Loss of Metabolic Plasticity Underlies Metformin Toxicity in Aged Caenorhabditis Elegans
Abstract
Current clinical trials are testing the life-extending benefits of the diabetes drug metformin in healthy individuals without diabetes. However, the metabolic response of a non-diabetic cohort to metformin treatment has not been studied. Here, we show in C. elegans and human primary cells that metformin shortens lifespan when provided in late life, contrary to its positive effects in young organisms. We find that metformin exacerbates ageing-associated mitochondrial dysfunction, causing respiratory failure. Age-related failure to induce glycolysis and activate the dietary-restriction-like mobilization of lipid reserves in response to metformin result in lethal ATP exhaustion in metformin-treated aged worms and late-passage human cells, which can be rescued by ectopic stabilization of cellular ATP content. Metformin toxicity is alleviated in worms harbouring disruptions in insulin-receptor signalling, which show enhanced resilience to mitochondrial distortions at old age. Together, our data show that metformin induces deleterious changes of conserved metabolic pathways in late life, which could bring into question its benefits for older individuals without diabetes.
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The enhanced toxicity to metformin in older worms was linked to reduced mitochondria abundance and the reduced ability to generate ATP.
“The enhanced toxicity to metformin in the older worms was linked to reduced mitochondria abundance and the reduced ability to generate ATP – see Table 1 for details (72).”
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 [72]
In old C. elegans all concentrations of metformin, 10, 25 and 50 mM, proved toxic and reduced lifespan.
“Furthermore, in old C. elegans all concentrations of metformin, 10, 25 and 50 mM, proved toxic and reduced lifespan (72).”
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 [72]
Despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and is notably less effective, or not effective, in older animals, including C. elegans.
“For instance, as discussed in the next section, despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and notably less, or not effective in older animals, including C. elegans (66, 72, 74, 75, 77, 78).”
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 [72]
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- Authors
- Espada, L., Dakhovnik, A., Chaudhari, P., Martirosyan, A., Miek, L., Poliezhaieva, T., Schaub, Y., Nair, A., Döring, N., Rahnis, N., Werz, O., Koeberle, A., Kirkpatrick, J., Ori, A., & Ermolaeva, M. A.
- Affiliations
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Friedrich Schiller University Jena (DE)
- Universität Innsbruck (AT)
- The Francis Crick Institute (GB)
- Corresponding author
- Ermolaeva, Maria A.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2020-11-02
- Volume
- 2
- Issue
- 11
- Pages
- 1316-1331
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W3096996875
- Cited by
- 100
- References
- 82
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 22 · 2023: 20 · 2022: 17 · 2021: 20 · 2020: 1
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (GRK 1715/2-TP27-Ermo)
- Deutscher Akademischer Austauschdienst (Poliezhaieva)
- 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 toxicity, metabolic plasticity, aging, Caenorhabditis elegans, lifespan, mitochondrial dysfunction, respiratory failure, glycolysis, insulin receptor signaling, insulin resistance, dietary restriction, drug safety in older adults
- MeSH terms
- Adenosine Triphosphate, Aging, Animals, Glycolysis, Humans, Hypoglycemic Agents, Life Expectancy, Metabolism, Metformin, Receptor, Insulin, Signal Transduction, Caenorhabditis elegans, Mitochondrial Diseases, Caloric Restriction, Lipid Metabolism, Primary Cell Culture, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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