Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1
Open Access
- 18 January 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 5 (1), e8758
- https://doi.org/10.1371/journal.pone.0008758
Abstract
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.Keywords
This publication has 90 references indexed in Scilit:
- The Glycogen-Binding Domain on the AMPK β Subunit Allows the Kinase to Act as a Glycogen SensorCell Metabolism, 2009
- Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegansCell, 2008
- An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegansCurrent Biology, 2007
- Overview of caloric restriction and ageingMechanisms of Ageing and Development, 2005
- The CREB coactivator TORC2 is a key regulator of fasting glucose metabolismNature, 2005
- Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contractionThe EMBO Journal, 2005
- Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegansNature, 2003
- Stochastic and genetic factors influence tissue-specific decline in ageing C. elegansNature, 2002
- A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegansNature, 1996
- A C. elegans mutant that lives twice as long as wild typeNature, 1993