Lai Giovanni, Bevilacqua Lisa, Giuliani Maria Elisa, Bigossi Giorgia, Marcozzi Serena, Casoli Tiziana, Abbrescia Pasqua, Frigeri Antonio, Malavolta Marco, Balietti Marta
Advanced Technology Center for Aging Research and, Geriatric Mouse Clinic, IRCCS INRCA, Via Birarelli 8, 60121, Ancona, Italy.
Center for Neurobiology of Aging, IRCCS INRCA, 60121, Ancona, Italy.
Geroscience. 2025 Jul 22. doi: 10.1007/s11357-025-01797-1.
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.
脉络丛（ChP）是一种复杂的脑室结构，在血液和脑脊液（CSF）之间形成半透性屏障。它负责脑脊液的分泌和清除，含有巨噬细胞，是中枢神经系统（CNS）中存在T细胞的少数部位之一。此外，脉络丛在检测外周炎症中起作用，这会导致其上皮细胞功能的调节。尽管脉络丛在维持脑稳态方面至关重要，但它常常被忽视，特别是关于其随年龄增长所经历的变化，如屏障功能降低、脑脊液生成受损和免疫监视改变。这些与年龄相关的改变可能导致多种有害影响，包括神经炎症和氧化损伤，可能使个体易患神经退行性疾病。虽然知识仍然有限，但肠道菌群失调和Klotho水平降低（脉络丛是主要来源之一）似乎是脉络丛损伤的重要因素。这篇叙述性综述将研究与年龄相关的肠道菌群失调对中枢神经系统的影响，重点关注脉络丛，并探讨该脑结构中Klotho水平降低的影响。我们还将提出一个假设，即联合使用能够恢复肠道微生物群正常状态的益生菌与基因疗法来上调脉络丛中的Klotho，可能有助于维持衰老大脑的结构和功能完整性。最后，我们将提供一个技术概述，以确保编码Klotho cDNA的载体对脉络丛具有最大特异性，从而避免脱靶效应。
