Promoting the nuclear retention of HMGB1 attenuates astrocyte senescence

Astrocytes are the primary source of 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. Specifically, by establishing a nuclear HMGB1 depletion model and interfering 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. Together, promoting the nuclear retention of HMGB1 is a new strategy for attenuating brain aging and related disorders.