bioRxiv : the preprint server for biologyMar 11, 2026

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

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Single-cell spatial proteomics in aging yeast suggests that aging hallmarks become connected through protein relocalization, aggregation, and loss of compartmental organization.

Evidence

This cellular atlas study mapped proteome-wide protein expression, localization, and aggregation across yeast replicative aging and compared hallmark-linked proteins with human aging changes.

Caveat

The mechanistic sequence is inferred primarily from yeast aging, so conservation in human aging remains indirect despite reported ortholog changes.

Simplified

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.