Responsiveness of epigenetic aging biomarkers to longevity interventions in humans.

Raghav Sehgal, Daniel Borrus, Jenel F Armstrong, John Gonzalez, Jessica Kasamoto, Yaroslav Markov, Ahana Priyanka, Ryan Smith, Natàlia Carreras-Gallo, Jessica Lasky-Su, Varun B Dwaraka, Michael J Corley, Albert Higgins-Chen

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. [email protected] of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. [email protected]. · pubmed

Paper

Abstract

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention without the need for decade-spanning trials. However, before the use of aging biomarkers, such as epigenetic clocks, as surrogate endpoints, their responsiveness to interventions that target aging must be tested. Here we curate TranslAGE, a harmonized database of 51 public and private longitudinal interventional studies, and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 94 other DNA methylation (DNAm) biomarkers that can help explain the changes observed for each clock. Using this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging show the strongest responses across all interventions and show consistent results with one another; pharmacological and lifestyle interventions drive the strongest responses from DNAm biomarkers; and the characteristics of the study population and study duration are key factors in determining the responsiveness of DNAm biomarkers to an intervention. Moreover, clocks with multiple subscores (that is 'explainable clocks') provide specificity and greater mechanistic insight into the responsiveness of interventions than single-score clocks. These findings can help to design future clinical trials by guiding the choice of interventions and of specific subsets of DNAm biomarkers to minimize multiple testing, study duration, study population and sample size, with the eventual aim of uncovering DNAm biomarkers that can be used as surrogate aging endpoints.

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Research summary

The paper curates a large database of interventional studies to demonstrate that epigenetic clocks, particularly those trained on mortality, are responsive to various interventions, thereby validating their potential use as surrogate endpoints for aging. This work is relevant because it addresses the critical bottleneck in longevity research: the need for rapid, reliable biomarkers to assess the efficacy of life-extension interventions without waiting for clinical endpoints like death. However, the impact is limited to methodological validation and resource creation rather than a novel biological discovery or a transformative new intervention, placing it in the category of solid but incremental research.

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