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

Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS). The results, compiled in online ProtAge catalog, unraveled age-related functional changes in regulators of translation, protein folding, and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging, causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction, and led to lifespan extension. Altogether, this comprehensive map of protein structural changes enables identifying mechanisms of age-related phenotypes and offers opportunities for their reversal. [Display omitted] •Proteome-wide catalog of aging-associated protein structural changes in budding yeast•Identification of functional changes in proteins that give rise to aging phenotypes•Age-related polymerization of glutamate synthase Glt1 disrupts amino acid homeostasis•Preventing Glt1 polymerization restores amino acid balance and extends lifespan Structure governs protein function. Paukštytė et al. employ LiP-MS to catalog aging-related protein structural changes in yeast, unveiling functional alterations in translation, folding, and metabolism, including aberrant polymerization of glutamate synthase Glt1. Inhibiting Glt1 polymerization restored amino acid balance in aged cells, enhanced mitochondrial function, and extended lifespan.