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bioRxiv · 10.64898/2026.02.26.708310

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

Yoo, S.·Vannur, L.·Li, L.·Young, C.·Liu, Q.·Wen, Z.·Zhang, Y.·Florens, L.·Si, K.·Zhuang, J.·Zheng, F.·Zhou, C.
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Abstract

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.

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Yoo, S., Vannur, L., Li, L., Young, C., Liu, Q., Wen, Z., Zhang, Y., Florens, L., Si, K., Zhuang, J., Zheng, F., Zhou, C.. 2026-03-01. The Spatiotemporal Proteome Landscape of Aging: Structural determinants of age-sensitive proteome remodeling. https://doi.org/10.64898/2026.02.26.708310

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