Whole genome sequencing reveals telomere associated genomic differences between healthy and unhealthy aging in a...

One of the major challenges in modern biogerontology is understanding the accumulation of molecular damage and the manifestation of phenotypic heterogeneity during aging. Notably, genomic instability caused by impaired DNA damage repair along with telomere attrition are primary drivers of aging. However, how these aging-related characteristics differ in individuals who age healthily without developing major age-associated diseases remains unclear. Here, whole genome sequencing (WGS) was performed on 100 healthy agers (≥ 60 years old, no age-related diseases) and 100 unhealthy agers (≥ 60 years old, at least one age-related disease/condition) based on a case-control study. Telomere length was measured using TelSeq and Computel. High-functional impact germline variant (gHFI) burden and alteration pattern at the pathway level were also analyzed. The GTEx dataset including 751 individuals was used to observe the functional impact of identified germline variants at the molecular level. Telomere length showed minimal differences before 65 years of age but declined rapidly in unhealthy agers beyond this age. Additionally, healthy agers had lower gHFI burden, particularly in DNA repair genes such as BLM. Pathway analysis revealed enrichment of oxidative stress-related mutations in healthy agers, correlated with reduced oxidative stress and upregulated antioxidant enzymes (SOD1 and SOD2). Overall, genomic instability preserved through slow telomere attrition and reduced DNA repair defects plays a key role in healthy aging. Improved oxidative stress resistance may contribute to healthier aging, highlighting the role of genetic factors in reducing age-related decline and supporting overall well-being in later life.