Acquisition of oxidative DNA damage during senescence: the first step toward carcinogenesis?

As a result of time and cumulative divisions in vitro and in vivo, normal cells enter an irreversible nonproliferative state termed replicative or cellular senescence that is thought to contribute to organism aging. Both telomere shortening and cumulative oxidative damage were shown to contribute to senescence, probably acting at different degrees according to proliferation index, cell type, or environment. Because of its associated cohort of damages and irreversible cell-cycle arrest induced by shortened telomeres, senescence is commonly considered as a tumor-suppressor mechanism that stops the proliferation of genetically altered cells (i.e., potentially cancerous). However, the incidence of the most frequent cancers in humans, carcinomas, exponentially increases with age; the phenotypes of progeroid syndromes are often associated with an increase in tumor incidence, and inversely when aging is delayed by caloric restriction, the cancer incidence decreases. How can this positive link between aging and tumorigenesis be explained if senescence is a tumor-suppressor mechanism? The present article considers data and arguments supporting a protumoral role of senescence. We focus on the importance of the oxidative damage that targets DNA during senescence. Indeed, because of its mutagenic effects, oxidative damage could affect oncogenes and/or tumor-suppressor genes in some senescent cells, hence promoting their evolution toward initiated cancer cells. This mechanism could be particularly relevant for age-associated carcinomas because senescence in epithelial cells is driven more by oxidative stress than by telomere shortening.