EFFECT OF FOOD RESTRICTION ON LIFE-SPAN AND IMMUNE FUNCTIONS IN LONG-LIVED FISCHER-344-X BROWN-NORWAY F1 RATS

Life-long food restriction is known to slow aging and reduce the rate of occurrence of age-associated disease processes, but the mechanism b y which this is accomplished is unknown. In this study we have examine d the effect of food restriction on the proliferative response of sple en cells to mitogens and lymphokine production in 6-, 18-, and 30-mont h-old AL and FR Fischer-344 X Brown Norway (F-344XBNF(1)) female rats whose average life span is 137 weeks on an ad libitum (AL) diet and 17 7 weeks on a food-restricted (FR) diet. In addition, the ability of fo od restriction to recall antigens was rested in 10-month-old rats by i mmunizing them with keyhole limper and hen's egg albumin and measuring proliferative response of draining lymph node cells to these antigens . Our results indicated that the spleen-cell proliferative response to phytohemagglutinin and concanavalin A (Con A) was equal in 6- and 18- month-old rats but declined significantly in 30-month-old AL rats comp ared to FR rats. Although flow cytometric analyses did not reveal diff erences for CD4, CD8, and Ig(+) cells with age, a significant rise in memory T cells (Ox-22(low)) in both CD4(+) and CD8(+) T-cell subset li neage was noted in AL-fed rats at 30 months of age. In FR rats, howeve r, only a minimal shift of naive T cells (OX-22(high)) to memory cells was observed. In FR rats, the observed changes in the naive and memor y T-cell subsets correlate well with the observed higher levels of the antiinflammatory interleukin-2 (IL-2) and lower levels of the proinfl ammatory cytokines such as IL-6 and tumor necrosis factor-alpha. The a bility of food-restricted animals to recall antigens was lower compare d to their age-matched controls, though the proliferative response to T-cell mitogen Con A and superantigen staphylococcal enterotoxin B was higher. These findings indicate that food restriction may selectively act to maintain a lower number of antigen-induced memory T cells with age, thereby maintaining the organism's ability to produce higher lev els of IL-2 with age. In summary, the increased cell-mediated immune f unction noted in aged FR rats appears to be due to the presence of a h igher number of naive T cells, which are known to produce elevated lev els of the antiinflammatory cytokines, which may in part be responsibl e for reducing the observed age-related rise in disease.