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

Area of Science:

• Cellular Biology
• Aging Research
• Proteomics

Background:

• Aging is characterized by conserved hallmarks like genomic instability and loss of proteostasis.
• The mechanistic links and spatial context of these aging hallmarks remain poorly understood.

Purpose of the Study:

• To create a proteome-wide, single-cell atlas of protein expression, localization, and aggregation during yeast replicative aging.
• To map aging hallmark-linked molecular remodeling in its spatial context.
• To identify connections between different aging hallmarks and establish a temporal sequence of cellular failures.

Main Methods:

• Utilized a proteome-wide, single-cell, subcellular atlas approach in yeast.
• Analyzed protein expression, localization, and aggregation across replicative aging.
• Integrated spatial phenotypes and performed temporal analysis.

Main Results:

• Identified hundreds of unappreciated molecular changes underlying major aging hallmarks.
• Demonstrated that hallmark phenotypes often involve compartment-specific loss of spatial confinement, relocalization, and aggregation.
• Found that 91.6% of identified yeast proteins have human orthologs that also change during human aging.
• Revealed molecular connections linking different hallmarks through integrated spatial phenotypes.
• Suggested that nucleolar ribosome biogenesis disorganization, proteostasis decline, and mitochondrial dysfunction precede other aging hallmarks.

Conclusions:

• Provided a deep molecular understanding of aging hallmarks and their spatial context.
• Established a framework for linking aging hallmarks into a hierarchical sequence of cellular failures.
• Highlighted the conservation of aging mechanisms between yeast and humans.