Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

By Brian Onken, Monica Driscoll. PLoS ONE, 2010

660 citations recorded by the source corpus.

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/095186a4db7c14066bc18711a5c51c48ca7dcf68

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Citations in the corpus

AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, positive): “Intriguingly, some of the AMPK activators described above, including resveratrol and metformin, extend healthy lifespan in Caenorhabditis elegans , and genetic studies show that the AMPK orthologue is required for these effects, as well as for the life-extending effects of dietary restrictio”
The hallmarks of aging. (2013, background): “There is evidence indicating that AMPK activation may mediate lifespan extension following metformin administration to worms and mice (Anisimov et al., 2011; Mair et al., 2011; Onken and Driscoll, 2010).”
Metformin as a Tool to Target Aging (2016, positive): “Also, other investigators have suggested additional mechanisms for metformin actions (De Haes et al., 2014; Onken and Driscoll, 2010) supporting widely pleotropic effects.”
Extending life span by increasing oxidative stress. (2011, background): “elegans activates AMPK and subsequently promotes adaptive processes involved in CR and oxidative stress response, culminating in extended life span [61].”
Epigenetics and aging (2016, background): “elegans (217, 218) and male mice (219), together with some of the benefits seen with CR.”
Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism (2013, background): “Strikingly, in a sams-1 mutant, metformin reduced lifespan ( 38%, p 0.001), reminiscent of the effect of metformin on eat-2 mutants (Onken and Driscoll, 2010).”