Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24–26 months) exhibit greater sensitivity to H2O2 treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5–6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153(chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H2O2 treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats.gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H2O2 treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H2O2. We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging.
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Published, JBC Papers in Press, February 27, 2003, DOI 10.1074/jbc.M300677200
This work was supported in part by a grant from the Claude D. Pepper Older Americans Independence Center at Yale (T30AG21342) and NIADDK, National Institutes of Health Grant T30-3489 awarded to the Yale Liver Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
