While metformin is approved to treat diabetes, it appears to target a number of aging-related mechanisms as well according to a 2016 review. Some of these crossover with the antidiabetic effect, but these may not be the most important mechanisms with respect to aging. Specifically for aging, metformin leads to decreased insulin levels, decreased insulin-like growth factor (IGF-1) signaling, inhibition of mechanistic target of rapamycin (mTOR), inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous production of reactive oxygen species, activation of AMP-activated kinase (AMPK), and reduction in DNA damage. Metformin also beneficially influences metabolic and cellular processes associated with age-related conditions (e.g. inflammation, autophagy, and cellular senescence). These actions give credence to the hypothesized downstream effects of metformin to improve longevity by affecting inflammation, cellular survival, stress defense, autophagy, and protein synthesis. [1]
Animal studies in C. elegans (roundworm) show metformin to extend lifespan by several mechanisms altering the microbiome, specifically changing microbial folate and methionine metabolism. Unfortunately, there is no similar evidence in humans. Studies in mice also showed metformin increased lifespan by about 40%, but this effect declined when metformin was started at older ages. The authors of this review propose a large clinical trial, the Targeting Aging with Metformin (TAME) study, which plans to enroll 3,000 patients aged 65-79 to assess the true effects of metformin on longevity in humans. [1]
Another review suggests metformin may be a promising candidate as an anti-aging medication. Microarray analyses show metformin induces the same gene expression profile and pathways as caloric restriction (CR), which has been shown to extend lifespan. Metformin also alters cellular energy by inhibiting gluconeogenesis and lipogenesis. Downstream effects also inhibit parts of the electron transport chain, which leads to decreased reactive oxygen species. Overall, metformin is well tolerated and helps improve survival in diabetic patients, many of the positive results regarding metformin's use for longevity have been obtained using doses that exceed therapeutic levels in humans. Animal studies suggest metformin has positive effects on the lifespan of worms, flies, mice, and rats, while studies in humans show increased survival with metformin in diabetic patients with cardiovascular disease. Moreover, metformin may contribute to the prevention of certain cancers and reduce the risk of cognitive decline and dementia. Because of its animal data and tolerability in humans, metformin is a promising candidate as a life-extending drug. [2]
A 2019 review discussing mechanisms of metformin relating to anti-aging notes that one of metformin's potential anti-aging properties targets the mitochondrial respiratory (electron transport) chain. By targeting mitochondrial complex I, metformin lowers the relative energy charge of the cell, raising AMP levels relative to ATP. Among other effects, the rise in AMP allosterically primes activation of the energy sensor AMPK, which is significant to metformin’s antihyperglycemic, pro-longevity, and anticancer effects. Another proposed mechanism is due to mechanistic target of rapamycin complex1 (mTORC1). The protein kinase mTORC1 plays a central role in regulating cell growth, proliferation, and survival in response to nutrient and energy availability. Metformin inhibits mTORC1 activity in cells in culture independently of AMPK. From a longevity perspective, metformin effects on mTORC1 and longevity are in line with the well-known ability of genetic and pharmacologic inhibition of mTORC1 to extend lifespan across multiple models. [3]
Furthermore, to supplement the lifespan-promoting activity of metformin in various model organisms, metformin is capable of reducing the mortality rate of diabetic patients from all causes independent of its effect on diabetes control. This is evident in the Metformin in Longevity Study (MILES) study which essentially showed metformin has the potential to restore youthful gene function in elderly persons with glucose intolerance. This suggests that metformin may provide anti-aging and reduction of aging disease properties (see Table 1). This concept will be further evaluated in the TAME trial. This study will aim to provide the concept that human aging can be targeted by metformin while simultaneously preventing a multitude of major age-related outcomes. This study is suggested to be launched soon; however, evidence of its initiation could not be found. [3], [4]
A 2017 meta-analysis evaluated metformin’s anti-aging effect in humans. Four studies compared diabetic patients being treated with metformin to the general population or nondiabetic patients. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.88 to 0.99). Furthermore, diabetics taking metformin compared to diabetics receiving other diabetic therapies had lower all-cause mortality (HR 0.72; 95% CI 0.65 to 0.80), insulin therapy (HR 0.68; 95% CI 0.63 to 0.75), and sulfonylurea therapy (HR 0.80; 95% CI 0.66 to 0.97). Metformin users also had reduced cancer and cardiovascular disease compared to non-diabetics and non-metformin users. This analysis suggests metformin may extend lifespan by acting as a geroprotective agent. [5]