A role for the cystathionine-β-synthase /H₂S axis in astrocyte dysfunction in the aging brain

Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H₂S supplementation or by re-expressing CBS. Conversely, the CBS/H₂S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H₂S supplementation. Here we reveal that in the aging brain, the CBS/H₂S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H₂S axis in astrocytes that may be disrupted in the aged brain.