Is metformin the fountain of youth?

Growing up, I was an avid listener of Paul Harvey. My parents would turn on the radio every morning so I could listen to “the rest of the story.” I would eat my breakfast on the floor, sitting in front of the radio- as if by sitting closer would bring me closer to the story. Each time I click onto the Apple Podcast app and open my preferred non-medical show, Tim Ferriss brings me back to my childhood living room floor. As much as I enjoy the conversation, education, and insight into all manner of topics, when a topic wades into an area I have some knowledge of, I start to ear a different story. 

The breadth and depth of discussion are what I’ve come to enjoy the most with the renaissance of this form of media. Because of the opportunities available to expand on ideas and hold a discussion, we’re often left with more questions than answers.  For me, the most enjoyable aspects of this are when the discussions wade into areas where I have some expertise. Each time any discussion involves a medication, drug (illicit or otherwise), supplement, or anything of a similar nature, I’ve started to compile a list of the things discussed. While the list continues to grow, there are items that routinely come up. One of which is the use of metformin as an agent to target aging. 

In a recent episode, Dr. Peter Attia and Tim Ferriss discussed a wide range of fascinating topics. One which caught my attention was their discussion of metformin to essentially “treat” aging. Precisely, how Dr. Attia has begun to question its impact on aging.

A better life, not longer life

Healthspan is used to describe the length of time that an individual’s life is spent in good health. That is free from the chronic diseases and disabilities of aging. One’s lifespan is divided into this period of healthspan followed by the onset of one or more age-related diseases. The intent of the research into “anti-aging” drugs isn’t necessarily seeking never-ending life, but rather extending the period of healthspan. A number of drugs have been studied in animal models in various stages of life and their impacts on changes to lifespan. 

In the discussion regarding this research, two medications are discussed in detail. Those medications are rapamycin and metformin. Before jumping into metformin, I want to call attention to rapamycin. If you are like me, rapamycin likely rings a bell, but you can’t quite pinpoint where you’ve heard it before. You’d be relieved to learn that rapamycin is a familiar drug otherwise known as SIROLIMUS. Without discussing the animal models of sirolimus for improving life-span, you can imagine whatever benefits are observed are offset (and then some) by the adverse events and toxicity of the drug. I can only speculate why the research largely refers to the compound as rapamycin and not its common name.

Metformin, the fountain of youth – if you have diabetes

Metformin, being the other hotly touted drug for improving healthspan has a much more favorable tolerance profile than sirolimus. Our understanding of the actions of metformin in this space is similar to that in diabetes: not fully elucidated. The frequent description of the particular action of metformin involves inhibition of complex I of the electron transport chain.[1-2] When I initially read this, I would have assumed this would be a negative action of metformin by decreasing mitochondrial respiration. But the hypothesis calls on the concept of hormesis to describe this favorable effect. By actually generating inflammation and oxygen radicals in the tissue which promotes an adaptive response through the development of long-term reduction in oxidative stress.

While the mechanism of action for improving healthspan isn’t known, the effects of metformin have been supported in humans. Many pharmacists are already familiar with these positive effects of metformin: improved overall survival of patients with Type 2 DM taking metformin, decreased the risk of all-cause mortality and CV morbidity, cancer incidence, and cognitive decline.[3-8] However, these benefits appear to be exclusive to patients who already have diabetes and have not been demonstrated in humans without diabetes.

In fact, in human subjects without diabetes, metformin appears to have negative effects. In a randomized, double‐blind trial, of men and women in their mid-60s without diabetes, participants were given metformin or placebo and performed 14 weeks of progressive resistance exercise training (PRT).[9] The placebo group outperformed the metformin group in several measures of PRT: placebo gained more lean body mass (p = 0.003) and thigh muscle mass (p < 0.001). There was a trend for blunted strength gains in metformin and did not impact satellite cell or macrophage abundance. The authors concluded that “these results underscore the benefits of PRT in older adults, but metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals.”

While PRT is certainly a surrogate for improving healthspan, metformin as underperformed in preventing disease as well. For non-diabetic patients given 4 months of metformin or a placebo after a STEMI with primary PCI, the use of metformin did not result in improved LVEF after 4 months.[10] Similarly, these authors concluded that these findings do not support the use of metformin in this setting. A discussion on the role of colchicine here is on the horizon.

Furthermore, in an unpublished study available on clinicaltrials.gov, assessed whether treatment with metformin would restore the gene expression profile of older adults with impaired glucose tolerance to that of young healthy subjects. In this study, metformin had no impact on any outcome measure when compared to the placebo. 

At best, when given to elderly patients, metformin could delay the onset of diabetes. However, it’s not clear whether metformin was treating undiagnosed diabetes, or if this was a drug effect. Furthermore, it’s not known whether this effect would be more pronounced in sustained PRT through healthspan life vs metformin alone.

As previously mentioned, sustained moderate to vigorous physical activity throughout life appears to be inversely related to premature mortality, and morbidity (sedentariness, CV disease, insulin sensitivity, and several cancers).[11]  It is not known whether metformin would impact these outcomes in this phase of healthspan.

And now, the rest of the story

To his credit, Dr. Attia was his own guinea pig with metformin and has since followed this literature. From what I understand, his current position is more skeptical of the magnitude of the effect of metformin for this use. Sirolimus plus caloric restriction appears to be the most reproducible intervention to extend healthspan in animal models. But I doubt this is safe in humans.

It’s easy to become cynical towards efforts such as these to explore new or existing drugs and chemicals for unique uses. I hold a controversial position in my space that I’m more optimistic about these treatments at the outset. The quip of primum non nocere to dismiss this discourse forgets all the time’s harm occurred in the name of medical science. Perhaps the recent large undertaking of psilocybin research could be held in a skeptical, yet hopeful light.

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Reference:

  1. Konopak AR, Miller BF.  Taming expectations of metformin as a treatment to extend healthspan. GeroScience. 2019 Apr; 41(2): 101–108.
  2. Brazilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016 Jun 14; 23(6): 1060–1065.
  3. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ. 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. Diabetes Obes Metab. 2014;16:1165–1173
  4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12; 352(9131):854-65
  5. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res Phila. 2014;7:867–885
  6. Wu JW, Boudreau DM, Park Y, Simonds NI, Freedman AN. Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature. Expert Opin Drug Saf. 2014;13:1071–1099
  7. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis. 2014;41:61–68
  8. Cheng C, Lin C-H, Tsai Y-W, Tsai C-J, Chou P-H, Lan T-H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A Biol Sci Med Sci. 2014;69:1299–1305.
  9. Walton RG, Dungan CM, Long DE, et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019 Dec; 18(6): e13039.
  10. Lexis CP, van der Horst IC, Lipsic E. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014 Apr 16;311(15):1526-35
  11. Physical Activity Committee (2018) Scientific Report – 2018 Physical Activity Guidelines – health.gov. Available at: https://health.gov/paguidelines/second-edition/report/

Is metformin the fountain of youth? Is metformin the fountain of youth?