Hong Xuanming, Cao Hui, Cao Weihua, Lv Jun, Yu Canqing, Huang Tao, Sun Dianjianyi, Liao Chunxiao, Pang Yuanjie, Hu Runhua, Gao Ruqin, Yu Min, Zhou Jinyi, Wu Xianping, Liu Yu, Yin Shengli, Gao Wenjing, Li Liming
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China.
Aging Cell. 2025 Mar;24(3):e14403. doi: 10.1111/acel.14403. Epub 2024 Nov 14.
Several crucial acceleration periods exist during aging process. Epigenetic clocks, serving as indicators of aging, are influenced by genetic factors. Investigating how the genetic contributions on these clocks change with age may provide novel insights into the aging process. In this study, based on 1084 adult twins from the Chinese National Twin Registry (CNTR), we established structural equation models (SEMs) to evaluate the trends in genetic influence with aging for epigenetic clocks, which include PC-Horvath, PC-Hannum, PC-PhenoAge, PC-GrimAge, and DunedinPACE. A decline in overall heritability was observed for all five clocks from ages 31 to 70, with a relatively stable trend at first. Subsequently, apart from PC-GrimAge, the other four clocks displayed a more evident drop in heritability: DunedinPACE and PC-PhenoAge experienced a clear decline between 55 and 65 years, while PC-Horvath and PC-Hannum showed a similar decrease between 60 and 70 years. In contrast, the heritability of PC-GrimAge remained stable throughout. An analysis of methylation sites (CpGs) from these clocks identified 41, 26, 4, and 36 CpG sites potentially underlying heritability changes in DunedinPACE, PC-Horvath, PC-Hannum, and PC-PhenoAge, respectively. Data from the CNTR were collected through two surveys in 2013 and 2018. Based on 308 twins with longitudinal data, declines in genetic components were observed at follow-up compared to baseline, with significant decreases in the four PC-clocks. DunedinPACE peaked in 5-year longitudinal genetic contribution changes at age 55-60, while PC-clocks consistently peaked at age 50-55. These findings may offer novel insights into the role of genetic variations in aging.
衰老过程中存在几个关键的加速期。表观遗传时钟作为衰老的指标，受到遗传因素的影响。研究遗传因素对这些时钟的影响如何随年龄变化，可能为衰老过程提供新的见解。在本研究中，基于来自中国国家双胞胎登记处（CNTR）的1084对成年双胞胎，我们建立了结构方程模型（SEM），以评估表观遗传时钟的遗传影响随年龄增长的趋势，这些时钟包括PC-Horvath、PC-Hannum、PC-PhenoAge、PC-GrimAge和达尼丁PACE。从31岁到70岁，所有五个时钟的总体遗传力均呈下降趋势，起初趋势相对稳定。随后，除PC-GrimAge外，其他四个时钟的遗传力下降更为明显：达尼丁PACE和PC-PhenoAge在55至65岁之间明显下降，而PC-Horvath和PC-Hannum在60至70岁之间出现类似下降。相比之下，PC-GrimAge的遗传力在整个过程中保持稳定。对这些时钟的甲基化位点（CpG）分析分别确定了41、26、4和36个CpG位点，可能是达尼丁PACE、PC-Horvath、PC-Hannum和PC-PhenoAge遗传力变化的潜在基础。CNTR的数据是通过2013年和2018年的两次调查收集的。基于308对有纵向数据的双胞胎，与基线相比，随访时观察到遗传成分下降，四个PC时钟显著下降。达尼丁PACE在55至60岁的5年纵向遗传贡献变化中达到峰值，而PC时钟在50至55岁时持续达到峰值。这些发现可能为遗传变异在衰老中的作用提供新的见解。
