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

Abstract

Multiple pathways are involved in accurate synthesis and distribution of DNA during replication, repair and maintenance of genomic integrity. An increased error rate, abovethe spontaneous mutation baseline, has been implicated in carcinogenesis and aging. Moreover, cytogenetic abnormalities are increased in Down's, Edwards', Patau's, and Klinefelter's syndromes with increasing maternal age, and in Marfan's and Apert's syndromes with paternal age. In response to DNA damage, multiple overlapping systems of DNA repair have evolved, preferentially repairing the transcribed strand within transcriptionally-active regions of the genome. These include direct reversal of dimers and specific adducts and pathways for base excision, nucleotide excision, and mismatch repair. A consensus has emerged that some DNA repair capacities decline with organism age, contradictory reports notwithstanding. As is the case for inborn defects in humans, knockout mice lacking components of 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 with age but decreases with caloric restriction. We review recent studies of long-lived C. elegans mutants which appear to involve metabolic attenuation, the role of telomere shortening and telomerase in cellular senescence, and the genetic bases of progeroid syndromes in humans. Finally, we discuss roles of extrinsic and intrinsic factors in skin aging, and their association with DNA damage, emphasizing preventive and protective measures and prospects for intervention by modulating DNA repair pathways in the skin.

Telomere homolog oligonucleotides and the skin: current status and future perspectives

“…Most, if not all, of these protective responses were accomplished through induction of p53 (33–35). Furthermore, three different model systems demonstrated that pretreatment with pTT before UV irradiation reduced subsequent mutation frequency, in agreement with the demonstrated enhanced DNA repair (36–38). These studies were expanded to an ex vivo model (39) where pTT was shown to increase pigmentation, inhibit cell proliferation and speed the removal of UVR‐induced cyclobutane pyrimidine dimers in human skin.…”

Telomerase and Cancer: A Complex Relationship

“…Telomerase expression may lower the risk of malignant transformation by stabilizing the genome [1], either via DNA repair or by preventing telomere ends from being recognized as double stranded breaks by DNA repair mechanisms, although the length of telomere (rather than telomerase expression per se) may be the defining factor. A number of studies [74][75][76] support the consensus that DNA repair declines with age [77]. In a number of diseases, it is telomere lengthening and the prevention of cell senescence that improves chromosome stability [78,80], not vice versa, suggesting that longer telomeres may be essential to chromosomal stability [84].…”

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest‐Old Population

“…As concerns about longevity increase, many research studies have investigated longevity using model organisms to understand the association between genetic contribution and lifespan [ 23 , 24 , 26 , 41 – 43 ]. However, human lifespan is too complex to clearly elucidate its biological and sociocultural factors.…”