Livrepository.liverpool.ac.uk



The Business of Anti-Aging ScienceJo?o Pedro de Magalh?es1,#,* Michael Stevens1,#, Daniel Thornton11Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom#Joint first authors*Correspondence. Telephone: +44 151 7954517; E-mail: jp@AbstractAge-related conditions are the leading causes of death and healthcare costs. Reducing the rate of aging would have enormous medical and financial benefits. Myriads of genes and pathways are known to regulate aging in model organisms, fostering a new crop of anti-aging companies. Approaches range from drug discovery efforts to big data methods and direct-to-consumer strategies. Challenges and pitfalls to commercialization include reliance on findings from short-lived model organisms, poor biological understanding of aging and hurdles in performing clinical trials for aging. A large number of potential aging-associated interventions and targets exist, yet given long validation times, only a small fraction of them can be explored for clinical applications. If even one company succeeds, though, the impact will be huge.Keywords: Biogerontology; geroscience; longevity; translational research; big pharma; pharmacologyTreating multiple age-related diseases by retarding the aging processThe dream of fending off old age is as old as human civilization. Given the global aging of the population, however, developing interventions that preserve health in old age and postpone the onset of age-related diseases is more important than ever. In addition, we now know it is possible to retard aging in animal models. Various genetic, dietary and pharmacological interventions have been shown to increase lifespan, in some cases dramatically (10-fold is the current record), in short-lived model organisms like yeast, worms, flies, killifish, mice and rats PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYWdhbGhhZXM8L0F1dGhvcj48WWVhcj4yMDEyPC9Z

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ADDIN EN.CITE.DATA [1-3]. Importantly, life-extending interventions not only increase longevity but can retard the onset of age-related diseases, resulting in the extension of healthspan (i.e., the length of time one lives in good health). These breakthroughs in the biology of aging and its impact on health and disease, referred to by some as “geroscience”, have led to the promise that we will be able to delay or slow down human aging, resulting in unprecedented health benefits ADDIN EN.CITE <EndNote><Cite><Author>Kennedy</Author><Year>2014</Year><RecNum>4</RecNum><DisplayText>[4]</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kennedy, B. K.</author><author>Pennypacker, J. K.</author></authors></contributors><auth-address>Buck Institute for Research on Aging, Novato, Calif. Electronic address: bkennedy@.&#xD;Buck Institute for Research on Aging, Novato, Calif.</auth-address><titles><title>Drugs that modulate aging: the promising yet difficult path ahead</title><secondary-title>Transl Res</secondary-title><alt-title>Translational research : the journal of laboratory and clinical medicine</alt-title></titles><periodical><full-title>Transl Res</full-title><abbr-1>Translational research : the journal of laboratory and clinical medicine</abbr-1></periodical><alt-periodical><full-title>Transl Res</full-title><abbr-1>Translational research : the journal of laboratory and clinical medicine</abbr-1></alt-periodical><pages>456-65</pages><volume>163</volume><number>5</number><edition>2013/12/10</edition><keywords><keyword>Aging/*drug effects/genetics/*physiology</keyword><keyword>Animals</keyword><keyword>Gene Expression Regulation/physiology</keyword><keyword>Humans</keyword><keyword>Translational Medical Research/*methods</keyword><keyword>United States</keyword></keywords><dates><year>2014</year><pub-dates><date>May</date></pub-dates></dates><isbn>1878-1810 (Electronic)&#xD;1878-1810 (Linking)</isbn><accession-num>24316383</accession-num><work-type>Review</work-type><urls><related-urls><url>;[4].Leading causes of death worldwide, and notably in industrialized countries, are age-related diseases like cardiovascular diseases, cancer and neurodegenerative diseases (Figure 1). Because of the strong relationship between the aging process and age-related diseases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZW5uZWR5PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA [5, 6], the benefits emerging from anti-aging science have enormous potential. Using a model of future health and spending in the USA, the effect of delayed aging resulting in 2.2 years additional life expectancy would yield $7 trillion in savings over 50 years; whereas addressing single pathologies such as cancer and heart disease would yield less, mostly due to competing risks ADDIN EN.CITE <EndNote><Cite><Author>Goldman</Author><Year>2013</Year><RecNum>7</RecNum><DisplayText>[7]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goldman, Dana P.</author><author>Cutler, David</author><author>Rowe, John W.</author><author>Michaud, Pierre-Carl</author><author>Sullivan, Jeffrey</author><author>Peneva, Desi</author><author>Olshansky, S. Jay</author></authors></contributors><titles><title>Substantial health and economic returns from delayed aging may warrant a new focus for medical research</title><secondary-title>Health Affairs (Project Hope)</secondary-title></titles><periodical><full-title>Health Affairs (Project Hope)</full-title></periodical><pages>1698-1705</pages><volume>32</volume><number>10</number><keywords><keyword>Age Factors, Aging, Biomedical Research, Cost Savings, Disabled Persons, Financing Health Care, Health Spending, Humans, Life Expectancy, Longevity, Medical Technology, Medicare, Population Dynamics, Social Security, United States</keyword></keywords><dates><year>2013</year><pub-dates><date>2013/oct/</date></pub-dates></dates><isbn>1544-5208</isbn><urls></urls><electronic-resource-num>10.1377/hlthaff.2013.0052</electronic-resource-num><language>eng</language></record></Cite></EndNote>[7]. Aging can be defined as a progressive deterioration of physiological function, accompanied by an increase in vulnerability and mortality with age ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2011</Year><RecNum>79</RecNum><DisplayText>[8]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">79</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>de Magalhaes, J. P.</author></authors><secondary-authors><author>Ian Stuart-Hamilton</author></secondary-authors></contributors><titles><title>The biology of ageing: A primer</title><secondary-title>An Introduction to Gerontology</secondary-title></titles><pages>21-47</pages><dates><year>2011</year></dates><pub-location>Cambridge</pub-location><publisher>Cambridge University Press</publisher><urls></urls></record></Cite></EndNote>[8]. Here, anti-aging based therapies are defined as those that delay the onset of multiple pathologies via core biological processes associated with age-related functional decline. While some therapies may be branded as single pathology for funding, business, or regulatory reasons, we include them nonetheless if they target aging-related processes or longevity-determining pathways and genes. Given its huge potential financial benefits, anti-aging science has tremendous commercial opportunities. The anti-aging industry has struggled in the past in terms of reputation ADDIN EN.CITE <EndNote><Cite><Author>Olshansky</Author><Year>2002</Year><RecNum>8</RecNum><DisplayText>[9]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Olshansky, S. J.</author><author>Hayflick, L.</author><author>Carnes, B. A.</author></authors></contributors><auth-address>University of Illinois at Chicago, USA.</auth-address><titles><title>No truth to the fountain of youth</title><secondary-title>Sci Am</secondary-title></titles><periodical><full-title>Sci Am</full-title></periodical><pages>92-5</pages><volume>286</volume><number>6</number><keywords><keyword>Aging/genetics/*physiology</keyword><keyword>Animal</keyword><keyword>Antioxidants/administration &amp; dosage/adverse effects</keyword><keyword>DNA Damage</keyword><keyword>Dietary Supplements/adverse effects</keyword><keyword>Energy Intake</keyword><keyword>Estrogen Replacement Therapy/adverse effects</keyword><keyword>Female</keyword><keyword>Hormones/administration &amp; dosage/adverse effects</keyword><keyword>Human</keyword><keyword>*Longevity</keyword><keyword>Male</keyword><keyword>Quality of Life</keyword><keyword>Research</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><accession-num>12030096</accession-num><urls><related-urls><url>;[9], yet driven by more recent scientific breakthroughs it has been growing substantially with several young companies supported by world-leading brands like Google ADDIN EN.CITE <EndNote><Cite><Author>Scott</Author><Year>2015</Year><RecNum>9</RecNum><DisplayText>[10]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scott, C. T.</author><author>DeFrancesco, L.</author></authors></contributors><auth-address>Nature Biotechnology.</auth-address><titles><title>Selling long life</title><secondary-title>Nat Biotechnol</secondary-title><alt-title>Nature biotechnology</alt-title></titles><periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></periodical><alt-periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></alt-periodical><pages>31-40</pages><volume>33</volume><number>1</number><edition>2015/01/13</edition><keywords><keyword>*Aging</keyword><keyword>Genome, Human</keyword><keyword>Humans</keyword><keyword>*Longevity</keyword><keyword>TOR Serine-Threonine Kinases/physiology</keyword></keywords><dates><year>2015</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1546-1696 (Electronic)&#xD;1087-0156 (Linking)</isbn><accession-num>25574633</accession-num><urls><related-urls><url>;[10]. In this piece, we first review companies and approaches in anti-aging biotech (Table 1). We then discuss some of the challenges and pitfalls in business development based on anti-aging science and lastly provide a vision for how the field may progress in the future.Anti-aging biotech companies and approachesPharmacological targeting of aging As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. This topic has been reviewed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWlzZXJtYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy

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ADDIN EN.CITE.DATA [1, 4, 11, 12], and therefore will only be briefly discussed in (Box 1).Notable examples of anti-aging drug discovery efforts include pharmacological manipulations of sirtuins, and sirtuin 1(SIRT1) in particular (targeted by resveratrol) and TOR (targeted by rapamycin), which are currently being explored ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Wuttke, D.</author><author>Wood, S. H.</author><author>Plank, M.</author><author>Vora, C.</author></authors></contributors><auth-address>University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool L69 7ZB, UK. jp@.</auth-address><titles><title>Genome-environment interactions that modulate aging: powerful targets for drug discovery</title><secondary-title>Pharmacol Rev</secondary-title><alt-title>Pharmacological reviews</alt-title></titles><periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></alt-periodical><pages>88-101</pages><volume>64</volume><number>1</number><edition>2011/11/18</edition><dates><year>2012</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-0081 (Electronic)&#xD;0031-6997 (Linking)</isbn><accession-num>22090473</accession-num><urls><related-urls><url>;[1]. TOR inhibition by rapamycin results in increased lifespan from yeast to mammals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJyaXNvbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

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ADDIN EN.CITE.DATA [14]. Because rapamycin has various side-effects, companies and labs are trying to develop safer analogues, known as “rapalogs”. One company focusing on the TOR pathway is Navitor Pharmaceuticals, which aims to treat diseases of aging through the selective regulation of the mTOR pathway. Another similar company focused on rapalogs, Mount Tam Biotechnologies, has worldwide licensing rights to the Buck Institute’s research assets related to auto-immune disease including the rapalog TAM-01 ().As for research on resveratrol and sirtuins, these were high-profile in 2008 when GlaxoSmithKline purchased sirtuin-focused biotech company Sirtris (based on the work of David Sinclair at Harvard Medical School) for $720 million. Enthusiasm in resveratrol and sirtuins as anti-aging compounds has arguably declined in more recent years. Briefly, results have been largely disappointing since then ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Wuttke, D.</author><author>Wood, S. H.</author><author>Plank, M.</author><author>Vora, C.</author></authors></contributors><auth-address>University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool L69 7ZB, UK. jp@.</auth-address><titles><title>Genome-environment interactions that modulate aging: powerful targets for drug discovery</title><secondary-title>Pharmacol Rev</secondary-title><alt-title>Pharmacological reviews</alt-title></titles><periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></alt-periodical><pages>88-101</pages><volume>64</volume><number>1</number><edition>2011/11/18</edition><dates><year>2012</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-0081 (Electronic)&#xD;0031-6997 (Linking)</isbn><accession-num>22090473</accession-num><urls><related-urls><url>;[1] with resveratrol failing to extend lifespan in studies in mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [15], among other controversies ADDIN EN.CITE <EndNote><Cite><Author>Schmidt</Author><Year>2010</Year><RecNum>15</RecNum><DisplayText>[16]</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmidt, C.</author></authors></contributors><titles><title>GSK/Sirtris compounds dogged by assay artifacts</title><secondary-title>Nat Biotechnol</secondary-title><alt-title>Nature biotechnology</alt-title></titles><periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></periodical><alt-periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></alt-periodical><pages>185-6</pages><volume>28</volume><number>3</number><edition>2010/03/10</edition><keywords><keyword>Animals</keyword><keyword>*Drug Industry</keyword><keyword>Humans</keyword><keyword>Longevity/*drug effects</keyword><keyword>Mice</keyword><keyword>Sirtuin 1/*physiology</keyword><keyword>Stilbenes/*pharmacology</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1546-1696 (Electronic)&#xD;1087-0156 (Linking)</isbn><accession-num>20212464</accession-num><work-type>News</work-type><urls><related-urls><url>;[16]. GSK has closed Sirtris, although research on sirtuins and on new chemical entities that are thought to active sirtuins PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWJiYXJkPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA [20]. While many dietary supplements still focus on antioxidants, few companies in the field maintain such a focus. One exception is Antoxis which, founded in 2005, designs and synthesizes therapeutic antioxidants.Telomeres, the protein bound structures at the ends of chromosomes, shorten with cell division and at least in some tissues with age PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYWdhbGhhZXM8L0F1dGhvcj48WWVhcj4yMDExPC9Z

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ADDIN EN.CITE.DATA [23, 24]. Therefore, the idea of activating telomerase as anti-aging remains a powerful one, even resulting in one self-experiment using gene therapy by BioViva ADDIN EN.CITE <EndNote><Cite><Author>Hamzelou</Author><Year>2017</Year><RecNum>66</RecNum><DisplayText>[25]</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hamzelou, Jessica</author></authors></contributors><titles><title>Time to stop getting old</title><secondary-title>New Scientist</secondary-title></titles><periodical><full-title>New Scientist</full-title></periodical><pages>22-23</pages><volume>233</volume><number>3107</number><dates><year>2017</year></dates><isbn>0262-4079</isbn><urls><related-urls><url>(17)30030-1</electronic-resource-num></record></Cite></EndNote>[25]. One notable company working on telomerase activation, Sierra Science, claims to have screened 250,000 compounds . Other companies focus on particular age-related diseases, such as Telocyte which is working on telomerase activation for Alzheimer’s disease.Telomere shortening, as well as various stressors, can cause proliferating cells to stop dividing and enter a pro-inflammatory senescent state. There is evidence that senescent cells accumulate with age, at least in some tissues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYWdhbGhhZXM8L0F1dGhvcj48WWVhcj4yMDExPC9Z

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ADDIN EN.CITE.DATA [8, 26]. In a landmark study, drug-induced clearance of p16Ink4a-positive cells (a marker of senescence) once a week from age one, extended the median lifespan in two normal strains of mice by 24-27%, though maximum lifespan was only (slightly) increased in one strain. Tumorigenesis and age-related deterioration in heart and kidney were delayed or slowed ADDIN EN.CITE <EndNote><Cite><Author>Baker</Author><Year>2016</Year><RecNum>23</RecNum><DisplayText>[27]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baker, Darren J.</author><author>Childs, Bennett G.</author><author>Durik, Matej</author><author>Wijers, Melinde E.</author><author>Sieben, Cynthia J.</author><author>Zhong, Jian</author><author>Saltness, Rachel A.</author><author>Jeganathan, Karthik B.</author><author>Verzosa, Grace Casaclang</author><author>Pezeshki, Abdulmohammad</author><author>Khazaie, Khashayarsha</author><author>Miller, Jordan D.</author><author>van Deursen, Jan M.</author></authors></contributors><titles><title>Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>184-189</pages><volume>530</volume><number>7589</number><keywords><keyword>Adipocytes, Aging, Animals, Apoptosis, Cell Aging, Cell Separation, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p16, Epithelial Cells, Female, Health, Kidney, Lipodystrophy, Longevity, Male, Mice, Myocardium, Organ Specificity, St</keyword></keywords><dates><year>2016</year><pub-dates><date>2016/feb/</date></pub-dates></dates><isbn>1476-4687</isbn><urls></urls><electronic-resource-num>10.1038/nature16932</electronic-resource-num><language>eng</language></record></Cite></EndNote>[27]. As a consequence, Unity Biotechnology, a company founded by researchers at the Mayo Clinic involved in the abovementioned work as well as the Buck Institute, has raised $116 million from investors, including Amazon's founder, Jeff Bezos, to develop senolytic (i.e., an agent that destroys senescent cells) treatments. Continuing research by the co-founders has focused on senolytic agents, including killing of senescent fibroblasts with piperlongumine and ABT-263 ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2016</Year><RecNum>26</RecNum><DisplayText>[28]</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Yingying</author><author>Chang, Jianhui</author><author>Liu, Xingui</author><author>Zhang, Xuan</author><author>Zhang, Suping</author><author>Zhang, Xin</author><author>Zhou, Daohong</author><author>Zheng, Guangrong</author></authors></contributors><titles><title>Discovery of piperlongumine as a potential novel lead for the development of senolytic agents</title><secondary-title>Aging</secondary-title></titles><periodical><full-title>Aging</full-title></periodical><pages>2915-2926</pages><volume>8</volume><number>11</number><keywords><keyword>ABT-263, Aging, piperlongumine, Reactive Oxygen Species, senescent cells, senolytic agents, synergistic effect</keyword></keywords><dates><year>2016</year><pub-dates><date>2016/nov/</date></pub-dates></dates><isbn>1945-4589</isbn><urls></urls><electronic-resource-num>10.18632/aging.101100</electronic-resource-num><language>eng</language></record></Cite></EndNote>[28]. Interestingly, they have also acquired a patent related to a senescent cell antibody for imaging and delivery of therapeutic agents ADDIN EN.CITE <EndNote><Cite><Author>Squires</Author><Year>2015</Year><RecNum>29</RecNum><DisplayText>[29]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">29</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Squires, Shayne (Coalville, UT, US)</author></authors></contributors><titles><title>COMPOSITIONS AND METHODS FOR DETECTING OR ELIMINATING SENESCENT CELLS TO DIAGNOSE OR TREAT DISEASE</title></titles><number>20150151001</number><dates><year>2015</year></dates><pub-location>United States</pub-location><publisher>CENEXYS, INC.</publisher><urls><related-urls><url>;[29].Other companies focusing on senolytics include Oisin Biotechnologies, although according to their website they seem to be developing a genetically-targeted intervention to clear senescent cells, suggesting a different approach than Unity. Moreover, Everon Biosciences has shown that a significant portion of cells with p16Ink4a expression may actually be a subclass of macrophages, termed SAMs (senescent associated macrophages) ADDIN EN.CITE <EndNote><Cite><Author>Hall</Author><Year>2016</Year><RecNum>30</RecNum><DisplayText>[30]</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hall, Brandon M.</author><author>Balan, Vitaly</author><author>Gleiberman, Anatoli S.</author><author>Strom, Evguenia</author><author>Krasnov, Peter</author><author>Virtuoso, Lauren P.</author><author>Rydkina, Elena</author><author>Vujcic, Slavoljub</author><author>Balan, Karina</author><author>Gitlin, Ilya</author><author>Leonova, Katerina</author><author>Polinsky, Alexander</author><author>Chernova, Olga B.</author><author>Gudkov, Andrei V.</author></authors></contributors><titles><title>Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells</title><secondary-title>Aging</secondary-title></titles><periodical><full-title>Aging</full-title></periodical><pages>1294-1315</pages><volume>8</volume><number>7</number><keywords><keyword>chronological aging, clodronate, inflammaging, Inflammation, p16INK4a, senescence-associated beta-galactosidase, senescence-associated secretory phenotype</keyword></keywords><dates><year>2016</year><pub-dates><date>2016/jul/</date></pub-dates></dates><isbn>1945-4589</isbn><urls></urls><electronic-resource-num>10.18632/aging.100991</electronic-resource-num><language>eng</language></record></Cite></EndNote>[30]. Following this discovery, Everon has announced that they will focus on these SAMolytic agents. Lastly, Siwa Therapeutics’ focuses on developing antibodies against senescent cell markers capable of identifying and removing senescent cells. Given the multiple genes, processes and pathways associated with aging, there are many opportunities for developing pharmacological approaches against one's favorite target. For example, the idea that protein homeostasis is important during aging has led to the creation of Proteostasis Therapeutics, which aims to develop drugs that control the body's protein homeostasis which in turn could lead to therapies against genetic and degenerative disorders that include several age-related diseases. Also, Retrotope focuses on drug development for restoring mitochondrial health. Their first product candidate, RT001, is being clinically tested in Friedreich’s ataxia. 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ADDIN EN.CITE.DATA [31]. Lastly, while most efforts mentioned thus far are based on discoveries in model organisms, drugs targeting human longevity-associated genes are also promising ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Wuttke, D.</author><author>Wood, S. H.</author><author>Plank, M.</author><author>Vora, C.</author></authors></contributors><auth-address>University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool L69 7ZB, UK. jp@.</auth-address><titles><title>Genome-environment interactions that modulate aging: powerful targets for drug discovery</title><secondary-title>Pharmacol Rev</secondary-title><alt-title>Pharmacological reviews</alt-title></titles><periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></alt-periodical><pages>88-101</pages><volume>64</volume><number>1</number><edition>2011/11/18</edition><dates><year>2012</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-0081 (Electronic)&#xD;0031-6997 (Linking)</isbn><accession-num>22090473</accession-num><urls><related-urls><url>;[1]. For example, Androcyte focuses on supercentenarians, individuals over 110 years of age, in the hope of identifying unique determinants of these human longevity outliers that may then be targeted pharmacologically.Basic Biology and Big DataWith a decidedly Silicon Valley-based confidence inspired by the successes of the high-tech industry spanning four decades, venture-capital funded big data approaches are being pursued in aging and longevity science. High profile players include Calico and Human Longevity Incorporated. Started as one of Google's moonshot projects in 2013, Calico is attempting to harness big data to improve understanding of the basic biology that controls lifespan. Not much is known about how this will look in practice, however, they have formed an up to $1.5 billion partnership with AbbVie to develop drugs targeting diseases related to old age (). Another high profile player is Human Longevity Incorporated (HLI) by Craig Venter. HLI is focused more directly on data than Calico, and aims to create the largest database of integrated high-throughput assays - genotypes, transcript and microbiome data, along with deep phenotypic data on patients in order to fully map genotype to phenotype to inform healthcare in general. Published efforts have focused on deep sequencing of human genomes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZWxlbnRpPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA [12]. This is an attractive approach as pharmaceutical companies incur $1.8 billion capitalized costs to develop and get approval for drugs from scratch, while the safety of approved drugs is already known ADDIN EN.CITE <EndNote><Cite><Author>Paul</Author><Year>2010</Year><RecNum>80</RecNum><DisplayText>[33]</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Paul, S. M.</author><author>Mytelka, D. S.</author><author>Dunwiddie, C. T.</author><author>Persinger, C. C.</author><author>Munos, B. H.</author><author>Lindborg, S. R.</author><author>Schacht, A. L.</author></authors></contributors><auth-address>Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. smpaulmd@</auth-address><titles><title>How to improve R&amp;D productivity: the pharmaceutical industry&apos;s grand challenge</title><secondary-title>Nat Rev Drug Discov</secondary-title><alt-title>Nature reviews. Drug discovery</alt-title></titles><periodical><full-title>Nat Rev Drug Discov</full-title><abbr-1>Nature reviews. Drug discovery</abbr-1></periodical><alt-periodical><full-title>Nat Rev Drug Discov</full-title><abbr-1>Nature reviews. Drug discovery</abbr-1></alt-periodical><pages>203-14</pages><volume>9</volume><number>3</number><edition>2010/02/20</edition><keywords><keyword>Clinical Trials as Topic</keyword><keyword>Drug Discovery/*methods</keyword><keyword>Drug Industry/*economics/trends</keyword><keyword>*Efficiency</keyword><keyword>Humans</keyword><keyword>Models, Economic</keyword><keyword>Research/economics</keyword><keyword>*Research Design</keyword><keyword>Time Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1474-1784 (Electronic)&#xD;1474-1776 (Linking)</isbn><accession-num>20168317</accession-num><work-type>Review</work-type><urls><related-urls><url>;[33]. While many companies do this, it forms a key component of some companies in longevity science. For one project, Insilico Medicine uses deep learning on multiple 'omic' data types to find new relationships between existing drugs and gene regulatory pathways effected in, or otherwise related to, aging-related diseases. Chronos Therapeutics, on the other hand, focuses on neurogenerative-specific age-related diseases. They patented the use of fujimycin, an already FDA-approved immunosuppressive drug for the treatment of eczema and organ transplants, to treat disorders related to cellular life-span which include many age-related diseases such as cardiovascular diseases, type II diabetes, Alzheimer’s, and osteoporosis by increasing cell lifespans through disruption of OBD1, a sirtuin inhibitor ADDIN EN.CITE <EndNote><Cite><Author>Mellor</Author><Year>2012</Year><RecNum>32</RecNum><DisplayText>[34]</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">32</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Mellor, Elizabeth Jane (Oxford, GB), Youdell, Michael (Oxford, GB), Ayling, Jonathan (Oxford, GB), Akoulitchev, Alexandre (Ewelme, GB)</author></authors></contributors><titles><title>METHOD OF TREATING AGE RELATED DISORDERS</title></titles><number>20120136046</number><dates><year>2012</year></dates><pub-location>United States</pub-location><publisher>Chronos Therapeutics Limited (Oxford, Oxfordshire, GB)</publisher><urls><related-urls><url>;[34]. While these approaches remain unproven in terms of translation, it is interesting to note that a network pharmacology approach was recently shown to be able to predict new life-extending compounds in worms ADDIN EN.CITE <EndNote><Cite><Author>Calvert</Author><Year>2016</Year><RecNum>50</RecNum><DisplayText>[35]</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Calvert, S.</author><author>Tacutu, R.</author><author>Sharifi, S.</author><author>Teixeira, R.</author><author>Ghosh, P.</author><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.</auth-address><titles><title>A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans</title><secondary-title>Aging Cell</secondary-title><alt-title>Aging cell</alt-title></titles><periodical><full-title>Aging Cell</full-title></periodical><alt-periodical><full-title>Aging Cell</full-title></alt-periodical><pages>256-66</pages><volume>15</volume><number>2</number><edition>2015/12/18</edition><dates><year>2016</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1474-9726 (Electronic)&#xD;1474-9718 (Linking)</isbn><accession-num>26676933</accession-num><urls><related-urls><url>;[35].Direct-To-Consumer ApproachesIn addition to reasons for spending on basic-research in general, anti-aging science has unusual potential to benefit from market forces due to particularly favorable demographics. The median wealth of US families 62 or older is over $200k dollars, compared to $100k and $14k for middle-aged and young families, respectively. This may in part be responsible for the increase in investment in even non-traditional therapies and direct-to-consumer (DTC) products and services aimed at extending healthy lifespan.One high-profile DTC company is Elysium Health which sells its Basis pill directly to consumers. Basis contains an NAD+ precursor, nicotinamide riboside, which declines with age and is required for sirtuin activity, and it also contains pterostilbene, which is similar to resveratrol. The systemic decline of NAD+ with age is a possible cause of age-associated changes in sirtuin activity in both the nucleus and mitochondria, with resulting age-associated dysfunction and pathologies ADDIN EN.CITE <EndNote><Cite><Author>Imai</Author><Year>2014</Year><RecNum>33</RecNum><DisplayText>[36]</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Imai, Shin-ichiro</author><author>Guarente, Leonard</author></authors></contributors><titles><title>NAD+ and sirtuins in aging and disease</title><secondary-title>Trends in Cell Biology</secondary-title></titles><periodical><full-title>Trends in Cell Biology</full-title></periodical><pages>464-471</pages><volume>24</volume><number>8</number><keywords><keyword>Aging, Animals, Circadian Rhythm, Disease, Humans, Mitochondria, NAD, NAD(+), nicotinamide mononucleotide, nicotinamide phosphoribosyltransferase, nicotinamide riboside, poly-ADP-ribose polymerases, Sirtuins</keyword></keywords><dates><year>2014</year><pub-dates><date>2014/aug/</date></pub-dates></dates><isbn>1879-3088</isbn><urls></urls><electronic-resource-num>10.1016/j.tcb.2014.04.002</electronic-resource-num><language>eng</language></record></Cite></EndNote>[36]. In addition to its role in redox reactions, NAD+ is an important substrate of several enzymes: sirtuins, ADP-ribose transferases, and PARPs, and CD38/CD157 (cADPR synthases) ADDIN EN.CITE <EndNote><Cite><Author>Verdin</Author><Year>2015</Year><RecNum>34</RecNum><DisplayText>[37]</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Verdin, Eric</author></authors></contributors><titles><title>NAD? in aging, metabolism, and neurodegeneration</title><secondary-title>Science (New York, N.Y.)</secondary-title></titles><periodical><full-title>Science (New York, N.Y.)</full-title></periodical><pages>1208-1213</pages><volume>350</volume><number>6265</number><keywords><keyword>Aging, Biosynthetic Pathways, Diabetes Mellitus, Type 2, DNA Damage, Fatty Liver, Humans, Mitochondria, NAD, Neurodegenerative Diseases, Obesity, Oxidation-Reduction, Poly(ADP-ribose) Polymerases, Sirtuins</keyword></keywords><dates><year>2015</year><pub-dates><date>2015/dec/</date></pub-dates></dates><isbn>1095-9203</isbn><urls></urls><electronic-resource-num>10.1126/science.aac4854</electronic-resource-num><language>eng</language></record></Cite></EndNote>[37].Elysium have already concluded a pre-registered 2 month randomized, double blind phase 1 trial for Basis using 120 healthy 60-80 year olds. 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ADDIN EN.CITE.DATA [38, 39].Caloric restriction (CR) is the most studied and most consistent intervention that increases both health- and life-span. While a CR diet is too harsh for most people, intermittent fasting (IF) has been proposed as a less restrictive alternative (Box 2). Based on this premise, L-Nutra was created to develop and market proprietary fasting-mimetic meals designed to provide the beneficial effects of IF. Their first formulation, ProLon, consists of five days of meals to be taken every 1 to 6 months. In a registered, randomized 38 person clinical trial, ProLon was shown to reduce levels of weight, abdominal fat, and maintain healthy levels of blood glucose, C-reactive protein (CRP), and insulin-like growth factor 1 (IGF1) ADDIN EN.CITE <EndNote><Cite><Author>Brandhorst</Author><Year>2015</Year><RecNum>38</RecNum><DisplayText>[40]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brandhorst, Sebastian</author><author>Choi, In Young</author><author>Wei, Min</author><author>Cheng, Chia Wei</author><author>Sedrakyan, Sargis</author><author>Navarrete, Gerardo</author><author>Dubeau, Louis</author><author>Yap, Li Peng</author><author>Park, Ryan</author><author>Vinciguerra, Manlio</author><author>Di Biase, Stefano</author><author>Mirzaei, Hamed</author><author>Mirisola, Mario G.</author><author>Childress, Patra</author><author>Ji, Lingyun</author><author>Groshen, Susan</author><author>Penna, Fabio</author><author>Odetti, Patrizio</author><author>Perin, Laura</author><author>Conti, Peter S.</author><author>Ikeno, Yuji</author><author>Kennedy, Brian K.</author><author>Cohen, Pinchas</author><author>Morgan, Todd E.</author><author>Dorff, Tanya B.</author><author>Longo, Valter D.</author></authors></contributors><titles><title>A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan</title><secondary-title>Cell Metabolism</secondary-title></titles><periodical><full-title>Cell Metabolism</full-title></periodical><pages>86-99</pages><volume>22</volume><number>1</number><keywords><keyword>Abdominal Fat, Adult, Aged, Aging, Animals, Body Weight, Cardiovascular Diseases, Cognition, Diet, Fasting, Female, Humans, Longevity, Male, Mice, Mice, Inbred C57BL, Middle Aged, Neoplasms, Neurogenesis, Pilot Projects, Psychomotor Performance, Regener</keyword></keywords><dates><year>2015</year><pub-dates><date>2015/jul/</date></pub-dates></dates><isbn>1932-7420</isbn><urls></urls><electronic-resource-num>10.1016/j.cmet.2015.05.012</electronic-resource-num><language>eng</language></record></Cite></EndNote>[40].Using long-lived "Methuselah" flies, Genescient uses genetic and gene expression network analysis to discover genetic determinates of this long lived strain. Their goal is to translate these findings into human targets by developing nutrigenomic-based therapies for chronic age-related diseases. Their proprietary combination of four herbal extracts had mixed results in extending lifespan in flies with greater effect on stressed flies ADDIN EN.CITE <EndNote><Cite><Author>Villeponteau</Author><Year>2015</Year><RecNum>39</RecNum><DisplayText>[41]</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Villeponteau, B.</author><author>Matsagas, K.</author><author>Nobles, A. C.</author><author>Rizza, C.</author><author>Horwitz, M.</author><author>Benford, G.</author><author>Mockett, R. J.</author></authors></contributors><auth-address>Genescient Inc., Fountain Valley, California, United States of America.&#xD;University of South Alabama, Mobile, Alabama, United States of America.&#xD;Genescient Inc., Fountain Valley, California, United States of America; University of California, Irvine, California, United States of America.</auth-address><titles><title>Herbal supplement extends life span under some environmental conditions and boosts stress resistance</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e0119068</pages><volume>10</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>*Dietary Supplements</keyword><keyword>Drosophila</keyword><keyword>Female</keyword><keyword>*Herbal Medicine</keyword><keyword>*Life Expectancy</keyword><keyword>Male</keyword><keyword>*Stress, Physiological</keyword></keywords><dates><year>2015</year></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>25879540</accession-num><urls><related-urls><url>;[41].Young BloodPerhaps most uniquely surprising, therapies are now being tested based on research into the effects of parabiosis (Box 3). 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ADDIN EN.CITE.DATA [25, 43]. Controversially, however, the company is planning to charge participants $8000, making this a pay-to-participate trial that has raised ethical concerns ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2016</Year><RecNum>59</RecNum><DisplayText>[43]</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, J.</author></authors></contributors><titles><title>BIOMEDICINE. Antiaging trial using young blood stirs concerns</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title></periodical><pages>527-8</pages><volume>353</volume><number>6299</number><edition>2016/08/06</edition><keywords><keyword>Aging/*blood</keyword><keyword>Animals</keyword><keyword>Blood Donors</keyword><keyword>Blood Transfusion/economics/*methods</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Fees, Medical</keyword><keyword>*Healthy Volunteers</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>*Plasma</keyword><keyword>*Rejuvenation</keyword><keyword>United States</keyword></keywords><dates><year>2016</year><pub-dates><date>Aug 05</date></pub-dates></dates><isbn>1095-9203 (Electronic)&#xD;0036-8075 (Linking)</isbn><accession-num>27493159</accession-num><work-type>News</work-type><urls><related-urls><url>;[43]. Stem Cells and Regenerative MedicineA number of companies have also been focusing on stem cells and regenerative medicine. Given the multiple uses of stem cells, the applications in regenerative medicine extend far beyond aging conditions and diseases. Nonetheless, a few companies have focused in particular on age-related conditions. Examples include BioTime which aims to develop embryonic/iPS stem cell therapies and regenerative medicine, Centagen that aims to activate adult stem cells and RepliCel Life Sciences which focuses on regenerative medicine to treat injured tendons, pattern baldness and skin damaged by sun and age.Challenges in developing human anti-aging therapiesA growing number of companies are now focusing on anti-aging science (Table 1). In a way this is surprising given that the first high-profile anti-aging company, Sirtris, while a success as an early investment, has thus far failed to live up to its anti-aging expectations. Modern advances, abundant aging-related targets and an aging population can arguably be driving the current crop of anti-aging biotechs. But how realistic is it that these will succeed? In a sense, there are few assumptions that we can be confident of. At present we can state that: 1) aging is a complex process; 2) although there are a number of theories of aging with vocal advocates, there is no consensus among scientists regarding the underlying causes of aging; 3) aging can be manipulated in short-lived model systems by genetic, dietary and pharmacological intervention. But that leaves many open questions (highlighted in the Outstanding Questions Box) and so the uncertainty concerning human anti-aging approaches remains very high.Humans are not huge worms or big miceAlthough findings from short-lived model organisms, in particular in terms of the plasticity of aging, have been a major breakthrough of the field, the degree to which those are relevant to humans is unknown. Human homologs of genes associated with aging in model organisms have been in some cases associated with human longevity, but these are rare (Figure 2) and thus our understanding of the genetic basis of human longevity remains largely unknown ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2014</Year><RecNum>47</RecNum><DisplayText>[44]</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>a Integrative Genomics of Ageing Group ; Institute of Integrative Biology ; University of Liverpool ; Liverpool , UK.</auth-address><titles><title>Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research</title><secondary-title>Cell Cycle</secondary-title></titles><periodical><full-title>Cell Cycle</full-title></periodical><pages>2671-3</pages><volume>13</volume><number>17</number><edition>2014/12/09</edition><dates><year>2014</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>1551-4005 (Electronic)&#xD;1551-4005 (Linking)</isbn><accession-num>25486354</accession-num><urls><related-urls><url>;[44]. 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ADDIN EN.CITE.DATA [45]. Therefore, it is perfectly plausible that most findings from short-lived model organisms will not be relevant to human beings ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2014</Year><RecNum>47</RecNum><DisplayText>[44]</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>a Integrative Genomics of Ageing Group ; Institute of Integrative Biology ; University of Liverpool ; Liverpool , UK.</auth-address><titles><title>Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research</title><secondary-title>Cell Cycle</secondary-title></titles><periodical><full-title>Cell Cycle</full-title></periodical><pages>2671-3</pages><volume>13</volume><number>17</number><edition>2014/12/09</edition><dates><year>2014</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>1551-4005 (Electronic)&#xD;1551-4005 (Linking)</isbn><accession-num>25486354</accession-num><urls><related-urls><url>;[44]. Briefly, the pathways necessary to extend lifespan in model systems may not only be often irrelevant to the comparatively long-lived human species, but to make matters worse, studies in model systems are mostly performed on genetically homogeneous laboratory strains that may not be representative of human populations ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2014</Year><RecNum>47</RecNum><DisplayText>[44]</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>a Integrative Genomics of Ageing Group ; Institute of Integrative Biology ; University of Liverpool ; Liverpool , UK.</auth-address><titles><title>Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research</title><secondary-title>Cell Cycle</secondary-title></titles><periodical><full-title>Cell Cycle</full-title></periodical><pages>2671-3</pages><volume>13</volume><number>17</number><edition>2014/12/09</edition><dates><year>2014</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>1551-4005 (Electronic)&#xD;1551-4005 (Linking)</isbn><accession-num>25486354</accession-num><urls><related-urls><url>;[44]. Besides, our understanding of aging manipulations is far superior in short-lived models like yeast and worms rather than rodents PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJhcmRvPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

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ADDIN EN.CITE.DATA [1, 2, 46], due to the ease of performing large-scale screens (Figure 2).Given the above concerns, a major open question is how effective anti-aging interventions can be in human beings. Even if they have benefits, how do these compare to mundane lifestyle choices like going to the gym? Likewise, while some anti-aging therapies might have benefits, they may not be beneficial for everyone. On the bright side, there are various efforts to develop alternative model systems, including dogs ADDIN EN.CITE <EndNote><Cite><Author>Check Hayden</Author><Year>2014</Year><RecNum>61</RecNum><DisplayText>[47]</DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Check Hayden, E.</author></authors></contributors><titles><title>Pet dogs set to test anti-ageing drug</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>546</pages><volume>514</volume><number>7524</number><edition>2014/10/31</edition><keywords><keyword>Aging/*drug effects</keyword><keyword>Animals</keyword><keyword>Clinical Trials as Topic/*veterinary</keyword><keyword>Dogs/*physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Longevity/*drug effects</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Models, Animal</keyword><keyword>Pets/*physiology</keyword><keyword>Pilot Projects</keyword><keyword>Sirolimus/administration &amp; dosage/adverse effects/*pharmacology</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct 30</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>25355339</accession-num><work-type>News</work-type><urls><related-urls><url>;[47] and primates ADDIN EN.CITE <EndNote><Cite><Author>Fischer</Author><Year>2011</Year><RecNum>62</RecNum><DisplayText>[48]</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fischer, K. E.</author><author>Austad, S. N.</author></authors></contributors><auth-address>Department of Physiology, University of Texas Health Science Center in San Antonio, USA.</auth-address><titles><title>The development of small primate models for aging research</title><secondary-title>ILAR J</secondary-title><alt-title>ILAR journal</alt-title></titles><periodical><full-title>ILAR J</full-title><abbr-1>ILAR journal</abbr-1></periodical><alt-periodical><full-title>ILAR J</full-title><abbr-1>ILAR journal</abbr-1></alt-periodical><pages>78-88</pages><volume>52</volume><number>1</number><edition>2011/03/18</edition><keywords><keyword>Aging/genetics/*metabolism/*physiology</keyword><keyword>Animals</keyword><keyword>Callithrix/genetics/metabolism/physiology</keyword><keyword>Cheirogaleidae/genetics/metabolism/physiology</keyword><keyword>Galago/genetics/metabolism/physiology</keyword><keyword>Models, Animal</keyword><keyword>Primates/genetics/*metabolism/*physiology</keyword></keywords><dates><year>2011</year></dates><isbn>1930-6180 (Electronic)&#xD;1084-2020 (Linking)</isbn><accession-num>21411860</accession-num><work-type>Research Support, N.I.H., Extramural&#xD;Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>;[48], though of course the limitation is that studies in such animals take much longer and are more expensive than in rodents.So many targets, so little time According to the GenAge database, we now know of >2,000 genes that modulate longevity in model organisms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWN1dHU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [46]. Given the volumes of data generated in the life sciences, various approaches in computational and systems biology have been developed to help identify and rank new candidates, identify regulatory genes and gather biological insights PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DZXZlbmluaTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

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ADDIN EN.CITE.DATA [35, 49-51], as reviewed in ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2016</Year><RecNum>67</RecNum><DisplayText>[52]</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">67</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Tacutu, R.</author></authors><secondary-authors><author>Kaeberlein, M.</author><author>Martin, G.M.</author></secondary-authors></contributors><titles><title>Integrative Genomics of Aging</title><secondary-title>Handbook of the Biology of Aging, 8th edition</secondary-title></titles><pages>263-285</pages><dates><year>2016</year></dates><pub-location>London, UK</pub-location><publisher>Academic Press</publisher><urls></urls></record></Cite></EndNote>[52]. Such approaches are imperative, as is the integration of different expertise in developing and prioritizing targets, drugs and therapies for testing. In spite of these advances, our capacity to identify interventions that will succeed in clinical trials remains poor.One crucial limitation in biotech is the long time it takes for clinical validation and for obtaining regulatory approval ADDIN EN.CITE <EndNote><Cite><Author>Pisano</Author><Year>2006</Year><RecNum>51</RecNum><DisplayText>[53]</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">51</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Pisano, Gary P</author></authors></contributors><titles><title>Science business: The promise, the reality, and the future of biotech</title></titles><dates><year>2006</year></dates><publisher>Harvard Business Press</publisher><isbn>1591398401</isbn><urls></urls></record></Cite></EndNote>[53]. Taking several years, clinical trials are long, expensive operations. In aging this is even more of an issue because aging is, compared to traditional diseases, a relatively long process and we still lack accepted aging biomarkers that can be used as endpoints. In addition, the field of life sciences is still immature in that our knowledge of human biology is still very incomplete ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2014</Year><RecNum>52</RecNum><DisplayText>[54]</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool , Liverpool, United Kingdom .</auth-address><titles><title>The scientific quest for lasting youth: prospects for curing aging</title><secondary-title>Rejuvenation Res</secondary-title><alt-title>Rejuvenation research</alt-title></titles><periodical><full-title>Rejuvenation Res</full-title></periodical><pages>458-67</pages><volume>17</volume><number>5</number><edition>2014/08/19</edition><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1557-8577 (Electronic)&#xD;1549-1684 (Linking)</isbn><accession-num>25132068</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>;[54]. As such, while the number of targets has increased dramatically thanks to advances in technologies like genomics, our capacity to validate those targets in a clinical setting has not substantially improved ADDIN EN.CITE <EndNote><Cite><Author>Pisano</Author><Year>2006</Year><RecNum>51</RecNum><DisplayText>[53]</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">51</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Pisano, Gary P</author></authors></contributors><titles><title>Science business: The promise, the reality, and the future of biotech</title></titles><dates><year>2006</year></dates><publisher>Harvard Business Press</publisher><isbn>1591398401</isbn><urls></urls></record></Cite></EndNote>[53]. In other words, the success rates of clinical trials remains very low ADDIN EN.CITE <EndNote><Cite><Author>Hay</Author><Year>2014</Year><RecNum>64</RecNum><DisplayText>[55]</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hay, M.</author><author>Thomas, D. W.</author><author>Craighead, J. L.</author><author>Economides, C.</author><author>Rosenthal, J.</author></authors></contributors><auth-address>BioMedTracker, Sagient Research Systems, San Diego, California, USA.&#xD;Biotechnology Industry Organization (BIO), Washington, DC, USA.&#xD;Biotech Strategy &amp; Analytics, Rockville, Maryland, USA.</auth-address><titles><title>Clinical development success rates for investigational drugs</title><secondary-title>Nat Biotechnol</secondary-title><alt-title>Nature biotechnology</alt-title></titles><periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></periodical><alt-periodical><full-title>Nat Biotechnol</full-title><abbr-1>Nature biotechnology</abbr-1></alt-periodical><pages>40-51</pages><volume>32</volume><number>1</number><edition>2014/01/11</edition><keywords><keyword>Biomedical Research</keyword><keyword>Drug Approval/*legislation &amp; jurisprudence</keyword><keyword>Drugs, Investigational/*therapeutic use</keyword><keyword>Humans</keyword><keyword>United States</keyword><keyword>United States Food and Drug Administration/legislation &amp; jurisprudence</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1546-1696 (Electronic)&#xD;1087-0156 (Linking)</isbn><accession-num>24406927</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>;[55], and pharmaceutical R&D efficiency has even declined ADDIN EN.CITE <EndNote><Cite><Author>Scannell</Author><Year>2012</Year><RecNum>63</RecNum><DisplayText>[56]</DisplayText><record><rec-number>63</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">63</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scannell, J. W.</author><author>Blanckley, A.</author><author>Boldon, H.</author><author>Warrington, B.</author></authors></contributors><auth-address>Sanford C. Bernstein Limited, 50 Berkeley Street, Mayfair Place, London W1J 8SB, UK. Jack.Scannell@</auth-address><titles><title>Diagnosing the decline in pharmaceutical R&amp;D efficiency</title><secondary-title>Nat Rev Drug Discov</secondary-title><alt-title>Nature reviews. Drug discovery</alt-title></titles><periodical><full-title>Nat Rev Drug Discov</full-title><abbr-1>Nature reviews. Drug discovery</abbr-1></periodical><alt-periodical><full-title>Nat Rev Drug Discov</full-title><abbr-1>Nature reviews. Drug discovery</abbr-1></alt-periodical><pages>191-200</pages><volume>11</volume><number>3</number><edition>2012/03/02</edition><keywords><keyword>Animals</keyword><keyword>Drug Delivery Systems/standards/trends</keyword><keyword>Drug Industry/*standards/trends</keyword><keyword>Efficiency, Organizational/*standards/trends</keyword><keyword>Humans</keyword><keyword>*Pharmaceutical Preparations/administration &amp; dosage</keyword><keyword>Research/*standards/trends</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 01</date></pub-dates></dates><isbn>1474-1784 (Electronic)&#xD;1474-1776 (Linking)</isbn><accession-num>22378269</accession-num><work-type>Review</work-type><urls><related-urls><url>;[56], in spite of what is generally agreed as substantial technological progress in recent decades. Therefore, biotech is a risky business that requires long-term involvement, and anti-aging biotech even more so.Clinical trials for aging and rejuvenationBecause of the time it takes for aging to develop, clinical trials for aging per se are not realistic at the moment. One effort led by Nir Barzilai, however, is trying to perform the first clinical trial for aging, using metformin, which would be an important proof of principle ADDIN EN.CITE <EndNote><Cite><Author>Barzilai</Author><Year>2016</Year><RecNum>53</RecNum><DisplayText>[57]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barzilai, N.</author><author>Crandall, J. P.</author><author>Kritchevsky, S. B.</author><author>Espeland, M. A.</author></authors></contributors><auth-address>Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: nir.barzilai@einstein.yu.edu.&#xD;Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.&#xD;Wake Forest Older Americans Independence Center and the Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.</auth-address><titles><title>Metformin as a Tool to Target Aging</title><secondary-title>Cell Metab</secondary-title><alt-title>Cell metabolism</alt-title></titles><alt-periodical><full-title>Cell Metabolism</full-title></alt-periodical><pages>1060-5</pages><volume>23</volume><number>6</number><edition>2016/06/16</edition><dates><year>2016</year><pub-dates><date>Jun 14</date></pub-dates></dates><isbn>1932-7420 (Electronic)&#xD;1550-4131 (Linking)</isbn><accession-num>27304507</accession-num><urls><related-urls><url>;[57]. Even if successful, there are many practical challenges in performing clinical trials for aging, including how long it will take and how much it will cost PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZXdtYW48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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AG==

ADDIN EN.CITE.DATA [1, 58, 59]. As abovementioned, we also still lack suitable biomarkers of aging, which is a major impediment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWxsaWthcmp1bjwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

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ADDIN EN.CITE.DATA [12]. Recent advances in developing epigenetic biomarkers of aging, an “epigenetic clock”, offer promise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3J2YXRoPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA [58, 59]. In addition, while commercialization of medical interventions is dominated by small molecule pharmaceuticals, investment stemming from advances in anti-aging science now include young blood therapies, senescent cell ablation, and DTC diets and nutraceuticals (Table 1).One important development in anti-aging therapies focuses on rejuvenation. Some anti-aging interventions like resveratrol and many longevity drugs promise to slow down aging, which for clinical testing entails a variety of problems described above. On the other hand, interventions like senolytic drugs and young blood promise rejuvenation which is less challenging from a validation perspective, and therefore much more attractive for commercial exploitation. Therefore, developing interventions that reverse at least some aspect of aging is a more powerful translational path than trying to slow down aging.Future prospects and concluding remarks Of the 4000 private and 600 public biotechnology companies worldwide only a few percent have shown increasing profitability. Historically, only one out of 5000 discovery-stage drug candidates obtain approval and only a third of those recoup their R&D costs ADDIN EN.CITE <EndNote><Cite><Author>Kolchinsky</Author><Year>2004</Year><RecNum>78</RecNum><DisplayText>[61]</DisplayText><record><rec-number>78</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">78</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kolchinsky, Peter</author></authors></contributors><titles><title>The Entrepreneur’s guide to a Biotech Startup</title><secondary-title>4th. Edition</secondary-title></titles><periodical><full-title>4th. Edition</full-title></periodical><dates><year>2004</year></dates><urls></urls></record></Cite></EndNote>[61]. Besides, as above mentioned, the success rate of clinical trials is not improving, even though we have more information, data and potential targets than ever before. Given the various constraints on studying aging, including the reliance on short-lived model organisms, long validation times and poor biological understanding, it would be very surprising if most companies described here are active a mere 5-10 years from now. Likewise, most companies in the anti-aging biotech sector are startups, and thus riskier. From an investor’s perspective this means that investors in anti-aging biotech are expecting to lose money but hoping to win big. Omics approaches are imperative, as is a multidisciplinary outlook, but while these have augmented the search space, attrition rates remain very high. Perhaps surprisingly, in spite of the so far failure of Sirtris, which would be expected to hurt the industry, anti-aging biotech is more vibrant than ever. Clearly, even such high-profile failure has not dissuaded investors, including many tech billionaires. As such, no doubt new technologies will be developed and new targets discovered in the coming years and decades, possibly opening new avenues for the commercialization of aging into other directions. The promise of fending off old age remains more powerful than ever and the financial gains for any company delivering on that promise will continue to be extremely attractive. Anti-aging biotech can then be seen as an extreme reflection of the biotech sector: risky, most likely to fail, but if one company is successful the outcomes are monumental.AcknowledgementsWork in our lab is supported by the Wellcome Trust (104978/Z/14/Z), the Leverhulme Trust (RPG-2016-015), LongeCity and the Methuselah Foundation.Conflict of interestJPM and MS are advisors to Androcyte. JPM has also performed consultancy work for Genescient. Table 1:Anti-aging Biotech Companies (also see: )NameFunding/Capital/SizeFoundedURLTherapeutic approachPharmacological targetingAntoxis$2.Anti-Genetic study of supercentenariansSierra ScienceResearch LLC, Marketing partner / defytime.jpTelomerase activating compoundsPrana Biotechnology$20M, public Neurodegenerative disease therapies. PBT2 in phase 2b trials.Biotie $152M, acquired by Acorda Therapeutics Neurodgenerative disease therapies. SYN-115 in phase 3 trialsNavitor Pharmaceuticals$RapalogsCohbar$9.2M, public Mitochondrial-based therapies. Planned clinical trial for MOTS-c analog.Telomerase activation for AlzheimersUnity$Senolytic agentsOisin Bio< $5M, Development/ Pre-Gene therapy based senescent cell clearanceEveron SAMolytic agentsSiwa Senescent cell antibodiesProteostasis Therapeutics$108M, public Drug-based control of protein homostasisRetrotope$Drug-based mitochrondrial restoration. RT001 in phase 1/2 trials for Friedreich’s ataxiaMount Tam BiotechnologiesPre-clinical, public Rapalogs. TAM-01 in pre-clinical trials for systemic lupus erythematosusresTORbio$15M, clinical subsidiary of Puretech Develop immunosenescence drugs. mTORC1 inhibitor, RTB101, in phase 2 trial.Big Develop drugs based on the biology that controls lifespanHLI$Integrate large omic data sets to find patterns in age-related diseasesInsilico MedicineVC funded C-corp start-Identify existing drugs effecting age-related gene pathwaysChronos Therapeutics$Repurpose drugs for neurogenerative disease, patented use of fujimycinGero$6M, Gene network analysis to identify anti-aging targets, worm study in progress. Also has activity-based wellness predictor phone app.Direct-To-ConsumerElysium Health$Neutricals. trial-tested, NAD+ precursor, Rat-tested oxidative stress reducer, JuvenonL-Nutra$10M round B2009l-Trial-tested, fasting mimetic diet, ProLonGenescient$Nutriceuticals based on genetic analysis of long-lived fliesYoung BloodAlkahest$Working with Grifols to develop plasma-based For profit clinical trial to study blood-based therapyStem Cell / RegenerativeBioTime$76M, public Develop cell Develop activators of adult stem cellsRepliCel Life Sciences$3M, Development Develop regeneration-based therapies, phase 1 clinical trials for achilles tendinosis and age-related skin damageBioVivaCrowdfunded2015bioviva-Gene-therapy to induce telomeraseBiomarkersGenox - subsidiary of NIKKEN Interleukin Genetics$65M (public 2003)Text Box 1: A plethora of potential drug targetsThe multitude of genes, processes and pathways modulating aging in short-lived model organisms provide a plethora of potential targets for drug discovery ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Wuttke, D.</author><author>Wood, S. H.</author><author>Plank, M.</author><author>Vora, C.</author></authors></contributors><auth-address>University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool L69 7ZB, UK. jp@.</auth-address><titles><title>Genome-environment interactions that modulate aging: powerful targets for drug discovery</title><secondary-title>Pharmacol Rev</secondary-title><alt-title>Pharmacological reviews</alt-title></titles><periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></alt-periodical><pages>88-101</pages><volume>64</volume><number>1</number><edition>2011/11/18</edition><dates><year>2012</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-0081 (Electronic)&#xD;0031-6997 (Linking)</isbn><accession-num>22090473</accession-num><urls><related-urls><url>;[1]. 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ADDIN EN.CITE.DATA [2], most of which can be grouped into common pathways and processes like insulin/insulin-like signaling, autophagy, oxidative phosphorylation and TOR signaling ADDIN EN.CITE <EndNote><Cite><Author>Fernandes</Author><Year>2016</Year><RecNum>72</RecNum><DisplayText>[6]</DisplayText><record><rec-number>72</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">72</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fernandes, M.</author><author>Wan, C.</author><author>Tacutu, R.</author><author>Barardo, D.</author><author>Rajput, A.</author><author>Wang, J.</author><author>Thoppil, H.</author><author>Thornton, D.</author><author>Yang, C.</author><author>Freitas, A.</author><author>de Magalhaes, J. P.</author></authors></contributors><auth-address>Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.&#xD;Research Group for Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), Gottingen, Germany.&#xD;School of Computing, University of Kent, Canterbury, UK.</auth-address><titles><title>Systematic analysis of the gerontome reveals links between aging and age-related diseases</title><secondary-title>Hum Mol Genet</secondary-title><alt-title>Human molecular genetics</alt-title></titles><periodical><full-title>Hum Mol Genet</full-title><abbr-1>Human molecular genetics</abbr-1></periodical><alt-periodical><full-title>Hum Mol Genet</full-title><abbr-1>Human molecular genetics</abbr-1></alt-periodical><pages>4804-4818</pages><volume>25</volume><number>21</number><edition>2017/02/09</edition><dates><year>2016</year><pub-dates><date>Nov 01</date></pub-dates></dates><isbn>1460-2083 (Electronic)&#xD;0964-6906 (Linking)</isbn><accession-num>28175300</accession-num><urls><related-urls><url>;[6]. There is also evidence that life-extending pathways tend to be evolutionarily conserved PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [62]. For instance, disruption of the insulin/insulin-like growth factor 1 (IGF1) pathway has been shown to extend lifespan in yeast, worms, flies, and mice, and IGF1R mutations have been associated with human longevity ADDIN EN.CITE <EndNote><Cite><Author>Kenyon</Author><Year>2010</Year><RecNum>3</RecNum><DisplayText>[3]</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kenyon, C. J.</author></authors></contributors><auth-address>Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA. cynthia.kenyon@ucsf.edu</auth-address><titles><title>The genetics of ageing</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>504-12</pages><volume>464</volume><number>7288</number><edition>2010/03/26</edition><keywords><keyword>Aging/*genetics</keyword><keyword>Animals</keyword><keyword>Cell Respiration/physiology</keyword><keyword>Humans</keyword><keyword>Insulin/metabolism</keyword><keyword>Insulin-Like Growth Factor I/metabolism</keyword><keyword>Longevity/genetics/physiology</keyword><keyword>Signal Transduction/*physiology</keyword><keyword>Transferases/metabolism</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar 25</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>20336132</accession-num><work-type>Review</work-type><urls><related-urls><url>;[3]. As such, evolutionarily conserved life-extending genes and pathways are important targets for drug discovery ADDIN EN.CITE <EndNote><Cite><Author>de Magalhaes</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Magalhaes, J. P.</author><author>Wuttke, D.</author><author>Wood, S. H.</author><author>Plank, M.</author><author>Vora, C.</author></authors></contributors><auth-address>University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool L69 7ZB, UK. jp@.</auth-address><titles><title>Genome-environment interactions that modulate aging: powerful targets for drug discovery</title><secondary-title>Pharmacol Rev</secondary-title><alt-title>Pharmacological reviews</alt-title></titles><periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></periodical><alt-periodical><full-title>Pharmacol Rev</full-title><abbr-1>Pharmacological reviews</abbr-1></alt-periodical><pages>88-101</pages><volume>64</volume><number>1</number><edition>2011/11/18</edition><dates><year>2012</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1521-0081 (Electronic)&#xD;0031-6997 (Linking)</isbn><accession-num>22090473</accession-num><urls><related-urls><url>;[1]. Text Box 2: Intermittent fasting is less restrictive than caloric restriction.Intermittent fasting (IF) - where for example, calories are reduced 40%, two days a week - has been argued by some experts to have the same range of benefits as chronic CR ADDIN EN.CITE <EndNote><Cite><Author>Mattson</Author><Year>2016</Year><RecNum>37</RecNum><DisplayText>[63]</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">37</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mattson, Mark P.</author><author>Longo, Valter D.</author><author>Harvie, Michelle</author></authors></contributors><titles><title>Impact of intermittent fasting on health and disease processes</title><secondary-title>Ageing Research Reviews</secondary-title></titles><periodical><full-title>Ageing Res Rev</full-title><abbr-1>Ageing research reviews</abbr-1></periodical><keywords><keyword>Alzheimer’s disease, Blood Pressure, Cardiovascular disease, Diabetes, Insulin resistance, Intermittent fasting, Ketone bodies, Obesity</keyword></keywords><dates><year>2016</year><pub-dates><date>2016/oct/</date></pub-dates></dates><isbn>1872-9649</isbn><urls></urls><electronic-resource-num>10.1016/j.arr.2016.10.005</electronic-resource-num><language>eng</language></record></Cite></EndNote>[63]. In a further refinement, a low calorie/low protein diet eaten for four days every two weeks, without effecting total long term caloric intake, appears to have similar effects. Middle-aged mice showed improvements in a broad set of age-related phenotypes including: reduced visceral fat, fewer incidence of some cancers, fewer tissues with inflammation, reduced immunosenescence, improvement of some types of memory, and an 11% increase in median lifespan ADDIN EN.CITE <EndNote><Cite><Author>Brandhorst</Author><Year>2015</Year><RecNum>38</RecNum><DisplayText>[40]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brandhorst, Sebastian</author><author>Choi, In Young</author><author>Wei, Min</author><author>Cheng, Chia Wei</author><author>Sedrakyan, Sargis</author><author>Navarrete, Gerardo</author><author>Dubeau, Louis</author><author>Yap, Li Peng</author><author>Park, Ryan</author><author>Vinciguerra, Manlio</author><author>Di Biase, Stefano</author><author>Mirzaei, Hamed</author><author>Mirisola, Mario G.</author><author>Childress, Patra</author><author>Ji, Lingyun</author><author>Groshen, Susan</author><author>Penna, Fabio</author><author>Odetti, Patrizio</author><author>Perin, Laura</author><author>Conti, Peter S.</author><author>Ikeno, Yuji</author><author>Kennedy, Brian K.</author><author>Cohen, Pinchas</author><author>Morgan, Todd E.</author><author>Dorff, Tanya B.</author><author>Longo, Valter D.</author></authors></contributors><titles><title>A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan</title><secondary-title>Cell Metabolism</secondary-title></titles><periodical><full-title>Cell Metabolism</full-title></periodical><pages>86-99</pages><volume>22</volume><number>1</number><keywords><keyword>Abdominal Fat, Adult, Aged, Aging, Animals, Body Weight, Cardiovascular Diseases, Cognition, Diet, Fasting, Female, Humans, Longevity, Male, Mice, Mice, Inbred C57BL, Middle Aged, Neoplasms, Neurogenesis, Pilot Projects, Psychomotor Performance, Regener</keyword></keywords><dates><year>2015</year><pub-dates><date>2015/jul/</date></pub-dates></dates><isbn>1932-7420</isbn><urls></urls><electronic-resource-num>10.1016/j.cmet.2015.05.012</electronic-resource-num><language>eng</language></record></Cite></EndNote>[40]. A similar diet, taken five days a month for three months, showed reduced fasting glucose, lower circulation IGF1, fat loss, reduced C-reactive protein for those with elevated cardiovascular disease risk in a 38 person pre-registered pilot trial ADDIN EN.CITE <EndNote><Cite><Author>Brandhorst</Author><Year>2015</Year><RecNum>38</RecNum><DisplayText>[40]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brandhorst, Sebastian</author><author>Choi, In Young</author><author>Wei, Min</author><author>Cheng, Chia Wei</author><author>Sedrakyan, Sargis</author><author>Navarrete, Gerardo</author><author>Dubeau, Louis</author><author>Yap, Li Peng</author><author>Park, Ryan</author><author>Vinciguerra, Manlio</author><author>Di Biase, Stefano</author><author>Mirzaei, Hamed</author><author>Mirisola, Mario G.</author><author>Childress, Patra</author><author>Ji, Lingyun</author><author>Groshen, Susan</author><author>Penna, Fabio</author><author>Odetti, Patrizio</author><author>Perin, Laura</author><author>Conti, Peter S.</author><author>Ikeno, Yuji</author><author>Kennedy, Brian K.</author><author>Cohen, Pinchas</author><author>Morgan, Todd E.</author><author>Dorff, Tanya B.</author><author>Longo, Valter D.</author></authors></contributors><titles><title>A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan</title><secondary-title>Cell Metabolism</secondary-title></titles><periodical><full-title>Cell Metabolism</full-title></periodical><pages>86-99</pages><volume>22</volume><number>1</number><keywords><keyword>Abdominal Fat, Adult, Aged, Aging, Animals, Body Weight, Cardiovascular Diseases, Cognition, Diet, Fasting, Female, Humans, Longevity, Male, Mice, Mice, Inbred C57BL, Middle Aged, Neoplasms, Neurogenesis, Pilot Projects, Psychomotor Performance, Regener</keyword></keywords><dates><year>2015</year><pub-dates><date>2015/jul/</date></pub-dates></dates><isbn>1932-7420</isbn><urls></urls><electronic-resource-num>10.1016/j.cmet.2015.05.012</electronic-resource-num><language>eng</language></record></Cite></EndNote>[40]. 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ADDIN EN.CITE.DATA [64].Text Box 3: Anti-aging effects of young bloodIn biology, parabiosis is the joining of two animals' circulatory systems. Historically it was noticed that connected healthy animals could extend the lifespan of treated animals ADDIN EN.CITE <EndNote><Cite><Author>Conboy</Author><Year>2013</Year><RecNum>40</RecNum><DisplayText>[65]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Conboy, Michael J.</author><author>Conboy, Irina M.</author><author>Rando, Thomas A.</author></authors></contributors><titles><title>Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity</title><secondary-title>Aging Cell</secondary-title></titles><periodical><full-title>Aging Cell</full-title></periodical><pages>525-530</pages><volume>12</volume><number>3</number><keywords><keyword>Age Factors, Aging, Animals, Cell Aging, Longevity, Parabiosis, Stem Cells</keyword></keywords><dates><year>2013</year><pub-dates><date>2013/jun/</date></pub-dates></dates><isbn>1474-9726</isbn><urls></urls><electronic-resource-num>10.1111/acel.12065</electronic-resource-num><language>eng</language></record></Cite></EndNote>[65], though such effects have not been subsequently validated. In a series of studies starting in the 1950's, it was observed that the older of the pair had better longevity and tissue function ADDIN EN.CITE <EndNote><Cite><Author>Conboy</Author><Year>2013</Year><RecNum>40</RecNum><DisplayText>[65]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Conboy, Michael J.</author><author>Conboy, Irina M.</author><author>Rando, Thomas A.</author></authors></contributors><titles><title>Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity</title><secondary-title>Aging Cell</secondary-title></titles><periodical><full-title>Aging Cell</full-title></periodical><pages>525-530</pages><volume>12</volume><number>3</number><keywords><keyword>Age Factors, Aging, Animals, Cell Aging, Longevity, Parabiosis, Stem Cells</keyword></keywords><dates><year>2013</year><pub-dates><date>2013/jun/</date></pub-dates></dates><isbn>1474-9726</isbn><urls></urls><electronic-resource-num>10.1111/acel.12065</electronic-resource-num><language>eng</language></record></Cite></EndNote>[65] whereas young mice exposed to old plasma showed a decrease ADDIN EN.CITE <EndNote><Cite><Author>Villeda</Author><Year>2011</Year><RecNum>41</RecNum><DisplayText>[66]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Villeda, Saul A.</author><author>Luo, Jian</author><author>Mosher, Kira I.</author><author>Zou, Bende</author><author>Britschgi, Markus</author><author>Bieri, Gregor</author><author>Stan, Trisha M.</author><author>Fainberg, Nina</author><author>Ding, Zhaoqing</author><author>Eggel, Alexander</author><author>Lucin, Kurt M.</author><author>Czirr, Eva</author><author>Park, Jeong-Soo</author><author>Couillard-Després, Sebastien</author><author>Aigner, Ludwig</author><author>Li, Ge</author><author>Peskind, Elaine R.</author><author>Kaye, Jeffrey A.</author><author>Quinn, Joseph F.</author><author>Galasko, Douglas R.</author><author>Xie, Xinmin S.</author><author>Rando, Thomas A.</author><author>Wyss-Coray, Tony</author></authors></contributors><titles><title>The aging systemic milieu negatively regulates neurogenesis and cognitive function</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>90-94</pages><volume>477</volume><number>7362</number><dates><year>2011</year><pub-dates><date>2011/aug/</date></pub-dates></dates><isbn>0028-0836</isbn><urls><related-urls><url>;[66]. Further, aged mice given young plasma showed improvement in age-related decline in hippocampal-dependent learning and memory ADDIN EN.CITE <EndNote><Cite><Author>Villeda</Author><Year>2014</Year><RecNum>42</RecNum><DisplayText>[67]</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Villeda, Saul A.</author><author>Plambeck, Kristopher E.</author><author>Middeldorp, Jinte</author><author>Castellano, Joseph M.</author><author>Mosher, Kira I.</author><author>Luo, Jian</author><author>Smith, Lucas K.</author><author>Bieri, Gregor</author><author>Lin, Karin</author><author>Berdnik, Daniela</author><author>Wabl, Rafael</author><author>Udeochu, Joe</author><author>Wheatley, Elizabeth G.</author><author>Zou, Bende</author><author>Simmons, Danielle A.</author><author>Xie, Xinmin S.</author><author>Longo, Frank M.</author><author>Wyss-Coray, Tony</author></authors></contributors><titles><title>Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice</title><secondary-title>Nature Medicine</secondary-title></titles><periodical><full-title>Nature Medicine</full-title></periodical><pages>659-663</pages><volume>20</volume><number>6</number><keywords><keyword>Age Factors, Aging, Animals, Blood Transfusion, Blotting, Western, Cell Line, Cognition Disorders, Cyclic AMP Response Element-Binding Protein, DNA Primers, Hippocampus, Immunohistochemistry, Mice, Mice, Inbred C57BL, Microarray analysis, Neuronal Plast</keyword></keywords><dates><year>2014</year><pub-dates><date>2014/jun/</date></pub-dates></dates><isbn>1546-170X</isbn><urls></urls><electronic-resource-num>10.1038/nm.3569</electronic-resource-num><language>eng</language></record></Cite></EndNote>[67]. However, 10-12 month CBA/Ca female mice (a strain with normal longevity) injected weekly with young plasma did not show increased lifespan ADDIN EN.CITE <EndNote><Cite><Author>Shytikov</Author><Year>2014</Year><RecNum>43</RecNum><DisplayText>[68]</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shytikov, Dmytro</author><author>Balva, Olexiy</author><author>Debonneuil, Edouard</author><author>Glukhovskiy, Pavel</author><author>Pishel, Iryna</author></authors></contributors><titles><title>Aged Mice Repeatedly Injected with Plasma from Young Mice: A Survival Study</title><secondary-title>BioResearch Open Access</secondary-title></titles><periodical><full-title>BioResearch Open Access</full-title></periodical><pages>226-232</pages><volume>3</volume><number>5</number><dates><year>2014</year><pub-dates><date>2014/oct/</date></pub-dates></dates><isbn>2164-7844</isbn><urls><related-urls><url>;[68]. Most recently, using a blood exchange device to exchange blood between young and old mice once, old mice had improved hepatogenesis and response to muscle injury while young animals showed no difference and injury response worsened hepatogenesis. For every other test -including physical performance and hippocampal neurogenesis – while young mice worsened, old mice showed no difference ADDIN EN.CITE <EndNote><Cite><Author>Rebo</Author><Year>2016</Year><RecNum>44</RecNum><DisplayText>[69]</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="rsfrrd2vi2xt90ex55gpwdzcfzat0vtfa0xv">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rebo, Justin</author><author>Mehdipour, Melod</author><author>Gathwala, Ranveer</author><author>Causey, Keith</author><author>Liu, Yan</author><author>Conboy, Michael J.</author><author>Conboy, Irina M.</author></authors></contributors><titles><title>A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood</title><secondary-title>Nature Communications</secondary-title></titles><periodical><full-title>Nature Communications</full-title></periodical><pages>13363</pages><volume>7</volume><dates><year>2016</year><pub-dates><date>2016/nov/</date></pub-dates></dates><isbn>2041-1723</isbn><urls></urls><electronic-resource-num>10.1038/ncomms13363</electronic-resource-num><language>eng</language></record></Cite></EndNote>[69]. Figure legendsFigure 1: Between the years 2010 and 2015 in the US, an average of 2,577,202 deaths per annum from an average yearly population size of 315,109,368 were recorded (0.818%). The chart shows the top 8 broad causes of death, with the major contributors being age-related and chronic diseases such as cancer, diseases of the heart, stroke and Alzheimer’s disease. The categories in the pie chart were grouped based on ICD codes as follows: Heart disease (I00-I09, I11, I13, I20-I51); Cancer (C00-C97); Chronic lower respiratory diseases (J40-J47); Stroke (I60-I69); Unintentional injuries (V01-X59,Y85-Y86); Alzheimer's disease (G30); Diabetes (E10-E14); Influenza and pneumonia (J09-J18). Data from the Centers for Disease Control and Prevention, CDC Wide-ranging ONline Data for Epidemiologic Research (CDC WONDER) - 2: Genetics of aging from model organisms to humans. 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