An epigenetic biomarker of aging for lifespan and healthspan

Abstract

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

Keywords

Affiliated Institutions

• Northwestern University US
• University of Mississippi Medical Center US
• University of California, Los Angeles US
• Fred Hutch Cancer Center US
• Stanford University US
• Columbia University US
• Jackson Memorial Hospital US
• National Institute on Aging US
• Robert H. Lurie Comprehensive Cancer Center of Northwestern University
• Azienda Usl Toscana Centro IT
• Rutgers, The State University of New Jersey US
• University of North Carolina at Chapel Hill US
• Rutgers New Jersey Medical School
• Wake Forest University US
• National Institutes of Health US

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