For the first time in the world, a Korean research team discovered how cellular aging can spread systemically through the bloodstream—offering new insights and a potential therapeutic strategy to combat aging-related decline.
Professor Ok Hee Jeon's research group at the Department of Convergence Medicine, Korea University's College of Medicine, discovered that High Mobility Group Box 1 (HMGB1),a key extracellular senescence-associated secretory phenotype (SASP) factor, plays a critical role in transmitting senescence from aging cells to distant tissues.
Senescent cells are known to secrete pro-inflammatory factors and signaling molecules—collectively known as SASP—which induce paracrine senescence in surrounding cells. Over time, these senescent cells accumulate in various tissues, impairing regenerative capacity and contributing to tissue dysfunction. However, the mechanism by which senescence spreads systemically remained unclear.
In their latest study published in Metabolism – Clinical and Experimental (Impact Factor 10.9, top 4.6% in endocrinology and metabolism), Professor Jeon's team provides the first evidence that reduced HMGB1 (ReHMGB1), a redox-sensitive isoform of HMGB1, circulates through the bloodstream and induces senescence in remote tissues.
Using both in vitro and in vivo models, the researchers demonstrated that extracellular ReHMGB1, but not its oxidized form (OxHMGB1), robustly induces senescence-like features in multiple human cell types—including fibroblasts, renal epithelial cells, and skeletal muscle cells. Mice systemically treated with ReHMGB1 exhibited elevated senescence markers (p21, p16), increased SASP factor expression, and impaired muscle function.
Furthermore, in a muscle injury model in middle-aged mice, administration of anti-HMGB1 antibodies not only reduced senescence markers but also enhanced muscle regeneration and improved physical performance. These findings highlight the therapeutic potential of targeting extracellular HMGB1 to reverse or mitigate age-related tissue dysfunction.
"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 Professor Jeon. "By blocking this pathway, we were able to restore tissue regenerative capacity, suggesting a promising strategy to treat aging-related diseases."
This research was supported by the Myokine Research Center (MRC) and the Mid-sized Research Support Project of the Ministry of Science and ICT. and was conducted in collaboration with internationally recognized experts in aging biology, including Professor Irina Conboy of UC Berkeley and Professor Christopher Wiley of Turfts University. The full study is published under the title: "Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state." (Metabolism: Clinical and Experimental, 2025, Vol. 168, 156259)
