Expression of p16^INK4a and other cell cycle regulator and senescence associated genes in aging human kidney.

Somatic cells in vitro have a finite life expectancy before entering a state of senescence. If this state has an in vivo counterpart, it could contribute to organ aging. We have previously shown that human kidney cortex displays telomere shortening with age. In the present study, we evaluated the relationship between renal age in humans and a number of phenomena associated with cellular senescence in vitro.

Human kidney specimens were obtained at 8 weeks to 88 years of age and were assessed for changes related to aging.

We found that human kidneys expressed relatively constant levels of mRNAs for genes potentially related to senescence. Among the candidate genes surveyed, the cell cycle regulator p16^INK4a emerged with the strongest association with renal aging for both mRNA and protein expression. Proliferation as measured by Ki-67 expression was inversely correlated with p16^INK4a expression, compatible with a role for p16^INK4a as an irreversible cell cycle inhibitor. Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA expression was elevated in older kidneys, associated with increased protein expression. Comparison of gene expression with age-related histologic changes revealed that glomerulosclerosis correlated with p16^INK4a and p53, whereas interstitial fibrosis and tubular atrophy were associated with p16^INK4a, p53, COX-1, transforming growth factor-β1 (TGF-β1), and heat shock protein A5 (HSPA5).

We conclude that some changes observed in cellular senescence in vitro do occur in human kidney with age, particularly in the renal cortex, in some cases correlating with histologic features. P16^INK4a emerged with the most consistent correlations with age and histologic changes and inversely correlated with cell replication.