Dataset Information

The proteomic navigator of human aging

ABSTRACT: Proteins are the cornerstone of human life, yet the proteomic landscape of aging across human tissues remains largely unexplored. Here, we present a comprehensive proteomic analysis of 520 samples from 15 human tissues, spanning a 50-year lifespan. Our study compiles a proteomic encyclopedia of multiple human organs, revealing an age-related decoupling between proteomic and transcriptomic profiles, and a loss of proteostasis characterized by the accumulation of amyloid proteins. We identified both shared and organ-specific proteomic signatures of aging, expanding the catalog of biomarkers for organ senescence. By pinpointing protein determinants of organ aging, we developed multi-organ proteomic aging clocks, uncovered disease risk factors, and potential therapeutic targets. Our dynamic analysis of proteomic temporal patterns indicates that organs experience a precipitous aging shift around age 50, with vasculature, which extensively interacts with other organs, showing early and notably aggressive senescence. Furthermore, we established a plasma proteomic signature of human aging, traced their organ origins, and identified key proteins driving endothelial senescence. Collectively, our work provides an unprecedented dynamic proteomic atlas of human aging, laying a foundation for decoding, assessing, and intervening in the aging process with proteins at the core.

ORGANISM(S): Homo Sapiens

SUBMITTER: Weiqi Zhang

PROVIDER: PXD058638 | iProX | Fri Dec 06 00:00:00 GMT 2024

REPOSITORIES: iProX

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Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures.

Ding Yingjie Y Zuo Yuesheng Y Zhang Bin B Fan Yanling Y Xu Gang G Cheng Zhongyi Z Ma Shuai S Fang Shuaiqi S Tian Ao A Gao Dandan D Xu Xi X Wang Qiaoran Q Jing Yaobin Y Jiang Mengmeng M Xiong Muzhao M Li Jiaming J Han Zichu Z Sun Shuhui S Wang Si S He Fuchu F Yang Jiayin J Qu Jing J Zhang Weiqi W Liu Guang-Hui GH

Cell 20250725 20

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized org ...[more]

PMID: 40713952

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Project description:BackgroundAging is a complex biological process characterized by progressive molecular alterations across multiple organ systems, significantly influencing disease susceptibility and mortality. Unraveling molecular interactions driving aging is crucial for interventions promoting healthy aging and mitigating senescence. However, the systemic mechanisms governing both inter-organ interactions and organ-specific aging trajectories remain incompletely characterized.MethodsTo investigate the molecular dynamics of aging, we conducted a systematic multi-omics analysis of 400 tissue samples collected from 10 organs (brain, heart, intestine, kidney, liver, lung, muscle, skin, spleen, and stomach) in mice at four distinct life stages: 4, 8, 12, and 20 months (from youth to elderly). Proteomic profiling was performed using data-independent acquisition (DIA) technology, while metabolomic analysis was performed in both positive and negative ion modes. Differential expression analysis of proteins and metabolites was employed to construct a comprehensive multi-organ aging dataset. ResultsProteomic profiling across ten organs at four age stages identified a total of 14,763 protein groups (PGs). Of these, 18 proteins, including Ighm, C4b, and Hpx, exhibited consistent age-related differential expression patterns across all ten organs. Functional enrichment analysis highlighted the humoral immune response as a primary driver of age-related expression changes. Additionally, this study mapped a set of age-unique proteins, such as Hp, Egf, and Arg, with distinct expression patterns in aging organs. Metabolic analysis identified 3,779 metabolites, with key aging-related metabolites such as NAD+, inosine, xanthine, and hypoxanthine showing significant expression changes across multiple organs. Pathway enrichment analysis revealed consistent alterations in purine metabolism, pyrimidine metabolism, riboflavin metabolism, and nicotinate/nicotinamide metabolism during multi-organ aging.ConclusionsThis study provides a multi-omics atlas of multi-organ aging, revealing both intra- and inter-organ similarities and heterogeneities. These findings offer valuable insights into the molecular mechanisms underlying geriatric health decline and serve as a foundational resource for organism-systematic early warning and targeted interventions against aging-associated pathologies.

Project description:The importance of brain-body interactions in the progresses of diseases are increasingly noticed, and understanding the associated processes could vastly improve the health of whole organism. A comprehensive, whole-organism analysis of organ dynamics to identify the molecular processes within and between organs after brain injury caused by ischemic stroke has been lacking. Mice models of 24 hours ischemic brain injury are constructed. Proteomics and metabolomics are used to detect the changes of organ’s proteome and metaboleome, respectively, and multiple bioinformatics analysis are performed to investigate the changing signatures across organs after stroke. Then, the organ proteomics data combined with aging mouse organ transcriptome data and mouse organ scRNA-seq data to reveal the biological age of organs and cellular resource of differentially expressed proteins (DEPs) of organs after stroke, respectively. Finally, we cross-referenced stroke-related DEPs in plasma with their corresponding protein expression in each organ to investigate the original source of plasma proteins by using spearman’s correlation analysis. Bioinformatics analysis showing the synchronization and asynchronization of the stroke-related proteins involved in multiple regulatory pathways are universally across organs. Although significant inter-organ correlations exist without influenced by stroke, the protein expression changes may better reflect the inter-organ correlation after brain injury by sharing some common changing signatures. Then, hundreds of DEPs in organs with the greatest numbers of DEPs are revealed in heart, and they are unique and common expressed between organs. Notably, an integrate analysis of these DEPs with mouse aging RNA-seq data reveal ageing-like changes in organs, suggesting increased biological ages of organs. Furthermore, a conjoint analysis of our proteomic data with scRNA-seq data confirms the cellular source of DEPs originated from intrinsic cells and immune cells, and the latter are widely located and activated in organs. Finally, we find that some DEPs in plasma are highly correlated with corresponding protein levels in distinct organs, potentially resulting in the stroke of the systemic circulation. Together, this study demonstrates a similar yet asynchronous inter- and intra-organ progression of stroke, providing a fundamental resource for understanding the molecular mechanisms underlying brain-body interaction and potential interventions for brain injury.

Dataset Information

The proteomic navigator of human aging

Publications

Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures.

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