Aging can be split up into specific categories in many different ways; age-related diseases as collections of symptoms, specific forms of cell and tissue damage that accumulate, dysfunctions separated by organ, and so forth. None of these categories exist in isolation from the others, however. All aspects of aging interact with one another. Kidney dysfunction affects the brain. Mitochondrial dysfunction influences the burden of cellular senescence. There are a hundred other interactions one might consider that blur the lines of any attempt at categorization of the progression of aging. Nothing is neat and contained, everything interacts.
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.
