Scientists at Korean universities have determined how aging signals are transmitted through the blood and pointed out a protein called HMGB1 that carries cellular damage from one tissue to a distant organ.
Their research shows that the simplified form of the protein acts like a molecular messenger, which spreads senescence (the biological state in which cells stop dividing and begin to secrete harmful substances) stimulates the entire body.
The finding explains why aging appears to accelerate over time and provides potential goals for interventions that may slow down age-related decline. When the researchers blocked HMGB1 in middle-aged mice, the animals showed improved muscle regeneration and physical manifestations after injury.
Aging spreads like wildfire
Cell senescence occurs when cells are damaged and stop dividing, entering a zombie-like state, which secretes inflammatory molecules. These senescent cells accumulate with age, leading to tissue dysfunction and disease. But how aging spreads from isolated damaged cells to affect the entire organ system.
The team used laboratory cell cultures and active animal models to track the spread of aging. They found that HMGB1, usually found in the nucleus, helps organize DNA, which is released into the blood as the cells become aging.
Crucially, they found that only reduced HMGB1 (REHMGB1) drives aging in distant tissues, while its oxidized counterpart remains largely inactive. This redox sensitivity means that the aging effect of a protein depends on the chemical environment it encounters.
Molecular pathway display
This study found the exact mechanism by which REHMGB1 propagates aging signals:
- REHMGB1 circulates through the blood and binds to anger 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 to secrete their own aging-promoting factors
- Perpetuate the cycle, spreading aging to adjacent tissues
Using RNA sequencing analysis, the researchers found that REHMGB1 treated cells exhibited nearly the same gene expression pattern as cells undergoing radiation-induced senescence. This protein essentially hijacks normal cellular machinery to produce artificial aging.
“This study shows that aging signals are not limited to individual cells but can be transmitted systematically through the bloodstream, and Rehmgb1 is the main driver,” explained Professor Ok Hee Jeon, who led the research team. “By preventing this pathway, we are able to restore tissue regeneration capabilities, which demonstrates a promising strategy for treating diseases associated with aging.”
From the laboratory to the living system
To test their findings in living organisms, the researchers injected rehmgb1 into young mice and observed the rapid development of aging markers throughout multiple tissues. Skeletal muscle showed increased expression of the aging proteins p16 and p21, while blood samples showed increased inflammatory cytokines.
The effects of proteins are not limited to immediate reactions. Time-track experiments show that REHMGB1 can still detect sufficient time in the cycle and affect distant tissue at least 24 hours after injection.
More importantly, the group showed therapeutic potential by treating middle-aged mice with anti-HMGB1 antibodies before inducing muscle injury. Antibody-treated mice showed reduced markers of aging, enhanced muscle regeneration, and improved physical performance for grip strength, balance and endurance tests compared to control animals.
Human relevance and clinical potential
Analysis of human blood samples confirmed the clinical relevance of the study. People in the 1970s and 1980s had significantly higher cyclic REHMGB1 levels than those in their 40s, suggesting that this pathway plays a role in human aging.
These findings provide multiple avenues for therapeutic interventions. Drugs targeting anger receptors, JAK/STAT signaling, or HMGB1 itself may slowly undergo systemic aging processes. Understanding how the redox state of a protein affects its activity may also guide strategies that regulate its effects.
However, there are still challenges in translating these findings into clinical applications. REHMGB1 has a serum half-life of only 17 minutes due to rapid oxidation of oxidation, making it difficult to study and target living systems. Future research will require the development of tools that can distinguish different forms of HMGB1 and the understanding of the natural occurrence of redox changes during aging.
The study fundamentally changes how scientists view progress in aging as a process of active transmission rather than deterioration over time rather than just passive cells.
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