ABSTRACT Plasma proteomic aging clocks estimate biological age and are linked to age‐related diseases, but thus far, there has been little focus on circulating extracellular matrix (ECM) proteins, which play a central role in tissue structure and age‐related decline. Here, we use publicly available proteomic datasets to profile plasma ECM protein abundances across the human lifespan and reveal a distinct U‐shaped trajectory with age. Our ECM‐based aging clock, constructed from 14 plasma proteins, accurately predicts chronological age and remains robust across independent validations and different biofluids. Notably, this ECM clock distinguishes between healthy and diseased states. Cross‐species comparisons show that while specific predictive ECM proteins differ between humans and rodents, species‐specific ECM clocks reliably track aging, and rejuvenation interventions can reverse ECM aging signatures. We prioritize ECM proteins implicated causally in disease and explored drugs targeting these proteins. These findings establish circulating ECM proteins as sensitive biomarkers of aging and disease and suggest that targeting ECM remodeling may offer new strategies for promoting healthy aging.
Coenen et al. (Wed,) studied this question.