Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease

ABSTRACT Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types—spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins—using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer’s disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Competing Interest Statement T.W.C. and H.O. are co-founders and scientific advisors of Teal Omics Inc. and have received equity stakes. T.W.C. is a co-founder and scientific advisor of Alkahest Inc. and Qinotto Inc. and has received equity stakes in these companies. All other authors have certified they have no competing interests to declare. C.C. has received research support from: GSK and EISAI. C.C. is a member of the scientific advisory board of Circular Genomics and owns stocks. C.C. is a member of the scientific advisory board of ADmit. J.M.S. has received research funding and PET tracer from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Alliance Medical, and has consulted for Roche, Eli Lilly, Biogen, MSD, GE Healthcare, Alamar Biosciences and Receptive Bio, and is Chief Medical Officer for Alzheimer's Research UK.