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Edited by Andy Dillin, University of California, Berkeley, CA, and accepted by the Editorial Board April 28, 2014 (received for review November 28, 2013)
Significance
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. We reveal a signaling cascade in which metformin is able to extend lifespan by increasing the production of reactive oxygen species (ROS). This allowed us to further work at the crossroads of human disease and aging research, identifying a key molecule that is able to translate the ROS signal into a prolongevity cue: an antioxidant peroxiredoxin is also able to activate a lifespan-promoting signaling cascade, here described in detail. Continued research efforts in this field lead toward a targeted improvement of aging-related complications.
Abstract
The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. 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.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: Liliane.Schoofs{at}bio.kuleuven.be.
Author contributions: W.D.H., B.P.B., L.S., and L.T. designed research; W.D.H., L.F., R.V.A., A.S., G.D., and J.B. performed research; W.D.H., L.F., R.V.A., A.S., and G.D. analyzed data; and W.D.H. and L.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. A.D. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1321776111/-/DCSupplemental.
Freely available online through the PNAS open access option.
Metformin functions through mitohormesis
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