Telomeres in aging: Links to clonal hematopoiesis, cardiovascular disease, and cancer

Telomeres protect chromosome ends and help preserve genomic integrity. Progressive telomere shortening with each cell division functions as a biologic clock that contributes to limited human lifespan. When telomeres become critically short with aging, DNA damage responses are activated, leading to cellular senescence or apoptosis. This process creates selective pressure that triggers the emergence of somatic mutations. Mutant hematopoietic stem cells driving clonal hematopoiesis acquire a fitness and survival advantage over normal hematopoietic stem cells. However, clonal hematopoiesis is associated with elevated risks of cardiovascular disease and cancer. In more extreme cases, continued proliferation driven by somatic mutations of p53 and other checkpoint genes, combined with critically short telomeres, can promote mutations in the TERT promoter gene. These mutations reactivate telomerase, enabling sustained proliferation, cellular immortality, and malignant transformation. Telomere maintenance and regulation therefore represent promising therapeutic targets for aging, cardiovascular disease, and cancer.