Genetic factors in immunity and aging.
Maximum life span is controlled by genes that regulate molecular mechanisms accounting for the synchrony of structural and functional changes in different cells and tissues of each member of a given species. The role of immune response genes was investigated in aging mice genetically selected for high (H) or low (L) antibody response (Biozzi mice). Results from genetic selection of over 1000 mice showed that genes expressed in the immune system affect life span and diseases. In most cases, the life span is longer in H than in L mice whereas the lymphoma incidence is remarkably higher in L than in H mice. Since DNA repair capacity is a property positively correlated with the maximum life span in several mammalian species, DNA repair was studied by use of hydroxyurea, a cell-synchronizing agent, and found to take place in irradiated human PBMC from young and, to a lesser extent, from adult subjects. Conversely, no repair was detected in irradiated PBMC from elderly subjects. DNA damage recognition and repair pathways involve several nuclear proteins, as double strand breaks are firstly recognized by proteins displaying helicase activity, such as ku 70/80, and then repair is carried out under the control of other proteins. Radiation-induced expression of activated ku(70/80) proteins, in terms of DNA-binding, was found in PBMC from young-adults but not from elderly subjects. Maintenance of DNA integrity is fundamental for normal immune functions, as suggested by the lack of V(D)J recombination in lymphocytes of knock-out mice deficient in ku 70 or ku 80 protein. However, whether the link between genetic factors and life span is mediated by the performance of the immune system remains to be demonstrated.
Doria
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G
Department of Biology, University of Rome "Tor Vergata", Rome, Italy. doriag@uniroma2.it
Frasca
D
D
D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D034961:Antigens, Nuclear; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005802:Genes, MHC Class II; D006801:Humans; D007109:Immunity / Q000235:genetics*; D000072200:Ku Autoantigen; D008136:Longevity / Q000235:genetics / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen