Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures
This paper presents a comprehensive proteomic atlas of human aging, analyzing 516 samples from 13 different tissues across a 50-year lifespan to uncover the molecular signatures and dynamics of how our organs age.
Major Discoveries
A central finding is that as we age, the link between our genes (transcriptome) and the proteins they code for (proteome) weakens, a phenomenon described as transcriptome-proteome decoupling. This decoupling is a hallmark of aging tissues and is accompanied by a decline in proteostasis, which is the cell’s ability to maintain a healthy balance of proteins. A key feature of this decline is the accumulation of amyloid proteins across various organs.
Organ-Specific Aging and “Senohubs”
The researchers developed tissue-specific “proteomic clocks” to measure the biological age of different organs. This revealed several key insights:
Asynchronous Aging: Organs do not age at the same rate.
Aging Inflection Point: Many tissues show a significant acceleration in proteomic changes around the age of 50.
Vascular Senescence: Blood vessels, particularly the aorta, are among the earliest and most dramatically aging tissues, acting as a potential “senohub” that drives systemic aging.
Key Proteins Driving Aging
The study identified specific circulating proteins, termed “senoproteins,” that appear to drive the aging process.
GAS6: This protein was identified as a key “senokine” (a cytokine released by senescent cells) that originates from aging vascular tissue. When administered to middle-aged mice, GAS6 was shown to promote vascular and systemic aging, impairing physical function and causing senescence-like changes in multiple organs.
SAP (Serum Amyloid P-component): Identified as a “ubiquitous upregulated protein with aging” (UUPA), SAP was found to be elevated in multiple aging tissues. Experiments showed that SAP promotes vascular aging by inducing senescence in human aortic endothelial cells.
Circulating Biomarkers: The study identified numerous plasma proteins (like GPNMB, COMP, and HTRA1) whose levels correspond to aging in specific tissues, offering a path toward non-invasive biomarkers for organ aging. Several of these proteins were shown to induce features of vascular senescence in lab experiments.
Overall, the research provides a foundational atlas for understanding human aging at the protein level, highlighting that vascular aging is a critical initiator of systemic decline and identifying specific circulating factors that could be targeted for future anti-aging therapies.