FOOD RESTRICTION ELIMINATES PRENEOPLASTIC CELLS THROUGH APOPTOSIS ANDANTAGONIZES CARCINOGENESIS IN RAT-LIVER

Restriction of dietary calories reduces cancer formation in experiment al animals and probably also in humans. This effect is generally attri buted to the inhibitory effect of fasting on cell proliferation. Here we studied the effect of fasting on physiological cell death through a poptosis by using rat liver as a model. (i) In normal liver, involutio n of hyperplasia by apoptosis was reinforced by food withdrawal and su ppressed by feeding. Complete food withdrawal for 8 days or food reduc tion by 40% for 3 months eliminated 20-30% of normal liver cells throu gh apoptosis. (ii) Putative preneoplastic liver foci exhibited several fold higher rates of DNA replication and apoptosis than unaltered live r. Food restriction lowered DNA replication but increased apoptosis, w hich reduced the number and volume of putative preneoplastic liver foc i by 85% within 3 months. Subsequent return to ad libitum feeding norm alized cell replication and apoptosis but clear differences in the vol ume and number of putative preneoplastic liver foci persisted througho ut the following 17 months. Treatment of animals after food restrictio n with nafenopin, a peroxisome proliferator and potent tumor promoter, produced only half as many hepatocellular adenomas and carcinomas as in animals fed unrestrictedly throughout their lifetime. This indicate s that food restriction had actually eliminated a part of the initiate d cells. This study demonstrates that food restriction preferentially enhances apoptosis of preneoplastic cells. This effect in combination with lowered cell replication provides protection from carcinogenesis.