Astrocytes make up a sizable fraction of the cells in brain tissue, responsible for supporting the functions of neurons and the microenvironment of the brain. Cellular senescence in these supporting populations grows with age and is thought to provide an important contribution to the aging of the brain and onset of neurodegenerative conditions. Lingering senescent cells secrete inflammatory signals, disrupting the function and structure of tissue in proportion to their numbers. The research community continues to investigate the biochemistry of the senescent state and how cells become senescent, details that may differ meaningfully from cell population to cell population, in search of novel approaches that might lead to drugs that can prevent senescence, destroy senescent cells, or even reverse the normally irreversible senescent state.
Astrocytes are the primary source of circulating high mobility group box-1 (HMGB1) which is intimately associated with aging and related disease in central nervous system (CNS). However, the multi-localization and multifunctional characteristics of HMGB1 indicate that it may regulate brain aging through various pathways and mechanisms which are not yet clearly defined. In this study, we find that the expression of HMGB1 decreases with aging in both human and mouse astrocytes. Conditional knockout of Hmgb1 in astrocytes induces the exacerbation of mice aging.
Physiologically, HMGB1 locates in the nucleus and acts as a DNA binding protein to modulate gene expression and DNA repair. During cell activation, injury or death, HMGB1 can also translocate to the extracellular microenvironment and serve as a damage-associated molecular pattern (DAMP) to activate immune responses. The roles of HMGB1 in cellular senescence are complicated. Some studies have observed that HMGB1 functions as a core senescence-associated secretory phenotype (SASP) component, being extracellularly released to drive inflammaging. Conversely, emerging evidence suggests that nuclear HMGB1 exhibits a protective role in cellular senescence by maintaining telomerase activity and telomere function.
By establishing a nuclear HMGB1 depletion model and interfering in the interactions of extracellular HMGB1, we find that nuclear HMGB1 is anti-senescent whereas extracellular HMGB1 is pro-senescent. Inhibiting HMGB1 nuclear export to enhance its nuclear retention effectively alleviates astrocyte senescence. Thus promoting the nuclear retention of HMGB1 is a new strategy for attenuating brain aging and related disorders.
