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MetforminWe strongly believe that Metformin is one of the most effective ‘wonder drugs’ available for optimizing human life. Metformin originates from the French Iliac, a plant that has been used for centuries in traditional folk medicine. In the last year, the media has paid significant attention to Metformin, using phrases such as “anti-aging” and “life-extension.”Recently, a long term study (Targeting Aging with Metformin, or “TAME”) started looking at Metformin as an anti-aging drug519. TAME is a novel clinical trial aimed at testing whether Metformin can delay the onset of age-related diseases and conditions including cancer, cardiovascular disease and Alzheimer’s disease.Metformin has been the primary treatment for diabetes for over 60 years, and as such it’s one of the most studied drugs in existence. There is also ample research data suggesting that Metformin has anti-aging and life-extending properties520. If you’re in doubt, Google “Metformin + Life Extension” and see for yourself. The number of citations touting the amazing effects of the drug is astounding. We would also encourage you to watch this fascinating live stream Jay did with Nelson Vergel, where they examined all of the relevant research data on Metformin521.NOTE: Unfortunately there is a contingent of people (including physicians) who claim that long-term usage of Metformin causes mitochondrial dysfunction. This leads to the increased risk of neurological disease, such as dementia and/or Alzheimer’s. Jay has spent a great deal of time countering the research522 supporting this group’s argument. The research in support of their argument is inherently flawed, and it involves a patient population group (obese diabetics) who are not using Metformin in the way we recommend, nor in the way the research documents the use of Metformin to support life extension.How Does it WorkMetformin’s mechanism of action (in relation to aging at the cellular level) is depicted in the picture above.Here is a summary from the study Metformin As a Tool to Target Aging524, which shows how Metformin targets multiple aging pathways in the chart shown:The figure depicts schematically the current consensus within the biology of aging community as to pathways that are important in order to target aging and indicates at which points Metformin has been shown to have effects. Key take-away: outside of the cell (1, top), Metformin has been shown to affect the receptors for cytokines525, insulin526, IGF-1527, and adiponectin528, all pathways that are activated with aging and, when modulated, are associated with longevity. (1) Intracellular (2, middle) Metformin inhibits the inflammatory pathway and activates AMPK, increasing inhibition of mTOR, which seems to be a major target to modulate aging. Through some of these mechanisms, it also modulates oxidative stress529 and removes senescent cells (the mitochondrial pathways are not shown, and the mechanisms by which Metformin induces senescent cell removal remain unclear). (2) These processes jointly (3, bottom) affect inflammation, cellular survival, stress defense, autophagy530, and protein synthesis531, which are major biological outcomes associated with aging/longevity.Metformin enhances insulin sensitivity and lowers blood levels of insulin, but it also reduces the formation of AGEs (advanced glycation end-products) that dramatically accelerate the process of heart disease. Cardiovascular diseases, such as heart attacks and strokes, kill more Americans per year than any other forms of disease532. Metformin is so effective in extending one’s lifespan that there is data showing people with type 2 diabetes living longer than those without diabetes when the former group (people with type 2 diabetes) is using Metformin533.This is a major discovery, considering that diabetics easily succumb to the effects of accelerated aging (i.e. increased whole body inflammation that is manifested as a development of cancer, heart disease, Alzheimer’s, dementia, or any number of age-related diseases). Therefore, Metformin’s life-extension effects comes from negating the unwanted metabolic effects of elevated glucose levels and insulin. Less insulin exposure over time will help make you more sensitive to it, leading to less inflammation and a longer lifespan.Secondly, by reducing the mTOR (mamalian Target Of Rapamycin) signaling pathway, Metformin integrates both intracellular and extracellular signals, thereby serving as a central regulator of cell metabolism, growth, proliferation and survival. Metformin also reduces blood levels of “growth factors” that accelerate both the heart disease and cancer-forming processes534.Thirdly, Metformin inhibits the liver’s ability to release glucose into the bloodstream535. When taken with the ingestion of carbs, it may inhibit the absorption of carbs into your bloodstream.In addition to its capacity to prevent the release of glucose from the liver, Metformin helps turn on adenosine monophosphate kinase (AMPK), an enzymatic “master switch” that is crucial for regulation of cellular energy, proper hormone expression and protein synthesis. Metformin upregulates AMPK536 and increases lipolysis (i.e. fat-burning), similar to how lipolysis increases while fasting537. From a bio-evolutionary standpoint, the presence of famine induces a metabolic shift, where we call upon our fat stores for energy production. By increasing the expression of AMPK, Metformin mimics the effects of caloric restriction (a.k.a. the only proven life-extension strategy in mammalian models).We know that Metformin has life-extending benefits for diabetics, but can it exert similar effects in people with normal insulin levels? From personal experience, most physicians shudder at the thought of using Metformin for an off-label purpose such as life extension. However, all of the recent research data on Metformin cannot be ignored.Pharmaceutical companies have zero interest in sponsoring trials such as TAME for medicines that potentially play a major role in disease prevention. Furthermore, there is no money in research for a product that has an expired patent. This is why Big Pharma is developing a new class of diabetic drugs that are combinations of Metformin and something else — that way, they can patent these combinations and make large sums of money off of them.Side EffectsMetformin has a fairly mild side effect profile and is usually well tolerated. In fact, one of the often-noted “side effects” is fat loss from lowered blood levels of insulin. Most of the side effects are experienced by people who possess an unhealthy and infected gut biome, which is caused by a diet high in refined carbs, sugar and alcohol. This often produces gastric distress in the form of nausea, flatulence or a stomach discomfort. These effects are usually short-lived, and will disappear over time with improved gut health and a cleaner diet.Our Recommended Dosage and UsageJim and Jay are extremely passionate in their advice about using Metformin, and they can’t promote its use more strongly. Almost everyone can (and should) start using Metformin ASAP.Discuss this book’s information with your doctor and don’t wait for the data from the TAME trial either. Inform your doctor of the available study data, as there’s a good chance they’ll be unaware of it.Go into their office and tell them the following:You want to use Metformin because it is cardioprotective, prevents cancer, and it is believed to stop the progress of neurodegenerative diseases such as Alzheimer’s and dementia. It’s also affordable and easily provided by your local pharmacist.We recommend that men start with 500 mg twice a day (once in morning and once at night) on an empty stomach to reduce their insulin production even further. Women should be taking half that dosage (250 mg, twice a day). For those of you with an inflamed gut biome, make sure to use the “XR” (extended release) form and be prepared for short-term side effects that may last a couple of weeks.With that said, there are people in the Life Extension Foundation (LEF) who are using dosages as high as 3 grams a day. Jim and Jay have been using Metformin for more than a decade, and have found that 1 gram taken twice a day (AM and PM) is highly effective in reducing insulin levels. This ultimately reduces their body fat levels and improves their inflammatory biomarkers. ................
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