Proteins are the cornerstone of life. However, the proteome blueprint of aging in various tissues of the human body remains an unknown territory.

On July 25, 2025, a research team led by Dr. Guanghui Liu from the Institute of Zoology, Chinese Academy of Sciences, Dr. Weiqi Zhang from the National Center for Biotechnology Information, Dr. Jing Qu from the Institute of Zoology, Chinese Academy of Sciences, and Professor Jiayin Yang from West China Hospital, Sichuan University, published a research paper in the journal Cell titled "Comprehensive Human Proteome Profiles Across a 50-Year Lifespan Reveal Aging Trajectories and Signatures."

This study first integrated ultra-sensitive mass spectrometry technology with machine learning algorithms to systematically construct a proteome aging map across a 50-year human lifespan, covering seven physiological systems and 13 key tissues, presenting a panoramic dynamic landscape of the organism's aging process from the protein perspective.

The study showed that humans experience an aging turning point around the age of 50, with blood vessels being one of the earliest aging and significantly susceptible tissues. It also identified candidate aging proteins, including GAS6, driving vascular and systemic aging.

Deciphering the Code of Aging: The First Multi-Organ Proteome Aging Map

The research team collected 516 samples from 76 people aged 14 to 68 (covering 13 organs such as the heart, aorta, lungs, and muscles) and used high-precision mass spectrometry to draw the world's first multi-tissue proteome map spanning half a century.

The study identified 12,771 proteins and established organ-specific protein expression features. The research team found that the correlation between mRNA and its translated proteins significantly decreased with age, especially in the spleen, muscles, and lymph nodes, where aging caused a "decoupling" phenomenon between the transcriptome and protein production.

The Core Mechanism of Aging: Protein Homeostasis Collapse

The study found that the "factories" maintaining protein quality declined across the board as age increased:

1. Decreased synthesis capacity: ribosomal proteins and amino acid synthases decreased;

2. Folding and transport failure: molecular chaperone proteins significantly decreased;

3. Accumulation of waste: amyloid proteins and immunoglobulins abnormally accumulated in multiple organs, forming an "amyloid protein-immunoglobulin-complement" inflammatory signaling axis.

These findings explain why the elderly are prone to chronic inflammatory diseases and provide new clues for amyloid-related diseases such as Alzheimer's disease.

Organ Aging Clock: Blood Vessels as the "Aging Pacemaker"

The research team used machine learning algorithms to build a proteomic biological age clock for 13 organs (predictive accuracy of 0.74-0.95), which showed that:

1. 50 years old is the aging turning point: there were significant fluctuations in the proteome during the age of 45-55;

2. Blood vessels age first: the aorta showed significant changes at 30 years old, much earlier than other organs.

The Accelerator of Aging: Pro-Aging Factors in the Blood

Blood vessels are not only victims of aging but also drivers of systemic aging, playing a central regulatory role as a "senohub," driving and amplifying the systemic aging process of multiple organs.

The study found that aging blood vessels highly express pro-aging proteins such as GAS6. Injecting GAS6 into middle-aged mice resulted in muscle weakness, vascular hardening, and multi-organ inflammation, symptoms of aging. Additionally, the study found that seven proteins, including GPNMB and COMP, simultaneously increased in the blood and organs, serving as aging biomarkers for non-invasive assessment of organ aging.

The corresponding author of the paper, Dr. Guanghui Liu, said that blood vessels may be like a pipeline, transporting pro-aging molecules to all corners of the body.

New Strategies for Anti-Aging: Targeting "Pro-Aging Proteins"

This study first revealed the spatiotemporal patterns of organ aging from the proteome dimension, providing a clear path for future anti-aging interventions:

  • Clearing senescent cells: developing CAR-T cell therapy targeting membrane proteins such as GPNMB;
  • Blocking pro-aging factors: using antibodies to neutralize circulating proteins such as GAS6 and SAP;
  • Early intervention window: protecting blood vessels before the age of 50 may delay systemic aging.

The highlights of this study:

  • Drawn a blueprint of the human organ proteome across 50 years;
  • Transcriptome-proteome decoupling and protein homeostasis imbalance are markers of aging tissues;
  • The organ proteome clock reveals the aging turning point and asynchrony;
  • Circulating aging proteins promote vascular and systemic aging.

In summary, the research team conducted comprehensive proteomics and histological analyses on 516 samples from 13 human tissues (heart, aorta, lungs, muscles, etc.), spanning five decades. This dynamic map revealed widespread transcriptome-proteome decoupling and a decline in protein homeostasis, characterized by the accumulation of amyloid proteins. Based on protein changes related to aging, the research team developed tissue-specific proteomic aging clocks and depicted aging trajectories at the organ level. Time analysis showed that humans experience an aging turning point around the age of 50, with blood vessels being one of the earliest aging and significantly susceptible tissues. The research team further defined a plasma proteome signature of aging that matches the tissue origin and identified candidate aging proteins, including GAS6, driving vascular and systemic aging.

This study, through the integration of proteome big data, artificial intelligence modeling, and multi-dimensional functional validation, proposed for the first time the "protein homeostasis imbalance - vascular aging hub" model, laying the foundation for comprehensively understanding human aging from the perspective of proteins and providing a new paradigm for systematic aging mechanisms.

Paper link:

https://www.cell.com/cell/abstract/S0092-8674(25)00749-4

Original article: https://www.toutiao.com/article/7531587117240304174/

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