THE BENEFICIAL-EFFECTS OF DIETARY RESTRICTION - REDUCED OXIDATIVE DAMAGE AND ENHANCED APOPTOSIS

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen spec ies in tumor initiation and promotion. Caloric restriction (CR) or ene rgy restriction retards age-associated increases in mitochondrial free -radical production and reduces the accumulation of oxidatively damage d cell components. CR has also been shown to slow down age-related dec lines in various repair capabilities, including some types of DNA repa ir. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, ami odarone, valinomycin, etc.), when used at extremely low doses, could m imic the effects of CR in model systems. The objective is to lower mit ochondrial free-radical production by decreasing the fraction of elect ron carriers in the reduced state. In addition to a variety of other e ffects, CR has been shown to increase the rate of apoptosis, particula rly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specifi c apoptosis and to upregulate gap-junction-mediated intercellular comm unication (GJIC). Tumor promoters like phorbol eaters have the opposit e effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a c entral role in apoptosis, in a manner that has been highly conserved i n evolution. There is good evidence that the apoptosis-associated Ca/M g-dependent DNA endonuclease is maintained in a latent form by being p oly (ADP-ribosylated). Apoptosis would require the removal of this pol ymer from the endonuclease, and, most likely, its removal from topoiso merase II and histone H1 as well. The role of poly (ADP-ribose) in apo ptosis, carcinogenesis, and aging could be studied by the use of modul ators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethan ol, etc.), inhibitors of poly (ADP-ribose) glycohydrolase activity (et hacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific pr otease (interleuken-1 beta converting enzyme (ICE)-like protease). Als o, it would be of interest to determine if CR can decrease the half-li fe of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors p otentially important in these processes.