Proteomic Analysis Reveals Aging Trajectories in 13 Human Organs

An international team of researchers led by the Chinese Academy of Sciences has created a proteomic atlas of human aging based on 13 organs, identifying tissue-specific biological clocks, transcriptome-proteome misalignment, and secreted proteins that can accelerate systemic decline.

Background: Why is this important?

Organ aging is a key factor in vulnerability to chronic diseases. Previously, the focus was on plasma proteins and DNA methylation, but systematic mapping of protein aging across organs had not been done. The new proteomic atlas fills this gap.

What the researchers did

• In the paper "Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures" ( Cell journal ), the scientists conducted a multi-tissue proteomic analysis spanning five decades of adult life.
• Samples from 76 people aged 14 to 68 years were analyzed: a total of 516 tissue samples + plasma.
• High-precision mass spectrometric profiling and parallel transcriptomic analysis were used.

Key Results

Quantitative data:

• More than 12,700 proteins from the cardiovascular, digestive, immune, endocrine, respiratory, skin and musculoskeletal systems were measured.
• Nuclear and mitochondrial proteins were predominant, especially in tissues with high metabolic activity.

Disruption of the connection between RNA and proteins:

• In all organs, a decrease in the correlation between mRNA and protein levels is observed with age, especially in the spleen, lymph nodes and muscle.
• Proteins responsible for synthesis, folding and utilization also decreased: ribosomal subunits, chaperones, etc.

Protein triad of aging:

• Accumulation of amyloid proteins (SAA1, SAA2), immunoglobulins and complement factors was detected.
• The authors described an amyloid-immunoglobulin-complement axis that drives inflammation and points to a collapse of protein quality control within cells and its link to systemic problems.

Biological clock and organ-specific aging

• A proteomic clock was constructed to estimate the biological age of various tissues (using elastic net regression).
• Forecast accuracy: Spearman coefficients from 0.74 to 0.95.
• TIMP3 (inhibitor of metalloproteinases) - was included in 9 organ-specific models.
• The most pronounced changes are in the aorta, especially between 45 and 55 years of age.

Secreted proteins and interorgan interactions

• Proteins that enhance aging at the systemic level have been identified.
• CXCL12, a chemokine associated with SASP (senescent secretory phenotype), was upregulated in 9 tissues.
• The aorta, spleen and adrenal glands emerged as the main sources of interorgan communication with age.

"Senohab" is a source of aging signals:

• 24 plasma ligand-receptor pairs associated with senescent cells were identified.
• The aorta has been called the "senohub" - the central node that initiates interorgan aging.

Examples of initiator molecules

• GAS6 (TAM receptor ligand):

• With age, it accumulates in plasma and aorta.
• Causes aging of endothelial and smooth muscle cells, inflammation, and disruption of angiogenesis.
• Mice injected with GAS6 showed vascular inflammation, decreased physical activity, and tissue degeneration.

• GPNMB:

• It also caused markers of aging, inflammation, and reduced cell migration and the ability to angiogenesis.
• In mice, it worsened motor function and increased vascular inflammation.

Additional observations

• General epigenetic instability;
• Coordinated decline in mitochondrial function;
• Remodeling of protein complexes;
• An early signal of aging comes from the adrenal glands.

Conclusion

The study shows that vascular tissues act as sensors and transmitters of aging, and secreted proteins (such as GAS6 and GPNMB) function as molecular agents of interorgan aging.

The resulting proteomic atlas of aging is a resource that may lead to new approaches in the diagnosis of biological age, prevention and therapy of age-associated diseases.