Many theories have been put forth to explain the mechanisms of aging, but at the present time the basic underlying biological mechanisms are unknown. The immune system has an important, perhaps crucial, function in the aging process. The long range goal of this project is to study the genetic basis for cellular aging in the immune system. Emphasis will be on the role of the H-2 gene complex in lymphocyte aging. The grant will focus on two mouse strains, the long-lived C57BL/6J (H-2b) strain and the short-lived A/J (H-2a) strain. Two types of chimeric mice will be produced to study lymphocytes from the short-lived strain and the long-lived strain in the environment of a single animal. Allophenic mice (primary chimeras) and bone marrow chimeras (secondary chimeras) will be produced and bled at two month intervals. The proportion of long-lived vs. short-lived lymphocytes will be determined by H-2 typing and the hypothesis that overall lifespan is determined by the percentage of lymphocytes from the long-lived strain will be tested. An Aged Mouse Colony will be produced from the C57BL/6J (P1) and A/J (P2) mouse strains. P1, P2, F1, F2 and backcross mice from the Aged Mouse Colony will be analyzed for lifespan and H-2 haplotype to test for linkage of gene(s) determining lifespan with the H-2 complex. Lymphocytes from animals in the Aged Mouse Colony will be used to quantitate the amount of H-2 and Ia antigens, at the protein and mRNA levels, as a function of age. Preliminary data has suggested that the amount of H-2 (Kk) protein increases on lymphocytes from the A strain with age. The hypothesis, that there is an optimal level of cell surface H-2 antigens on lymphocytes, necessary for optimal immune function, will be tested. Too high a concentration of H-2 antigens on the cell surface of aged animals may be as deleterious to immune function as too low a concentration in young animals.
