Podocyte-specific CerS6 Drives Renal Aging via C16 Ceramide-mediated p53-p21 Senescence

Aging is a major driver of chronic kidney disease and glomerulosclerosis, yet the underlying molecular mechanisms remain unclear. Here, we show that podocyte ceramide synthase 6 (CerS6) is a key driver of renal aging. In naturally aged non-human primates (common marmosets), CerS6 upregulation in podocytes causes glomerular C16 ceramide accumulation, p53–p21 pathway activation, and cellular senescence, which strongly correlate with proteinuria and glomerular injury. Conversely, podocyte-specific CerS6 deletion in mice prevents C16 ceramide accumulation, suppresses p53–p21 signaling, reduces podocyte senescence and expression of senescence-associated secretory phenotype, and protects against glomerulosclerosis, fibrosis, and proteinuria during aging. Mechanistic studies in cultured podocytes confirm that CerS6 acts upstream of p53 to drive stress-induced senescence. Together, our findings establish the CerS6-C16 ceramide-p53-p21 axis as a central driver of podocyte senescence during renal aging and identify CerS6 as a therapeutic target to mitigate age-related kidney decline.