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. 2025 Sep;5(9):1880-1896.
doi: 10.1038/s43587-025-00958-3. Epub 2025 Sep 15.

Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems

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Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems

Raghav Sehgal et al. Nat Aging. 2025 Sep.

Abstract

Aging occurs at different rates across individuals and physiological systems, but most epigenetic clocks provide a single age estimate, overlooking within-person variation. Here we developed systems-based DNA methylation clocks that measure aging in 11 distinct physiological systems-Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone and Metabolic-using data from a single blood draw. By integrating supervised and unsupervised machine learning with clinical biomarkers, functional assessments and mortality risk, we derived system-specific scores that outperformed existing global clocks in predicting relevant diseases and aging phenotypes. We also created a composite Systems Age score to capture overall multisystem aging. Clustering individuals based on these scores revealed distinct biological aging subtypes, each associated with unique patterns of health decline and disease risk. This framework enables a more granular and clinically relevant assessment of biological aging and may support personalized approaches to monitor and target system-specific aging processes.

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Conflict of interest statement

Competing interests: The approach and framework for developing system-specific scores described in this paper is the subject of an invention declaration at Yale University and a provisional patent application for which M.E.L, R.S., A.T.H.-C. and M.M. are named as inventors, and Yale University is named as owner. Variations on the system scores have been developed using different input samples, CpGs and clinical biomarkers as well as different feature selection and feature engineering approaches. In the past, M.E.L. was a Scientific Advisor for Elysium Health from July 2019 to October 2021. M.E.L. also holds licenses for epigenetic clocks that she has developed. A.T.H.-C. has received consulting fees from TruDiagnostic and FOXO Biosciences. R.S. is a Scientific Advisor for TruDiagnostic and has received consulting fees from the company as well. R.S. has received consulting fees from the Longevity Tech Fund, the Healthy Longevity Clinic and Cambrian BioPharma unrelated to this publication. M.E.L. is an employee of Altos Labs. The other authors declare no competing interests.

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