title: Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction.
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.
authors.affiliation: 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, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pearson
authors.forename: Kaitlyn N
authors.initials: KN
authors.lastname: Lewis
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Price
authors.forename: Joy W
authors.initials: JW
authors.lastname: Chang
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Cascajo
authors.forename: Kellie L
authors.initials: KL
authors.lastname: Tamashiro
authors.forename: Suresh
authors.initials: S
authors.lastname: Poosala
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.forename: Placido
authors.initials: P
authors.lastname: Navas
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D012680:Sensitivity and Specificity; D015996:Survival Rate
chemical_list: D007328:Insulin; D051267:NF-E2-Related Factor 2; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase