Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate

Abstract

Protein 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.

Global analysis of aging-related protein structural changes uncovers enzyme polymerization-based control of longevity

“…In addition, aging is associated with alterations in the abundance, turnover or folding of proteins that are typically linked to defective protein homeostasis [33][34][35] . Folding changes in turn can lead to protein aggregation, which is a shared feature of aging across organisms and tissue types 36,37 , and is infamously linked to age-related neurodegenerative diseases 38 . However, it is currently unclear whether cellular aging results in other types of protein structural changes beyond aggregation.…”

A deeply conserved protease, acylamino acid-releasing enzyme (AARE), acts in ageing in Physcomitrella and Arabidopsis

“…In mammals, elevated levels of oxidized proteins are associated with age-related pathologies, such as Alzheimer's disease, diabetes and different types of carcinomas 120 . If proteolytic clearance fails, further accumulation of oxidized proteins causes protein aggregation, which is a hallmark of ageing in animals 96,121,122 . A connection between protein oxidation and ageing was less well studied in plants.…”

A deeply conserved protease, acylamino acid-releasing enzyme (AARE), acts in ageing in Physcomitrella and Arabidopsis

“…In mammals, elevated levels of oxidized proteins are associated with age-related pathologies, such as Alzheimeŕs disease, diabetes and different types of carcinomas (Dalle-Donne et al, 2003). If proteolytic clearance fails, further accumulation of oxidized proteins causes protein aggregation, which is a hallmark of ageing in animals (López-Otín et al, 2013; Hipp et al 2019; Chen et al, 2022). A connection between protein oxidation and ageing was less well studied in plants.…”