Upregulation of Apoptosis with Dietary Restriction: Implications for Carcinogenesis and Aging

Abstract

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 indicate subsequent risk of carcinogenesis. Apoptotic cell death, as opposed to necrotic cell death, provides a protective mechanism by selective elimination of senescent, preneoplastic, or superfluous cells that could negatively affect normal function and/or promote cell transformation. The relative efficiency or dysfunction of the cell death program could therefore have a direct impact on the risk of degenerative or neoplastic disease. Dietary restriction of rodents is a noninvasive intervention that has been reproducibly shown to retard tumor development and most physiologic indices of aging relative to ad libitum-fed animals. 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 (DR) induces an increase in spontaneous apoptotic rate and a decrease in cell proliferation rate in hepatocytes of 1 2-month-old B6C3F1 DR mice relative to ad libitum (AL)-fed mice. This diet-induced shift in cell death/proliferation rates was associated with a marked reduction in subsequent development of spontaneous hepatoma and a marked increase in disease-free life span in DR relative to AL-fed mice. These results suggest that total caloric intake may modulate the rates of cell death and proliferation in a direction consistent with a cancer-protective effect in DR mice and a cancerpromoting effect in AL mice. To determine whether the 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 significantly and consistently higher in DR mice regardless of age. In double-labeling experiments, an age-associated increase in the glutathione S-transferase-ll expression in putative preneoplastic hepatocytes in AL mice was rapidly reduced by apoptosis upon initiation of DR. Thus, interventions that promote a low-level increase in apoptotic cell death may be expected to protect genotypic and phenotypic stability with age. If during tumor promotion an adaptive increase in apoptosis effectively balances the dysregulated increase proliferation, the risk of permanent genetic error and carcinogenesis would be minimized.Environ Health Perspect 106(Suppl 1): 307-312 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-1/ 307-312james/abstract.html

Tissue-specific regulation of SIRT1 by calorie restriction

“…4A,B). Liver size reduction, which is triggered in part by apoptosis after imposition of CR (Grasl-Kraupp et al 1994;James et al 1998), also occurred normally in LKO mice (Fig. 4C).…”

“…First, because SIRT1 coactivates LXR, the reduced activity of this sirtuin in CR will decrease fat synthesis (Li et al 2007). Second, reduced SIRT1 activity may activate liver apoptosis, which is known to occur in response to CR (Grasl-Kraupp et al 1994;James et al 1998). Third, while SIRT1 deacetylation of PGC-1␣ activates mitochondrial biogenesis in the muscle, deacetylation of this coactivator by SIRT1 does not affect mitochondrial gene expression in the liver (Rodgers et al 2005).…”

How does calorie restriction work?

“…However, in some organs with rapidly dividing cells, apoptosis actually increases during CR, for example, in the liver (James et al 1998) and the gut (Holt et al 1998). This increase, along with the known shrinkage of cells during CR (Birchenall-Sparks et al 1985), may both contribute to the down-sizing of these organs in the restricted animal.…”

“…This increase, along with the known shrinkage of cells during CR (Birchenall-Sparks et al 1985), may both contribute to the down-sizing of these organs in the restricted animal. The increased rate of apoptosis may minimize the risk of cancer during CR (James et al 1998). The increase in apoptosis in these organs appears at odds with any central role for SIR2.…”

Biomarkers of Dietary Energy Restriction in Women at Increased Risk of Breast Cancer

“…Periods of intermittent restriction may thus be required to maintain these beneficial effects (10). Energy restriction is known to reduce cell proliferation and increase apoptotic rate in both normal tissues and cancers (60)(61)(62)(63). The inhibition of glycolysis has been shown to impair the growth of tumor cells (64,65), and suppression of glycolysis and fatty acid synthesis specifically in the breast epithelium may prevent breast carcinomas from developing and progressing.…”