Mapping Aging Signatures: Human Proteome Analysis Across 13 Organs

A collaborative research effort led by the Chinese Academy of Sciences has developed an extensive proteomic atlas illustrating how human organs age differently. The study, published in Cell, sheds light on tissue-specific aging processes, revealing unique biological aging markers and the molecular changes that occur across various organs over a 50-year span. The researchers analyzed tissue and plasma samples from 76 individuals aged 14 to 68, utilizing high-resolution mass spectrometry and transcriptomic assays to quantify over 12,700 proteins across key organ systems including cardiovascular, immune, endocrine, respiratory, and musculoskeletal tissues.

Subcellular localization showed a dominance of intracellular proteins, especially within nuclei and mitochondria, emphasizing cellular and mitochondrial aging. Comparative analysis identified both organ-enriched signatures and shared proteins vital for cellular functions. A significant finding was the disruption of mRNA-protein correlation with age, particularly in the spleen, lymph nodes, and muscle, coupled with declines in machinery responsible for protein synthesis, folding, and degradation.

The accumulation of amyloid proteins such as SAA1 and SAA2 was notable, forming an amyloid-immunoglobulin-complement axis that links misfolded protein deposition to immune activation and inflammation. Proteins were grouped based on their age trajectories, with some steadily increasing like serum amyloid P-component (SAP), and others, such as PRPF4, decreasing consistently. These proteins influence cellular senescence and inflammation; for instance, SAP was shown to induce aging signs in vascular cells.

To quantify biological aging, the team constructed tissue-specific proteomic clocks, achieving high accuracy in age prediction. The analyzed proteins, including TIMP3, offered insights into midlife aging dynamics, especially in the aorta. Secretory proteins, like CXCL12, correlated with senescence-associated secretory phenotype (SASP) profiles, and cross-organ signaling pathways were mapped, revealing the aorta and adrenal glands as key communication hubs that evolve with age.

The study also identified systemic aging mediators, notably GAS6, which promotes cellular senescence and vascular dysfunction when elevated. Experimental validation demonstrated GAS6’s role in aging-related vascular decline in humans and mice. Several plasma proteins increased with age and mirrored tissue changes, underscoring their potential as biomarkers or therapeutic targets. Functional assays identified molecules like GPNMB and HTRA1 as inducers of senescence and inflammation.

Overall, this comprehensive proteomic analysis uncovers pivotal molecular pathways and inter-organ communication mechanisms that drive human aging. It emphasizes the role of vascular-derived factors in systemic aging, providing a foundation for developing targeted interventions to mitigate age-related decline.