Age-associated decreases in human DNA repair capacity: Implications for the skin

Multiple pathways are involved in accurate synthesis and distribution of DN A during replication, repair and maintenance of genomic integrity. An incre ased error rate, above the spontaneous mutation baseline, has been implicat ed in carcinogenesis and aging. Moreover, cytogenetic abnormalities are inc reased in Down's, Edwards', Patau's, and Klinefelter's syndromes with incre asing maternal age, and in Marfan's and Apert's syndromes with paternal age . In response to DNA damage, multiple overlapping systems of DNA repair hav e evolved, preferentially repairing the transcribed strand within transcrip tionally-active regions of the genome. These include direct reversal of dim ers and specific adducts and pathways for base excision, nucleotide excisio n, and mismatch repair. A consensus has emerged that some DNA repair capaci ties decline with organism age, contradictory reports notwithstanding. As i s the case for inborn defects in humans, knockout mice lacking components o f nucleotide excision repair or DNA-damage checkpoint arrest have increased frequencies of skin and internal cancers, whereas mice overexpressing DNA repair genes have fewer spontaneous cancers. Oxidative stress and resultant free radicals can damage genomic and mitochondrial DNA; damage increases w ith age but decreases with caloric restriction. We review recent studies of long-lived C. elegans mutants which appear to involve metabolic attenuatio n, the role of telomere shortening and telomerase in cellular senescence, a nd the genetic bases of progeroid syndromes in humans. Finally, we discuss roles of extrinsic and intrinsic factors in skin aging, and their associati on with DNA damage, emphasizing preventive and protective measures and pros pects for intervention by modulating DNA repair pathways in the skin.