DNA Damage and Senescence Responses Alter Brain Function

Unrepaired or misrepaired DNA damage is thought to be a major cause of numerous aging phenotypes and pathologies. One common response to DNA damage is cellular senescence, a complex stress response that entails an essentially irreversible arrest of cell proliferation, relative resistance to cell death, and a multi-faceted, often pro-inflammatory, senescence-associated secretory phenotype (SASP). Senescent cells accumulate in many tissues, including the brain, in response to overt DNA damage such as that caused by radiation, genotoxic chemotherapies or other environmental exposures, which are also known to accelerate aging. Further, senescent cells accumulate in many tissues during natural aging. In the brain, astrocytes are a prominent cell type that undergoes senescence, although other cell types, including microglia, endothelial cells and even neurons, can also display senescence-associated markers. Senescent astrocytes express a SASP that shares several features of the SASPs of other cell types, including pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs). In addition, senescent astrocytes express unique features, including a marked reduction in genes that encode proteins designed to facilitate glutamate uptake. Upon senescence, human astrocytes become deficient in protecting human neurons from glutamate toxicity. Importantly, genetic or pharmacological ablation of senescent cells in mice protects against some forms of neurodegeneration and loss of brain function. On the horizon are a relatively new class of drugs, termed senolytics, that selectively target senescent cells for elimination and thus hold promise for ameliorating some of the pro-aging phenotypes associated with genomic damage.