Cardiovascular-Derived Circulating Cell-Free DNA Fragments Are Associated With Frailty and Increased Cardiovascular Events in Older Adults

Lolita S Nidadavolu¹, David W Sosnowski², Nikita Sivakumar³, Alessandra Merino Gomez¹, Yuqiong Wu¹, Thomas Laskow¹, Taylor Bopp¹, Nicholas Milcik¹, Anne Le⁴, Cissy Zhang⁴, Pratik Khare⁴, Andrea Zammit⁵, Francine Grodstein⁵, Jeremy D Walston¹, David A Bennett⁵, Rasika A Mathias⁶, Jude M Phillip^{3

7

8}, Brion S Maher², Esther S Oh¹, Peter M Abadir¹

Affiliations

¹ Division of Geriatrics and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
³ Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
⁴ Gigantest, Baltimore, Maryland, USA.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷ Department of Chemical and Biomolecular Engineering, Institute for Nanobiotechnology, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
⁸ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 40235369
PMCID: PMC12314505 (available on 2026-04-15)
DOI: 10.1093/gerona/glaf081

Cardiovascular-Derived Circulating Cell-Free DNA Fragments Are Associated With Frailty and Increased Cardiovascular Events in Older Adults

Lolita S Nidadavolu et al. J Gerontol A Biol Sci Med Sci. 2025.

. 2025 Jun 10;80(7):glaf081.

doi: 10.1093/gerona/glaf081.

Authors

Affiliations

¹ Division of Geriatrics and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
³ Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
⁴ Gigantest, Baltimore, Maryland, USA.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷ Department of Chemical and Biomolecular Engineering, Institute for Nanobiotechnology, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
⁸ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 40235369
PMCID: PMC12314505 (available on 2026-04-15)
DOI: 10.1093/gerona/glaf081

Abstract

Increased cellular damage in aging tissues releases circulating cell-free genomic DNA (ccf-gDNA) into the bloodstream, and these fragments are associated with a higher risk of frailty and dementia. We hypothesized that identifying the tissue of origin for ccf-gDNA using methylation signatures can distinguish subgroups of participants with distinct clinical outcomes, biological aging rates, and energy use. Serum ccf-gDNA from 181 participants in the Religious Orders Study or Rush Memory and Aging Project (ROS-MAP) was assessed for DNA methylation at one timepoint using the Illumina MethylationEPIC array. Clinical outcomes 6 years after ccf-gDNA measurement were determined for the following: frailty, cognitive test scores, and cardiovascular disease. Hierarchical clustering identified major clusters based on the predominance of ccf-gDNA source: cardiovascular, erythrocyte progenitor, and immune cell. Participants with cardiovascular-enriched ccf-gDNA (CV ccf-gDNA) had higher rates of myocardial infarction (39%) at the last study visit compared to other subgroups (Immune ccf-gDNA: 21%; Erythrocyte ccf-gDNA: 23%), and similar findings were observed for congestive heart disease and stroke. There were no significant associations between cognitive test scores and ccf-gDNA subgroups. Individuals with CV ccf-gDNA demonstrated 3.1 times higher odds of being frail compared to the other groups and showed increased epigenetic age acceleration for the fragments compared to the other subgroups, indicating that this group was enriched with ccf-gDNA originating from older cells. The CV ccf-gDNA subgroup exhibited dysregulation of glycine and serine metabolism and pathways integral to cardiovascular health, endothelial function, and inflammation. We demonstrate that ccf-gDNA methylation patterns can detect high-turnover tissues and identify older adults at higher risk of frailty and cardiovascular disease.

Keywords: Cardiovascular; Coronary heart disease; DNA; DNA methylation.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Cardiovascular-Derived Circulating Cell-Free DNA Fragments Are Associated With Frailty and Increased Cardiovascular Events in Older Adults

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Cardiovascular-Derived Circulating Cell-Free DNA Fragments Are Associated With Frailty and Increased Cardiovascular Events in Older Adults

Authors

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Abstract

Conflict of interest statement

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