Editors' ChoiceMetabolism

Microbes Hold the Key to Metformin-Induced Longevity

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Science Translational Medicine  17 Apr 2013:
Vol. 5, Issue 181, pp. 181ec65
DOI: 10.1126/scitranslmed.3006316

Eternal youth is just a myth, but man’s quest for longer life is alive and well. Involuntary caloric restriction prolongs life span in many animals, but medications that mimic caloric restriction may be a more realistic way to delay aging in humans. Metformin—used worldwide to reduce hyperglycemia and hyperinsulinemia in diabetics—is one such medication that mimics caloric restriction across animal phyla and prolongs life in rodents and nematodes.

Cabreiro and colleagues wanted to elucidate the mechanism by which metformin extends life in a common nematode model of aging, Caenorhabditis elegans. They assumed that metformin’s effects in C. elegans would be a result of activation of adenosine 5´-monophosphate–activated protein kinase and related pathways, which has been observed in humans and other animals on metformin. Instead, they found a surprising dependence of metformin’s anti-aging effects on the Escherichia coli bacteria on which the worms subsisted. In a series of experiments, they showed that live bacteria are necessary for life span extension by metformin and that bacterial pretreatment with metformin is sufficient to prolong life span of the worms, without direct drug exposure. Correspondingly, axenic growth media and ultraviolet treatment of E. coli before feeding removed the anti-aging effects of metformin. Dissecting this relationship further, the authors show that metformin-induced alterations in bacterial folate metabolism were responsible for increasing life span in the host, primarily by limiting the amount of methionine produced by bacteria and available for uptake. Notably, dietary methionine restriction has been previously associated with life-span extension in fruit flies and rodents, and metformin has been associated with folate deficiency in humans, supporting the validity of these findings.

This study represents a potential breakthrough in understanding the mechanisms by which metformin mimics dietary and caloric restriction to confer health benefits in diabetic and nondiabetic patients. The results need to be confirmed in mammals before being translated into humans, but they suggest that the microbiome may contribute to the therapeutic response in patients receiving metformin. Future clinical trials of metformin should include analysis of the microbiome and metabolism of folate and methionine.

F. Cabreiro et al., Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013). [Abstract]

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