The aging choroid plexus and its relationship with gut dysbiosis and Klotho decline: possible intervention strategies

The choroid plexus (ChP) is a complex ventricular structure that forms a semi-permeable barrier between the blood and cerebrospinal fluid (CSF). It is responsible for CSF secretion and clearance, contains macrophages, and is one of the few sites within the central nervous system (CNS) where T cells are present. Additionally, the ChP plays a role in detecting peripheral inflammation, which leads to the modulation of its epithelial cell function. Despite its critical importance in maintaining brain homeostasis, the ChP is often overlooked, particularly concerning the changes it undergoes with aging, such as reduced barrier function, impaired CSF production, and altered immunosurveillance. These age-related alterations may contribute to several harmful effects, including neuroinflammation and oxidative damage, potentially predisposing individuals to neurodegenerative conditions. Although knowledge is still limited, gut dysbiosis and decreased Klotho levels-of which the ChP is one of the main sources-appear to be significant contributors to ChP impairments. This narrative review will examine the impact of age-related gut dysbiosis on the CNS, focusing on the ChP, and explore the effects of reduced Klotho levels in this brain structure. We will also propose the hypothesis that combining the administration of probiotics capable of restoring gut microbiota eubiosis with gene therapy to upregulate Klotho in the ChP could help preserve the structural and functional integrity of the aging brain. Finally, we will provide a technical overview to ensure that vectors encoding Klotho cDNA achieve maximum specificity for the ChP, thereby avoiding off-target effects.