Nature medicineJun 15, 2026

Blood protein patterns linked to cell aging that may predict human diseases

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 16, 2026

Abstract

Analysis of over 7,000 plasma proteins from 60,542 individuals revealed that 20-25% exhibited accelerated aging in a single cell type.

Machine learning models were developed to estimate biological age across more than 40 different cell types.
Cellular aging signatures were found to be associated with disease status and could predict disease incidence and mortality over a 15-year follow-up period.
Individuals with the APOE4 genotype exhibited older astrocytes but younger macrophages compared to those with the APOE3 genotype, while the APOE2 genotype showed opposite effects.
Extreme aging of astrocytes was linked to a tripled risk of developing Alzheimer's Disease in individuals with two APOE4 alleles.
Aged skeletal myocytes were associated with a 12.7-fold increased risk of amyotrophic lateral sclerosis compared to youthful myocytes.
In smokers, extreme aging of respiratory epithelial cells was correlated with a 58% higher risk of lung cancer compared to smoking alone.

Simplified

Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer's Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.