UP-REGULATION OF APOPTOSIS WITH DIETARY RESTRICTION - IMPLICATIONS FOR CARCINOGENESIS AND AGING

The maintenance of cell number homeostasis in normal tissues reflects a highly regulated balance between the rates of cell proliferation and cell death. Under pathologic conditions such as exposure to cytotoxic , genotoxic, or nongenotoxic agents, an imbalance in these rates may i ndicate subsequent risk of carcinogenesis. Apoptotic cell death, as op posed to necrotic cell death, provides a protective mechanism by selec tive elimination of senescent, preneoplastic, or superfluous cells tha t could negatively affect normal function and/or promote cell transfor mation. The relative efficiency or dysfunction of the cell death progr am could therefore have a direct impact on the risk of degenerative or neoplastic disease. Dietary restriction of rodents is a noninvasive i ntervention that has been reproducibly shown to retard tumor developme nt and most physiologic indices of aging relative to ad libitum-fed an imals. As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and cancer. In a rece nt study we established that chronic dietary restriction (DR) induces an increase in spontaneous apoptotic rate and a decrease in cell proli feration rate in hepatocytes of 12-month-old B6C3F1 DR mice relative t o ad libitum (AL)-fed mice. This diet-induced shift in cell death/prol iferation rates was associated with a marked reduction in subsequent d evelopment of spontaneous hepatoma and a marked increase in disease-fr ee life span in DR relative to AL-fed mice. These results suggest that total caloric intake may modulate the rates of cell death and prolife ration in a direction consistent with a cancer-protective effect in DR mice and a cancer-promoting effect in AL mice. To determine whether t he increase in spontaneous apoptotic rate was maintained over the life span of DR mice, apoptotic rates were quantified in 12-, 18-, 24- and 30-month-old DR and AL mice. The rate of apoptosis was elevated with age in both diet groups; however, the rate of apoptosis was significan tly and consistently higher in DR mice regardless of age. In double-la beling experiments, an age-associated increase in the glutathione S-tr ansferase-II expression in putative preneoplastic hepatocytes in AL mi ce was rapidly reduced by apoptosis upon initiation of DR. Thus, inter ventions that promote a low-level increase in apoptotic cell death may be expected to protect genotypic and phenotypic stability with age. I f during tumor promotion an adaptive increase in apoptosis effectively balances the dysregulated increase proliferation, the risk of permane nt genetic error and carcinogenesis would be minimized.