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

Cabreiro, F., et al. Cell 153, 228-239 (2013)

Speaker: Jui-Chieh Yin (尹睿婕)                  Time: 14:10~15:00, Dec.18, 2013

Commentator: Dr. Chang-Shi Chen (陳昌熙老師)    Place: Room 601

Abstract

Metformin is a biguanide drug commonly used to treat type-II diabetes and to reduce the risk of cancer. Metformin treatment increases the lifespan of Caenorhabditis elegans through AMP-dependent protein kinase (AMPK) upregulation under standard culture with E. coli as a food source(1). Gut microbes influence animal and human health and thus, are potential targets for interventions that slow aging (2). Here, the authors want to clarify the role that E. coli plays in mechanisms of metformin-induced lifespan expansion of C. elegans. In this study, they excluded several possible bacterial effects from metformin-induced lifespan expansion of C. elegans, including respiratory deficiency, different LPS types and blockade of bacterial proliferation. However, only live E. coli contributes to metformin-induced lifespan expansion of C. elegans. According to another report, C. elegans lives longer with reduced folate levels (2). The authors further verified that disruption of E.coli folate metabolism increased C. elegans lifespan however with little effect on folate levels of C. elegnas. In addition, they used mutations of worm methionine synthase and S-adenosylmethionine synthase to confirm metformin-mediated disruption in methionine metabolism of C. elegans and E. coli. On the other hand, metformin-induced worm AMPK α subunit AAK-2 and gst-4 (glutathione S-transferase 4) activations mainly protected C. elegans from drug toxicity due to metformin. Furthermore, metformin-induced lifespan expansion was sensitive to glucose concentration. In conclusion, metformin-induced lifespan expansion of C. elegans is mediated by disrupting folate and methionine metabolism of E. coli. This study demonstrates some interesting interactions among drug, host and microbiota, and offers a new venue for future drug development.

References:

1.    Onken, B. & Driscoll, M. 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, e8758 (2010).

2.    Virk, B., et al. Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model. BMC Biology 10, 67 (2012).