Abstract
SummaryThe 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 cocultured 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.PaperClip
Highlights
Metformin is the world’s most widely prescribed drug, as an oral antihyperglycemic agent for type 2 diabetes (T2D) and in the treatment of metabolic syndrome
The real and potential benefits of metformin therapy go beyond its prescribed usage, including reduced risk of cancer (Dowling et al, 2011) and, in animal models, delayed aging, an effect seen in rodents (Anisimov et al, 2011) and in the nematode Caenorhabditis elegans (Onken and Driscoll, 2010)
One possibility is that metformin recapitulates the effects of dietary restriction (DR), the controlled reduction of food intake that can improve late-life health and increases lifespan in organisms ranging from nematodes and fruit flies to rodents and rhesus monkeys (Mair and Dillin, 2008)
Summary
The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin increases lifespan in Caenorhabditis elegans cocultured 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-induced alteration of microbial metabolism could contribute to therapeutic efficacy—and to its side effects, which include folate deficiency and gastrointestinal upset
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