Metformin Induces a Dietary Restriction-Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1 and SKN-1
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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.
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In C. elegans the beneficial effects of metformin on lifespan are, at least in part, argued to be mediated through changing the microbiome and modifying microbial folate and methionine metabolism and potentially due to an anti-oxidant action via transcription factors SKN-1/Nrf2, a requirement for AMPK and the upstream serine-threonine kinase LKB1.
“In C. elegans the beneficial effects of metformin on lifespan are, at least in part, argued to be mediated through changing the microbiome and modifying microbial folate and methionine metabolism and potentially due to an anti-oxidant action via transcription factors, SKN-1/Nrf2, a requirement for AMPK and the upstream serine-threonine kinase, liver kinase B1 (LKB1) (67, 71, 86).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [71]
Metformin was reported to extend lifespan in some animal models, acting as a diet mimetic agent.
“Metformin was also reported to extend lifespan in some animal models, acting as a diet mimetic agent (15–17).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [15]
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- Authors
- Onken, B., & Driscoll, M.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Driscoll, Monica
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-01-18
- Volume
- 5
- Issue
- 1
- Pages
- e8758
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2807458
- OpenAlex
- W2082603625
- Cited by
- 671
- References
- 101
- Citations by year
- 2026: 23 · 2025: 35 · 2024: 40 · 2023: 34 · 2022: 55 · 2021: 45 · 2020: 58 · 2019: 53 · 2018: 33 · 2017: 45 · 2016: 50 · 2015: 46 · 2014: 40 · 2013: 44 · 2012: 23
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (R01AG024882)
- National Center for Research Resources
- National Center for Complementary and Integrative Health (P50AT002776)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- metformin, healthspan extension, dietary restriction, AMPK, LKB1, SKN-1, Nrf2, oxidative stress response, aging, Caenorhabditis elegans, lipofuscin accumulation, insulin signaling, biguanides, sensory neurons, intestine
- MeSH terms
- Adenylate Kinase, Animals, DNA-Binding Proteins, Hypoglycemic Agents, Insulin, Metformin, Transcription Factors, Signal Transduction, Oxidative Stress, Caenorhabditis elegans Proteins, Caloric Restriction
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