote><Cite><Author>Gredilla</Author><Year>2001</Year><RecNum>276</RecNum><DisplayText>(Gredilla et al., 2001)</DisplayText><record><rec-number>276</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">276</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gredilla, Ricardo</author><author>Sanz, Alberto</author><author>Lopez-Torres, Monica</author><author>Barja, Gustavo</author></authors></contributors><titles><title>Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart</title><secondary-title>The FASEB Journal</secondary-title></titles><periodical><full-title>The FASEB Journal</full-title></periodical><pages>1589-1591</pages><volume>15</volume><number>9</number><dates><year>2001</year><pub-dates><date>July 1, 2001</date></pub-dates></dates><urls><related-urls><url>;(Gredilla et al., 2001). Therefore, there is a prevailing hypothesis within gerontology, that the positive effects of this dietary regime are mediated through a reduction in ROS. However, it is possible that the beneficial effects of CR on health-span extend beyond this particular aspect of ageing, as evidence suggests, that metabolic rate is unaffected by CR in murine models (Hempenstall et al., 2010).Moreover, it is considered that ageing is associated with the accumulation of ROS and oxidative damage. Conversely, recent evidence has suggested that low grade oxidative damage may be beneficial. As an example, glucose restriction has been associated with an increase in oxidative stress in Caenorhabditis elegans, which is thought to increase resistance to further oxidative stress, and thus extend life-span via mitochondrial hormesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2h1bHo8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Schulz et al., 2007). Alternatively, murine models have demonstrated that calorie restriction can prevent the age-related decline of heat shock proteins (HSPs), which are induced following exposure to stress to protect cells and organs from the stressor ADDIN EN.CITE <EndNote><Cite><Author>Colotti</Author><Year>2005</Year><RecNum>255</RecNum><DisplayText>(Colotti et al., 2005)</DisplayText><record><rec-number>255</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">255</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Colotti, C.</author><author>Cavallini, G.</author><author>Vitale, R. L.</author><author>Donati, A.</author><author>Maltinti, M.</author><author>Del Ry, S.</author><author>Bergamini, E.</author><author>Giannessi, D.</author></authors></contributors><titles><title>Effects of Aging and Anti-Aging Caloric Restrictions on Carbonyl and Heat Shock Protein Levels and Expression</title><secondary-title>Biogerontology</secondary-title><alt-title>Biogerontology</alt-title></titles><pages>397-406</pages><volume>6</volume><number>6</number><keywords><keyword>aging</keyword><keyword>caloric restriction</keyword><keyword>chaperones</keyword><keyword>heart</keyword><keyword>heat shock proteins</keyword></keywords><dates><year>2005</year><pub-dates><date>2005/12/01</date></pub-dates></dates><publisher>Kluwer Academic Publishers</publisher><isbn>1389-5729</isbn><urls><related-urls><url>;(Colotti et al., 2005). CR has also been shown to have a positive effect on cholesterol metabolism in mammals. For instance, Edwards et al. (1988) investigated the effect of CR on LDL-C over a five year period in Rhesus monkeys and found this regime reduced LDL-C levels when compared to a control group ADDIN EN.CITE <EndNote><Cite><Author>Edwards</Author><Year>1998</Year><RecNum>277</RecNum><DisplayText>(Edwards et al., 1998)</DisplayText><record><rec-number>277</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">277</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Edwards, I. J.</author><author>Rudel, L. L.</author><author>Terry, J. G.</author><author>Kemnitz, J. W.</author><author>Weindruch, R.</author><author>Cefalu, W. T.</author></authors></contributors><auth-address>Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. iedwards@wfubmc.edu</auth-address><titles><title>Caloric restriction in rhesus monkeys reduces low density lipoprotein interaction with arterial proteoglycans</title><secondary-title>J Gerontol A Biol Sci Med Sci</secondary-title><alt-title>The journals of gerontology. Series A, Biological sciences and medical sciences</alt-title></titles><periodical><full-title>J Gerontol A Biol Sci Med Sci</full-title><abbr-1>The journals of gerontology. Series A, Biological sciences and medical sciences</abbr-1></periodical><alt-periodical><full-title>J Gerontol A Biol Sci Med Sci</full-title><abbr-1>The journals of gerontology. Series A, Biological sciences and medical sciences</abbr-1></alt-periodical><pages>B443-8</pages><volume>53</volume><number>6</number><edition>1998/11/21</edition><keywords><keyword>Animals</keyword><keyword>Arteries/*metabolism</keyword><keyword>Drug Interactions</keyword><keyword>*Energy Intake</keyword><keyword>Lipids/blood</keyword><keyword>Lipoproteins, LDL/blood/chemistry/*physiology</keyword><keyword>Macaca mulatta</keyword><keyword>Proteoglycans/*physiology</keyword></keywords><dates><year>1998</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1079-5006 (Print)
1079-5006</isbn><accession-num>9823741</accession-num><urls></urls><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(Edwards et al., 1998). Much more recently, it has also been suggested CR improves metabolic health generally ADDIN EN.CITE <EndNote><Cite><Author>Ristow</Author><Year>2010</Year><RecNum>229</RecNum><DisplayText>(Ristow and Zarse, 2010)</DisplayText><record><rec-number>229</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ristow, M.</author><author>Zarse, K.</author></authors></contributors><auth-address>Dept. of Human Nutrition, Institute of Nutrition, University of Jena, Germany. mristow@ <mristow@></auth-address><titles><title>How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)</title><secondary-title>Exp Gerontol</secondary-title></titles><pages>410-8</pages><volume>45</volume><number>6</number><edition>2010/03/31</edition><keywords><keyword>Caloric Restriction</keyword><keyword>Exercise/physiology</keyword><keyword>Glucose/genetics/metabolism</keyword><keyword>Glycolysis</keyword><keyword>Humans</keyword><keyword>Insulin-Like Growth Factor I/genetics/metabolism</keyword><keyword>Longevity/genetics/ physiology</keyword><keyword>Mitochondria/genetics/ metabolism</keyword><keyword>Oxidative Stress/ physiology</keyword><keyword>Reactive Oxygen Species/metabolism</keyword></keywords><dates><year>2010</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1873-6815 (Electronic)
0531-5565 (Linking)</isbn><accession-num>20350594</accession-num><urls></urls><electronic-resource-num>10.1016/j.exger.2010.03.014</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ristow and Zarse, 2010). For instance, Colman et al. (2014) demonstrated a 2.9 times increased risk for all age-related causes of death, in Rhesus monkeys undertaking a control diet, when compared to those undertaking a 30% CR diet. CR also increased the survival rate of those animals by 3.63 times ADDIN EN.CITE <EndNote><Cite><Author>Colman</Author><Year>2014</Year><RecNum>221</RecNum><DisplayText>(Colman et al., 2014)</DisplayText><record><rec-number>221</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">221</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Colman, Ricki J.</author><author>Beasley, T. Mark</author><author>Kemnitz, Joseph W.</author><author>Johnson, Sterling C.</author><author>Weindruch, Richard</author><author>Anderson, Rozalyn M.</author></authors></contributors><titles><title>Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys</title><secondary-title>Nature Communications</secondary-title></titles><pages>3557</pages><volume>5</volume><dates><year>2014</year><pub-dates><date>04/01
10/12/received
03/05/accepted</date></pub-dates></dates><publisher>Nature Pub. Group</publisher><isbn>2041-1723</isbn><accession-num>PMC3988801</accession-num><urls><related-urls><url>;(Colman et al., 2014). The Comprehensive Assessment of Long-Term Effects of Reducing Calorie Intake (CALERIE) study provides information on the effect of CR in humans. Phase one of this program examined healthy, but overweight individuals (BMI 25-29.9kg/m2) from three centres across America who underwent 20-25% CR. From these studies it was determined two biomarkers of longevity, fasting insulin and body temperature were reduced following 6 months of 25% CR. The authors of this study postulated that CR increases longevity via a reduction in metabolic rate ADDIN EN.CITE <EndNote><Cite><Author>Heilbronn</Author><Year>2006</Year><RecNum>284</RecNum><DisplayText>(Heilbronn et al., 2006)</DisplayText><record><rec-number>284</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">284</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heilbronn, Leonie K.</author><author>de Jonge, Lilian</author><author>Frisard, Madlyn I.</author><author>DeLany, James P.</author><author>Meyer, D. Enette Larson</author><author>Rood, Jennifer</author><author>Nguyen, Tuong</author><author>Martin, Corby K.</author><author>Volaufova, Julia</author><author>Most, Marlene M.</author><author>Greenway, Frank L.</author><author>Smith, Steven R.</author><author>Williamson, Donald A.</author><author>Deutsch, Walter A.</author><author>Ravussin, Eric</author></authors></contributors><titles><title>Effect of 6-mo. calorie restriction on biomarkers of longevity, metabolic adaptation and oxidative stress in overweight subjects</title><secondary-title>JAMA : the journal of the American Medical Association</secondary-title></titles><periodical><full-title>JAMA : the journal of the American Medical Association</full-title></periodical><pages>1539-1548</pages><volume>295</volume><number>13</number><dates><year>2006</year></dates><isbn>0098-7484
1538-3598</isbn><accession-num>PMC2692623</accession-num><urls><related-urls><url>;(Heilbronn et al., 2006). In terms of a direct impact on lipid metabolism, CR was shown to decrease weight, fat mass and visceral adipose tissue in participants. These changes were associated with an increase in insulin sensitivity ADDIN EN.CITE <EndNote><Cite><Author>Larson-Meyer</Author><Year>2006</Year><RecNum>259</RecNum><DisplayText>(Larson-Meyer et al., 2006)</DisplayText><record><rec-number>259</rec-number><foreign-keys><key app="EN" db-id="peet59r5iz5f0qev9rlxxpeowzwta5rwszef" timestamp="1450273560">259</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larson-Meyer, D. Enette</author><author>Heilbronn, Leonie K.</author><author>Redman, Leanne M.</author><author>Newcomer, Bradley R.</author><author>Frisard, Madlyn I.</author><author>Anton, Steve</author><author>Smith, Steven R.</author><author>Maplstat, Anthony Alfonso</author><author>Ravussin, Eric</author><author>Pennington, Calerie Team</author></authors></contributors><titles><title>Effect of Calorie Restriction With or Without Exercise on Insulin Sensitivity, β-Cell Function, Fat Cell Size, and Ectopic Lipid in Overweight Subjects</title><secondary-title>Diabetes care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>1337-1344</pages><volume>29</volume><number>6</number><dates><year>2006</year></dates><isbn>0149-5992
1935-5548</isbn><accession-num>PMC2677812</accession-num><urls><related-urls><url>;(Larson-Meyer et al., 2006). The project has recently progressed to phase 2 trials, to examine the effects of CR on healthy nonobese (BMI 22-28kg/m2) individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA (Stewart et al., 2013). The effects of CR in humans has also been investigated by Fontana et al. (2004). In this study, the lipoprotein profile and carotid artery intima-media thickness of 18 members of the Caloric Restriction Society, whose members practice long term self-imposed CR (3-15 years), was compared with 18 control individuals. This investigation revealed a number of interesting findings about the interaction of CR with lipid metabolism, including a decline in total cholesterol, LDL-C, and triacylglycerol by 19.1, 29.5 and 63.8%, respectively following CR. HDL-C was also affected by CR, with a 51.2% elevation in levels. This was in addition to a reduction in other risk factors associated with CVD including, blood pressure and the inflammatory marker C-reactive protein (CRP).Together with the carotid intima-media thickness reduction of approximately 40%, CR appears to have an atheroprotective effect ADDIN EN.CITE <EndNote><Cite><Author>Fontana</Author><Year>2004</Year><RecNum>227</RecNum><DisplayText>(Fontana et al., 2004)</DisplayText><record><rec-number>227</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">227</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fontana, Luigi</author><author>Meyer, Timothy E.</author><author>Klein, Samuel</author><author>Holloszy, John O.</author></authors></contributors><titles><title>Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America</secondary-title></titles><pages>6659-6663</pages><volume>101</volume><number>17</number><dates><year>2004</year><pub-dates><date>April 27, 2004</date></pub-dates></dates><urls><related-urls><url>;(Fontana et al., 2004). We can conclude from these studies, although it is clear that CR increases life-span in many species, the underlying mechanisms are still ambiguous. However, in mammals a favourable lipid profile could be one component of a much broader cardioprotective protective effect brought on by CR which ultimately contributes to life span extension.7.0 Sirtuins, mTOR and Cholesterol BiosynthesisMechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase of the phosphatidylinositol-3-OH kinase (PI(3)K)-related family that regulates an array of anabolic and catabolic pathways at the mRNA expression level ADDIN EN.CITE <EndNote><Cite><Author>Johnson</Author><Year>2013</Year><RecNum>279</RecNum><DisplayText>(Johnson et al., 2013)</DisplayText><record><rec-number>279</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">279</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Johnson, Simon C.</author><author>Rabinovitch, Peter S.</author><author>Kaeberlein, Matt</author></authors></contributors><titles><title>mTOR is a key modulator of ageing and age-related disease</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>338-345</pages><volume>493</volume><number>7432</number><dates><year>2013</year><pub-dates><date>01/17/print</date></pub-dates></dates><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><isbn>0028-0836</isbn><work-type>10.1038/nature11861</work-type><urls><related-urls><url>;(Johnson et al., 2013). mTOR acts as a key metabolic sensor in a wide range of biological activities, both at a cellular and organism level. This ability to act as a regulator causes it to respond to a plethora of both intrinsic and extrinsic cellular signals ADDIN EN.CITE <EndNote><Cite><Author>Mc Auley</Author><Year>2015</Year><RecNum>278</RecNum><DisplayText>(Mc Auley et al., 2015)</DisplayText><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mc Auley, Mark T </author><author>Mooney, Kathleen M</author><author>Angell, Peter J</author><author>Wilkinson, Stephen J</author></authors></contributors><titles><title>Mathematical modelling of metabolic regulation in aging</title><secondary-title>Metabolites</secondary-title></titles><periodical><full-title>Metabolites</full-title></periodical><pages>232-251</pages><volume>5</volume><number>2</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>(Mc Auley et al., 2015). These metabolic cues include changes to oxygen, nutrient and hormonal levels. mTOR forms the catalytic subunit of two discrete signalling complexes, known as mTOR complexes 1 and 2 (mTORC1 and mTORC2). The mTOR pathway impacts cell growth and proliferation by provoking anabolic processes, including biosynthesis of proteins, lipids and organelles, and by restricting catabolic processes, such as autophagy. There is a large body of evidence which has been generated from several animal models that link the activities of mTORC1 to the beneficial effects of CR, and thus longevity. Discussing these studies is beyond the scope of this review, rather we will focus on how mTOR impacts cholesterol biosynthesis. Central to the regulation of cholesterol biosynthetic gene expression is the SREBP family of transcription factors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3J0b248L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Peterson et al., 2011). Moreover, a recent study that examined non-alcoholic fatty liver disease under conditions of inflammation in apolipoprotein E knockout mice, demonstrated the inhibition of mTORC1 activity blocked the translocation of SCAP/SREBP-2 complex from the endoplasmic reticulum to the Golgi, and decreased the expression of LDLr and SREBP-2. These effects were accompanied by an increase in LDLr degradation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Liu et al., 2015). Thus, this study suggests that there could be an important link between mTOR and LDLr turnover, which has significant implications for whole body cholesterol balance and healthy ageing. Sirtuins have also been shown to impact cholesterol biosynthesis. There are 7 known mammalian sirtuins, that function as NAD+-dependent deacetylases, which are involved in a wide range of cellular activities including nutrient sensing and DNA repair PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFuZzwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Satoh et al., 2011; Wei et al., 2011). SIRT1 also deacetylates the nuclear receptor liver X receptor α (LXRα) to induce synthesis of the transporter ABCA1, a mediator of HDL and RCT. SIRT1 KO mice display reduced plasma HDL-C levels in addition to an accumulation of cholesterol in the liver PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Planavila et al., 2011). In contrast, it has been demonstrated that inhibition of SIRT2 can reduce sterol biosynthesis by decreased trafficking of SREBP-2, as a mechanism of neuroprotection in cellular and invertebrate models of Huntingtons Disease ADDIN EN.CITE <EndNote><Cite><Author>Luthi-Carter</Author><Year>2010</Year><RecNum>262</RecNum><DisplayText>(Luthi-Carter et al., 2010)</DisplayText><record><rec-number>262</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">262</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luthi-Carter, Ruth</author><author>Taylor, David M.</author><author>Pallos, Judit</author><author>Lambert, Emmanuel</author><author>Amore, Allison</author><author>Parker, Alex</author><author>Moffitt, Hilary</author><author>Smith, Donna L.</author><author>Runne, Heike</author><author>Gokce, Ozgun</author><author>Kuhn, Alexandre</author><author>Xiang, Zhongmin</author><author>Maxwell, Michele M.</author><author>Reeves, Steven A.</author><author>Bates, Gillian P.</author><author>Neri, Christian</author><author>Thompson, Leslie M.</author><author>Marsh, J. Lawrence</author><author>Kazantsev, Aleksey G.</author></authors></contributors><titles><title>SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis</title><secondary-title>Proceedings of the National Academy of Sciences</secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences</full-title></periodical><pages>7927-7932</pages><volume>107</volume><number>17</number><dates><year>2010</year><pub-dates><date>April 27, 2010</date></pub-dates></dates><urls><related-urls><url>;(Luthi-Carter et al., 2010). Moreover, Tao et al. (2013) have suggested that Sirt6 is a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice resulted in elevated serum and hepatic cholesterol levels. Sirt6 is recruited by forkhead box O (FoxO)3 to Srebp2, where Sirt6 deacetylates histone H3 at lysines 9 and 56, thus promoting a repressive chromatin state. It was found that Sirt6 or FoxO3 overexpression improved hypercholesterolemia in diet-induced or genetically obese mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Tao et al., 2013). Therefore, Sirt6 and FoxO3 could have a crucial role to play in the regulation of cholesterol homeostasis 8.0 Can Diet Mitigate the Effect Ageing has on Cholesterol Metabolism?During the 1950s, the Seven Countries Study (SCS) began exploring the role of diet and lifestyle on disease rates in populations from various countries. Amongst the findings reported from these studies were the causal association between, serum cholesterol, blood pressure and smoking and CHD mortality rates PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZW5vdHRpPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA (Menotti et al., 1998; Menotti et al., 2004a; Menotti et al., 2004b), whereas, diets high in saturated fat, and trans fats were associated with higher serum cholesterol and thus CHD risk PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lcm9taG91dDwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lcm9taG91dDwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+
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ADDIN EN.CITE.DATA (Kromhout et al., 1995). Conversely, diets high in vegetables, rich in fibre and antioxidants, promoted significant reductions in CHD risk PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWlqc3NlPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA (Buijsse et al., 2008; Streppel et al., 2008). Dietary regime is therefore an important factor that should be analysed and adjusted in order to reduce CHD risk and promote longevity. The important role of dietary and other lifestyle interventions on life-span can be emphasised by analysing the North Karelia Project. Internationally, Finnish males, especially those in the province of North Karelia, had the highest rate of CHD in the late 1960s, as a result of a diet high in salt and saturated fat, and low in vegetables, in addition to high rates of smoking and physical inactivity ADDIN EN.CITE <EndNote><Cite><Author>Puska</Author><Year>2008</Year><RecNum>28</RecNum><DisplayText>(Puska, 2008)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puska, P.</author></authors></contributors><titles><title>The North Karelia Project: 30 years successfully preventing chronic diseases</title><secondary-title>Diabetes Voice</secondary-title></titles><pages>26-29</pages><volume>53</volume><number>Special Issue</number><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>(Puska, 2008). In order to combat this burden, a low-resource, community-based intervention study titled the North Karelia Project was implemented in 1972 ADDIN EN.CITE <EndNote><Cite><Author>Puska</Author><Year>1973</Year><RecNum>26</RecNum><DisplayText>(Puska, 1973)</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puska, P.</author></authors></contributors><titles><title>The North Karelia project: an attempt at community prevention of cardiovascular disease</title><secondary-title>WHO Chron</secondary-title></titles><pages>55-8</pages><volume>27</volume><number>2</number><edition>1973/02/01</edition><keywords><keyword>Cardiovascular Diseases/ prevention & control/rehabilitation/therapy</keyword><keyword>Evaluation Studies as Topic</keyword><keyword>Finland</keyword><keyword>Health Education</keyword><keyword>Humans</keyword><keyword>Hypertension/prevention & control</keyword><keyword>Mass Screening</keyword><keyword>Population Surveillance</keyword></keywords><dates><year>1973</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0042-9694 (Print)
0042-9694 (Linking)</isbn><accession-num>4695971</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Puska, 1973). The North Karelia Project aimed to reduce CHD morbidity and mortality rates by reducing LDL-C concentrations and blood pressure by improving diet and exercise patterns; and reducing smoking rates. The project resulted in the most rapid decline in CHD mortality in the world. Within 5 years, a 4.1 and 1.2% reduction in serum cholesterol was exhibited in men and women, respectively ADDIN EN.CITE <EndNote><Cite><Author>Puska</Author><Year>1979</Year><RecNum>25</RecNum><DisplayText>(Puska et al., 1979)</DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puska, P.</author><author>Tuomilehto, J.</author><author>Salonen, J.</author><author>Neittaanm?ki, L.</author><author>Maki, J.</author><author>Virtamo, J.</author><author>Nissinen, A.</author><author>Koskela, K.</author><author>Takalo, T.</author></authors></contributors><titles><title>Changes in coronary risk factors during comprehensive five-year community programme to control cardiovascular diseases (North Karelia project)</title><secondary-title>British Medical Journal</secondary-title></titles><pages>1173-1178</pages><volume>2</volume><number>6199</number><dates><year>1979</year></dates><isbn>0007-1447</isbn><accession-num>PMC1597253</accession-num><urls><related-urls><url>;(Puska et al., 1979). These figures increased further to a 21% and 23% decline in total cholesterol under re-examination in 2007 ADDIN EN.CITE <EndNote><Cite><Author>Vartiainen</Author><Year>2010</Year><RecNum>24</RecNum><DisplayText>(Vartiainen et al., 2010)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vartiainen, E.</author><author>Laatikainen, T.</author><author>Peltonen, M.</author><author>Juolevi, A.</author><author>Mannisto, S.</author><author>Sundvall, J.</author><author>Jousilahti, P.</author><author>Salomaa, V.</author><author>Valsta, L.</author><author>Puska, P.</author></authors></contributors><auth-address>National Institute for Health and Welfare, Helsinki, Finland. erkki.vartiainen@thl.fi</auth-address><titles><title>Thirty-five-year trends in cardiovascular risk factors in Finland</title><secondary-title>Int J Epidemiol</secondary-title></titles><pages>504-18</pages><volume>39</volume><number>2</number><edition>2009/12/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Biological Markers/blood</keyword><keyword>Blood Pressure</keyword><keyword>Body Mass Index</keyword><keyword>Cholesterol/ blood</keyword><keyword>Coronary Disease/ mortality</keyword><keyword>Female</keyword><keyword>Finland/epidemiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Obesity/ epidemiology</keyword><keyword>Population Surveillance</keyword><keyword>Prevalence</keyword><keyword>Smoking/ epidemiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1464-3685 (Electronic)
0300-5771 (Linking)</isbn><accession-num>19959603</accession-num><urls></urls><electronic-resource-num>10.1093/ije/dyp330</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Vartiainen et al., 2010). The initial five year study resulted in a 17.4 and 11.5% reduction in CHD risk in males and females, respectively. Following a further 25 years of implementation, this decline was amplified to a 60% reduction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYXJ0aWFpbmVuPC9BdXRob3I+PFllYXI+MjAxMDwvWWVh
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ADDIN EN.CITE.DATA (Puska et al., 1979; Vartiainen et al., 2010). This 30 year project reflected an 85% decrease in CHD-related mortality ADDIN EN.CITE <EndNote><Cite><Author>Puska</Author><Year>2008</Year><RecNum>28</RecNum><DisplayText>(Puska, 2008)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puska, P.</author></authors></contributors><titles><title>The North Karelia Project: 30 years successfully preventing chronic diseases</title><secondary-title>Diabetes Voice</secondary-title></titles><pages>26-29</pages><volume>53</volume><number>Special Issue</number><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>(Puska, 2008). The impact of lifestyle on cholesterol metabolism, and consequently CVD risk is therefore significant. The role diet and lifestyle plays in reducing risk of age related diseases and in extending life-span is also apparent in those who consume a Mediterranean diet. This dietary pattern has been studied extensively, particularly, the role it plays in optimising lipoprotein profile and reducing CVD risk8.1 Mediterranean DietThe Mediterranean diet is characterised by a high intake of vegetables, fruits, legumes, nuts, cereals and olive oil, and a low intake of dairy, and red and processed meats ADDIN EN.CITE <EndNote><Cite><Author>Trichopoulou</Author><Year>1997</Year><RecNum>212</RecNum><DisplayText>(Trichopoulou and Lagiou, 1997)</DisplayText><record><rec-number>212</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trichopoulou, A.</author><author>Lagiou, P.</author></authors></contributors><auth-address>Department of Nutrition and Biochemistry, National School of Public Health, Athens, Greece.</auth-address><titles><title>Healthy traditional Mediterranean diet: an expression of culture, history, and lifestyle</title><secondary-title>Nutr Rev</secondary-title></titles><pages>383-9</pages><volume>55</volume><number>11 Pt 1</number><edition>1998/01/08</edition><keywords><keyword>Coronary Disease/prevention & control</keyword><keyword>Cultural Characteristics</keyword><keyword>Diet</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Life Style</keyword><keyword>Male</keyword><keyword>Mediterranean Region</keyword><keyword>Neoplasms/prevention & control</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0029-6643 (Print)
0029-6643 (Linking)</isbn><accession-num>9420448</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Trichopoulou and Lagiou, 1997). Richard et al. (2012) demonstrated a five week Mediterranean diet decreased LDL-C by 9.9%, even in the absence of weight loss in men with metabolic syndrome. It was suggested this dietary pattern was able to effect LDL-C levels, by increasing LDL-C clearance as well as reducing cholesterol absorption. This was thought to be due to an increase of dietary phytosterols, nutrients, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), fish oils and fibre PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA (Richard et al., 2012; Woodside et al., 2015). The Mediterranean diet affects cholesterol metabolism as follows. Firstly, it is postulated PUFA increases LDLr expression ADDIN EN.CITE <EndNote><Cite><Author>Fernandez</Author><Year>2005</Year><RecNum>270</RecNum><DisplayText>(Fernandez and West, 2005)</DisplayText><record><rec-number>270</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">270</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fernandez, Maria Luz</author><author>West, Kristy L.</author></authors></contributors><titles><title>Mechanisms by which Dietary Fatty Acids Modulate Plasma Lipids1</title><secondary-title>The Journal of Nutrition</secondary-title></titles><periodical><full-title>The Journal of Nutrition</full-title></periodical><pages>2075-2078</pages><volume>135</volume><number>9</number><dates><year>2005</year><pub-dates><date>September 1, 2005</date></pub-dates></dates><urls><related-urls><url>;(Fernandez and West, 2005). Furthermore, studies have indicated plant sterols can reduce cholesterol absorption by 30-50% ADDIN EN.CITE <EndNote><Cite><Author>Law</Author><Year>2000</Year><RecNum>271</RecNum><DisplayText>(Law, 2000)</DisplayText><record><rec-number>271</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">271</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Law, M.</author></authors></contributors><auth-address>Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, London EC1M 6BQ. M.R.Law@mds.qmw.ac.uk</auth-address><titles><title>Plant sterol and stanol margarines and health</title><secondary-title>Bmj</secondary-title><alt-title>BMJ (Clinical research ed.)</alt-title></titles><periodical><full-title>Bmj</full-title><abbr-1>BMJ (Clinical research ed.)</abbr-1></periodical><alt-periodical><full-title>Bmj</full-title><abbr-1>BMJ (Clinical research ed.)</abbr-1></alt-periodical><pages>861-4</pages><volume>320</volume><number>7238</number><edition>2000/03/24</edition><keywords><keyword>Adult</keyword><keyword>Cardiovascular Diseases/*prevention & control</keyword><keyword>Cholesterol, LDL/blood</keyword><keyword>Costs and Cost Analysis</keyword><keyword>*Diet</keyword><keyword>Humans</keyword><keyword>Intestinal Absorption/drug effects</keyword><keyword>*Margarine</keyword><keyword>Middle Aged</keyword><keyword>Phytosterols/*administration & dosage/adverse effects/therapeutic use</keyword></keywords><dates><year>2000</year><pub-dates><date>Mar 25</date></pub-dates></dates><isbn>0959-8138 (Print)
0959-535x</isbn><accession-num>10731187</accession-num><urls></urls><custom2>Pmc1127206</custom2><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(Law, 2000), although the expression of ABCG5/G8 and NPC1L1 are thought to be unaffected by sterol ingestion ADDIN EN.CITE <EndNote><Cite><Author>Field</Author><Year>2004</Year><RecNum>272</RecNum><DisplayText>(Field et al., 2004)</DisplayText><record><rec-number>272</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">272</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Field, F. J.</author><author>Born, E.</author><author>Mathur, S. N.</author></authors></contributors><auth-address>Department of Veterans Affairs, University of Iowa, Iowa City, IA 52242, USA. f-jeffrey-field@uiowa.edu</auth-address><titles><title>Stanol esters decrease plasma cholesterol independently of intestinal ABC sterol transporters and Niemann-Pick C1-like 1 protein gene expression</title><secondary-title>J Lipid Res</secondary-title><alt-title>Journal of lipid research</alt-title></titles><periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></periodical><alt-periodical><full-title>J Lipid Res</full-title><abbr-1>Journal of lipid research</abbr-1></alt-periodical><pages>2252-9</pages><volume>45</volume><number>12</number><edition>2004/09/03</edition><keywords><keyword>ATP-Binding Cassette Transporters/biosynthesis/*genetics</keyword><keyword>Animals</keyword><keyword>Anticholesteremic Agents/pharmacology</keyword><keyword>Cholesterol/*blood</keyword><keyword>Cholestyramine Resin/pharmacology</keyword><keyword>Cricetinae</keyword><keyword>Lovastatin/pharmacology</keyword><keyword>Male</keyword><keyword>Membrane Transport Proteins/biosynthesis/*genetics</keyword><keyword>RNA, Messenger/blood</keyword><keyword>Sitosterols/*metabolism</keyword></keywords><dates><year>2004</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-2275 (Print)
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ADDIN EN.CITE.DATA (Benetou et al., 2008; Estruch et al., 2013; Salas-Salvadó et al., 2011). Furthermore, individuals, from Spain or Italy for example, born in 2000, are expected to live on average 2 years longer than individuals from the UK or USA. In addition, the healthy life expectancy of these individuals is also 2 years more ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2015</Year><RecNum>3</RecNum><DisplayText>(WHO, 2015)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">3</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Life expectancy data by country</title></titles><dates><year>2015</year></dates><urls><related-urls><url>;(WHO, 2015). Thus, the Mediterranean diet is believed to play a role in prolonging both health-span and life-span. The Mediterranean diet has also been utilised as a strategy to treat age-related disease onset. For example, de Lorgeril et al. (1999) reported a 9.11% reduction in the rate of secondary cardiovascular events in patients who adhered to a Mediterranean diet compared to those that followed a standard diet. It was determined that each 1mmol/L increase in total cholesterol resulted in a 20-30% increase in the risk of recurrence ADDIN EN.CITE <EndNote><Cite><Author>de Lorgeril</Author><Year>1999</Year><RecNum>20</RecNum><DisplayText>(de Lorgeril et al., 1999)</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Lorgeril, Michel</author><author>Salen, Patricia</author><author>Martin, Jean-Louis</author><author>Monjaud, Isabelle</author><author>Delaye, Jacques</author><author>Mamelle, Nicole</author></authors></contributors><titles><title>Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction: Final Report of the Lyon Diet Heart Study</title><secondary-title>Circulation</secondary-title></titles><pages>779-785</pages><volume>99</volume><number>6</number><dates><year>1999</year><pub-dates><date>February 16, 1999</date></pub-dates></dates><urls><related-urls><url>;(de Lorgeril et al., 1999). Therefore, a Mediterranean diet that results in decreased cholesterol levels is not only protective against primary cardiovascular events but also secondary events. The substantial evidence demonstrating the potential benefit of a Mediterranean diet on prolonging health-span as well as life-span has resulted in large-scale studies, such as the NU-AGE project arising PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW50b3JvPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA (Santoro et al., 2014).9.0 The Recent Emergence of the Gut Microbiome The gut microbiome has a range of metabolic roles which maintain host heath, including; facilitating the digestion of starch, fibre, and sugars (Szilagyi et al., 2010); producing short-chain fatty acids (den Besten et al., 2013; Yu et al., 2010); vitamin absorption (Beulens et al., 2013); enhancing host immunity; preventing allergies (Shen and Clemente, 2015) and facilitating enterohepatic circulation of bile acids (section 3.2). Alteration to the microbiome can impact host health and this has increasingly been investigated as a contributor to disease. The close relationship between the microbiome and its human host has resulted in humans being described as metaorganisms ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2012</Year><RecNum>127</RecNum><DisplayText>(Biagi et al., 2012)</DisplayText><record><rec-number>127</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Candela, Marco</author><author>Fairweather-Tait, Susan</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author></authors></contributors><titles><title>Ageing of the human metaorganism: the microbial counterpart</title><secondary-title>Age</secondary-title></titles><pages>247-267</pages><volume>34</volume><number>1</number><dates><year>2012</year><pub-dates><date>02/24
12/22/received
01/30/accepted</date></pub-dates></dates><pub-location>Dordrecht</pub-location><publisher>Springer Netherlands</publisher><isbn>0161-9152
1574-4647</isbn><accession-num>PMC3260362</accession-num><urls><related-urls><url>;(Biagi et al., 2012). The impact of the microbiome on overall health was recently illustrated by a female subject that underwent a faecal transplant from her overweight, but otherwise healthy daughter for the treatment of recurrent Clostridium difficile infection. Post-transplant, the recipient experienced substantial weight gain, resulting in a weight gain of 41 pounds and an increase in BMI from 26 to 34.5 at 36 months observation ADDIN EN.CITE <EndNote><Cite><Author>Alang</Author><Year>2015</Year><RecNum>92</RecNum><DisplayText>(Alang and Kelly, 2015)</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alang, Neha</author><author>Kelly, Colleen R.</author></authors></contributors><titles><title>Weight Gain After Fecal Microbiota Transplantation</title><secondary-title>Open Forum Infectious Diseases</secondary-title></titles><volume>2</volume><number>1</number><dates><year>2015</year><pub-dates><date>January 1, 2015</date></pub-dates></dates><urls><related-urls><url>;(Alang and Kelly, 2015). This suggests ‘obesity promoting’ microbiota can be transmitted from human to human, as previously observed in rodents ADDIN EN.CITE <EndNote><Cite><Author>Ridaura</Author><Year>2013</Year><RecNum>93</RecNum><DisplayText>(Ridaura et al., 2013)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">93</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ridaura, Vanessa K.</author><author>Faith, Jeremiah J.</author><author>Rey, Federico E.</author><author>Cheng, Jiye</author><author>Duncan, Alexis E.</author><author>Kau, Andrew L.</author><author>Griffin, Nicholas W.</author><author>Lombard, Vincent</author><author>Henrissat, Bernard</author><author>Bain, James R.</author><author>Muehlbauer, Michael J.</author><author>Ilkayeva, Olga</author><author>Semenkovich, Clay F.</author><author>Funai, Katsuhiko</author><author>Hayashi, David K.</author><author>Lyle, Barbara J.</author><author>Martini, Margaret C.</author><author>Ursell, Luke K.</author><author>Clemente, Jose C.</author><author>Van Treuren, William</author><author>Walters, William A.</author><author>Knight, Rob</author><author>Newgard, Christopher B.</author><author>Heath, Andrew C.</author><author>Gordon, Jeffrey I.</author></authors></contributors><titles><title>Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice</title><secondary-title>Science</secondary-title></titles><volume>341</volume><number>6150</number><dates><year>2013</year><pub-dates><date>September 6, 2013</date></pub-dates></dates><urls><related-urls><url>;(Ridaura et al., 2013). Understanding the role of the microbiome in health is challenging, due to complex bidirectional interactions with many biological systems. For example, it has been implicated in enhancing alveolar macrophage function in lung infections ADDIN EN.CITE <EndNote><Cite><Author>Schuijt</Author><Year>2015</Year><RecNum>105</RecNum><DisplayText>(Schuijt et al., 2015)</DisplayText><record><rec-number>105</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schuijt, Tim J</author><author>Lankelma, Jacqueline M</author><author>Scicluna, Brendon P</author><author>de Sousa e Melo, Felipe</author><author>Roelofs, Joris J T H</author><author>de Boer, J Daan</author><author>Hoogendijk, Arjan J</author><author>de Beer, Regina</author><author>de Vos, Alex</author><author>Belzer, Clara</author><author>de Vos, Willem M</author><author>van der Poll, Tom</author><author>Wiersinga, W Joost</author></authors></contributors><titles><title>The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia</title><secondary-title>Gut</secondary-title></titles><dates><year>2015</year><pub-dates><date>October 28, 2015</date></pub-dates></dates><urls><related-urls><url>;(Schuijt et al., 2015) and is thought to influence brain morphology and function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZXJuYW5kZXotUmVhbDwvQXV0aG9yPjxZZWFyPjIwMTU8
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ADDIN EN.CITE.DATA (Fernandez-Real et al., 2015). Conversely, in a classic study, Killian et al. (1998) showed mice exposed to stress exhibited altered intestinal function ADDIN EN.CITE <EndNote><Cite><Author>Kiliaan</Author><Year>1998</Year><RecNum>111</RecNum><DisplayText>(Kiliaan et al., 1998)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">111</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kiliaan, A. J.</author><author>Saunders, P. R.</author><author>Bijlsma, P. B.</author><author>Berin, M. C.</author><author>Taminiau, J. A.</author><author>Groot, J. A.</author><author>Perdue, M. H.</author></authors></contributors><auth-address>Intestinal Disease Research Program, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.</auth-address><titles><title>Stress stimulates transepithelial macromolecular uptake in rat jejunum</title><secondary-title>Am J Physiol</secondary-title></titles><pages>G1037-44</pages><volume>275</volume><number>5 Pt 1</number><edition>1998/11/14</edition><keywords><keyword>Animals</keyword><keyword>Atropine/pharmacology</keyword><keyword>Biological Transport</keyword><keyword>Endocytosis</keyword><keyword>Endosomes/drug effects/ physiology/ultrastructure</keyword><keyword>Horseradish Peroxidase/ pharmacokinetics</keyword><keyword>Intestinal Absorption</keyword><keyword>Intestinal Mucosa/drug effects/physiology/ physiopathology</keyword><keyword>Jejunum/physiology/ physiopathology</keyword><keyword>Male</keyword><keyword>Microscopy, Electron</keyword><keyword>Microvilli/drug effects/physiology/ultrastructure</keyword><keyword>Rats</keyword><keyword>Rats, Inbred WKY</keyword><keyword>Restraint, Physical</keyword><keyword>Stress, Psychological/ physiopathology</keyword></keywords><dates><year>1998</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0002-9513 (Print)
0002-9513 (Linking)</isbn><accession-num>9815034</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kiliaan et al., 1998). Moreover, administration of probiotic strains impact behaviour by improving mood and decreasing anxiety symptoms in both rodent and humans PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXZpZ25hYzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (Messaoudi et al., 2011; Savignac et al., 2015; Steenbergen et al., 2015). Thus, a bidirectional relationship exists between the gut and brain and it is likely that a similar relationship exists for other organ systems. 9.1 The Gut Microbiome and CVDThere is an association between the microbiota and CVD risk. This could be mediated via its effects on bile acid metabolism, or by its contribution to choline diet-induced trimethylamine N-oxide (TMAO) production PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2V0aDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Gregory et al., 2015). Moreover, gut microbiota dysbiosis has been associated with increased low-grade inflammation, which is linked with the development of atherosclerosis ADDIN EN.CITE <EndNote><Cite><Author>Chistiakov</Author><Year>2015</Year><RecNum>126</RecNum><DisplayText>(Chistiakov et al., 2015)</DisplayText><record><rec-number>126</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">126</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chistiakov, Dmitry A.</author><author>Bobryshev, Yuri V.</author><author>Kozarov, Emil</author><author>Sobenin, Igor A.</author><author>Orekhov, Alexander N.</author></authors></contributors><titles><title>Role of gut microbiota in the modulation of atherosclerosis-associated immune response</title><secondary-title>Frontiers in Microbiology</secondary-title></titles><pages>671</pages><volume>6</volume><dates><year>2015</year><pub-dates><date>06/30
12/19/received
06/19/accepted</date></pub-dates></dates><publisher>Frontiers Media S.A.</publisher><isbn>1664-302X</isbn><accession-num>PMC4485310</accession-num><urls><related-urls><url>;(Chistiakov et al., 2015). To examine the role of the gut microbiome on CVD risk, Fu et al. (2015) explored the potential relationships between operational taxonomic units (OTUs) with BMI, and blood lipids. High bacterial diversity was associated with a decreased BMI, and triglyceride levels, whilst a positive correlation was observed with HDL-C levels. A total of 66 OTUs were associated with BMI, while 114 were associated with triglycerides, and 34 OTUs with HDL. In particular Clostridiaceae/Lachnospiracease was able to modulate LDL-C levels. Fu et al. (2015) estimated that the gut microbiota is independently responsible for ≤6% of blood lipid level variation ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>2015</Year><RecNum>5</RecNum><DisplayText>(Fu et al., 2015)</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, Jingyaun</author><author>Bonder, Marc Jan</author><author>Cenit, María Carmen</author><author>Tigchelaar, Ettje</author><author>Maatman, Astrid</author><author>Dekens, Jackie A.M.</author><author>Brandsma, Eelke</author><author>Marczynska, Joanna</author><author>Imhann, Floris</author><author>Weersma, Rinse K.</author><author>Franke, Lude</author><author>Poon, Tiffany W.</author><author>Xavier, Ramnik J.</author><author>Gevers, Dirk</author><author>Hofker, Marten H.</author><author>Wijmenga, Cisca</author><author>Zhernakova, Alexandra</author></authors></contributors><titles><title>The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids</title><secondary-title>Circulation Research</secondary-title></titles><dates><year>2015</year><pub-dates><date>September 10, 2015</date></pub-dates></dates><urls><related-urls><url>;(Fu et al., 2015).9.2 The Gut Microbiome and AgeingDue to inter-individual variation, there is conflicting evidence on microbiome changes during ageing. In an elderly Irish cohort (65-96 years), the proportion of Bacteriodetes ranged from 3-92%, while Firmicutes ranged from 7-94% ADDIN EN.CITE <EndNote><Cite><Author>Claesson</Author><Year>2011</Year><RecNum>115</RecNum><DisplayText>(Claesson et al., 2011)</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Claesson, Marcus J.</author><author>Cusack, Siobhán</author><author>O'Sullivan, Orla</author><author>Greene-Diniz, Rachel</author><author>de Weerd, Heleen</author><author>Flannery, Edel</author><author>Marchesi, Julian R.</author><author>Falush, Daniel</author><author>Dinan, Timothy</author><author>Fitzgerald, Gerald</author><author>Stanton, Catherine</author><author>van Sinderen, Douwe</author><author>O'Connor, Michael</author><author>Harnedy, Norma</author><author>O'Connor, Kieran</author><author>Henry, Colm</author><author>O'Mahony, Denis</author><author>Fitzgerald, Anthony P.</author><author>Shanahan, Fergus</author><author>Twomey, Cillian</author><author>Hill, Colin</author><author>Ross, R. Paul</author><author>O'Toole, Paul W.</author></authors></contributors><titles><title>Composition, variability, and temporal stability of the intestinal microbiota of the elderly</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America</secondary-title></titles><pages>4586-4591</pages><volume>108</volume><number>Suppl 1</number><dates><year>2011</year><pub-dates><date>06/22</date></pub-dates></dates><publisher>National Academy of Sciences</publisher><isbn>0027-8424
1091-6490</isbn><accession-num>PMC3063589</accession-num><urls><related-urls><url>;(Claesson et al., 2011). Further differences in the gut microbiome have also been observed in other population groups. For example, Clostridium cluster XIVa has been observed to decrease with age in Japanese, Finnish, and Austrian cohorts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdnVva2tvPC9BdXRob3I+PFllYXI+MjAxMDwvWWVh
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ADDIN EN.CITE.DATA (Hayashi et al., 2003; Hippe et al., 2011; Makivuokko et al., 2010), whereas an increase has been observed in German and Italian cohorts ADDIN EN.CITE <EndNote><Cite><Author>Mueller</Author><Year>2006</Year><RecNum>121</RecNum><DisplayText>(Mueller et al., 2006)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mueller, Susanne</author><author>Saunier, Katiana</author><author>Hanisch, Christiana</author><author>Norin, Elisabeth</author><author>Alm, Livia</author><author>Midtvedt, Tore</author><author>Cresci, Alberto</author><author>Silvi, Stefania</author><author>Orpianesi, Carla</author><author>Verdenelli, Maria Cristina</author><author>Clavel, Thomas</author><author>Koebnick, Corinna</author><author>Zunft, Hans-Joachim Franz</author><author>Doré, Jo?l</author><author>Blaut, Michael</author></authors></contributors><titles><title>Differences in Fecal Microbiota in Different European Study Populations in Relation to Age, Gender, and Country: a Cross-Sectional Study</title><secondary-title>Applied and Environmental Microbiology</secondary-title></titles><pages>1027-1033</pages><volume>72</volume><number>2</number><dates><year>2006</year><pub-dates><date>06/27/received
09/02/accepted</date></pub-dates></dates><publisher>American Society for Microbiology</publisher><isbn>0099-2240
1098-5336</isbn><accession-num>PMC1392899</accession-num><urls><related-urls><url>;(Mueller et al., 2006). Biagi et al. (2010) reported higher levels of the Clostridium cluster XIVa in elderly Italians (49%), when compared to younger individuals (44%), although the levels did reduce slightly in centenarians (34%) ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010). These conflicting results make it difficult to establish an overall picture of how ageing effects the microbiome. However, it is likely that diet, lifestyle, antibiotic usage, and host health status accounts for much of this variation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFlc3NvbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA (Claesson et al., 2012). Furthermore, a carnivorous or herbivorous diet can induce changes to the microbiome composition to favour metabolism of protein or carbohydrates ADDIN EN.CITE <EndNote><Cite><Author>David</Author><Year>2014</Year><RecNum>114</RecNum><DisplayText>(David et al., 2014)</DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>David, Lawrence A.</author><author>Maurice, Corinne F.</author><author>Carmody, Rachel N.</author><author>Gootenberg, David B.</author><author>Button, Julie E.</author><author>Wolfe, Benjamin E.</author><author>Ling, Alisha V.</author><author>Devlin, A. Sloan</author><author>Varma, Yug</author><author>Fischbach, Michael A.</author><author>Biddinger, Sudha B.</author><author>Dutton, Rachel J.</author><author>Turnbaugh, Peter J.</author></authors></contributors><titles><title>Diet rapidly and reproducibly alters the human gut microbiome</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>559-563</pages><volume>505</volume><number>7484</number><dates><year>2014</year><pub-dates><date>01/23/print</date></pub-dates></dates><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><isbn>0028-0836</isbn><work-type>Letter</work-type><urls><related-urls><url>;(David et al., 2014). Moreover, Evard et al. (2012) demonstrated that a high fat diet decreased the expression of regenerating islet-derived 3 gamma (Reg3g), an antimicrobial lectin with activity against Gram-positive species. This reduction of Reg3g increases colonisation of the intestinal epithelium, causing alterations in the microbiome, including a decrease in the Firmicutes/Bacteroides ratio. However, prebiotic administration is able to counteract this decrease in Reg3g ADDIN EN.CITE <EndNote><Cite><Author>Everard</Author><Year>2014</Year><RecNum>251</RecNum><DisplayText>(Everard et al., 2014)</DisplayText><record><rec-number>251</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">251</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Everard, Amandine</author><author>Lazarevic, Vladimir</author><author>Gaia, Nadia</author><author>Johansson, Maria</author><author>Stahlman, Marcus</author><author>Backhed, Fredrik</author><author>Delzenne, Nathalie M.</author><author>Schrenzel, Jacques</author><author>Francois, Patrice</author><author>Cani, Patrice D.</author></authors></contributors><titles><title>Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity</title><secondary-title>ISME J</secondary-title></titles><pages>2116-2130</pages><volume>8</volume><number>10</number><keywords><keyword>metagenomic</keyword><keyword>gut microbiota</keyword><keyword>type 2 diabetes</keyword><keyword>antimicrobial peptides</keyword><keyword>Reg3g</keyword><keyword>prebiotics</keyword></keywords><dates><year>2014</year><pub-dates><date>10//print</date></pub-dates></dates><publisher>International Society for Microbial Ecology</publisher><isbn>1751-7362</isbn><work-type>Original Article</work-type><urls><related-urls><url>;(Everard et al., 2014). Bacteria from the plyla Bacteroidetes and Fimicutes contribute to 95% of faecal microbiota across ages, however a slight decline has been observed in centenarians (93%) ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010), while the Firmicutes/Bacteroidetes ratio also lowers with age ADDIN EN.CITE <EndNote><Cite><Author>Park</Author><Year>2015</Year><RecNum>95</RecNum><DisplayText>(Park et al., 2015)</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Park, Se-Hoon</author><author>Kim, Kyung-Ah</author><author>Ahn, Young-Tae</author><author>Jeong, Jin-Ju</author><author>Huh, Chul-Sung</author><author>Kim, Dong-Hyun</author></authors></contributors><titles><title>Comparative analysis of gut microbiota in elderly people of urbanized towns and longevity villages</title><secondary-title>BMC Microbiology</secondary-title></titles><pages>49</pages><volume>15</volume><number>1</number><dates><year>2015</year></dates><isbn>1471-2180</isbn><accession-num>doi:10.1186/s12866-015-0386-8</accession-num><urls><related-urls><url>;(Park et al., 2015). In addition, Claesson et al. (2011) demonstrated Firmicutes increased from 40% to 51%, and Bacteriodetes decreased from 57% to 41%, when comparing a young cohort (28-46 years old) to an elderly cohort (≥65 years old) (Claesson et al., 2011). In contrast, Biagi et al. (2010) found that the Firmicutes/Bacteroidetes ratio increased from 3.9 in young individuals to 5.1 in elderly individuals, before decreasing to 3.6 in centenarians ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010). 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ADDIN EN.CITE.DATA (Hopkins and Macfarlane, 2002; Wang et al., 2015). Hopkins and Macfarlane (2002) found that species diversity of Bifidobacterium and Lactobacillus decreased by 57.1 and 45.5% respectively between healthy young adults aged 21-34, and healthy elderly individuals, aged 67-73 years old. The number of Bifidobacterium and Lactobacillus species, measured as log10 CFU/g wet weight of faeces, decreased by 53.2 and 52.2% respectively with age ADDIN EN.CITE <EndNote><Cite><Author>Hopkins</Author><Year>2002</Year><RecNum>44</RecNum><DisplayText>(Hopkins and Macfarlane, 2002)</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hopkins, M. J.</author><author>Macfarlane, G. T.</author></authors></contributors><auth-address>MRC Microbiology and Gut Biology Group, University of Dundee Medical School. m.j.hopkins@dundee.ac.uk</auth-address><titles><title>Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection</title><secondary-title>J Med Microbiol</secondary-title></titles><pages>448-54</pages><volume>51</volume><number>5</number><edition>2002/05/07</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Bacteroides/isolation & purification</keyword><keyword>Bifidobacterium/isolation & purification</keyword><keyword>Clostridium/isolation & purification</keyword><keyword>Clostridium Infections/ microbiology</keyword><keyword>Clostridium difficile/isolation & purification</keyword><keyword>Diarrhea/ microbiology</keyword><keyword>Enterobacteriaceae/isolation & purification</keyword><keyword>Enterococcus/isolation & purification</keyword><keyword>Eubacterium/isolation & purification</keyword><keyword>Feces/ microbiology</keyword><keyword>Humans</keyword><keyword>Lactobacillus/isolation & purification</keyword><keyword>Prevotella/isolation & purification</keyword></keywords><dates><year>2002</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-2615 (Print)
0022-2615 (Linking)</isbn><accession-num>11990498</accession-num><urls></urls><electronic-resource-num>10.1099/0022-1317-51-5-448</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Hopkins and Macfarlane, 2002). In addition, with age, there is an increase of potentially pathogenic facultative anaerobes. For example, Proteobacteria increased from 1.2% to 2.6% in human centenarians, whilst bacilli increased from 5% to 12% ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010).Evidence suggests centenarians have further altered gut microbiota than elderly cohorts ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010). For example, when comparing the gut microbiota of cohorts exhibiting ‘normal life-spans’ (urbanised town communities, UTC) with those exhibiting exceptional longevity (longevity village communities, LVC) in South Korea, LVC individuals displayed significantly higher numbers of Bacteroides, Prevotella, and Lachnospira, while levels of Dialister, Subdoligranulum, Megamonas, EF401882_g, and AM275436_g were greater in UTC individuals. The content of pro-inflammatory LPS was also significantly lower in the faecal samples of the LVC cohort. Higher LPS levels were associated with increased meat intake, decreased vegetable intake, and the presence of several bacterial species found only in the UTC cohort ADDIN EN.CITE <EndNote><Cite><Author>Park</Author><Year>2015</Year><RecNum>95</RecNum><DisplayText>(Park et al., 2015)</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Park, Se-Hoon</author><author>Kim, Kyung-Ah</author><author>Ahn, Young-Tae</author><author>Jeong, Jin-Ju</author><author>Huh, Chul-Sung</author><author>Kim, Dong-Hyun</author></authors></contributors><titles><title>Comparative analysis of gut microbiota in elderly people of urbanized towns and longevity villages</title><secondary-title>BMC Microbiology</secondary-title></titles><pages>49</pages><volume>15</volume><number>1</number><dates><year>2015</year></dates><isbn>1471-2180</isbn><accession-num>doi:10.1186/s12866-015-0386-8</accession-num><urls><related-urls><url>;(Park et al., 2015). These factors could influence the progression of low-grade inflammation. This view is consolidated as bacteria associated with anti-inflammatory effects were significantly higher in the LVC cohort, making it possible that factors such as diet, influence microbiome composition, and result in a drop in pro-inflammatory LPS and a concomitant reduction in inflammaging. Additionally, Biagi et al. (2010) found that an age-related increase in potentially pathogenic Proteobacteria was correlated with the upregulation of pro-inflammatory IL-6 or IL-8 ADDIN EN.CITE <EndNote><Cite><Author>Biagi</Author><Year>2010</Year><RecNum>118</RecNum><DisplayText>(Biagi et al., 2010)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biagi, Elena</author><author>Nylund, Lotta</author><author>Candela, Marco</author><author>Ostan, Rita</author><author>Bucci, Laura</author><author>Pini, Elisa</author><author>Nikk?la, Janne</author><author>Monti, Daniela</author><author>Satokari, Reetta</author><author>Franceschi, Claudio</author><author>Brigidi, Patrizia</author><author>De Vos, Willem</author></authors></contributors><titles><title>Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians</title><secondary-title>PLoS ONE</secondary-title></titles><pages>e10667</pages><volume>5</volume><number>5</number><dates><year>2010</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Biagi et al., 2010). 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ADDIN EN.CITE.DATA (Biagi et al., 2010; Park et al., 2015).The microbiome also affects metabolism. By investigating the bacterial genetic material in human faecal samples, Rampelli et al. (2013) revealed an increase in the bacterial genes involved in tryptophan metabolism with age. It is plausible that this age-dependent increase in bacterial tryptophan metabolism, decreases host bioavailability, a phenomenon which is implicated in a variety of inflammatory related conditions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXB1cm9uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA (Capuron et al., 2011; Murr et al., 2015). Furthermore, the abundance of genes involved in SCFA production reduced with age. Moreover there was a decrease in bacterial saccharolytic potential, while an increase in proteolytic potential, diverted metabolism towards putrefaction. Furthermore, increasing age corresponded with the enrichment of genes relating to pathobionts such as Escherichia ADDIN EN.CITE <EndNote><Cite><Author>Rampelli</Author><Year>2013</Year><RecNum>117</RecNum><DisplayText>(Rampelli et al., 2013)</DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rampelli, S.</author><author>Candela, M.</author><author>Turroni, S.</author><author>Biagi, E.</author><author>Collino, S.</author><author>Franceschi, C.</author><author>O'Toole, P. W.</author><author>Brigidi, P.</author></authors></contributors><auth-address>Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy;</auth-address><titles><title>Functional metagenomic profiling of intestinal microbiome in extreme ageing</title><secondary-title>Aging (Albany NY)</secondary-title></titles><pages>902-12</pages><volume>5</volume><number>12</number><edition>2013/12/18</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging</keyword><keyword>Bacteria/ classification/genetics/ metabolism</keyword><keyword>Feces/ microbiology</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation, Bacterial</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Transcriptome</keyword></keywords><dates><year>2013</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1945-4589 (Electronic)
1945-4589 (Linking)</isbn><accession-num>24334635</accession-num><urls></urls><custom2>PMC3883706</custom2><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Rampelli et al., 2013). Future investigations will no doubt explore further bidirectional relationships between the regulation of lipid metabolism, the gut microbiome and intrinsic ageing.10.0 Current and Future Therapeutic StrategiesThe emerging bi-directional relationship between the gut microbiome and human host promotes this as a potential therapeutic target for the regulation of many host systems. Probiotic administration has been highlighted as an effective immunomodulator, which can have potential benefits on many diseases ADDIN EN.CITE <EndNote><Cite><Author>Patel</Author><Year>2015</Year><RecNum>240</RecNum><DisplayText>(Patel et al., 2015)</DisplayText><record><rec-number>240</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">240</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Patel, Seema</author><author>Shukla, Rishikesh</author><author>Goyal, Arun</author></authors></contributors><titles><title>Probiotics in valorization of innate immunity across various animal models</title><secondary-title>Journal of Functional Foods</secondary-title></titles><pages>549-561</pages><volume>14</volume><keywords><keyword>Probiotics</keyword><keyword>Functional food</keyword><keyword>Immunomodulator</keyword><keyword>Innate immunity</keyword><keyword>Adaptive immunity</keyword><keyword>Prebiotics</keyword></keywords><dates><year>2015</year><pub-dates><date>4//</date></pub-dates></dates><isbn>1756-4646</isbn><urls><related-urls><url>;(Patel et al., 2015). For example, Makino et al. (2010) demonstrated that a daily probiotic intake for 8-12 weeks resulted in a 2.6 times lower risk of becoming infected with the influenza virus in individuals ≥40 years old ADDIN EN.CITE <EndNote><Cite><Author>Makino</Author><Year>2010</Year><RecNum>252</RecNum><DisplayText>(Makino et al., 2010)</DisplayText><record><rec-number>252</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">252</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Makino, S.</author><author>Ikegami, S.</author><author>Kume, A.</author><author>Horiuchi, H.</author><author>Sasaki, H.</author><author>Orii, N.</author></authors></contributors><auth-address>Food Science Institute, Meiji Dairies Corporation, 540 Naruda, Odawara, Kanagawa 250-0862, Japan. seiya_makino@meiji-</auth-address><titles><title>Reducing the risk of infection in the elderly by dietary intake of yoghurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1</title><secondary-title>Br J Nutr</secondary-title></titles><pages>998-1006</pages><volume>104</volume><number>7</number><edition>2010/05/22</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Animals</keyword><keyword>Common Cold/immunology/ prevention & control/virology</keyword><keyword>Diet</keyword><keyword>Female</keyword><keyword>Fermentation</keyword><keyword>Humans</keyword><keyword>Killer Cells, Natural/ drug effects/metabolism</keyword><keyword>Lactobacillus delbrueckii</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Probiotics/pharmacology/ therapeutic use</keyword><keyword>Quality of Life</keyword><keyword>Risk Factors</keyword><keyword>Treatment Outcome</keyword><keyword>Yogurt/ microbiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1475-2662 (Electronic)
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ADDIN EN.CITE.DATA (Boge et al., 2009; Nagafuchi et al., 2015). As well as this, probiotics have been found to influence cholesterol metabolism. Al-Sheraji et al. (2012) demonstrated an 8 week probiotic supplementation in an elderly murine model significantly reduced plasma total cholesterol, triglycerides, LDL-C, and VLDL-C, in addition to increasing HDL-C levels. Moreover, probiotic supplementation significantly reduced the atherosclerotic index of these animals ADDIN EN.CITE <EndNote><Cite><Author>Al-Sheraji</Author><Year>2012</Year><RecNum>94</RecNum><DisplayText>(Al-Sheraji et al., 2012)</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Al-Sheraji, S. H.</author><author>Ismail, A.</author><author>Manap, M. Y.</author><author>Mustafa, S.</author><author>Yusof, R. M.</author><author>Hassan, F. A.</author></authors></contributors><auth-address>Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.</auth-address><titles><title>Hypocholesterolaemic effect of yoghurt containing Bifidobacterium pseudocatenulatum G4 or Bifidobacterium longum BB536</title><secondary-title>Food Chem</secondary-title></titles><pages>356-61</pages><volume>135</volume><number>2</number><edition>2012/08/08</edition><keywords><keyword>Animals</keyword><keyword>Anticholesteremic Agents/ metabolism</keyword><keyword>Bifidobacterium/ metabolism</keyword><keyword>Cholesterol/blood/metabolism</keyword><keyword>Humans</keyword><keyword>Hypercholesterolemia/ diet therapy/metabolism/microbiology</keyword><keyword>Male</keyword><keyword>Probiotics/metabolism/ therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Yogurt/analysis/ microbiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Nov 15</date></pub-dates></dates><isbn>0308-8146 (Print)
0308-8146 (Linking)</isbn><accession-num>22868099</accession-num><urls></urls><electronic-resource-num>10.1016/j.foodchem.2012.04.120</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Al-Sheraji et al., 2012). These alterations in plasma cholesterol levels could be due to a number of factors, including, the generation of SCFAs which may reduce the rate of hepatic cholesterol synthesis, the increase in bile acid deconjugation resulting in reduced cholesterol absorption, and the increase in bile acid excretion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJhPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Al-Sheraji et al., 2012; Begley et al., 2006; Hara et al., 1999).Furthermore, dietary interventions such as the Dietary Approaches to Stop Hypertension (DASH) and portfolio diets, which target the risk factors for CVD, hypertension and hypercholesterolaemia respectively, can be utilised PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWZhaTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWZhaTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Jenkins et al., 2015; Keith et al., 2015; Rifai and Silver, 2015). For example, a recent meta-analysis determined the DASH diet lowered systolic pressure by 6.74mmHg, and diastolic blood pressure by 3.54 mmHg ADDIN EN.CITE <EndNote><Cite><Author>Saneei</Author><Year>2014</Year><RecNum>250</RecNum><DisplayText>(Saneei et al., 2014)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">250</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saneei, P.</author><author>Salehi-Abargouei, A.</author><author>Esmaillzadeh, A.</author><author>Azadbakht, L.</author></authors></contributors><titles><title>Influence of Dietary Approaches to Stop Hypertension (DASH) diet on blood pressure: A systematic review and meta-analysis on randomized controlled trials</title><secondary-title>Nutrition, Metabolism and Cardiovascular Diseases</secondary-title></titles><pages>1253-1261</pages><volume>24</volume><number>12</number><keywords><keyword>DASH-diet</keyword><keyword>Systolic blood pressure</keyword><keyword>Diastolic blood pressure</keyword><keyword>Randomized controlled trials</keyword><keyword>Meta-analysis</keyword></keywords><dates><year>2014</year><pub-dates><date>12//</date></pub-dates></dates><isbn>0939-4753</isbn><urls><related-urls><url>;(Saneei et al., 2014). Although the portfolio diet is less successful in lowering blood pressure, it is effective at modifying the lipoprotein profile. Jenkins et al. (2011) observed a 13.1 and 13.8% reduction in LDL-C in individuals undertaking the routine and intensive portfolio diets over a 6 month period. Adherence to the routine or intensive portfolio diet resulted in a respective calculated 10 year CHD risk reduction of 10.8 and 11.3% respectively ADDIN EN.CITE <EndNote><Cite><Author>Jenkins</Author><Year>2011</Year><RecNum>248</RecNum><DisplayText>(Jenkins et al., 2011)</DisplayText><record><rec-number>248</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">248</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jenkins, D. A.</author><author>Jones, P. H.</author><author>Lamarche, B.</author><author>et al.,</author></authors></contributors><titles><title>Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: A randomized controlled trial</title><secondary-title>JAMA</secondary-title></titles><pages>831-839</pages><volume>306</volume><number>8</number><dates><year>2011</year></dates><isbn>0098-7484</isbn><urls><related-urls><url>;(Jenkins et al., 2011). As there is a significant risk reduction for CHD, and few adverse reactions associated with these diets, wide-scale utilisation in elderly individuals may play a role in maintaining good health in later years. Further to this, dependence on pharmaceutical intervention may be reduced. Moreover, many of the food items associated with these diets contain phytochemicals that can positively modulate infection and/or inflammaging and its related diseases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb25kb248L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Mc Auley and Mooney, 2015b; Paalvast et al., 2015; Parton et al., 2015), therefore our aim here is not to review each of these models, but to provide a synopsis of how mathematical models of cholesterol metabolism, and its associated processes can be used to enhance our understanding of how ageing impacts this core biological system. We addressed this problem recently by constructing a whole body mathematical model of cholesterol metabolism and its age associated dysregulation ADDIN EN.CITE <EndNote><Cite><Author>Mc Auley</Author><Year>2012</Year><RecNum>74</RecNum><DisplayText>(Mc Auley et al., 2005; Mc Auley et al., 2012)</DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mc Auley, Mark T.</author><author>Wilkinson, Darren J.</author><author>Jones, Janette J. L.</author><author>Kirkwood, Thomas B. L.</author></authors></contributors><titles><title>A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation</title><secondary-title>BMC Systems Biology</secondary-title></titles><pages>130-130</pages><volume>6</volume><dates><year>2012</year><pub-dates><date>10/10
02/28/received
09/21/accepted</date></pub-dates></dates><publisher>BioMed Central</publisher><isbn>1752-0509</isbn><accession-num>PMC3574035</accession-num><urls><related-urls><url> Auley</Author><Year>2005</Year><RecNum>11</RecNum><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="2x9sxrvvu9ae9vezrr3x0f20trvwzad0z5s9">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mc Auley, Mark</author><author>Jones, Janette</author><author>Wilkinson, Darren</author><author>Kirkwood, Tom</author></authors></contributors><titles><title>Modelling Lipid Metabolism to Improve Healthy Ageing</title><secondary-title>BMC Bioinformatics</secondary-title></titles><periodical><full-title>BMC Bioinformatics</full-title></periodical><pages>P21</pages><volume>6</volume><number>Suppl 3</number><dates><year>2005</year></dates><isbn>1471-2105</isbn><accession-num>doi:10.1186/1471-2105-6-S3-P21</accession-num><urls></urls></record></Cite></EndNote>(Mc Auley et al., 2005; Mc Auley et al., 2012). Within this framework we included several key mechanisms, including LDLr turnover, intestinal cholesterol absorption, and endogenous cholesterol synthesis. Using the model, a number of mechanisms were explored. Firstly, using an in silico simulation we gradually reduced the efficiency of cholesterol absorption. Interestingly, by increasing cholesterol absorption from 50% to 80% by 65 years, we were able to show that LDL-C increased by 34 mg/dL from its baseline value of 100mg/dL at 20 years of age in a healthy adult male. However, the key finding of the model centred on hepatic LDLr. Using the model we were able to show that by decreasing the activity of the LDLr to 50% by age 65 years, this produced a rise in LDL-C of 116 mg/dL from a base line value of 100mg/dL at age 20 years in a healthy male. Our model is coded in the Systems Biology Markup Language, SBML PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWNrYTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Hucka et al., 2003), and is archived in the BioModels database ADDIN EN.CITE <EndNote><Cite><Author>Le Novere</Author><Year>2006</Year><RecNum>76</RecNum><DisplayText>(Le Novere et al., 2006)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Le Novere, N.</author><author>Bornstein, B.</author><author>Broicher, A.</author><author>Courtot, M.</author><author>Donizelli, M.</author><author>Dharuri, H.</author><author>Li, L.</author><author>Sauro, H.</author><author>Schilstra, M.</author><author>Shapiro, B.</author><author>Snoep, J. L.</author><author>Hucka, M.</author></authors></contributors><auth-address>European Bioinformatics Institute EMBL, Wellcome-Trust Genome Campus, Hinxton, CB10 1SD, UK. lenov@ebi.ac.uk</auth-address><titles><title>BioModels Database: a free, centralized database of curated, published, quantitative kinetic models of biochemical and cellular systems</title><secondary-title>Nucleic Acids Res</secondary-title></titles><pages>D689-91</pages><volume>34</volume><number>Database issue</number><edition>2005/12/31</edition><keywords><keyword>Biochemical Phenomena</keyword><keyword>Cell Physiological Phenomena</keyword><keyword>Databases, Factual</keyword><keyword>Genes</keyword><keyword>Internet</keyword><keyword>Kinetics</keyword><keyword>Models, Biological</keyword><keyword>User-Computer Interface</keyword><keyword>Vocabulary, Controlled</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1362-4962 (Electronic)
0305-1048 (Linking)</isbn><accession-num>16381960</accession-num><urls></urls><custom2>PMC1347454</custom2><electronic-resource-num>10.1093/nar/gkj092</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Le Novere et al., 2006) (). This makes the model straightforward to adapt and update. Recently other groups have adapted the model, for example, Mishra et al. (2014) included the variables body weight and physical activity and explored cholesterol absorption in depth ADDIN EN.CITE <EndNote><Cite><Author>Mishra</Author><Year>2014</Year><RecNum>77</RecNum><DisplayText>(Mishra et al., 2014)</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">77</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mishra, Shekhar</author><author>Somvanshi, Pramod R</author><author>Venkatesh, KV</author></authors></contributors><titles><title>Control of cholesterol homeostasis by entero-hepatic bile transport–the role of feedback mechanisms</title><secondary-title>RSC Advances</secondary-title></titles><pages>58964-58975</pages><volume>4</volume><number>103</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>(Mishra et al., 2014). Moreover, Paalvast and colleagues used the model to conduct an in silico experiment utilizing the statin, simvastatin ADDIN EN.CITE <EndNote><Cite><Author>Paalvast</Author><Year>2015</Year><RecNum>73</RecNum><DisplayText>(Paalvast et al., 2015)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Paalvast, Yared</author><author>Kuivenhoven, Jan Albert</author><author>Groen, Albert K.</author></authors></contributors><titles><title>Evaluating computational models of cholesterol metabolism</title><secondary-title>Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids</secondary-title></titles><pages>1360-1376</pages><volume>1851</volume><number>10</number><keywords><keyword>Mathematical modeling</keyword><keyword>Apolipoprotein</keyword><keyword>Atherosclerosis</keyword><keyword>Reverse cholesterol transport</keyword><keyword>Systems biology</keyword></keywords><dates><year>2015</year><pub-dates><date>10//</date></pub-dates></dates><isbn>1388-1981</isbn><urls><related-urls><url>;(Paalvast et al., 2015). To simulate this effect, the authors reduced hepatic cholesterol synthesis by 75%. This resulted in a reduction in LDL-C of 14% and 33% in six weeks and one year respectively. In recent years a number of other models have mathematically represented various aspects of cholesterol metabolism. Briefly, these include models of cholesterol biosynthesis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dGFjaGFyeWE8L0F1dGhvcj48WWVhcj4yMDE0PC9Z
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ADDIN EN.CITE.DATA (Chapman et al., 2010; Hübner et al., 2008; Shorten and Upreti, 2005; Sips et al., 2014), LDLr regulation ADDIN EN.CITE <EndNote><Cite><Author>Shankaran</Author><Year>2007</Year><RecNum>141</RecNum><DisplayText>(Shankaran et al., 2007)</DisplayText><record><rec-number>141</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">141</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shankaran, Harish</author><author>Resat, Haluk</author><author>Wiley, H. Steven</author></authors></contributors><titles><title>Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study</title><secondary-title>PLoS Comput Biol</secondary-title></titles><pages>e101</pages><volume>3</volume><number>6</number><dates><year>2007</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;(Shankaran et al., 2007), hepatic LDL-C endocytosis ADDIN EN.CITE <EndNote><Cite><Author>Wattis</Author><Year>2008</Year><RecNum>142</RecNum><DisplayText>(Wattis et al., 2008)</DisplayText><record><rec-number>142</rec-number><foreign-keys><key app="EN" db-id="vd59wwa9htw29oe595kv20ty9zftzwsdrwvp">142</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wattis, J. A.</author><author>O'Malley, B.</author><author>Blackburn, H.</author><author>Pickersgill, L.</author><author>Panovska, J.</author><author>Byrne, H. M.</author><author>Jackson, K. G.</author></authors></contributors><auth-address>Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK. Jonathan.Wattis@nottingham.ac.uk</auth-address><titles><title>Mathematical model for low density lipoprotein (LDL) endocytosis by hepatocytes</title><secondary-title>Bull Math Biol</secondary-title></titles><pages>2303-33</pages><volume>70</volume><number>8</number><edition>2008/08/22</edition><keywords><keyword>Apolipoprotein B-100/metabolism</keyword><keyword>Cells, Cultured</keyword><keyword>Cholesterol, LDL/ metabolism</keyword><keyword>Clathrin-Coated Vesicles/metabolism</keyword><keyword>Endocytosis/physiology</keyword><keyword>Endosomes/metabolism</keyword><keyword>Feedback, Physiological/physiology</keyword><keyword>Hepatocytes/ physiology</keyword><keyword>Lysosomes/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Receptors, LDL/metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1522-9602 (Electronic)
0092-8240 (Linking)</isbn><accession-num>18716843</accession-num><urls></urls><custom2>PMC2784520</custom2><electronic-resource-num>10.1007/s11538-008-9347-9</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Wattis et al., 2008), and RCT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Lu et al., 2014). Most of these models do not focus on the ageing process as such, but it is possible they could be adapted and merged to explore in depth some of the changes that occur within cholesterol metabolism during ageing, discussed in this review, in particular the interaction of the gut microbiome with cholesterol metabolism. 12.0 DiscussionDeveloped populations are ageing, resulting in an increase in the diseases associated with ageing. Of the diseases whose prevalence increases with age, CVD related morbidity is by far the most common. The risk factors for CVD are many, however together with classic factors such as chronological age, smoking, sex, blood pressure and diabetes; lipid biomarkers have become the cornerstone in determining CVD risk. It is generally accepted the relationship between CVD risk and the dysregulation of lipid metabolism is at least in part due to the strong association that exists between elevated total cholesterol/LDL-C and atherosclerotic plaque formation. Conversely, due to its role in RCT, HDL-C is widely regarded as being anti-atherogenic, and evidenced by the inverse correlation between HDL-C levels and CVD. Fundamentally, cholesterol metabolism is maintained by a subtle balancing act between dietary ingestion, intestinal absorption, whole-body synthesis and excretion. These processes work in a coordinated fashion over a diverse range of spatial and temporal scales to help maintain whole body cholesterol balance. Changes to any of these processes can have a direct impact on the levels of LDL-C and HDL-C, thus indirectly influencing CVD risk. Changes to any of these processes can have a direct impact on the levels of LDL-C and HDL-C, thus indirectly influencing CVD risk, a finding of paramount importance, when considering the complex interactions that exist between cholesterol metabolism and the ageing process. This review has highlighted the ageing process does not affect cholesterol metabolism at solely one, or even a number of sites, but rather each regulatory component of cholesterol metabolism is affected by the ageing process. Worryingly, there is a paucity of studies detailing the mechanistic changes that occur during metabolism of this nutrient and ageing, and of those that exist, the majority tend to focus on murine models and were completed several decades ago. Despite this, our review uncovered a number of important findings about how cholesterol metabolism affects ageing. It was revealed that NPC1L1 expression significantly increases in the duodenum and jejunum with age, while ABCG5/G8 expression is suppressed. Moreover, in humans it has been found that the rate of bile acid synthesis declines with age and occurs with a concomitant reduction in the hepatic expression of the rate limiting enzyme of bile acid synthesis, CYP7AI. Also, from an intestinal perspective it has been suggested that the rise in LDL-C that accompanies ageing is due to a decline in BSH+ species, such as Lactobacillus and Bifidobacterium. However, when we examined how lipoprotein dynamics change with age, it was suggested that the mechanistic explanation for the rise in LDL-C during ageing is due to a reduction in the clearance rate for LDL-C from the circulation. This assertion is certainly in line with the central finding from our recent mechanistic model of whole body cholesterol metabolism, which revealed that a reduction in the hepatic clearance rate of LDL-C is the central driver in dysregulating cholesterol metabolism. However, for the purposes of abstraction our model did not incorporate many of the mechanisms outlined in this review. Therefore, it is our opinion that the dysregulation of cholesterol metabolism is the cumulative effect of ageing on all the components of cholesterol metabolism and it is na?ve to single out any one aspect in particular. This view is supported by additional findings from this review that revealed how other important aspects of cholesterol metabolism are effected by the ageing. For instance, oxidative stress was shown not only to be involved in the progression of atherosclerosis but to also be involved in the oxidation of HDL particles. Moreover, various molecular mechanisms involved intracellular cholesterol homeostasis and biosynthesis have been shown to be effected by the metabolic regulators mTOR and sirtuins. These cellular metabolic hubs are widely regarded as having a key role to play in intrinsic ageing and health-span. For instance, mTORC1 regulates SREBP levels which in turn results in altered LDLr expression. In addition, Sirt6 has been identified as being involved in Srebp2 gene regulation. Collectively these findings emphasize that it not the dysregulation of one or even a few biological mechanisms; rather, age related dyslipidaemia is likely to be the result of a combination of several factors and future therapeutic interventions should be underpinned by this. This review also revealed diet has a key role to play in modulating cholesterol metabolism and could be a key therapeutic avenue to mitigate the effects ageing has on lipid metabolism. The central dietary paradigm of ageing research has been CR. This regime has been shown to have a positive cardioprotective effect in humans, part of which is brought about by an improvement in blood lipid profile in subjects undertaking this diet. More conventional diets also affect cholesterol metabolism. The high levels of dietary phytosterols, MUFA, and PUFA typically found in the Mediterranean diet for instance, have been shown to modulate cholesterol metabolism, by increasing hepatic expression of LDLr, in addition to reducing cholesterol absorption. Thus, experimental evidence suggests employment of healthy diets such as the Mediterranean diet, and supplementation with probiotics for example, could be utilised to slow the rate of LDL-C accumulation, associated with the ageing process. On way in which we could explore the relationship between diet, ageing and cholesterol metabolism further would be to use mechanistic mathematical models. Recently, mathematical models have been used to explore the dynamics of cholesterol metabolism and the effect that both ageing and dietary changes have on it. One area that a mathematical model could be used to explore in greater depth, is the bi-directional relationship between the gut microbiome and cholesterol metabolism. Thus, modelling could help to identify alternative therapeutic targets, which could reduce the dependence on pharmaceutical intervention in older people to improve blood lipid profile. 13.0 ConclusionIt is evident, the breakdown of cholesterol metabolism associated with ageing results in increased LDL-C and has important implications for health-span. Dietary intervention offers a potential non-pharmacological avenue that could be invaluable for mitigating the insidious effects ageing has on this system. In recent years, there have been an increase in the use of mechanistic mathematical models to explore complex systems such as cholesterol metabolism in a more integrated and non-reductionist fashion. Such models should be increasingly used to determine new targets for therapeutic intervention.AcknowledgementsAmy Morgan wishes to thank the Faculty of Science and Engineering for funding her doctoral scholarship.FiguresFigure 1. Overview of cholesterol metabolism and age associated changes to mechanisms. Briefly outlined is 1) ingestion of dietary cholesterol, 2) intestinal absorption, 3) chylomicron transport, 4) cholesterol biosynthesis, 5) VLDL-C production and hydrolysis to IDL-C and LDL-C, 6) hepatic uptake of LDL-C, 7) peripheral uptake of LDL-C, 8) reverse cholesterol transport, 9) bile acid synthesis, and 10) enterohepatic circulation of bile acids and bacterial modification. The age-related changes highlighted centre on some of the mechanisms responsible for the rise in LDL-C with age; the increase in intestinal absorption of cholesterol, the reduction of bile acid synthesis, the decrease in LDL-C clearance, and the decrease in BSH+ species in the digestive microbiome.References ADDIN EN.REFLIST Abbott, R.D., Garrison, R.J., Wilson, P.W., Epstein, F.H., Castelli, W.P., Feinleib, M., LaRue, C., 1983. Joint distribution of lipoprotein cholesterol classes. The Framingham study. 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