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

@entity5 @entity157 @entity19 @entity74
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 @entity5 . 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 @entity5 . As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and @entity5 . 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 @entity19 and is associated with a significant reduction in the subsequent development of spontaneous @entity157 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 @entity19 at age intervals of 12, 18, 24, and 30 months. The incidence of apoptotic bodies was enumerated in non- @entity5 -bearing @entity19 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 @entity19 , relative to the ad libitum-fed @entity19 , 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 @entity74 and age-related @entity5 . An increase in the intrinsic rate of apoptotic cell death may contribute, in part, to decreased @entity5 incidence and increased life span potential with dietary restriction.
