Deletion of Ku86 causes early onset of senescence in mice

DNA double-strand breaks formed during the assembly of antigen receptors or after exposure to ionizing radiation are repaired by proteins important fo r nonhomologous end joining that include Ku86, Ku70, DNA-PKCS, Xrcc4, and D NA ligase IV. Here me show that ku86-mutant mice, compared with control lit termates, prematurely exhibited age-specific changes characteristic of sene scence that. include osteopenia, atrophic skin, hepatocellular degeneration , hepatocellular inclusions, hepatic hyperplastic foci, and age-specific mo rtality. Cancer and likely sepsis (indicated by reactive immune responses) partly contributed to age-specific mortality for both cohorts, and both con ditions occurred earlier in ku86(-/-) mice. These data indicate that Ku86-d ependent chromosomal metabolism is important for determining the onset of a ge-specific changes characteristic of senescence in mice.