Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

• Published in: Cell 2013-03, Vol.153 (1), p.228-239
• Main Authors: Cabreiro, Filipe, Au, Catherine, Leung, Kit-Yi, Vergara-Irigaray, Nuria, Cochemé, Helena M., Noori, Tahereh, Weinkove, David, Schuster, Eugene, Greene, Nicholas D.E., Gems, David
• Format: Article
• Language: English
• Subjects: Adenylate Kinase - metabolism; adverse effects; Aging - drug effects; Animals; bacteria; Biguanides - metabolism; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - metabolism; Caenorhabditis elegans - microbiology; Caenorhabditis elegans Proteins - metabolism; Caloric Restriction; coculture; Diabetes Mellitus, Type 2 - drug therapy; dietary restriction; DNA-Binding Proteins - metabolism; Escherichia coli; Escherichia coli - metabolism; folic acid; Folic Acid - metabolism; gastrointestinal system; glucose; Humans; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; intestinal microorganisms; longevity; Longevity - drug effects; mammals; mechanism of action; metabolic syndrome; metabolism; Metagenome; metformin; Metformin - metabolism; Metformin - pharmacology; methionine; Methionine - metabolism; methionine adenosyltransferase; methionine synthase; mutation; noninsulin-dependent diabetes mellitus; Transcription Factors - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.02.035

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 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. [Display omitted] [Display omitted] ► The antidiabetic drug metformin disrupts bacterial folate and methionine cycles ► This effect in C. elegans microbiota increases lifespan via methionine restriction ► Metformin increases lifespan only if microbiota are present and is otherwise toxic ► Microbiota may mediate metformin effects on mammalian health and aging Metformin, widely prescribed to treat diabetes, induces longevity in worms by altering host-microbiota interactions. By disrupting microbial folate and methionine cycles, metformin induces methionine restriction in the worm, which increases lifespan.