Caloric restriction decelerates premature aging and cognitive decline in mice with deficient DNA repair

Accumulation of DNA damage, particularly oxidative DNA damage, is a major molecular driver of senescence and aging. The enzyme apurinic/apyrimidinic endonuclease-1 (Apex1) is essential for base-excision repair, but its role in protecting the brain from age-related deterioration remains unclear. Here we show that conditional knockout (cKO) of Apex1 in forebrain neurons causes early and progressive cognitive impairment in mice. Apex1 cKO mice display deficits in spatial learning and memory (8-12 weeks), alongside reduced synaptic proteins, altered neuronal morphology, and impaired long-term potentiation at 48 weeks. We further show that a 30% caloric restriction (CR) regimen at 8-48 weeks markedly attenuates these premature aging features and improves cognitive outcomes in Apex1 cKO mice. These findings confirm Apex1 as a critical genomic maintenance factor in the aging brain and highlight the Apex1 cKO model as a valuable tool for studying endogenous defenses and dietary interventions against aging.