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

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 T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.

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Journal
Aging Cell
Published
2025-10-24
DOI
https://doi.org/10.1111/acel.70279
Citations
1
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.81
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article

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

Christina A. Castellani, Daniel L. Levy, Tianxiao Huan, Emmanuel Saake et al.
1 citations
Aging Cell
Epigenetics and DNA Methylation
0.81
article

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

Christina A. Castellani, Daniel L. Levy, Tianxiao Huan, Emmanuel Saake, Lifang Hou, Kent D. Taylor, Jiantao Ma, Drew R. Nannini, Laura M. Raffield, Yinan Zheng, Roby Joehanes, Nicole J. Lake, Stephen S. Rich, M M Lai, April P. Carson, Ching‐Ti Liu, Xiuqing Guo, Dan Arking, Kai Zhang, Chunyu Liu, Xue Liu, Myriam Fornage, Jerome I. Rotter, Mengyao Wang
article en
1 citations

Abstract

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 T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.

Aging CellVol. 24(12)
Boston University (US), Northwestern University (US), University of North Carolina at Chapel Hill (US), Tufts University (US), Western University (CA), New York State Department of Health (US), Johns Hopkins University (US), Duke University (US), Johns Hopkins Medicine (US), UCLA Medical Center (US), University of Mississippi Medical Center (US), Yale University (US), University of Massachusetts Boston (US), Albany College of Pharmacy and Health Sciences (US), University at Albany, State University of New York (US), National Heart, Lung, and Blood Institute (US), Framingham Heart Study (US), Duke Medical Center (US), Brown Foundation (US), University of Virginia (US), The University of Texas Health Science Center at Houston (US)
Openalex Percentile: Top 22%
Epigenetics and DNA Methylation
0.81
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