Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1.
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.
Onken
Brian
B
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, United States of America.
Driscoll
Monica
M
D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D031204:Caloric Restriction; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D018384:Oxidative Stress; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D008687:Metformin; D000263:Adenylate Kinase