Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes

Abstract

Metformin, the most commonly prescribed anti‐diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti‐aging drug—the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose‐dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.

Exercise preserves fitness capacity during aging through AMPK and mitochondrial dynamics

“…The anti-diabetic drug metformin has many effects on metabolism, including stimulating AMPK indirectly (56). It may be consistent with our results that metformin not only extends C. elegans lifespan but also delays the decline in swimming capacity with aging (57).…”

CeLab, a microfluidic platform for the study of life history traits, reveals metformin and SGK-1 regulation of longevity and reproductive span

“…We also tested metformin, the biguanide diabetes drug that has been reported to increase lifespan in a range of organisms, including C. elegans ; 43 a recent study confirmed that metformin has lifespan and healthspan benefits for several (but not all) Caenorhabditis species. 44 A previous study had concluded that metformin's effects on C. elegans lifespan are mediated by perturbation of bacterial folate cycle metabolism, resulting in methionine restriction, rather than through metformin's effects on the worm itself. 45 However, those and prior assays were performed with very high (25–100 mM) levels of metformin in the plates.…”

A familial natural short sleep mutation promotes healthy aging and extends lifespan inDrosophila

“…Finally, we tested whether non-genetic means of promoting health could also induce changes to sleep in WT animals. Administering low doses of mitochondria-targeted agents, such as Rotenone and Metformin, can improve health and extend lifespan by eliciting hormetic responses (De Haes et al, 2014;Martin-Montalvo et al, 2013;Na et al, 2015;Na et al, 2013;Onken et al, 2022;Schmeisser et al, 2013;Yuyun et al, 2013). Therefore, we examined sleep in WT flies that were fed 0.1 µM of Rotenone or 5 mM of Metformin, which are the optimal doses required for improved health span (Na et al, 2015;Schmeisser et al, 2013).…”