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SUMMARYProtein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue-specific, and not simply driven by protein expression differences. Experimental interrogation, combined with machine learning, indicates that this specificity is linked to both protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during aging and reveal strong, tissue-specific associations with dysfunction and disease.HIGHLIGHTSTissue-specific protein aggregation is prevalent during vertebrate agingBoth protein biophysical properties and tissue-specific protein homeostasis patterns impact aggregationA segmental progeria model with accelerated aging exhibits selectively increased protein aggregation in affected tissuesMany aggregates that accumulate during physiological aging are linked to disease |
