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Updated: Dec 2, 2025
Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans
Published on: September 7, 2021
Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans
Lilia Espada1, Alexander Dakhovnik1, Prerana Chaudhari1
1Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
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.
Insights
Metformin, a diabetes drug, may shorten lifespan in older individuals by worsening mitochondrial dysfunction and causing energy depletion. This contrasts with its benefits in younger organisms, raising questions about its use in non-diabetic aging populations.
Area of Science:
- Gerontology
- Metabolism
- Molecular Biology
Background:
- Current clinical trials investigate metformin's life-extending potential in healthy individuals.
- The metabolic effects of metformin in non-diabetic aging populations remain uncharacterized.
Purpose of the Study:
- To investigate the impact of metformin on lifespan and metabolic pathways in aged non-diabetic organisms and cells.
- To elucidate the mechanisms underlying metformin's effects on aging-associated mitochondrial function and energy metabolism.
Main Methods:
- Studies were conducted using Caenorhabditis elegans and human primary cells.
- Assessed lifespan, mitochondrial respiration, glycolysis, lipid mobilization, and ATP levels.
- Investigated the role of insulin-receptor signaling in metformin's effects.
Main Results:
- Metformin shortened lifespan in aged C. elegans and late-passage human cells, exacerbating mitochondrial dysfunction and leading to ATP exhaustion.
- Age-related impairment in glycolysis and lipid mobilization contributed to metformin-induced toxicity.
- Reduced insulin-receptor signaling conferred resilience to metformin's detrimental effects.
Conclusions:
- Metformin induces harmful metabolic changes in conserved pathways during late life.
- The findings question the potential benefits of metformin for older individuals without diabetes.
- Metformin's efficacy and safety in aging populations warrant further investigation.
