When OGG1 and APE1 activity fall with age, unrepaired 8-oxoG lesions trigger PARP1 hyperactivation and an NAD+/ATP crisis that activates AMPK‑ULK1‑dependent autophagy. This autophagy is traditionally viewed as an energy‑rationing measure that fuels BER by recycling metabolites and clearing ROS‑producing mitochondria. However, the same autophagic flux also depletes cytosolic nucleotide pools through enhanced salvage and catabolism of nucleic‑acid‑rich organelles. Polymerase β, the key gap‑filling enzyme in BER, depends on a steady supply of dNTPs to complete repair after APE1 incision. If autophagy excessively consumes dNTP precursors, the nuclear dNTP concentration drops below the Km of polymerase β, causing accumulation of toxic repair intermediates (abasic sites and single‑strand breaks) that further stimulate PARP1. Thus, autophagy shifts from a supportive response to a direct aggravator of the very DNA lesion it aims to alleviate.

Testable predictions: (1) In primary cultured neurons with CRISPR‑mediated OGG1 knockdown, pharmacological induction of autophagy (e.g., rapamycin) will reduce lysosomal dNTP levels measured by LC‑MS, coinciding with increased γH2AX and 8-oxoG foci despite unchanged mitochondrial ROS. (2) Supplementing neurons with membrane‑permeable dNTP precursors (deoxyribonucleosides) during autophagy induction will rescue BER completion, lower PARP1 activity, and improve ATP/NAD+ ratios without altering autophagosome count. (3) In aged mouse brains, neuron‑specific overexpression of a lysosomal dNTP transporter (e.g., NT5C2) will attenuate the correlation between LC3‑II accumulation and DNA damage markers, breaking the predicted vicious cycle.

Falsifiable outcomes: If autophagy induction does not lower cytosolic dNTP pools, or if dNTP supplementation fails to mitigate DNA damage despite restored autophagy flux, the hypothesis that autophagy‑mediated nucleotide starvation drives BER insufficiency would be refuted. This reframes autophagy in aging neurons not merely as a failing energy‑recycling system but as a potential sink for the nucleotides essential for nuclear DNA repair, offering a new target for interventions that decouple protective mitophagy from harmful nucleotide depletion.