Role of immune responsiveness and DNA repair capacity genes in ageing

The genetic factors that determine immune responsiveness and DNA repair capacity are reviewed as major elements influencing the life span. Within this framework two sets of new data obtained in mice and humans are reported and discussed. As to the first set, the role of immune response genes was investigated in Biozzi mice genetically selected for high (H) or low (L) antibody response. After 15-20 generations of assortative mating, H and L mice exhibited almost complete intraline homozygosity and interline polymorphism including distinct H-2 haplotypes, such as q in H and s in L mice. In order to analyze the impact of quantitative trait loci (QTL) on the antibody response as well as on the DNA repair capacity in cells of the immune system independently of the selected H-2 haplotype, congenic Hq and Hs as well as Lq and Ls mice were produced and analysed. Both the antibody response and DNA repair capacity were found to be independent of the H-2 haplotype and determined by QTL. As to the second set of data, DNA repair was also studied in irradiated peripheral blood mononuclear cells (PBMC) from ageing humans. The levels of ku 70, ku 80, DNA-PKcs, phosphorylated ku 80 as well as the DNA-binding activity of the ku70/ku 80 heterodimer were determined in the cytoplasmic and nuclear extracts obtained, before and after irradiation, from young and elderly subjects. The results of this study suggest that the decreased DNA repair capacity in PBMC from elderly subjects may be related to impaired migration of the phosphorylated ku 80 from the cytoplasm to the nucleus. This finding helps to elucidate questions related to the impairment of DNA repair during ageing.