Proc. Natl. Acad. Sci. USA https://doi.org/10.1073/pnas.1808609115 (2018)

Aging is associated with progressive systemic increases in inflammation that can contribute to neurodegeneration. In the Proceedings of the National Academy of Sciences, Mucke and colleagues use a mouse model to investigate the choroid plexus (CP), a major gateway that regulates entry of cells of the immune system into the brain. They observe that expression of the anti-aging protein Klotho decreases in the CP of aged mice. Experimental depletion of Klotho specifically in the CP results in increased inflammatory signatures in the CP, infiltration by macrophages and enhanced microglial activation in the brain in response to lipopolysaccharide challenge. In vitro modeling shows that Klotho regulates inflammation by cooperating with signaling via the fibroblast growth factor FGF23 to reduce activation of the NLRP3 inflammasome. High levels of Klotho in the CP might therefore enhance blood–brain barrier integrity.