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Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.<\/jats:p>","DOI":"10.64898\/2026.02.26.708335","type":"posted-content","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T15:10:10Z","timestamp":1772291410000},"source":"Crossref","is-referenced-by-count":1,"title":["Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging"],"prefix":"10.64898","author":[{"given":"Seungmin","family":"Yoo","sequence":"first","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Young","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Li","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingraj","family":"Vannur","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junming","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiying","family":"Wu","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie K.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuankai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026030310101013000_2026.02.26.708335v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"2026030310101013000_2026.02.26.708335v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"2026030310101013000_2026.02.26.708335v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.R120.002234"},{"key":"2026030310101013000_2026.02.26.708335v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2021.100186"},{"key":"2026030310101013000_2026.02.26.708335v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature11654"},{"key":"2026030310101013000_2026.02.26.708335v1.6","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71196"},{"key":"2026030310101013000_2026.02.26.708335v1.7","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48186"},{"key":"2026030310101013000_2026.02.26.708335v1.8","doi-asserted-by":"publisher","DOI":"10.1101\/2021.11.05.467477"},{"key":"2026030310101013000_2026.02.26.708335v1.9","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.104530.2"},{"key":"2026030310101013000_2026.02.26.708335v1.10","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi326"},{"key":"2026030310101013000_2026.02.26.708335v1.11","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E11-10-0884"},{"key":"2026030310101013000_2026.02.26.708335v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16083"},{"key":"2026030310101013000_2026.02.26.708335v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00754-5"},{"key":"2026030310101013000_2026.02.26.708335v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00368-20"},{"key":"2026030310101013000_2026.02.26.708335v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25205-2"},{"key":"2026030310101013000_2026.02.26.708335v1.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC118.003325"},{"key":"2026030310101013000_2026.02.26.708335v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80493-6"},{"key":"2026030310101013000_2026.02.26.708335v1.18","doi-asserted-by":"crossref","unstructured":"He, C. , Zhou, C. , and Kennedy, B.K . 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