The Spatiotemporal Proteome Landscape of Aging: Structural determinants of age-sensitive proteome remodeling

Aging is marked by a decline in cellular functions accompanied by widespread changes in mRNA and protein abundance, yet whether aging broadly remodels subcellular protein localization and concentration-and why some proteins change while others remain stable-remains unclear. This gap matters because cellular function depends not only on expression levels but also on correct spatial organization. Using yeast replicative aging as a model, we built a robotic pipeline to enrich old cells from 5,661 strains, acquired 90 million single-cell 3D images, and applied machine learning to map proteome-wide changes in localization, concentration, and aggregation throughout aging. This age-resolved single-cell atlas uncovers widespread proteome remodeling and rewiring of protein interaction networks. Moreover, structural analysis reveals biophysical determinants of age-sensitive proteome remodeling across ages and species. Together, these results reveal a structure-encoded intrinsic principle underlying spatial proteome breakdown during aging and provide a resource to dissect mechanistic links among aging hallmarks.