Journal
CELL
Volume 153, Issue 1, Pages 228-239Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.02.035
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Funding
- Wellcome Trust (Strategic Award)
- European Union (LifeSpan)
- MRC [J003794]
- BBSRC [BB/H01974X/1] Funding Source: UKRI
- MRC [G0800339, MR/J003794/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H01974X/1] Funding Source: researchfish
- Medical Research Council [MR/J003794/1, G0800339] Funding Source: researchfish
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The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans co-cultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy-and also to its side effects, which include folate deficiency and gastrointestinal upset.
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