The signal molecules secreted by senescent cells can encourage other nearby cells to also become senescent. Thus the high burden of lingering senescent cells in aged tissues is both directly harmful to tissue structure and function, but also indirectly harmful by encouraging further growth of that burden of cellular senescence. The research community has investigated which of the many different components of the senescence-associated secretory phenotype (SASP) are most important in producing bystander senescence. Here, researchers presents evidence for the unoxidized form of HMGB1 to be a good target for suppression of this transmission of the senescent state between cells.
Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence. We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.
Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration. Thus targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.