Genomic
Instability

DNA damage comes from two directions: endogenous sources (mitochondrial reactive oxygen species, replication errors, hydrolysis) and exogenous sources (UV, ionizing radiation, chemical mutagens). A healthy 20-year-old repairs the overwhelming majority within hours via base excision repair (BER), nucleotide excision repair (NER), and homologous recombination (HR).

The critical failure mode of aging is not increased damage rate — it’s declining repair capacity. PARP1 and SIRT1, the sentinel repair enzymes, both consume NAD+ as substrate. As NAD+ falls ~50% between age 20 and 60, repair throughput collapses. Misrepaired breaks → chromosomal rearrangements → oncogenic mutations → senescent cells → systemic inflammation.

Telomere erosion is a specialized form of genomic instability. Telomeres shorten by ~50–200 bp per replication cycle because DNA polymerase cannot replicate the lagging strand end. After enough replications, telomeres reach the Hayflick limit — cells either senesce or mis-repair telomere ends as double-strand breaks, causing chromosomal fusions and further instability.

The third axis is epigenomic instability: oxidative damage to histones and aberrant DNMT3a activity scramble methylation patterns, silencing tumor suppressors and activating oncogenes without changing the sequence. This is the substrate of Horvath’s epigenetic clock — the ratio of maintained vs. drifted CpG sites directly tracks biological age.