Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction

doi:10.1073/pnas.0712162105

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction

Laboratories of *Experimental Gerontology,
^††Clinical Investigation, and
^‡‡Immunology and
^§Research Resources Branch, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224;
^†Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas, and El Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Carretera de Utrera km 1, 41013 Seville, Spain;
^‡Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
^¶Department of Physiology, New York Medical College, Valhalla, NY 10595;
^‖Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21202;
**Center for Tsukuka Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan; and
^§§Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808

Communicated by Paul Talalay, Johns Hopkins University School of Medicine, Baltimore, MD, December 27, 2007 (received for review November 23, 2007)

Abstract

Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogen-detoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR.

Footnotes

^¶¶To whom correspondence should be addressed. E-mail: decabora{at}grc.nia.nih.gov
Author contributions: K.J.P., D.K.I., P.N., and R.d.C. designed research; K.J.P., K.N.L., N.L.P., J.W.C., E.P., M.V.C., K.L.T., S.P., A.C., Z.U., and R.d.C. performed research; M.Y. contributed new reagents/analytic tools; K.J.P., K.N.L., A.C., Z.U., T.W.K., J.M.E., D.L.L., D.K.I., P.N., and R.d.C. analyzed data; and K.J.P., K.N.L., T.W.K., J.M.E., D.L.L., D.K.I., P.N., and R.d.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0712162105/DC1.
Freely available online through the PNAS open access option.