Effects of aging and caloric restriction on the genotoxicity of four carcinogens in the in vitro rat hepatocyte/DNA repair assay

Abstract

The effects of aging and chronic caloric restriction (CR) on the genotoxicity of four carcinogens, representing four different classes of chemicals, in the in vitro rat hepatocyte/DNA repair assay were investigated. Hepatocyte cultures were isolated from young, middel-aged, and old male Fischer (F344) rats which were maintained on either an ad libitum (AL) or a CR diet (60% of AL). Hepatocyte cultures from old AL rats, treated with 2-acetylaminofluorene (2-AAF), aflatoxin B₁ (AFB₁), 7,12-dimethylbenz[a]anthracene (DMBA) and dimethylnitrosamine (DMN), exhibited age-related decreases in DNA repair as compared to young AL rats. By contrast, cultures from young CR rats exhibited significant diet-related decreases in DNA repair with 2-AAF, AFB₁, DMBA and DMN, when compared to results from young AL diet-fed rats. Old CR F344 rat derived cultures exhibited no significant age-related dose-dependent decrease in the DNA repair response with any of the chemicals tested. However, in cultures from old CR rats 10.0 μM AFB₁ produced an age-related decrease in DNA repair from the response observed in young CR rats. When hepatocytes were isolated from Aroclor 1254-induced rats, increases in DNA repair were observed. These data indicate an age- and diet-related decrease in DNA repair and/or DNA damage and suggest that this decrease is due to a decrease in metabolic activation of these carcinogens to genotoxic species.