ArticleNature metabolism2020
Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans.
Article in Nature metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 2 syntheses or guidelines pooled it, 98 citations in OpenAlex.
- Repurposing effect of cardiovascular-metabolic drug to increase lifespan: a systematic review of animal studies and current clinical trial progress.Frontiers in pharmacology · 2024Pooled it
- Pooled it
- Exploring the impacts of type 2 diabetes and metformin use on Parkinson's disease: Mendelian randomization analysis and a national cohort study.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- Metformin beyond Glycemic Control: New Mechanistic Insights and Expanding Therapeutic Horizons.Diabetes & metabolism journal · 2026Review
- Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.Nature communications · 2026Article
- Host Oxidative Response Capacity Determines Longevity Outcomes of Microbial Interventions.Aging cell · 2026Article
- Multilayered regulation of longevity in Caenorhabditis elegans.Molecules and cells · 2026Review
- Reporting quality, effect sizes, and biases for aging interventions: a methodological appraisal of the DrugAge database.npj aging · 2025Article
- Tumor microenvironment-activated ROS enhancers for effective inhibition of osteosarcoma.BMC biotechnology · 2025Article
- Lactate promotes longevity through redox-driven lipid remodeling inbioRxiv : the preprint server for biology · 2025Article
- Altered translation elongation contributes to key hallmarks of aging in the killifish brain.Science (New York, N.Y.) · 2025Article
- Biotransformation of Tire-Derived 6PPD and 6PPD-Q in Soil NematodeEnvironmental science & technology · 2025Article
- Environmental factors capable of broadly interfering with nutritional lifespan extension paradigms.iScience · 2025Article
- Article
- Article
- Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation.Nature communications · 2025Article
- Silybin A fromTheranostics · 2025Article
- Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms.PloS one · 2025Article
- Premature cognitive decline in a mouse model of tuberous sclerosis.Aging cell · 2024Article
- Geroprotective effects of GdVOBiogerontology · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.