A number of potential mechanisms have been proposed to explain the inhibitory effect of caloric restriction on normal aging (Masoro, 1996). While some of these theories, including a retarda- tion of “growth” and the decrease in endogenous formation of reactive oxygen molecules, can be applied to the effect of caloric restriction on carcinogenesis, other mechanistic factors undoubt- edly play a role (Hocman, 1988b).
Paramount among the mechanisms of the effect of caloric restriction on aging and neo- plastic development are endogenous hormones. A striking effect is that described by Schwartz and Pashko (1994) in the demonstration that adrenalectomy could reverse the inhibition of skin papilloma development by food restriction in a two-stage carcinogenesis experiment involving DMBA initiation and TPA promotion. Furthermore, these authors demonstrated that adrenalec- tomy 2 weeks before initiating food restriction abolished the effect of the latter on the induction of pulmonary adenomas in A/J mice by DMBA (Pashko and Schwartz, 1996). The inhibition of mammary carcinogenesis by caloric restriction is also accompanied by a reduction in serum con- centrations of prolactin and estrogens in rats (Sylvester, 1986) and decreases in serum insulin- like growth factor I and insulin (Ruggeri et al., 1989).
A major potential mechanism for both the antiaging and anticarcinogenic effects of dietary restriction is the latter’s effect on intracellular oxidative stress (Yu, 1996). Caloric restriction inhibits the oxidative damage to DNA that occurs normally (Djuric et al., 1992; Gao and Chou,1992). The significance of this finding is emphasized by the demonstration that caloric restric- tion enhances activities of enzymes involved in antioxidant processes including superoxide dis- mutase, catalase, and glutathione peroxidase (G. Rao et al., 1990). However, these authors demonstrated that the effects on antioxidant enzymes did not occur in all tissues—e.g., intestinal mucosa—and in other tissues varied quite significantly (Xia et al., 1995). On the other hand, mitochondria in general and the electron transport system in particular are probably the most significant sources of active oxygen radicals (Feuers et al., 1993). Xenobiotic metabolism is sig- nificantly affected by caloric restriction. In Table 8.6 may be seen the effect of caloric restriction on some phase I and phase II enzyme levels in ad libitum and calorie-restricted animals (cf. Hart et al., 1992). Similarly, the formation of aflatoxin B1-DNA adducts in liver of calorie-restricted animals is decreased (Chou and Chen, 1997) and increased with dimethylnitrosamine (Prasanna et al., 1989). In the skin, food restriction inhibits the formation of DMBA-DNA adducts
Table 8.6 Effect of Caloric Restriction on Selected Hepatic Drug-Metabolizing Enzymes
(Schwartz and Pashko, 1986) after DMBA application but increases the formation of benzo[a]pyrene-DNA adducts in the lung of the mouse, with a concomitant increase in cyto- chrome P4501A1, which metabolizes benzo[a]pyrene en route to its active form (Chen et al.,
1996). Furthermore, caloric restriction increases the formation of endogenous I compounds (Chapter 3), spontaneous DNA adducts of largely unknown structure (Randerath et al., 1993). Thus, the role(s) of oxidative stress, xenobiotic metabolism, and DNA adduct formation in the mechanism of the antiaging and anticarcinogenic effect of caloric restriction are not entirely clear, but a lowering of intracellular oxidant reactions is a universal effect of caloric restriction.