Genome Maintenance Theory

What it proposes

DNA damage accumulates throughout life from endogenous (replication errors, ROS, hydrolytic damage) and exogenous (UV, ionising radiation, chemicals) sources. Each cell experiences tens of thousands of lesions per day. Multiple repair pathways exist:

• Base excision repair (BER) for small lesions.
• Nucleotide excision repair (NER) for bulky lesions / UV damage.
• Mismatch repair (MMR) for replication errors.
• Double-strand break repair (homologous recombination, NHEJ).
• Translesion synthesis for unrepaired lesions during replication.

When damage rate exceeds repair capacity, mutations accumulate, genomic instability rises, and downstream events (senescence, cancer, neurodegeneration) follow.

Evidence

• Progeroid syndromes caused by inherited defects in DNA repair (Werner, xeroderma pigmentosum, Cockayne, ATM) recapitulate features of accelerated aging.
• NER-deficient mice show progeroid phenotypes and shortened lifespan.
• DNA damage markers (γH2AX foci) accumulate in aged tissues.
• Caloric restriction modestly improves DNA repair capacity.

What it doesn’t explain

• Why some long-lived species have unremarkable DNA-damage levels.
• Why caloric restriction extends lifespan so robustly via apparently non-DNA mechanisms.
• The systemic (inter-tissue) component of aging.
• Why aging proceeds in post-mitotic cells where mutation accumulation is irrelevant.

Therapeutic implications

• Avoid avoidable damage: sun protection, smoking cessation, minimise unnecessary radiation.
• NAD⁺ repletion may enhance PARP-mediated DNA repair.
• Cellular reprogramming may reset some DNA-damage–driven aging signatures.

Related entries

Genomic instability, Telomere attrition, Cellular senescence, NAD+ precursors.