Abstract Aims Ageing leads to a progressive loss in structural integrity and a functional decline of human organs, alongside telomere attrition and alterations in DNA methylation patterns. Their relationships in the human kidney in the context of ageing remain elusive. Methods and results We analysed 200 participants from the Human Kidney Tissue Resource (HKTR) with matching information on kidney histology, renal function, blood leukocyte and kidney telomere length, as well as kidney genome-wide DNA methylation profiles. Additional 71 HKTR individuals without telomere data were used in validation analyses. Kidney telomere length showed a significant inverse association with age (β = -0.029, confidence interval = -0.043 to -0.016, P = 0.00003). Shorter kidney telomeres were strongly associated with both renal structure and function, independent of demographic and clinical confounders. Nephrosclerosis score showed a gradual increase with age categories, while kidney telomere length dropped simultaneously. Leukocyte telomere length was not related to the extent of age-related changes in kidney function or structure. Kidney DNA methylation analysis revealed that kidney CpGs, genes, pathways and chromatin patterns associated with kidney telomere length are partly independent of these associated with chronological age. Consisted of 57 CpGs, epigenetic clock of kidney telomere length showed a predictive potential for nephrosclerosis, independent of clinical cofounders, chronological and epigenetic age. Conclusion Our study revealed that gradual age-related structural involution of human kidney and a decline in its filtration capacity are accompanied by shortening of telomeres in renal cells and that changes in the kidney epigenome (i.e., DNA methylation) may contribute to nephrosclerosis (at least in part) independently of chronological age.
Akinnibosun et al. (2026) studied this question.