DNA damage response overactivation proposed as driver of aging

A new review published in the journal Aging proposes that the chronic overactivation of the DNA damage response (DDR) may act as a primary driver of biological aging. Authored by Patrick E. Sewell of Triple Helix Science, the framework suggests that aging is not solely driven by mutations, as seen in cancer, but rather by the persistent dysregulation of intact tumor-suppressor pathways.

In healthy young tissues, DDR signaling activates temporarily to repair damage and then subsides. However, the review posits that factors such as telomere attrition, mitochondrial dysfunction, and epigenetic erosion can cause DDR to remain active. This chronic signaling can stabilize p53 and increase p21 and p16INK4a, leading to cell-cycle arrest and cellular senescence. These senescent cells may then release inflammatory mediators through the senescence-associated secretory phenotype (SASP), which can disrupt tissue homeostasis and contribute to systemic inflammation.