Arguing that Metformin Extends Life via Hormesis

The evidence for metformin to modestly slow aging and extend life in mammals is very mixed, with study results falling all over the map. This is worth bearing in mind when reading any new paper claiming metformin to extend life in other species, as this is just one more item in a distribution of results that does not show clear, compelling, easily replicated evidence of life extension. So that said, here researchers are suggesting that metformin extends life via hormetic effects. Since they are proposing a mechanism, this should lead to ways to better test and replicate the claim without involving metformin itself:

Recently it has been suggested that metformin, the most commonly used antidiabetic drug, might also possess general health-promoting properties. Elucidating metformin's mode of action will vastly increase its application range and will contribute to healthy aging.

Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance.

We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.



The data on metformin's (in)ability to slow aging and extend life in mammals is not really mixed at all. There are a whole bunch of studies in diabetic and/or obese and/or cancer-prone and/or toxin-administered and/or otherwise buggered-with mice. None of these are informative on this question. Then there is a reasonably good negative result in rats, and two excellent negative results from the NIA's Interventions Testing Protocol and the intrepid Dr. Stephen Spindler, reporting jointly that metformin has a very slight effect on mean life expectancy, but none on maximum lifespan.

In sum: consistently, metformin does not retard aging in otherwise-normal, healthy mammals.

Smith, DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. 2010 May; J Gerontol A Biol Sci Med Sci 65 (5): 468–74. doi:10.1093/gerona/glq033. PMID 20304770

Martin-Montalvo, A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. 2013 Jul;Nature Communications 4: 2192. doi:10.1038/ncomms3192. PMID 2390024.

Posted by: Michael at June 8th, 2014 6:43 PM

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