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Metformin is staggeringly cheap, it also happens to be an anti-aging agent with a high potential. Of course, tell your friends you are experimenting with a diabetic drug when you have no diabetes, and watch their face turn to horror at the idea that you would do anything to a sacred healthy body...so how does Metformin work for anti-aging? (Stardust does not encourage experimentation with any pharmaceutical drugs without the supervision and guidance of qualified medical professionals).

Well the results are not conclusive yet, but an ever-expanding group of scientists and their clinical trials are looking to validate Metformin as the first FDA approved anti-aging drug. There are also many potential pitfalls and downsides to Metformin that we will cover in this article.

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“I would consider this an early "hint" that Metformin may be more useful than just treating diabetes . Diabetes is a known cause of early aging and early death, and has been speculated that everyone develops diabetes eventually via aging, so being able to prevent or delay it is a BIG deal.

10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.

Findings: ...Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo...

“Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.

Metformin directly acts on mitochondria to alter cellular bioenergetics

Results We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival.

“CONCLUSIONS: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.

RESULTS:

We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy.

“B12 goes down when Metformin is used?

Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages?

Despite metformin is widely used and extensively studied, randomized controlled trials performed to explore the effects of metformin on vitamin B12 and folate are limited. Besides, whether short-term treatment causes vitamin deficiency is a pending issue. We postulate that even a few-month treatment with metformin results in the decrease of vitamin B12 and folate. However, supplementation of vitamin B12 rather than the combination of vitamin B12 and folate might be profitable based on the mechanism of metformin on vitamins in patients with type 2 diabetes. This viewpoint differs from those of majority that a combined supplementation of vitamin B12 and folate is inclined to be advised.

“Metformin may decrease Testosterone by up to 27% , may be causing erectile dysfunction in people with Diabetes type 2

Erectile Dysfunction and Low Sex Drive in Men with Type 2 DM: The Potential Role of Diabetic Pharmacotherapy

https://prostate.net/articles/metformin-wonder-drug-harmful-hype

This Thread has some anecdotal and bloodwork on Metformin potentially lowering testosterone:

https://www.diabetesdaily.com/forum/type-2-diabetes/24768-metformin-lowers-testosterone-how-much/

Results

Total testosterone serum levels were high in sulfonylurea treated patients as compared to metformin treated patients’ p < 0.0001. Similarly, SHBG levels were significantly higher in sulfonylurea treated patients compared to metformin treated patients p < 0.0001. FT was also significantly higher in sulfonylurea treated patients compared to metformin treated patients p =0.014 and significantly low compared to the control p =0.0002. FAI was also significantly higher in sulfonylurea treated patients compared to metformin treated patients p < 0.0001. On other hand Bioavailable testosterone (BT) was low in metformin treated patients (2.75±1.12 nmol/L) compared to the control p< 0.0001. SHIM was low in metformin treated patients 10.61±3.22 which significantly differed from control and sulfonylurea treated patients p< 0.0001, intergroup differences was significant p=0.001.

Conclusion

Metformin leads to significant reduction in testosterone levels, sex drive and induction of low testosterone-induced erectile dysfunction, whereas; sulfonylurea leads to significant elevation in testosterone levels, sex drive and erectile function.

What is Metformin?

Metformin (Sometimes marketed with its trade name Glucophage) is a well-known drug, that has been in use since 1958. It is the first line and gold standard for the treatment in type 2 diabetes. It may also be useful for treating prediabetes. (R)

It is generally low in side effects and is very cheap being a generic and widely sold medication. Of course, it is more expensive in the USA than in every other country with a price of $5 USD to $25 USD.

It's safety profile is also highly established since it has millions of people who take it daily.

Mechanism of Action

Metformin works by decreasing liver glucose production, leading to lower blood sugar levels, for diabetics, this obviously is the lifesaver, as high blood sugar is what causes diabetics problems.

The molecular mechanisms of how Metformin achieves this is not completely understood. Metformin acts on multiple pathways, too much to describe in detail here, as it is not the point of this Research Topic.

Briefly, Metformin activates AMPK (AMPK-activated protein kinase), reduce activation of PKA (protein kinase A), inhibition of mitochondrial functions and a whole bunch of other purported effects.

From Wikipedia:

 

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What Has Metformin Got to Do With Anti-Aging?

It turns out, quite a lot potentially. So much so that there are entire groups of scientists seeking to confirm Metformin as the first official anti-aging medication by the FDA approved human study. (In-Progress)

The theory is that by activating the AMPK pathway, which is an enzyme inside cells that triggers lower blood sugar by increasing energy utilization. 

In other words, Metformin increases the energy consumption of cells, the cells then suck up sugar lowering the amount of sugar in the blood, this is how it helps people with diabetes.

However, quick minds will quickly realize this means, Metformin is actually a metabolism booster.

Boosting AMPK activity and other indirect pathways Metformin activates turns out to have many benefits that go beyond blood sugar control, such as on aging, cardiovascular disease, cancer and more.

Metformin may reduce many factors that accelerate aging. Metformin possibly also facilitates DNA repair, improve mitochondrial function and protect DNA against glycation.

It is important to know that AMPK activity can also be triggered by curcumin, ketogenic diet, intermittent fasting, exercise and other things.

In a twist of irony, diabetics taking Metformin were shown to live 15% longer than healthy individuals without diabetes. (R)

What is AMPK (AMPK-activated protein kinase)?

AMPK short for AMPK-activated protein kinase is an enzyme. It is critical in regulating energy balance. It is actually made of 3 proteins (known as sub-units) that merge together to create a functional enzyme. An enzyme is something that facilitates a chemical reaction within the body.

In other words, its a kind of critical control switch for cell metabolism. When cells use up their batteries from things such as stress and stimulation and so on. AMPK is the enzyme that says "it's time to refill those batteries by taking sugar from the blood circulating around".

AMPK activates a surge of events within the cells in the body, it is an important part of cellular homeostasis.

Activating this pathway triggers a signalling cascade that affects ketogenesis, hepatic fatty acid oxidation, inhibition of cholesterol synthesis, triglyceride synthesis, lipogenesis, glucose uptake and skeletal muscle fatty acid oxidation. A lot of these effects are essential to regulating metabolic processes in the liver, heart, skeletal muscle, pancreas and adipose tissue.


To facilitate all these actions, glucose uptake has to be increased which is a key function of AMPK and what Metformin activates. Skeletal muscles account for more than 70% of glucose consumption. Exercise and stress are also strong activators of AMPK activation in skeletal muscle.

In fact, insulin does a lot of similar things as Metformin which explains why the inability to produce it is so detrimental to people with diabetes. Without AMPK activation basically, cells are not encouraged to suck up the glucose (sugar) in the blood, leaving way too much sugar in the blood, which causes cellular damage all around the body.

The exact mechanisms of AMPK and Metformin is very complicated and not even all discovered, so we will not cover too much, instead, we will focus on what increasing AMPK signaling can mean for anti-aging.

Boosting AMPK Signalling for Anti-Aging

As we age, AMPK activation progressively declines. (R)

The reason why boosting AMPK signaling may be good for anti-aging, is that a lot of the things this pathway activates are things that ALSO decline as we age, things like fat metabolism, sugar control, these things ultimately increases the risk of developing a disease that kills us, such as a cardiovascular problem.

So how exactly does AMPK signaling help anti-aging?


  1. Burns fat - AMPK blocks the production of cholesterol, triglycerides and fatty acids and triggers the burning of fat. Older people also get fatter easier, so no explanation necessary for why this is good for anti-aging. 

    Metformin is an effective drug to reduce weight in a naturalistic outpatient setting in insulin sensitive and insulin resistant overweight and obese patients.

    Effectiveness of Metformin on Weight Loss in Non-Diabetic Individuals with Obesity | Request PDF. Available from: https://www.researchgate.net/publication/233404614_Effectiveness_of_Metformin_on_Weight_Loss_in_Non-Diabetic_Individuals_with_Obesity .

  2. Regulates metabolism - AMPK causes an increase of glucose uptake and production and reduces energy usage. Fat oxidation increased as well as upregulation of themogenesis (R)
  3. Produces sugar from the liver and promotes the breaking down of glucose for ATP. (R)
  4. Inhibits protein production, a process that requires high energy, this may be problematic since one of the problems of aging is losing muscle. (R)
  5. Acts as antioxidant: AMPK plays an essential role in boosting the body’s antioxidant defense in the event of oxidative stress. It stimulates the production of various antioxidant proteins, including superoxide dismutase, uncoupling protein 2, and NRF2. (R)
  6. Promotes Autophagy - By facillitating Mitochondrial Fission in cells with decreased cellular energy levels. (R)
  7. Reduce Inflammation - AMPK reduces inflammatory responses and cellular senescence in pulmonary emphysema. (R)
  8. Reproduces benefits of exercise. - Increase of glucose uptake, fatty acid oxidation, mitochondrial genesis and insulin sensitivity, replicates the effects of exercise. Exercise also promotes AMPK activation. (R)

Research on Anti-Aging - Human Studies

Metformin's potential as an anti-aging agent has been well known amongst longevity enthusiasts for a while, however serious medical field interests have only started a little earlier than 2016, as a result directly studies on anti-aging / life extension for Metformin have not been concluded yet.

As of October 2018, Metformin is currently undergoing human clinical trials for anti-aging, but the results are NOT OUT YET.

However, Metformin is extremely well studied in humans and there is plethora of studies that point towards Metformin being beneficial and reducing of age related diseases for humans regardless of being diabetic or not, these studies were not specific to lifespan directly.

Here is a summary of all the research (copied directly from Metformin as a Tool to Target Aging from the Institute of Aging Research) that points towards better cardiovascular performance, less cancer risk and even better cognitive function, again these studies were not specific to anti-aging , and can only be interpreted as is:

 

Clinical Trials

 

The Diabetes Prevention Program (DPP)

The DPP was a randomized trial in U.S. adults at high risk for T2DM by virtue of obesity and impaired glucose tolerance (). Over 3,000 subjects were randomly assigned to placebo, metformin (850 mg twice daily), or a lifestyle-modification program. Metformin reduced the incidence of T2DM by 31% compared to placebo over a mean follow-up of ~3 years and was effective in all age categories in preventing diabetes, defined by HbA1C level, including the ~20% who were age 60 or older at baseline (). Further, metformin treatment was associated with improvement in cardiovascular disease (CVD) risk factors () and subclinical atherosclerosis (coronary artery calcium) in male participants ().

 

The United Kingdom Prospective Diabetes Study

Patients with T2DM allocated to metformin compared with conventional treatment had risk reduction of ~20% (p = 0.032) for CVD and 42% (p = 0.017) for diabetes-related death (). This evidence from UKPDS provides rationale for metformin’s designation as first-line therapy for most patients with T2DM.

 

Other Trials

In the HOME trial of insulin-treated T2DM patients, addition of metformin resulted in 40% reduction (compared with placebo) in a CVD composite after 4 years of follow-up (). In non-diabetic subjects, the GIPS III study () failed to demonstrate the benefit of short-term metformin treatment (4 months) on left ventricular ejection fraction, major adverse cardiovascular events, and mortality in post-myocardial infarction patients, and the CAMERA trial () showed no effect of metformin (18 months) on carotid intimal medial thickness.

Observational Studies

The majority of observational data support metformin benefit in CVD, but residual bias and confounding cannot be ruled out (e.g., most studies have been conducted in patients with diabetes and include an active comparator, which could itself be cardio-toxic). Metformin’s potential CVD benefits—particularly in the area of primary prevention—remain an active area of research, including an ongoing randomized trial in the UK (The Glucose Lowering In Non-diabetic hyperglycaemia Trial, GLINT, http://www.isrctn.com/ISRCTN34875079).

Observational Studies Suggest Metformin Decreases Cancer Incidence

Several epidemiologic studies have shown that metformin use is associated with reduced cancer incidence and mortality (). While one meta-analysis () did not show that metformin prevents cancer, a more thorough analysis that included more data and accounted for heterogeneous comparators showed that overall cancer incidence was reduced by 31% and cancer mortality by 34% (). There is also evidence from studies performed both in vitro and in vivo of metformin’s role in attenuating tumorigenesis (). The mechanisms proposed relate to reduced insulin levels, improved insulin action, decreased IGF-1 signaling, and activation of AMPK. Numerous ongoing studies are testing the effect of metformin as adjuvant cancer therapy, with a recently published trial showing negative results in advanced pancreatic cancer (). Although no trials yet have reported effects of chronic treatment on cancer prevention, studies in early-stage cancer or pre-malignancy suggest this may be fruitful ().

Association of Metformin with Better Cognitive Function

Emerging evidence suggests that metformin may preserve cognitive function. In the Singapore Longitudinal Aging Study, metformin use was associated with a 51% reduced risk of cognitive impairment (defined by modified Mini-Mental Status Exam score % 23), which remained robust to adjustment for vascular and non-vascular risk factors. Further, the lowest risk was seen in those with longer-term (> 6 years) metformin use (). A large observational study of metformin-treated T2DM patients reported lower rates of dementia than in those treated with other diabetes medications (). One study suggested that T2DM patients treated with metformin had increased risk for poor cognitive performance (); however, it had a number of methodological flaws () and has not been replicated. In one small clinical trial, T2DM patients with depression (n = 58) were treated with metformin or placebo for 24 weeks (). The metformin group showed improved cognitive performance and reduced depressive symptoms, concurrent with improved glycemic control. In an unpublished trial, non-diabetic subjects (n = 80) with mild cognitive impairment showed significant improvements in some cognitive domains after 12 months of metformin treatment (). No definitive trials have been conducted.

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Downside! - Metformin Can Cause Vitamin B12 Deficiency

It is not well known that Metformin can trigger vitamin B12 deficiency, however, there is research that proves this to be the case, what is unclear is whether this deficiency is significant at low dosages.

B12 is an extremely essential vitamin for brain function deficiency causes memory loss, cognitive fatigue and a whole host of other undesirable side effects. Metformin in the long term will lead to higher levels of artery-clogging homocysteine if B12 is not supplemented) (R) (R)

A decline in B12 is also no immediately noticeable, meaning the side effects of vitamin B12 deficiency can slowly creep up.

However given Metformin's extremely high safety profile, the risks may be overplayed, since a extremely large amount of healthy individuals take Metformin without issue.

B12 can also be supplemented or naturally found in many animal products. It is important to note a vegan diet often is lacking in B12, and a B12 supplement is crucial. Finally, oral B12 supplementation may sometimes be insufficient to offset B12 deficiency in the short-term.

This means people experimenting on themselves should test their B12 levels if possible, as any B12 deficiency will offset any advantages gained from Metformin for anti-aging.

Downside! - Metformin Can Be Deadly in Kidney Impaired Individuals

Doctors have been unwilling to prescribe Metformin for people without diabetes because Metformin belongs to a class of drugs known as Biguanides, they can cause a FATAL condition called lactic acidosis, where the body becomes too acidic due to excess lactic acid. 

Biguanide drugs were taken out of the market because of lactic acidosis risk, however, doctors are slightly off with that myth, because Metformin does not cause this fatal side effect in healthy people.

HOWEVER - That does mean that if somebody has impaired organ functions such as impaired kidney or liver functions, they may not be able to remove the excess lactic acid caused by Metformin leading to potential death or further damage to organs. (R) . Dehydration significantly makes excess lactic acid worst.

Metformin still DOES produce excess lactic acid. Kidney function should be tested to be healthy, especially for older individuals.

However, again the safety profile of Metformin is stellar, which means this is a mixed downside in my opinion, and not a net negative.

A potential complication of metformin is the development of type B (non-hypoxic) lactic acidosis. Although metformin associated lactic acidosis is a rare condition, with an estimated prevalence of one to five cases per 100 000 population,3 it has a reported mortality of 30-50%.4 Prognosis seems to be unrelated to plasma metformin concentration or lactate level.5

Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good.

Metformin-induced lactic acidosis: no one left behind (Research Link)

 

Can Metformin Affect Protein Synthesis and Increase Sarcopenia Risk?

In aging individuals, Sarcopenia is a substantial problem, increasing risks of falls and other muscle weakness related injuries. There is currently no widely accepted therapies for sarcopenia.

There is at least one study which theorizes potential consequences of chronic AMPK boosting, continous stimulation of AMPK activity may result in muscle fiber atrophy and death (sarcopenic muscle).

However, fiber atrophy and diminished capacity for growth are likely simultaneous consequences of chronic AMPK activation in aged fast-twitch fibers. Such potentially detrimental effects must be considered if AMPK is to be examined as a pharmacological target for metabolic diseases. - Does AMP-Activated Protein Kinase Negatively Mediate Aged Fast-Twitch Skeletal Muscle Mass? (R)

Furthermore, it is important to emphasize that some of the pathways modulated by CRMs are critical for skeletal muscle homeostasis casting some doubts as to their potential benefit in sarcopenia. For these reasons, it is imperative to identify tissue-specific alterations and responses to therapies in aging. (R)

Metformin inhibits some cellular protein synthesis, but this does not mean the net effects are that of muscle loss. In fact some research points to the contrary:

In one study Metformin reduced the signs of sarcopenia in old rats, the benefits gained in metabolism from AMPK activation may offset this effect.

Metformin may indeed promote muscle hypertrophy and strength gains via the other mechanisms. The research on this is ongoing and not conclusive at the moment.

It is also important to note that anabolism has been linked to aging. It is currently suggested that cycles of anabolism may be better than constant.

In this study on burn injuries, Metformin promoted a significant anabolic effect on muscle protein. 

The evidence seems to point to that Metformin has a net effect of being anti-catabolic at least in people with injuries (where muscle catabolism and glucose intolerance is heightened), meaning it promotes muscle growth instead of reducing it.

From Research " Influence of Metformin on Glucose Intolerance and Muscle Catabolism Following Severe Burn Injury " 

 

Results:

Patients receiving metformin had a significant decrease in their plasma glucose concentration, the rate of glucose production, and an increase in glucose clearance. Metformin administration was also associated with a significant increase in the fractional synthetic rate of muscle protein and improvement in net muscle protein balance. Glucose kinetics and muscle protein metabolism were not significantly altered in the patients receiving placebo.

Conclusions:

Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury. Therefore, therapies that improve glucose tolerance such as metformin may be of clinical value in ameliorating muscle catabolism in critically injured patients.

Metformin Dosage for Anti-Aging

There is no widely known consensus based on human trials (because the results are not out yet).

The slow release form 500mg tablets is preferred. 

Supplementation of at least 300mcg of vitamin B12 is a MUST. 5000mcg of folic acid is what one study says.

The doses used in the human clinical trial (results not published yet) - The doses start at 500 mg twice daily, then titrated up to 1000mg in the morning and 500mg in the evening.

Metformin can cause stomach issues in people not used to it, so low starting dose is suggested. 250 mg before a large meal in the first week, and may be increased after a week to 250mg before 3 meals a day. After a month it is suggested to raise to 500mg before each of the 3 meals, totaling 1500mg per day. This is quite a lot of work to remember and maintain.

850mg before meal is the upper limit and is likely to be unnecessary. 

Conclusion

There is ample evidence to suggest that Metformin probably does work for anti-aging purposes, however, is it worth the trouble? AMPK can also be activated by a CR (calorie restricting) diet, Intermittent Fasting, Curcumin, and others.

Also, the extent of life-extension / anti-aging is not known directly in rat or human studies, everything is just postulation from the huge amount of studies done on humans, which were not anti-aging focused.

If one is not in a rush for anti-aging, it may be wise to wait for the results of the human anti-aging study currently in progress.

Metformin does have ample evidence of reducing the chances of developing diseases that become riskier with age like heart problems, cancer and so on.

Whilst Metformin is likely beneficial, it CAN backfire, a BATTERY of tests should be taken before and during Metformin, most notably ensuring kidney and other organ functions are optimal before taking Metformin in case of the aforementioned lactic acid problem.

There is also a single study showing Metformin decreases Testosterone levels, but this is the only study I can find regarding it.

B12 levels are also of concern and should be supplemented and tested after being on Metformin for a while. Homocysteine levels should be tested too, to ensure B12 deficiency isn't causing artery clogging.

Additionally, Metformin can also cause hypoglycemia (very very rare) for people with low blood sugar.

The advantage of Metformin is that it is very cheap, and if the aforementioned issues can be tackled and kept track of, then it is a anti-aging agent with an extremely high safety profile, and likely to bring many benefits of AMPK activation. Reduction in the risk of developing diabetes is a pretty big one though.

To reiterate Metformin's safety profile as a drug:

 

Metformin has been used with an excellent safety record for over 60 years. Side effects are monitored closely within clinical trials, and the safety of met-formin use in DPP/DPPOS was reported on in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time ~20% of the cohort was age 70 or older (mean age ~64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Program Research Group, 2012). Mild anemia occurred in ~12% of metformin-treated participants versus ~8% in the placebo group (p = 0.04). Vitamin B12 deficiency occurred in ~7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990). Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).

Comment by SnellYaLater (PHP Student??)

From Reason: https://www.fightaging.org/archives/2016/12/a-summary-of-the-nia-interventions-testing-program/ Hi there, Just a 2 cent. I am too share that opinion. I don't understand why there is so much energy, still, being put in these methods of anti-aging. It has been characterized as mostly a failed avenue. What works in mice is not very translatable in humans (for a ton of reasons), in general. In general, yes we see similarities, but the results the differ between mice and humans. Calorie Restriction (which we have been talking for about 10 years now at least if more) is something, almost mythical, that has now been shown to be much weaker in humans (as you said, where is the account of someone living 125 years on Calorie Restriction - nowhere, because it doesn't exist). One recent study did Calorie Restriction (about 40% CR, mild-to-hard restriction in calories) in old world monkey Rhesus Macaques (that live 30 years) for a quite a long period (many years) - the results were non-surprising - if slightly : CR did absolutely nothing on their lifespan and changed squat-all on most of their advancing biological aging parameters. What it did do is reduce mortality a bit (a good thing, calorie restriction reduces proteasome junk/helps autophagy, improves redox and inhibits AGEs/crosslink formation by reduced glucose exposure/glycoxidation while getting enough calorie for energy daily kJ need). Mice results of Huge Lifespan Extension (50%) do not translate at all in Rhesus Macaques or Humans (which have Far more in common in biology and length of lifespan, being old-world monkeys while humans are apes descendant like Chimpanzees. Not just some 'other' mammal, but a bipedal mammal. It's a direct ancestry link and thus the highest probability of result translation). Thus, we can infer CR only helps human to have a better 'healthy aging' profile rather than be fighting disease as unhealthy aging. Centenarians show us, and prove us, that aging is complicated than we though as there can be 3 types of centenarians : Delayers, Escapers and Survivors (I might be in that category since I went through some sh..). Delayers delay any disease but soon enough disease come, they represent 20-30%. Escapers, the very lucky ones completely evade/escape most of all diseases altogher - they are 10-20% - the very genetics lucky ones. And then, the Survivors - my favorite ones, they went through lots of Sh...they had at least one major disease (cardiac problems, hyper tension (many), osteoporosis, dementia, pneumonia, skin cancer). They are 'unhealthy' centenrians - and reached the age of 100 - unhealthy. (all centenarians are 'unhealthy', the difference lies in the 'degree' of 'how unhealthy' - it is 'liveable (no big pain)' or 'unliveable (big pain)) Quality of Life-to-Health'. If survivors - could reach - a 100 and still suffer greatly, as survivors. It means that damage theory is far more complex and muddied than we though. My 2 cents is down to susceptibility. How susceptible certain macromolecular DNA elements are that is what is going on. Some people are 'more susceptible' to 'oxidative stress caused damage' to many types of epigenetic DNA methylation and gene transcript changes - despite having better redox properties; we are not built (Genetically and bodily) exactly the same way (that's why you see survivors, escpers and delayers). Also, redox 'allows' someone, such as a survivor, to 'Survive' intense oxidative challenges which Do damage him/her but the Cell survives and is less susceptible (oxidative-stress resistance theory, NRF2, ARE/EpRE/Heme Oxygenase(Small Heat-Shock Proteins Chaperons who help lipofuscin lysosome docking/cell cycle dilution and refold undenature/unfolded crucial proteins; this is visible through a reduction of Nucleic Acid oxidation (Telomeres/Telomeric DNA is spared and maintained capped)) creating DNA single strand breaks and then Double frags. I believe rejuvenation, especially removal of proteasome/autophagic junk (lipofuscin), as power to increase liefspan a bit (not as much as we think sadly, because CR shows already that damage reduction is moot actually since it does not nothing in Rhesus Macaques yet slows mortality - showing damages are small contribution - where it lies is in epigenetic part and 'programming' telomere part/cell cycling mechanism (replicative senescence/Hatyflick) which humans are very much bound by). CR is now done for and will improve your health (a bit and allow you a longer lifespan, depending on 'how' your body reacts to CR; you may very well not get many benefits from CR or you may reap a bit more depending onyour phenotype/morphology). Metformin and Rapamycin, will help for a longer life (controls diabetes, my father takes Metformin daily for T2D now for many years, was on and off, back on now...it did not change his aging speed - at all...gray hair keep coming, so does skin leathering/thinning and wrinkling (a proof DNA methylation is getting low on global methylation levels and skin telomeres are shortening (reducing cell cycles/closing-in on replicative senescence onset for a proliferative tissue that exhibits high oxidatio such as skin)). But what it does it control hyper-glucose levels, hyperinsulinemia and glycated hemoglobin (HbA1c) to 'normal'..metformin and rapamycin + CR in mice equals longer life, in humans longer 'healthiness' thus longer life - but not by that much (as seen with CR doing almost nothing in Macaques but reducing premature mortality from inflammation in diseases). Aspirin (which is salicylic acid and salicin extracted from willow tree bark) works about the same way as Rapamycin and does a small CR effect too, in fact centenarians/elders who took one aspirin here and there and NSAIDs (some developed gastric ulcers on aspirins/Advil) lived longer and aspirin acts on neuron in a very CR fashion (my guess is it is anti-oxidative (salicylate scavenges ROS), blood thinning, acting on neuron and neuro-endocrine system (it plays on ghrelin and leptin hormones, just like CR, then on Testosterone and Estrogen, agin like CR through mTOR and Insulin/IGF/IGF-Receptors in the brain). Aspirin or salicylic acid can save your life from a heart attack (one aspirin taken during heart attack). Always have some closeby in case something terrible happened. CR is greatly overrated sadly and its damage reduction is now not as important as we thought - what is, is the susceptibility of the Cell to said damages - that is far more important - it's why certain animals delay, escape and survive the Exact same oxidative burden of other (because they are more equipped to deal with that stress, some have better redox, some have better enzyme, some have better DNA repair and nucleotide lesion repair (BER, NER), some have more p53 copies, some have less, some are just less susceptible through many 'Adapted' genetic mechanism.. Just a 2 cent.

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