Genomic Instability

What it is

Genomic instability is the gradual accumulation of damage to DNA — point mutations, double-strand breaks, copy-number changes, chromosomal rearrangements, and damage from reactive oxygen species. The damage itself isn’t the problem; everyone’s cells experience tens of thousands of lesions per day. Aging arises when the cellular machinery that detects and repairs that damage falls behind the rate at which damage is generated.

Why it matters in aging

The two main consequences are (1) loss of cellular function when essential genes are mutated or silenced and (2) clonal expansion of damaged cells, including cells with cancer-driver mutations. Progeroid syndromes such as Werner syndrome, Hutchinson–Gilford progeria, and xeroderma pigmentosum are caused by inherited defects in DNA-repair or nuclear-envelope proteins and broadly recapitulate features of normal aging at an accelerated rate.

Mechanisms

• Endogenous sources: replication errors, reactive oxygen species, hydrolytic depurination, aldehyde adducts from metabolism.
• Exogenous sources: UV, ionising radiation, chemotherapy, tobacco smoke.
• Repair pathways: base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, non-homologous end joining.
• Telomere maintenance and nuclear architecture (lamin A/C) are tightly coupled to genomic stability.

What’s being studied

NAD⁺–dependent enzymes (sirtuins, PARPs) sit at the intersection of metabolism and DNA repair; declining NAD⁺ with age is one proposed reason repair efficiency slips. Senolytics, caloric restriction, and rapamycin all show effects on genomic-instability readouts in animal models, but human-translation evidence is limited.

Related entries

See also: Telomere attrition, Cellular senescence, Epigenetic alterations.