Mapping Structural Aging of Human Tissue reveals tissue-specific trajectories and coordinated deterioration

1. Abstract Tissue structure, the organization of cells, vasculature and extracellular matrix, underpins organ function. Yet how it deteriorates with age remains largely uncharacterized. Current aging research focuses primarily on molecular changes, missing this structural dimension. Here we present PathStAR (Pathology-based Structural Aging Rate), a computational framework that quantifies tissue structural aging from histopathology images without training on chronological age. Applying PathStAR to 25,306 postmortem biopsies spanning 40 tissue types from 970 individuals aged 21–70, we show that structural aging unfolds through non-linear phases rather than gradual decline. We identify three distinct temporal programs: early-aging tissues (vascular system, peaking in the 30s), late-aging tissues (uterus and vagina, peaking around menopause) and biphasic-aging tissues (digestive and male reproductive organs, with two acceleration periods). During accelerated phases, tissues exhibit common molecular signature of increased inflammation, decreased energy production, regeneration and quality control alongside tissue-specific pathway disruptions related to its function: Artery-specific decline of peroxisomal function, responsible for fatty acid breakdown and testis-specific decline of spermatogenesis. Cross-organ analysis reveals coordinated deterioration within individuals, not only within expected organ systems but also unexpectedly between digestive and reproductive tissues, traced to shared sex hormone signaling. This reveals a role for sex hormones in maintaining structural integrity of non-reproductive organs during aging. Genome-wide association analysis identifies 123 germline variants associated with organ-specific accelerated structural aging, including variants in the longevity regulator SIRT6 linked specifically to vascular structural decline. As proof of concept, PathStAR captures the established non-linear functional decline of the ovary, fertility loss in the 30s and menopause in the 50s, that bulk transcriptomic and methylation profiles from matched samples fail to detect. PathStAR provides a systematic map of structural aging across the human body: when tissues structure decline, what molecular programs define each phase, and how organs deteriorate in coordination.