Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.

Mar 11, 2026bioRxiv : the preprint server for biology

Single-cell protein mapping reveals how key aging processes are linked

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Abstract

91.6% of human counterparts to yeast proteins linked to aging exhibit changes during human aging.

Aging is associated with genomic instability, changes in gene expression regulation, loss of protein balance, and problems with cellular energy production.
Mapping protein expression and aggregation in yeast reveals extensive molecular alterations related to aging.
Compartment-specific changes in protein organization and aggregation occur as aging hallmarks manifest.
Temporal analysis indicates that disruptions in ribosome production, protein balance, and mitochondrial function occur before other aging-related changes.
Molecular connections among different aging hallmarks have been identified, suggesting a hierarchical sequence of cellular failures.

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Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. 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.

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Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.

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