When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.
- 1Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- 2Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT, USA
- 3Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
Abstract
Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance. We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable PC-based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria. These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.
Related
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- Biological Versus Technical Reliability of Epigenetic Clocks and Implications for Disease Prognosis and Intervention Response
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BibTeX
@article{borrus2026when,
title = {{When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.}},
author = {Daniel S. Borrus and Raghav Sehgal and Judith Armstrong and Jessica Kasamoto and John T. González and Albert Higgins‐Chen},
journal = {Aging cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70756},
url = {https://europepmc.org/article/MED/42850743},
note = {CC BY},
}
RIS
TY - JOUR
TI - When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.
AU - Daniel S. Borrus
AU - Raghav Sehgal
AU - Judith Armstrong
AU - Jessica Kasamoto
AU - John T. González
AU - Albert Higgins‐Chen
PY - 2026
DA - 2026/10/01
JO - Aging cell
DO - 10.1111/acel.70756
UR - https://europepmc.org/article/MED/42850743
AB - Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance. We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable PC-based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria. These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.
SN - 1474-9718
SN - 1474-9726
SN - 1474-9728
ER -