膀胱癌是一种与年龄相关的疾病，超过四分之三的病例发生在 65 岁及以上的人群中。加速的生物衰老与癌症风险升高有关。表观遗传时钟是生物年龄的良好预测因子，但尚不清楚它们是否与膀胱癌风险相关。在这项大型病例对照研究中，我们评估了四种成熟的表观遗传时钟（HannumAge、HorvathAge、GrimAge 和 PhenoAge）与膀胱癌风险之间的关联。利用全基因组关联研究 (GWAS) 中鉴定的单核苷酸多态性 (SNP)，将这些时钟作为工具链接起来，我们为每个时钟构建了加权遗传风险评分 (GRS)。我们发现，较高的 HannumAge 和 HorvathAge GRS 与膀胱癌风险增加显着相关（每 SD 增加 OR = 1.69，95% CI，1.44-1.98，p = 1.56 × 10-10，每 SD 增加 OR = 1.09，95% CI ，1.00-1.19，p = 0.04，分别）。采用基于汇总统计的孟德尔随机化 (MR) 方法、逆方差加权 (IVW)，我们发现 HannumAge 和 HorvathAge 的膀胱癌风险估计一致。使用加权中值分析和 MR-Egger 回归进行的敏感性分析进一步支持了 IVW 方法的有效性。然而，GrimAge 和 PhenoAge 与膀胱癌风险无关。总之，我们的数据提供了第一个证据，表明生物衰老加速与膀胱癌风险升高相关。

Bladder cancer is an age-related disease, with over three-quarters of cases occurring in individuals aged 65 years and older. Accelerated biological aging has been linked to elevated cancer risks. Epigenetic clocks serve as excellent predictors of biological age, yet it remains unclear whether they are associated with bladder cancer risk. In this large case-control study, we assessed the associations between four well-established epigenetic clocks-HannumAge, HorvathAge, GrimAge, and PhenoAge-and bladder cancer risk. Utilizing single nucleotide polymorphisms (SNPs), which were identified in a genome-wide association study (GWAS), linked to these clocks as instruments, we constructed a weighted genetic risk score (GRS) for each clock. We discovered that higher HannumAge and HorvathAge GRS were significantly associated with increased bladder cancer risk (OR = 1.69 per SD increase, 95% CI, 1.44-1.98, p = 1.56 × 10-10 and OR = 1.09 per SD increase, 95% CI, 1.00-1.19, p = 0.04, respectively). Employing a summary statistics-based Mendelian randomization (MR) method, inverse-variance weighting (IVW), we found consistent risk estimates for bladder cancer with both HannumAge and HorvathAge. Sensitivity analyses using weighted median analysis and MR-Egger regression further supported the validity of the IVW method. However, GrimAge and PhenoAge were not associated with bladder cancer risk. In conclusion, our data provide the first evidence that accelerated biological aging is associated with elevated bladder cancer risk.