Disrupted drainage in the aging brain: Meningeal lymphatic decline as a convergent axis of vulnerability.

Abstract

The aging brain depends on coordinated fluid transport, immune surveillance, and clearance of metabolic byproducts to preserve cognitive and physiological homeostasis. While peripheral lymphatic decline is well established, growing evidence implicates brain-draining lymphatic pathways, particularly meningeal lymphatic vessels and their downstream drainage to deep cervical lymph nodes, as an aging-sensitive axis that intersects with neuroinflammation and neurodegenerative vulnerability. Here, we systematically analyzed peer-reviewed studies published between 2003 and 2025 that examined age-related changes in intracranial and cervical lymphatic circuits across human imaging, histopathology, and experimental models. Ninety-six studies met the inclusion criteria. Four themes emerged. First, aging is associated with coordinated lymphatic remodeling across peripheral and central compartments, including reduced vessel integrity, stromal remodeling, and involution of draining lymph nodes. Second, meningeal lymphatic vessels exhibit age-related, region-specific structural and molecular alterations that may coincide with impaired cerebrospinal and interstitial fluid handling and altered immune regulation. Third, advanced magnetic resonance imaging, including contrast-enhanced and non-contrast approaches, reveals reproducible age-associated changes in dural and cervical lymphatic-related signals across the lifespan, while remaining an indirect proxy for flow and transport. Fourth, early therapeutic efforts suggest that brain-draining lymphatic function may be modifiable. These approaches include augmenting meningeal lymphangiogenic signaling with VEGF-C or its cofactor; and, in selected translational settings. Collectively, the evidence supports meningeal and cervical lymphatic decline as a plausible, potentially modifiable contributor to aging-related brain vulnerability across disorders such as Alzheimer's disease and Parkinson's disease, while underscoring the need for more direct functional measurements and longitudinal human studies.