Do DNA Double-Strand Breaks Drive Aging?

Abstract

DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.

Figure 1. Models to study DSB-induced aging

Two methods to induce clean DSBs provide tools to dissect the age-related consequences stemming from DSBs alone. The first method induces DSBs via adenoviral delivery of a restriction enzyme, SacI, which is under control of tetracycline and tamoxifen (White et al., 2015). The second method, a transgenic mouse model, induces DSBs conditionally using the I-PpoI restriction enzyme fused to GFP under control of tamoxifen, and in a tissue-specific manner using Cre recombinase (Kim et al., 2015).

Figure 2. DNA double-strand breaks (DSBs), cellular consequences, and the pathways leading to aging

DSBs, arising endogenously or exogenously, activate the DDR that directs cells to repair the break, enter apoptosis, or undergo cellular senescence. The resulting molecular and cellular end points can cause the physiologically detrimental consequences over time leading to the overall decline of an organism, ultimately resulting in disease and death.