Food restriction-like effects of dehydroepiandrosterone: decreased lymphocyte numbers and functions with increased...

Both dietary dehydroepiandrosterone (DHEA) and food restriction can prevent or modulate the initiation or progression of a number of diseases in rodents and prolong life span. We sought to determine if these interventions have common mechanisms of action in regulating lymphocyte functions and cell numbers. We observed that male C57BL/6 mice receiving DHEA in the diet (0.45%, w/w) ate approximately 50% as much food as mice on the DHEA-free diet, and this was reflected in decreased body weights throughout a 10-week period. Mice either fed the DHEA-containing diet or pair-fed to the DHEA-treated mice had decreased spleen and thymus weights and lymphocyte cell numbers compared to mice having free access to the control diet. Mice were fed these diets for 2 weeks before and 2 weeks after exposure to sublethal irradiation (500 cGy). In mice fed DHEA or pair-fed, there was a decrease in spleen cell numbers, and B cells were the most severely affected. The frequency of apoptosis in peripheral blood cells increased from <5% in nonirradiated controls to >50% within 4 days after starting DHEA or pair-feeding. Shortly after irradiation, >87% of blood lymphocytes were hypodiploid (apoptotic) in all groups. By 9 days only 27% of lymphocytes in mice on the control diet were hypodiploid compared to 62% in DHEA and 74% in pair-fed mice. In addition, both DHEA and pair-fed mice had significant reductions in T-cell function (contact hypersensitivity to dinitrofluorobenzene), B cell function (antibody response to trinitrophenolated-lipopolysaccharide), and NK cell function (lung clearance of radiolabeled YAC-1 tumor cells) 2 weeks after irradiation. In a complementary study, peripheral blood lymphocytes from naïve mice were treated overnight with various concentrations of either DHEA or hydrocortisone 21-acetate. Only glucocorticoid-treated cells underwent apoptosis. Thus, DHEA induces apoptosis in vivo but not in vitro. We conclude that dietary DHEA induces apoptosis and decreased lymphocyte production and function in C57BL/6 mice largely by reducing food intake.