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Nrf2 Mediates Cancer Protection but Not Prolongevity Induced by Caloric Restriction

Kevin J. Pearson, Kaitlyn N. Lewis, Nathan L. Price, Joy W. Chang, Evelyn Perez, Maria Victoria Cascajo, Kellie L. Tamashiro, Suresh Poosala, Anna Csiszar, Zoltan Ungvari, Thomas W. Kensler, Masayuki Yamamoto, Josephine M. Egan, Dan L. Longo, Donald K. Ingram, Placido Navas and Rafael de Cabo
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 7 (Feb. 19, 2008), pp. 2325-2330
Stable URL: http://www.jstor.org/stable/25451465
Page Count: 6
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Nrf2 Mediates Cancer Protection but Not Prolongevity Induced by Caloric Restriction
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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.

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