Metformin: an anti-diabetic drug that is also anti-aging?
Posted Feb 09 2010 11:45pm
To the growing list of small-molecule drugs that have a measurable effect on lifespan or healthspan (e.g., resveratrol and rapamycin) we should add metformin, an anti-diabetic drug that has shown promise as a calorie restriction mimetic. Onken & Driscoll determined some of the genetic requirements for metformin’s anti-aging properties in the worm C. elegans:
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.
Some of those genes might sound familiar…
SKN-1 encodes a transcription factor required for longevity enhancement by calorie restriction (CR) (but not intermittent fasting ) in worms and flies . The observation that metformin requires SKN-1 in order to extend median lifespan strongly suggests that the drug is acting via the same metabolic pathway as CR.
A quick aside about model systems: As it says in the first sentence of the abstract, metformin has already been studied in mice — so, why go “backward” to a simpler, smaller, and more divergent model system? Why not move forward, into humans? The answer has to do with the comparative ease with which certain types of genetic experiments can be performed in different systems; it’s simply easier in worms. Now that the genetics have been worked out, it will be more straightforward to do meaningful experiments in mammalian systems that are closer to our beloved H. sapiens.
Onken, B., & Driscoll, M. (2010). Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008758