Cell Replication and Apoptosis during Caloric Restriction
Generally, as one might expect, caloric restriction tends to decrease cell replication, DNA and RNA synthesis in various tissues of both the rat (Merry and Holehan, 1985) and the mouse (Lok et al., 1990). Interesting exceptions to this generalization have been noted, however. Klurfeld et al. (1987) found, in concert with earlier studies, that caloric restriction inhibited by almost 50% the formation of colon neoplasms in rats administered 1,2-dimethylhydrazine. However, caloric restriction induced a significant increase in the DNA labeling index of normal colonic mucosal cells. Similarly, Keenan and associates (1994) noted that both male and female rats fed for a year at a level of 65% of the ad libitum caloric intake exhibited a dramatic increase in the labeling index of hepatocytes. The mechanism of this effect may be related to a compensatory hyperpla- sia of the liver, resulting from the increased rate of apoptosis of hepatocytes that occurs with caloric restriction (James and Muskhelishvili, 1994; Grasl-Kraupp et al., 1994) in both mice and rats. Both of these groups suggested that the enhanced apoptotic rate occurring in the liver dur- ing caloric restriction might also explain the effect of caloric restriction in inhibiting the devel- opment of spontaneous neoplasms. Muskhelishvili et al. (1996) presented evidence for this in demonstrating that dietary restriction induced apoptosis in approximately 70% of putatively ini- tiated glutathione S-transferase-π-positive hepatocytes, occurring after only 1 week of dietary restriction to 2-year-old ad libitum–fed mice. Grasl-Kraupp et al. (1994) and associates reported a similar experiment in rats, utilizing a 95-day period of caloric restriction with subsequent ad- ministration of nafenopin, a promoting agent and peroxisome proliferator (Chapter 7). These authors continued their study to 900 days, examining both preneoplastic and neoplastic lesions, and demonstrated a dramatic decrease in the growth of preneoplastic lesions as well as the num- ber of neoplastic lesions (Figure 8.6). These studies, taken together, offer substantial evidence for a major role in the altered regulation of cell turnover in the calorically restricted animal by the elimination of initiated cells as well as the inhibition of proliferation and enhancement of apoptosis of cells in the stage of promotion, leading to lower rates of development of preneo- plastic lesions (Wachsman, 1996).