Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction.
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.
Pearson
Kevin J
KJ
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.
Lewis
Kaitlyn N
KN
Price
Nathan L
NL
Chang
Joy W
JW
Perez
Evelyn
E
Cascajo
Maria Victoria
MV
Tamashiro
Kellie L
KL
Poosala
Suresh
S
Csiszar
Anna
A
Ungvari
Zoltan
Z
Kensler
Thomas W
TW
Yamamoto
Masayuki
M
Egan
Josephine M
JM
Longo
Dan L
DL
Ingram
Donald K
DK
Navas
Placido
P
de Cabo
Rafael
R
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
D007328:Insulin; D051267:NF-E2-Related Factor 2; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase