Association of Epigenetic Age Acceleration and Mitochondrial DNA ‐Based Aging Metrics Provides Insights Into Mechanisms of Aging‐Related Diseases

作者：Mengyao Wang, Yinan Zheng, M M Lai, Emmanuel Saake, Xue Liu, Xiuqing Guo, Kent D. Taylor, Tianxiao Huan, Roby Joehanes, Drew R. Nannini, Kai Zhang, Nicole J. Lake, Christina A. Castellani, Stephen S. Rich, Jerome I. Rotter, Ching‐Ti Liu, Laura M. Raffield, April P. Carson, Myriam Fornage, Jiantao Ma, Dan Arking, Lifang Hou, Daniel L. Levy, Chunyu Liu · 发表于：Aging Cell · 年份：2025 · DOI：10.1111/acel.70279 · 被引用次数：2 · 研究领域：Epigenetics and DNA Methylation、Birth, Development, and Health、RNA modifications and cancer

Investigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2D...