Metformin is a biguanide drug widely prescribed for the treatment of type 2 diabetes (T2D) worldwide. Metformin has been used in the clinic for over 6 decades and has an excellent safety record thus far. The medical history of metformin dates back to the 17th century, where the extracts of French lilac (Galega officinalis), which contains a metformin-like guanidine compound, was used as an herbal remedy to treat intense urination. This was the typical symptom of the disease that later came to be known as diabetes mellitus. In 1994, metformin was approved in the U.S. by the FDA to treat type 2 diabetes and is now the most prescribed anti-diabetic medication worldwide, taken by over 150 million people each year. Metformin is an effective glucose-lowering agent while also increasing peripheral sensitivity to insulin, thereby reducing the risk of all diabetes-related complications including death. Despite the long history and widespread use in the clinic, the modes of metformin's action underlying these favorable effects are complex and remain elusive. Metformin is not metabolized in humans or animals and is eliminated unchanged by renal clearance. After oral administration, approximately 70% of metformin is absorbed from the small intestine and then delivered directly to the liver where it acts primarily to reduce hepatic gluconeogenesis. In addition to the liver, the intestines are also identified as an important target organ for metformin's actions. Metformin can stimulate anaerobic glucose metabolism in enterocytes, suppress hepatic glucose production via liver-gut-brain crosstalk, and alter the gut microbiome in ways that contribute to antihyperglycemic effects, weight loss and inflammation suppression in individuals with T2D.
Metformin is not only used in T2D management but also has gained significant attention as a potential geroprotective agent. Administration of metformin to various model organisms, including C. elegans and mice, can mitigate aging, improve health and thereby increase lifespan through mechanisms beyond blood glucose regulation. The favorable effects of metformin on health and lifespan have been attributed to AMPK activation, mitohormesis, the lysosomal pathway, and alterations of the microbiome, specifically by changing microbial folate and methionine metabolism. In mice, metformin has been shown to extend lifespan and improve health in both short- and long-lived mouse models, yet the effects seen in long-lived mouse strains appear to be more modest. Some of these studies also suggest a greater health benefit of metformin in female mice. In spite of ample evidence that supports the protective effect of metformin against aging, a study conducted by the Aging Interventions Testing Program reported a non-significant effect of metformin on the lifespan of outbred mice. The authors suggested that the lack of benefit may be attributed to the doses used in the study. Given that the outbred mice have been deemed to be genetically heterogenous, these results also indicate that the lifespan response to metformin is subject to genetic variations. Therefore, individualized and precision approaches are needed to implement metformin in aging.
Nonetheless, a consensus exists that metformin targets and delays aging. Its administration in humans provides overall protection against age-related diseases, including but certainly not limited to diabetes, as well as, frailty in general. The geroprotective property of metformin can be evidenced by a wealth of retrospective observational studies, in which metformin use in diabetic patients is associated with reduced incidence of cancer, cardiovascular disease, cognitive impairment, and all-cause mortality. Even when compared to age- and sex-matched non-diabetic groups, metformin treated diabetic patients had a slightly longer survival, despite the fact that diabetic patients were obese and had higher levels of morbidity at baseline. A meta-analysis study has replicated these findings, reaching a similar conclusion on the protective effects of metformin against all-cause mortality and diseases of aging when compared to the general and non-diabetic population. To explicitly answer the question concerning the anti-aging effects of metformin in non-diabetic individuals, the double-blinded, placebo-controlled multicenter trial Targeting Aging with Metformin (TAME) has been devised. TAME is the first so called 'geroscience' guided aging outcomes trial designed for metformin and plans to enroll ~3,000 non-diabetic men and women aged 65-79 years for a 6-years trial period. In contrast to traditional FDA approved trials that only look for a single disease endpoint, TAME has a composite primary endpoint, consisting of stroke, heart failure, dementia, myocardial infarction, cancer, and death. This is in particular important to evaluate the efficacy of healthy aging drugs, considering the premise that slowing down aging will automatically postpone or eliminate multiple diseases of old age.
Metformin holds great potential to target aging and increase human healthspan. However, when it comes to the widespread use as an anti-aging therapy, some uncertainty still exists regarding whether metformin is effective and safe across the entire population for aging. One concern regards metformin responders versus non-responders, an issue that has been apparent among patients who take metformin for glycemic control. Genetic variation in the organic cation transporters that mediate the transport of metformin in body tissues are suggested to account for the differential responses to metformin. In spite of this, understanding of the underlying mechanisms remains superficial. Another uncertainty concerns the interaction between metformin and lifestyle modification such as exercise. Although exercise and metformin independently improve metabolic health, and decrease the risk of age-related diseases, the combination may elicit unfavorable antagonistic effects on physiological function. An additional consideration regards age of treatment. While metformin can be used safely and is the preferred initial therapy in many older adults with type 2 diabetes, a study in C. elegans demonstrated that late-life treatment with metformin exacerbates aging-associated mitochondrial dysfunction and shortens lifespan. Furthermore, although metformin has been used with an excellent safety record for over 60 years, its long-term use is still associated with some potential side effects. Among them, gastrointestinal disturbances, such as diarrhea, nausea, vomiting, flatulence, and loss of appetite, occur most frequently. Very rarely, lactic acidosis may also occur upon metformin use, but the risk appears to be highly related to renal function. Altogether, precision medicine approaches will be critical to implement metformin intervention as an anti-aging therapy in humans.