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

Abstract

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.

Keywords: Choroid plexus; Gene-based delivery strategies; Gut dysbiosis; Klotho; Neurodegeneration; Probiotics.

Fig. 1

Schematic representation of the effects of gut dysbiosis and reduced Klotho levels on the aged choroid plexus (ChP). During aging, the gut microbiota undergoes changes in composition and function, a condition known as gut dysbiosis. This results in altered nutrient processing and reduced production of essential molecules (e.g., lower levels of short-chain fatty acids, SCFAs), accompanied by a decline in immune protection, increased local inflammation, and a significant weakening of the gut’s selective barrier function (a condition known as “leaky gut” syndrome), ultimately leading to systemic inflammation and neuroinflammation. Aging is also associated with a reduction in Klotho levels, particularly in the ChP, one of the main sources of this protein. The combination of gut dysbiosis and reduced Klotho synthesis causes significant impairment of the ChP’s structural integrity and immune function—partly due to microglial dysregulation—accompanied by decreased cerebrospinal fluid (CSF) production and clearance, as well as increased inflammation and oxidative stress. The image was created using the BioRender software

Fig. 2

Restoring gut microbiota eubiosis and recovering Klotho levels in the choroid plexus (ChP) as a potential preventive strategy for the onset of neurodegenerative phenomena in older adults. The administration of probiotics, particularly those genera that synthesize short-chain fatty acids, such as Lactobacillus and Bifidobacterium, not only helps counteract gut microbiota dysbiosis but also influences the gut-brain axis. These probiotics can reduce inflammation and strengthen tight junctions, thereby improving the structure and function of barriers, including the ChP. On the other hand, upregulating Klotho levels in the ChP would have a cumulative effect on maintaining barrier integrity, cerebrospinal fluid (CSF) production and clearance, and immunosurveillance. Ensuring selective Klotho synthesis in the ChP is crucial. At the construct level, the Transthyretin (TTR) promoter can be utilized, incorporating liver-enriched microRNA recognition sequences to target degradation in hepatic cells (e.g., miR-122a and miR-199a). Regarding the viral capsid, adeno-associated viruses (AAVs) can selectively target the ChP, particularly when engineered using the Multiplex-CREATE (M-CREATE) method. The image was created using the BioRender software