Figure 1.

A hypothetical model: Genomic instability plays a central role during the aging process, triggered by two main stimuli, telomere shortening and DNA damage. (1) Telomere-dependent aging: Telomeres are essential for chromosomal stability. Telomere shortening and dysfunction can trigger DNA damage responses and are sufficient to induce cellular senescence. (2) DNA damage-initiated aging: DNA damage accumulates, along with DNA repair deficiencies, resulting in genomic instability and accelerated cellular senescence. Both mechanisms depend strongly on p53. These two mechanisms can act cooperatively to increase the overall level of genomic instability and trigger the onset of human aging phenotypes.