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American Journal of Pathology, Vol 147, 20-24, Copyright © 1995 by American Society for Investigative Pathology

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Age-related changes in the intrinsic rate of apoptosis in livers of diet-restricted and ad libitum-fed B6C3F1 mice

L Muskhelishvili, RW Hart, A Turturro and SJ James
Division of Nutritional Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, Arkansas, USA.

Cancer incidence increases progressively with age. This observation suggests that a mechanistic relationship may exist at the cellular level between these two apparently diverse processes. Indirect evidence for this fundamental relationship is derived from the fact that interventions that retard the rate of aging simultaneously retard the incidence of many forms of cancer. Dietary restriction of rodents is a noninvasive manipulation that reproducibly retards most physiological indices of aging as well as the incidence of spontaneous and chemically induced tumors. As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and cancer. In a recent study, we established that chronic dietary restriction induces an increase in the spontaneous rate of apoptotic cell death in hepatocytes of 12-month-old B6C3F1 mice and is associated with a significant reduction in the subsequent development of spontaneous hepatoma in this genetically susceptible strain. The purpose of the present investigation was to extend and confirm these original observations by determining whether the increased rate of spontaneous apoptosis with chronic dietary restriction is maintained throughout the life span in this strain. We quantified the spontaneous apoptotic rate by histological examination of liver sections from diet-restricted and ad libitum-fed B6C3F1 mice at age intervals of 12, 18, 24, and 30 months. The incidence of apoptotic bodies was enumerated in non-tumor- bearing mice by scoring 50,000 hepatocytes per liver by in situ end- labeling immunohistochemistry and was expressed as the mean incidence per 100 cells. The rate of apoptotic cell death was found to be elevated with age in both diet groups; however, the rate of apoptosis was significantly and consistently higher in the diet-restricted mice, relative to the ad libitum-fed mice, regardless of age. It has been proposed that apoptosis, or physiological cell death, provides a protective mechanism whereby DNA-damaged or potentially neoplastic cells are selectively eliminated. Thus, interventions that increase cellular sensitivity to apoptotic cell death would tend to protect genotypic and phenotypic stability with age; on the other hand, the failure to initiate or respond to appropriate signals for apoptosis would tend to accelerate the accumulation of age-associated genetic lesions and age-related neoplasia. An increase in the intrinsic rate of apoptotic cell death may contribute, in part, to decreased tumor incidence and increased life span potential with dietary restriction.

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