This study demonstrated that Klotho overexpression significantly increased Lamin B1 levels, reduced p16, p21, and PAI-1 expression, and decreased the proportion of SA-β-Gal-positive cells in HK-2 cells exposed to AGE, underscoring Klotho’s protective role against senescence in hyperglycemia. Here, CDKN2A is linked to Hyperglycemia.