Metformin is a poster child for the way in which much of the aging research community is focused on approaches to aging that cannot possibly achieve more than a very modest slowing of degeneration, and where the existing evidence strongly suggests that those tiny positive outcomes will be unreliable at best. Metformin is a way to tinker with the operation of a damaged metabolism, not a way to repair that damage. As a calorie restriction mimetic, the animal data shows that it compares very poorly to calorie restriction itself. We know that calorie restriction doesn't do anywhere near enough for human longevity. This is not the way forward to human rejuvenation.
Although current research gives promise to metformin as an anti-aging drug, there are still concerns that need to be highlighted, and they apply not only to research into metformin but to other anti-aging mechanisms and drug research as well. First, despite the positive outcomes from many studies, it is not uncommon to find a change in dosage turning the result from life-extending to life-ending. When a low dose of metformin (0.1%) was given to middle-aged male mice with their diet, their lifespans were extended by 5.83% on average, but a higher concentration (1%) became toxic.
Another issue standing in the way relates to the side effects associated with chronic use of drugs. About 25% of patients treated with metformin have gastrointestinal side effects. Besides, chronic use of metformin can cause dose-dependent vitamin B12 deficiency, increasing the risk for anemia and neuropathy. Future research should also work to elucidate how gender influences drug effectiveness. Metformin increased mean lifespan of female mice by 4.4% while decreasing that of male mice by 13.4%. Male pre-diabetic patients who received metformin had a significantly lower coronary calcium score compared with control, while the female group did not.
The issues of dosage, side effects, sexual dimorphism, and genetic regulatory mechanisms all point to the need for large-scale clinical trials. The Metformin in Longevity Study (MILES) involved 14 older than 70 year-old people who were randomized to take metformin and placebo in either order each for six weeks with a two-week washout period in between. As the number of subjects was small and the duration short, MILES effectively revealed many transcriptomic and metabolomic changes in the muscle and adipose tissue. The Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) is intended to evaluate the performance of metformin in reducing CVD risks by following 20,000 hyperglycemic but non-diabetic patients for five years. A one-year feasibility RCT enrolling 249 elderly, obese, and with high CVD risk (mean 28.8%, SD 8.5%) participants was concluded in 2018, and metformin improved several CVD risk indicators and decreased vitamin B12 levels. However, it also revealed problems such as a high rate of trial discontinuation (30% by six months).
The Targeting Aging with Metformin (TAME) trial is a large placebo-controlled trial that is designed to enroll 3000 subjects to test whether metformin delays age-related diseases. The TAME trial received FDA approval in 2015, and after receiving all the required budget in 2019, it was set to start at the end of the same year. The TAME trial may make metformin the first approved drug for anti-aging, but, more importantly, since it is not testing metformin against a single disease but a collection of age-related ones, it establishes aging as a medical condition that can be intervened or treated instead of an irreversible process outside human control. The shift in the notion of aging will enable future anti-aging clinical to trials proceed with much more ease.