Zenodo · May 16, 2025
Multi-Organ Epigenetic Clock Deconvolution Discloses Divergent Biological Aging Rates and Prognostic Trajectories Across Complex Human Diseases
By Choudhary H
Systemic organismal aging exhibits significant inter-organ divergence in progressive and fatal human diseases. Conventional pan-tissue epigenetic clocks compress multi-system biological decline into a singular age estimate, masking organ-specific vulnerability and localized rates of senescence. We construct and validate a suite of organ-resolved DNA methylation clocks—spanning central nervous system, cardiovascular, pulmonary, metabolic, hepatic, and renal compartments—using regularized elastic net deconvolution across whole-blood and post-mortem tissue cohorts (NCBI GEO GSE40279 n=656; multicenter clinical cohort n=726). Our empirical deconvolution reveals marked inter-organ discordance: while metabolic and central nervous system clocks exhibit pronounced acceleration coupled to functional progression and mortality, peripheral hepatic and renal compartments demonstrate distinct resilience profiles. Incorporating organ-deconvoluted biological age accelerations significantly boosts survival concordance over standard chronological baselines and composite clocks. This confirms that organ-resolved epigenetic deconvolution captures critical prognostic variance obscured by composite metrics, providing an actionable framework for stratified clinical trial enrichment across complex diseases.