Metformin improves healthspan and lifespan in mice
Open accessAbstract
Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
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In mice and C. elegans, metformin extends lifespan and improves several healthspan indicators.
“In mice and C. elegans, metformin extends lifespan and improves several indicators of healthspan”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Martin-Montalvo et al. 2013
Metformin activates AMPK via an LKB1-dependent mechanism, mediating lifespan and healthspan extension in mice and C. elegans.
“metformin activates AMPK via LKB1-dependent mechanism, mediating its effect on lifespan and healthspan extension in mice and C. elegans”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Martin-Montalvo et al. 2013
The diabetes drugs metformin and acarbose prolong lifespan in mice that do not have diabetes.
“Existing diabetes therapies, namely metformin and acarbose, extend lifespan in nondiabetic mice (86,87).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [87]
Metformin prolonged the healthy lifespan of mice in 2013.
“In 2013, metformin prolonged the healthy lifespan of mice.53”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [53]
In relatively long-lived C57BL/6 mice and genetic hybrid mice, a similar phenomenon was observed.
“In subsequent recent studies, in the relatively long-lived C57BL/6 mice and genetic hybrid mice, a similar phenomenon was observed [179, 180].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [180]
Long-term treatment with 0.1% metformin w/w supplemented in the diet beginning in middle age increased healthspan and lifespan in male mice.
“The lifespan-extending effects of metformin have been investigated by Martin-Montalvo et al. in male mice, and indicate that long-term treatment with 0.1 percent metformin w/w supplemented in the diet and beginning in middle age, increased healthspan and lifespan (76) (see Table 1).”
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 [76]
The effects of metformin were reported to be similar to those of calorie restriction, including improved insulin sensitivity and lower cholesterol levels.
“The effects of metformin were reported to be similar to those of calorie restriction, including improved insulin sensitivity and lower cholesterol levels (76).”
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 [76]
Collectively, these results demonstrated that the mTOR pathway has a role in lifespan extension in mammals.
“Collectively, these results demonstrated that the mTOR pathway has a role in lifespan extension in mammals, but raise the question as to why, with the exception of the study by Martin-Montalvo et al., metformin does not extend lifespan in mammals whereas rapamycin does (76).”
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 [76]
With the exception of the study by Martin-Montalvo et al., metformin does not extend lifespan in mammals whereas rapamycin does.
“Collectively, these results demonstrated that the mTOR pathway has a role in lifespan extension in mammals, but raise the question as to why, with the exception of the study by Martin-Montalvo et al., metformin does not extend lifespan in mammals whereas rapamycin does (76).”
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 [76]
A higher dose of 1% metformin w/w was toxic and decreased the average lifespan of mice by 14.4%.
“A higher dose of 1% metformin w/w, on the other hand, was toxic and decreased the average lifespan of mice by 14.4% (76).”
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 [76]
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 [16]
The effects of metformin on transcription mimic the gene expression profile of animals on CR through the transcriptional regulatory pathways controlling lifespan extension.
“There are now several reports demonstrating that the effects of metformin on transcription mimic the gene expression profile of animals on CR through the transcriptional regulatory pathways controlling lifespan extension (Anisimov et al., 2011b; Martin-Montalvo et al., 2013).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Martin-Montalvo et al., 2013
Metformin increases mean and maximum lifespan in different female mouse strains predisposed to high incidence of mammary tumors.
“Metformin increases mean and maximum lifespan in different female mouse strains predisposed to high incidence of mammary tumors (Anisimov et al., 2011b; Martin-Montalvo et al., 2013).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Martin-Montalvo et al., 2013
Metformin extends longevity in mice.
“metformin was shown to extend longevity in worms(2) and mice(3) (although not in Drosophila(275)).”
Metformin targets several age-related pathways.
“Metformin has now been found to target several age-related pathways(3, 276, 277)”
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Self-citation
- Authors
- Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., Schwab, M., Pollak, M., Zhang, Y., Yu, Y., Becker, K. G., Bohr, V. A., Ingram, D. K., Sinclair, D. A., Wolf, N. S., Spindler, S. R., Bernier, M., & de Cabo, R.
- Affiliations
- National Institutes of Health (US)
- The University of Sydney (AU)
- University of California, Riverside (US)
- Harvard University (US)
- McGill University (CA)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- Pennington Biomedical Research Center (US)
- University of Washington (US)
- ORCID
- Venue
- Nature Communications
- Published
- 2013-07-30
- Volume
- 4
- Issue
- 1
- Pages
- 2192-2192
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3736576
- OpenAlex
- W2164361361
- Cited by
- 1,445
- References
- 54
- Citations by year
- 2026: 93 · 2025: 107 · 2024: 113 · 2023: 134 · 2022: 154 · 2021: 157 · 2020: 116 · 2019: 121 · 2018: 101 · 2017: 93 · 2016: 84 · 2015: 92 · 2014: 68 · 2013: 10
- FWCI
- 30.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- GlaxoSmithKline
- National Institutes of Health
- National Institute on Aging (Z01AG000363)
- 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 › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- metformin, healthspan, lifespan extension, aging, AMPK, oxidative damage, chronic inflammation, insulin sensitivity, lipid metabolism, dose-dependent toxicity, type 2 diabetes
- MeSH terms
- Animals, Antioxidants, Electron Transport, Enzyme Activation, Health, Inflammation, Longevity, Male, Metformin, Mice, Inbred C57BL, Mitochondria, Biomarkers, Survival Analysis, Caloric Restriction, Mice, AMP-Activated Protein Kinases, Transcriptome
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