A Skeptical Review of the Evidence for Metformin

This review paper more or less leans towards my thoughts on metformin as a treatment to slow aging: the animal data is not great, the human data is a single study, the effect size on life span is far too small to care about, and the detrimental side effects are large in comparison to that effect size. The strategy of upregulating stress response mechanisms via drugs such as metformin is a poor strategy for long-lived species, as we clearly don't exhibit the sizable gains in life span that occur in short lived species such as mice under these circumstances. Metformin, in turn, is a low performance example of this strategy, much worse than, say, the practice of calorie restriction or mTOR inhibitors.

Metformin is sometimes proposed to be an "anti-aging" drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage, or running, to find a new use (or indication) for an aging population. In 2015, Nir Barzilai met with regulators from the FDA to discuss the now famous phase III multi-site TAME (Targeting Aging with Metformin) trial. The acronym chosen and the intention behind it - namely, that aging is a "disorder" that can be treated like any other disease - was a clear provocation. The FDA's mandate is to regulate medications and devices to cure diseases or aid in their diagnosis, but aging is not (yet) an indication. Interestingly, frailty is missing from the proposed composite outcome. Other ongoing trials (e.g., NCT02570672) with metformin provide arguments that frailty may be an important endpoint. It will be interesting to compare the results with the ongoing fisetin trial (NCT03675724).

Although widely cited as evidence for the small effects of 0.1% metformin in the diet on the lifespan of older male inbred mice, earlier results obtained by researchers should be dismissed: the National Institute on Aging Interventions Testing Program could not replicate the findings regarding an extension of the lifespan with 0.1% metformin. The negative results were obtained at three different locations using genetically heterogeneous female and male mice.

The rationale for the ongoing or planned metformin trials is almost exclusively based on observations (associations) of potential benefits in a diabetic (or prediabetic) population. Its efficacy even in an at-risk cohort of aged people has not yet been proven. Metformin is associated with a higher risk of vitamin B12 and vitamin B6 deficiency, which may result in an increased risk of cognitive dysfunction. Supplementation is strongly recommended to metformin users.

Of greater concern are the results of small trials in which the effects of metformin on metabolic responses to exercise or on cardiorespiratory fitness were tested. In a placebo-controlled, double-blind, crossover trial with healthy young subjects, metformin caused a small but significant decline in maximal aerobic capacity. A double-blind, placebo-controlled landmark trial with older adults with one risk factor for type 2 diabetes investigated the effects of metformin and 12 weeks of aerobic exercise. Contrary to expectations - namely, that the effects of exercise and the drug would be additive - "metformin attenuated the increase in whole-body insulin sensitivity and abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration."

Link: https://doi.org/10.1159/000502257

Comments

Thank you for this article; I'm also bored of people acting like Metformin is on the same level as rejuvenation therapies like senolytics, when in reality, Metformin clearly does not repair molecular and/or cellular damage.

Posted by: Quinn at September 27th, 2019 5:38 AM

I recall it been sligh inhibitor of mTOR so there should be some effect. For me the best outcome of TAME would be the FDA acknowledgment of aging as a disease

Posted by: Andriy at September 27th, 2019 7:10 AM

I'm having to take the stuff to bring my A1C back down to normal. I'm aware of its affects on exercise. I've been trying to time the half life with when I exercise. That way there is none or very little in my system at that point. I don't know if that helps or not with the issue of exercise plus metformin, hopefully so.

Posted by: Nate at September 27th, 2019 7:57 AM

Ignorant and counter intuitive to previous posts. Metformin activates AMPK. AMPK good for longevity, MTOR bad. Is that simple enough for you all?
This blog has turned into a hack job. - here this paper has nice pictures so maybe you all will understand https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30642-8.pdf

Posted by: Steven at September 27th, 2019 2:26 PM

Aspirin does the same steven, inhibits mTOR signaling and activates AMPK. why should i use something like Metformin when i can achieve the same results with something much cheaper, it doesn't require prescription, has fewer side-effects at least in small doses, and unlike Metformin we have literally thousands of years experience for it's safety and efficacy.

Posted by: Brsnxx at September 28th, 2019 2:08 AM

Brsnxx, I appreciate your attempt at having a polite conversation with Steven, but since he resorted to being condescending, I suggest to avoid wasting your time; it's against the rules of this blog to either be rude to other commenters or give trolls attention.

For what it's worth, as it should be clear from my previous comment, I agree with you that the hype around Metformin as being some kind of rejuvenation therapy is unwarranted.

Posted by: Quinn at September 28th, 2019 5:29 AM

Did anyone notice fightaging.org is referenced in the paper? :-)

Posted by: Matt at September 28th, 2019 3:21 PM

@Matt

FA is one of if not the best resources on the web in this area. Reason has performed a formidable job of finding and integrating refresh papers and publications.
Too bad FA doesn't have the general weight as the new outlets

Posted by: Cuberat at September 28th, 2019 6:11 PM

This article states:

"If observational studies (cohort, case-control, and cross-sectional studies) are included and the onset or prevalence of "diseases of aging" (cancer, CVD, kidney failure, fracture, or cognitive impairment) is measured, the results suggest that diabetics taking metformin had a lower rate of all-cause mortality and of developing any cancer even compared to the general nondiabetic control population."

To be reflexively and mindlessly hostile to fisetin, rapamycin, metformin, and other potentially-effective longevity-enhancing drugs is evil.

Posted by: Zan at September 29th, 2019 8:53 PM

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