As we age, some cells, become old and stop functioning properly. These "senescent" cells don't just sit there; they start sending out distress signals, a sort of molecular pollution. This "pollution" can spread and make other healthy cells also become old and dysfunctional. The scientist from Korea University College of Medicine and Yonsei University College of Medicine in South Korea shed light on the molecule HMGB1 in the research article published in Metabolism Journal.  

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The Body's Double Agent

HMGB1 acts as messenger molecule within your cells. Normally, it helps organize your DNA inside the cell's nucleus. But when a cell gets stressed or damaged, HMGB1 can sneak out into the space between cells. Once it's outside, it changes its role completely, becoming a signal that can trigger inflammation and contribute to aging.

Here's the twist: HMGB1 isn't always the same when it's outside the cell. It can exist in different "redox states," which basically means its chemical form can change depending on the environment.

The research team lead by Dr Ji-Won Shin in this study discovered that only one specific form, called Reduced HMGB1 (ReHMGB1), is the troublemaker when it comes to spreading aging. The other forms, like the "oxidized" version (OxHMGB1), don't seem to have the same effect.

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ReHMGB1's Role in Cellular Aging

The scientists conducted experiments to understand how ReHMGB1 promotes aging. They found that when healthy cells were exposed to ReHMGB1, they started showing signs of senescence, similar to what happens when cells age naturally or are damaged by radiation. The cells stopped dividing as much and activated specific genes and pathways associated with aging and inflammation. This happened across different types of cells, including skin, kidney, and muscle cells, suggesting ReHMGB1 has a widespread impact.

The research also pinpointed how ReHMGB1 achieves this. It binds to a specific "receptor" on the surface of cells called RAGE. This binding then triggers two major signalling pathways inside the cell: the JAK/STAT pathway and the NF-κB pathway. Pathways are like command centers that tell the cell to do two critical things: first, to produce more of those "molecular pollution" signals (known as SASP factors), which further spread aging, and second, to stop dividing, essentially pushing the cell into a senescent state. When the researchers blocked these pathways, they could prevent ReHMGB1 from causing cells to age.

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ReHMGB1's Impact on the Entire Body and Future Treatments

The team of researchers also perform experiments on living mice. The team found that levels of ReHMGB1 significantly increased in older mice and even in older human samples. When young, healthy mice injected with ReHMGB1, the mice showed elevated levels of inflammatory signals and markers of senescence in various tissues, especially in their muscles and liver. The experiment suggests that ReHMGB1 isn't just affecting nearby cells but can travel through the bloodstream and spread aging throughout the body.

The good news is blocking HMGB1 in middle-aged mice that had muscle injuries, saw remarkable results. The mice had less cellular senescence, reduced inflammation, and muscles healed much better. This points to a potential exciting new avenue for treating age-related conditions.

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Why This Matters

This research highlights that ReHMGB1 acts as a key "pro-aging" factor, driving the spread of cellular senescence. By understanding how ReHMGB1 works and identifying it as a circulating factor, scientists are now one step closer to developing therapies that could target this molecule. The hope is that by controlling ReHMGB1, we might be able to slow down the aging process and prevent or treat many age-related diseases.

The study opens new possibilities for interventions that could not only extend healthy lifespan but also improve our quality of life as we get older.

DOI: https://doi.org/10.1016/j.metabol.2025.156259