Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration.

<h4>Introduction</h4>Genome maintenance is increasingly recognized as a shared vulnerability across aging, cancer, and neurodegeneration, yet the therapeutic implications of pathway-specific dysregulation of DNA repair remain incompletely defined.<h4>Areas covered</h4>This review integrates recent mechanistic and translational literature on how base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, canonical non-homologous end joining, and alternative end joining are remodeled across these conditions. We discuss how oxidative stress, replication stress, telomere(definition) dysfunction, mitochondrial injury, and persistent DNA damage response signaling drive senescence(definition) and inflammation; how tumor cells exploit repair rewiring to survive genotoxic stress and acquire resistance; and how post-mitotic neurons are limited by restricted repair redundancy. We also summarize biomarkers for repair-state stratification and emerging strategies targeting PARP, ATR, ATM, DNA-PK, POLQ, and cGAS-STING.<h4>Expert opinion</h4>Clinical translation will depend less on single-gene alterations than on defining context-specific repair states and pathway dependencies. Such stratification should enable rational combinations that either restore repair fidelity in aging and neurodegeneration or exploit repair addiction in cancer.