DNA is a key molecular target for age-related deterioration. DNA damages (abasic sites, oxidized bases, deaminated purines, glyoxal and methylglyoxal adducts, DNA-protein crosslinks, indigenous DNA adducts, and double-strand breaks, but not O6-methyldeoxyguanine and single-strand DNA breaks), somatic mutations (transitions and transversions, transposon excisions and insertions) and chromosome aberrations are accumulated with age simultaneously with the decrease of efficiency of some DNA repair pathways, including mismatch repair, base and nucleotide excision repair, non-homologous end joining. Age-related increase of DNA damage level leads to alterations in gene expression, cellular senescence and cancer. The mutations in genes involved in maintenance of DNA fidelity (WRN, RECQL4, BLM, lmna, XPA, -B, -C, -D, -F, -G, CSA, CSB, ATM, and NBS1) leads to accelerating aging syndromes. The dysfunction of numerous genes results in decreased lifespan, but this can be caused not only by the acceleration of healthy aging, but also by specific aging-independent pathologies. Studies of the lifespan of animals with overexpressed candidate longevity-assurance genes appear more promising. A recent our study has shown that overexpression of the stress response and DNA repair gene GADD45 in nervous system decreases the number of spontaneous single-strand DNA breaks and prolongs the maximum lifespan (27-33%) of Drosophila flies without the decreasing of life quality parameters (physical activity or reproduction). We have tested as well the life span and the health span of fruit flies with overexpression of DNA damage response genes (component of 9-1-1 complex Hus1, checkpoint kinase Chk2), homologous recombination genes (Rad51, Brca2), Werner syndrome gene Drosophila homolog WRNexo, excision nucleotide repair genes (XPG and ERCC1/XPF homologs). We would like to thank the Science for Life Extension Foundation (Mikhail Batin) and the Institute of Biology of Aging (Alex Peregudov) for financial support of the project.
DNA damage response