The guardian paradox: DNA damage response overactivation as an integrative driver of aging - a tumor suppressor-negative regulator framework.

Aging is multi-causal, yet its molecular hallmarks may converge on a few upstream integrating nodes. We advance the hypothesis that chronic, largely mutation-independent overactivation of the DNA damage response (DDR) is one such node, dysregulating the cell's intact guardian pathways-the tumor-suppressor networks and their negative regulators-to induce senescence, deplete stem-cell pools, and drive inflammaging. Unlike cancer, where mutations inactivate these guardians, aging more often reflects functional dysregulation of wild-type pathways, either chronically overactivated (p53, p16INK4a) or epigenetically silenced (SIRT1, FOXO3, NRF2, Klotho). That the very programs guarding against cancer can, when chronically engaged, come to drive aging we term the guardian paradox. We organize 16 candidate axes-which we term the aging axis-across three evidence tiers, mapped onto the hallmarks of aging, outlining for each a conceptual diagnostic signature and an illustrative restoration strategy, with all numeric biomarker bands and vector details confined to the Supplementary Information as non-clinical placeholders. We set this DDR-integrator hypothesis against mitochondria-, proteostasis-, and reprogramming-first models and pre-specify longitudinal, mediation, and head-to-head tests that could support, demote, or refute it. No integrated human interventional data yet exist; we therefore present a falsifiable research agenda, not a therapeutic protocol.