For years, scientists have known that aging begins in the smallest units of life: cells. But what turns this cellular decline into a whole-body unraveling has been harder to explain.
Now, a team of researchers in South Korea says it has found one of the clearest answers yet. The researchers at Korea University’s College of Medicine report that a single molecule — called reduced High Mobility Group Box 1, or ReHMGB1 — can act like a courier for aging, carrying “senescence signals” from cell to cell through the bloodstream.
“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,” said Ok Hee Jeon, the study’s senior author.
A Molecular Messenger of Decline
Cells that stop dividing are known as senescent cells. Although they no longer contribute to normal tissue function, these cells are not dead. They enter this limbo state when they’ve experienced too much stress or damage — say, from DNA mutations, oxidative stress, or simply old age.
At first, senescence is protective. It’s the body’s way of quarantining damaged cells so they don’t turn cancerous. But over time, these cells release a cocktail of inflammatory chemicals, growth factors, and enzymes collectively called the senescence-associated secretory phenotype, or SASP. These substances can damage nearby healthy cells, triggering them to age prematurely.
Until now, scientists have only been able to observe this so-called “paracrine” effect locally, within a patch of tissue. The Korean team discovered that ReHMGB1, a specific chemical form of the HMGB1 protein, can move those signals far beyond their point of origin.
HMGB1 has several chemical states, but the researchers found that only its reduced form, ReHMGB1, was capable of triggering senescence in cells far from where it was released. The oxidized form, OxHMGB1, had no such effect.
In lab experiments, adding ReHMGB1 to cultures of human fibroblasts, kidney epithelial cells, or skeletal muscle cells rapidly caused them to show hallmarks of senescence. These include stopping cell division, activating genes such as p16 and p21, and producing inflammatory factors like interleukin-6.
The team then moved to mice. Young animals given injections of ReHMGB1 showed elevated senescence markers in muscles, liver, and other tissues, along with reduced muscle performance. In older mice, ReHMGB1 levels in the blood were naturally higher than in younger ones.
Blocking the Signal of Aging
The next step was to see if blocking ReHMGB1 could slow or reverse this process. In middle-aged mice with muscle injuries, the researchers administered antibodies that neutralized HMGB1. Compared with untreated controls, these mice showed fewer senescent cells in muscle tissue. They also showed stronger muscle regeneration and improved grip strength and endurance.
The experiments also pinpointed how ReHMGB1 works: it binds to a receptor called RAGE, which then triggers inflammatory signaling pathways — JAK/STAT and NF-κB — that reinforce senescence and inflammation. They found that blocking either the receptor or the signaling pathway reduced the damage.
So, where does this leave us? The findings hint at a possible therapy to slow the systemic spread of aging. However, the leap from mouse models to human medicine is considerable. ReHMGB1 is unstable in the bloodstream and difficult to target precisely. Any treatment would need to be safe enough to block harmful forms of HMGB1 without interfering with the protein’s normal, essential roles.
Still, the study adds weight to an emerging view of aging: it is not just wear and tear, but a coordinated process driven by signals that travel through the body. If scientists can interrupt those signals, they might be able to slow the clock — not just in one organ, but everywhere at once.
The findings were reported in the journal Metabolism.
