Proteomic aging atlas identifies senoproteins as drivers of vascular and systemic senescence

Mammalian aging is a natural process marked by the progressive decline of organ function and increased vulnerability to chronic diseases. Organs follow distinct aging trajectories—some age earlier than others—yet, they act in concert to shape the overall organismal aging [1]. However, our understanding of organ-specific aging patterns and the heterogeneity of systemic aging remains limited, and the mechanisms underlying multi-organ interaction during aging are still unclear. These gaps hindered the development of reliable aging biomarkers and quantitative metrics to accurately assess organ-specific biological age and to effectively evaluate interventions targeting specific aging processes. Proteins are fundamental to cellular function, and loss of proteostasis(definition) is recognized as a major hallmark of aging [2]. However, proteomic alterations in aged human organs remain poorly characterized, as most studies focused primarily on plasma proteomics while overlooking the proteostasis decline in organ-specific context. A recent study by Ding et al. closed these long-standing gaps in aging research by conducting comprehensive proteomic, transcriptomic, and histological analyses across five decades of life in 13 kinds of human tissues [3]. This large-scale dataset reveals widespread transcriptome–proteome decoupling and an unsynchronized progressive decline in proteostasis across multiple organs during aging. The authors further developed proteomic age clocks to characterize heterogeneous dynamics in tissue-specific aging trajectories and identified candidate senoproteins driving vascular and systemic aging. Utilizing state-of-the-art mass spectrometry and parallel transcriptomic assay, the authors conducted a quantitative proteomic analysis of tissues from individuals aged 14 to 68, encompassing seven bodily systems: cardiovascular (heart and aorta), digestive (liver, pancreas, and intestine), immune (spleen and lymph node), endocrine (adrenal gland and white adipose), respiratory (lung), integumentary (skin), and musculoskeletal (muscle), along with blood samples (Fig. 1). A total of 12,771 distinct proteins were identified, covering the protein-coding genes across all chromosomes. Notably, when comparing the proteomic profiles with transcriptomic data, they observed only moderate correlation between protein and mRNA levels across multiple organs. This positive correlation declined markedly with age, indicating an age-dependent decoupling of the proteome and transcriptome. Further analysis provided insights that the translational levels of several key proteins involved in protein synthesis, as well as proteins responsible for folding, assembly, and transport, were found to decrease across multiple tissues with age. Alongside the deterioration of protein quality control, organ aging was also marked by excessive activation of immune pathways, as evidenced by the accumulation of amyloid proteins, immunoglobulins, and complement components. The proteomic aging atlas constructed from 13 tissues spanning over 50 years of life. Comprehensive proteomic and transcriptomic profiling revealed age-associated divergence between the proteome and transcriptome, enabled the construction of tissue-specific proteomic age clocks to capture diverse aging trajectories of organs, and uncovered candidate senoproteins as potential aging drivers contributing to vascular and multi-organ degeneration. Created in BioRender. Bi. C (2025) The comprehensive age-stratified proteomic dataset enabled the identification of age-dependent differentially expressed proteins (DEPs) that exhibited altered expression in at least one organ during human aging. The majority of these DEPs were found to be tissue-specific, with only approximately 40% shared across at least two tissues, highlighting the organ-selective deterioration of tissue function with age. Nevertheless, the authors identified a subset of upregulated DEPs that consistently increased with age across multiple tissues. These proteins were predominantly involved in complement activation, immune response, and amyloid fibril formation. In contrast, commonly downregulated DEPs across tissues were enriched in proteins associated with Golgi vesicle transport and protein maturation. Notably, 31 proteins were uniformly downregulated in more than 6 tissues without upregulation in any organ. These were designated as ubiquitous downregulated proteins with aging, and include PRPF4, a key component involved in pre-mRNA splicing. Conversely, 29 proteins were consistently upregulated across more than 6 tissues and termed ubiquitous upregulated proteins with aging (UUPA). These proteins were enriched in pathways related to complement activation, inflammatory responses, and cell adhesion. Among them, serum amyloid P-component (SAP, encoded by APCS)—a canonical amyloid-related factor and a representative example of mRNA-protein decoupling, particularly evident in the liver—emerged as the most prominent UUPA. Further efforts were made to establish an aging hallmark assessment system to elucidate proteomic alterations in aging organs, using aging hallmarks such as cell cycle arrest, genomic instability, loss of heterochromatin, inflammation, and fibrosis. Among these hallmarks, mitochondrial proteins involved in mitochondrial biogenesis, homeostasis, and respiration were found to be consistently downregulated across multiple organs, as revealed by gene set enrichment analysis, highlighting the important role of mitochondrial dysfunction(definition) in aging. Epigenetic instability was also evident, with YTHDC1 identified as the most consistently downregulated epigenetic regulator across tissues. Recognizing that proteins often function as complexes, the authors analysed 816 protein complexes, integrating both proteomic and transcriptomic data. Upregulated complexes were predominantly enriched in inflammasome-related pathways, while downregulated complexes were associated with nuclear hormone receptors, nucle