Acquisition of Oxidative DNA Damage during Senescence

摘要

As a result of time and cumulative divisions in vitro andin vivo, normal cells enter an irreversible nonproliferative state termedreplicative or cellular senescence that is thought to contribute to organ-ism aging. Both telomere shortening and cumulative oxidative damagewere shown to contribute to senescence, probably acting at different de-grees according to proliferation index, cell type, or environment. Becauseof its associated cohort of damages and irreversible cell-cycle arrest in-duced by shortened telomeres, senescence is commonly considered as atumor-suppressor mechanism that stops the proliferation of geneticallyaltered cells (i.e., potentially cancerous). However, the incidence of themost frequent cancers in humans, carcinomas, exponentially increaseswith age; the phenotypes of progeroid syndromes are often associatedwith an increase in tumor incidence, and inversely when aging is delayedby caloric restriction, the cancer incidence decreases. How can this pos-itive link between aging and tumorigenesis be explained if senescenceis a tumor-suppressor mechanism? The present article considers dataand arguments supporting a protumoral role of senescence. We focuson the importance of the oxidative damage that targets DNA duringsenescence. Indeed, because of its mutagenic effects, oxidative damagecould affect oncogenes and/or tumor-suppressor genes in some senescentcells, hence promoting their evolution toward initiated cancer cells. Thismechanism could be particularly relevant for age-associated carcinomasbecause senescence in epithelial cells is driven more by oxidative stressthan by telomere shortening.