Blood Protein Spreads Cellular Aging Throughout Body

Scientists at Korea University have identified how aging signals travel through the bloodstream, pinpointing a protein called HMGB1 that carries cellular damage from one tissue to distant organs.

Their research reveals that the reduced form of this protein acts like a molecular messenger, spreading senescence—the biological state where cells stop dividing and start secreting harmful substances—across the entire body.

The discovery explains why aging appears to accelerate over time and offers a potential target for interventions that could slow age-related decline. When researchers blocked HMGB1 in middle-aged mice, the animals showed improved muscle regeneration and better physical performance after injury.

Senescence Spreads Like Wildfire

Cellular senescence occurs when cells become damaged and stop dividing, entering a zombie-like state where they secrete inflammatory molecules. These senescent cells accumulate with age, contributing to tissue dysfunction and disease. But how senescence spreads from isolated damaged cells to affect entire organ systems remained unclear.

The research team used both laboratory cell cultures and live animal models to track how senescence propagates. They discovered that HMGB1, normally found inside cell nuclei helping organize DNA, gets released into the bloodstream when cells become senescent.

Crucially, they found that only the reduced form of HMGB1 (ReHMGB1) drives senescence in distant tissues, while its oxidized counterpart remains largely inactive. This redox sensitivity means the protein’s aging effects depend on the chemical environment it encounters.

Molecular Pathway Revealed

The study uncovered the precise mechanism by which ReHMGB1 spreads aging signals:

• ReHMGB1 circulates through blood and binds to RAGE receptors on healthy cells
• This binding activates JAK/STAT and NF-κB signaling pathways
• Activated pathways trigger inflammatory responses and cell cycle arrest
• Affected cells begin secreting their own aging-promoting factors
• The cycle perpetuates, spreading senescence to neighboring tissues

Using RNA sequencing analysis, researchers found that ReHMGB1-treated cells exhibited gene expression patterns nearly identical to cells that had undergone radiation-induced senescence. The protein essentially hijacked normal cellular machinery to create artificial aging.

“This study reveals that aging signals are not confined to individual cells but can be systemically transmitted via the blood, with ReHMGB1 acting as a key driver,” explained Professor Ok Hee Jeon, who led the research team. “By blocking this pathway, we were able to restore tissue regenerative capacity, suggesting a promising strategy to treat aging-related diseases.”

From Lab to Living Systems

To test their findings in living organisms, researchers injected young mice with ReHMGB1 and observed rapid development of aging markers throughout multiple tissues. Skeletal muscles showed increased expression of senescence proteins p16 and p21, while blood samples revealed elevated inflammatory cytokines.

The protein’s effects weren’t limited to immediate responses. Time-course experiments showed that ReHMGB1 remained detectable in circulation for at least 24 hours after injection, providing sufficient time to reach and affect distant tissues.

More importantly, the team demonstrated therapeutic potential by treating middle-aged mice with anti-HMGB1 antibodies before inducing muscle injury. Compared to control animals, antibody-treated mice showed reduced senescence markers, enhanced muscle regeneration, and improved physical performance in grip strength, balance, and endurance tests.

Human Relevance and Clinical Potential

Analysis of human blood samples confirmed the research’s clinical relevance. People in their 70s and 80s had significantly higher levels of circulating ReHMGB1 compared to those in their 40s, suggesting this pathway operates in human aging.

The findings offer multiple avenues for therapeutic intervention. Drugs targeting RAGE receptors, JAK/STAT signaling, or HMGB1 itself could potentially slow systemic aging processes. Understanding how the protein’s redox state influences its activity might also guide strategies for modulating its effects.

However, challenges remain in translating these discoveries to clinical applications. ReHMGB1 has a serum half-life of only 17 minutes due to rapid oxidation, making it difficult to study and target in living systems. Future research will need to develop tools that can distinguish between different HMGB1 forms and understand how redox changes occur naturally during aging.

This research fundamentally changes how scientists view aging progression, revealing it as an actively transmitted process rather than simply passive cellular deterioration accumulating over time.