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.

Graphical Abstract.

Conceptual schematic of age-associated changes in meningeal lymphatic architecture and cervical drainage pathways.

(A) In younger individuals, studies support lymphatic-associated handling of cerebrospinal and interstitial fluids (CSF/ISF) across dorsal (convexity-associated) and skull base–associated dural compartments, with drainage pathways that can connect to structurally intact deep cervical lymph nodes (dCLNs). Additional pathways including the spinal meningeal drainage and nasopharyngeal drainage pathways are represented. Solid green arrows indicate proposed directions of efflux reported across experimental and human studies, without implying relative magnitude or dominance of individual pathways. Bulk CSF absorption through arachnoid granulation-to-dural venous sinus pathways is shown with solid blue arrows, reflecting the predominant route of CSF clearance in adult humans.

(B) With aging, emerging evidence across models and human datasets suggests structural remodeling of meningeal lymphatic vessels and age-associated alterations in cervical lymph nodes that may constrain drainage capacity. Dashed arrows indicate potential attenuation or dysregulation of efflux rather than measured flow rates. Concurrently, dCLNs may exhibit fibrotic remodeling and reduced receptivity to afferent lymphatic input, consistent with a disruption of central–peripheral drainage continuity. These changes may contribute to altered CSF/ISF handling, neuroimmune dysregulation, and accumulation of metabolic byproducts in the aging brain. Bulk CSF absorption through arachnoid granulations remains preserved and is represented with solid blue arrows.

Insets illustrate representative ultrastructural features reported in dorsal and skull base–associated meningeal lymphatics and dCLNs, including vessel wall thickening, altered perivascular organization, nodal involution, and change in meningeal lymphatic flow relative to maintained arachnoid granulation function as represented in proximity to the superior sagittal sinus. This schematic integrates multiple lines of emerging evidence, including non-contrast MRI and human histological analyses, and is intended as a conceptual framework rather than a quantitative depiction of compartment-specific flow or hierarchy. The figure summarizes a proposed trajectory of structural and functional vulnerability that may contribute to increased susceptibility to neurodegenerative disease, perioperative complications, and delayed recovery in older adults.

Introduction

As advances in public health and clinical medicine continue to extend life expectancy, societies worldwide are experiencing a profound demographic shift toward aging populations. With increased longevity comes a parallel emergence of biological vulnerabilities that are only now being more fully appreciated. Among the most consistent is a gradual, systemic decline in immune competence, which increases susceptibility to common viral and bacterial infections in older adults. Traditionally attributed to hematopoietic exhaustion and thymic involution, this phenomenon is increasingly being reconsidered through the lens of lymphatic system aging (Liang et al., 2022; Lins & Dos Santos Reis, 2025; Masters et al., 2017; Palmer, 2013).

Accumulating evidence suggests that the lymphatic system, once considered structurally stable throughout adulthood, undergoes progressive, age-related deterioration. Secondary lymphoid organs such as lymph nodes (LNs) and peripheral lymphatic vessels show characteristic degenerative changes, including stromal fibrosis, lipomatosis, and vascular remodeling, with consequences that may extend to fluid balance, antigen clearance, and immune surveillance (Hadamitzky et al., 2010).

Importantly, the central nervous system, once regarded as immune-privileged and lymphatically isolated, is now known to be served by a specialized network of meningeal lymphatic vessels. These vessels contribute to cerebrospinal fluid (CSF) drainage and facilitate neuroimmune communication across the dura–cervical interface (Barker et al., 2025; Pinho-Correia et al., 2025; Zhao et al., 2025). Functionally coupled to the deep cervical lymph nodes (dCLNs), this brain-to-neck lymphatic axis enables solute clearance and immune regulation across the neurovascular unit (Yoon et al., 2024). Concurrently, advances in magnetic resonance imaging (MRI), including both contrast-enhanced (CE-MRI) and non-contrast (NC-MRI) modalities, have expanded our ability to visualize human meningeal and cervical lymphatic structures. These imaging approaches have proven instrumental in delineating anatomical continuity and regional variability across brain-draining lymphatic circuits. Across the aging spectrum, MRI offers the capacity to detect subtle changes in lymphatic architecture and fluid-sensitive signals that may relate to impaired clearance and immune dysfunction. The ability to capture such shifts has opened new avenues for investigating the physiological basis and clinical relevance of lymphatic decline in late life.

In this review, we synthesize current understanding of lymphatic remodeling in aging, spanning peripheral immune organs and extending to brain-draining lymphatic circuits. We examine progressive deterioration of lymphatic vessel structure and stromal support networks, assess species-specific differences in meningeal lymphatic anatomy, and explore mechanistic links between lymphatic dysfunction, brain homeostasis, and cognitive vulnerability. Drawing on histopathological studies, advanced imaging, and experimental models, we propose reframing the lymphatic system, particularly the meningeal lymphatics, as an age-sensitive and potentially clinically modifiable contributor to late-life brain health.

1. Methods

The protocol guiding this review, including the literature search strategy, screening criteria, and data extraction framework, is detailed in the Supplementary Materials.

1.1. Literature Search and Selection Criteria

The search strategy and guiding research question were developed a priori to comprehensively capture literature on aging-related alterations in central lymphatic function. A systematic electronic search was conducted in December 2025 using two databases: PubMed and Scopus, in accordance with PRISMA 2020 guidelines (Page et al., 2021). Search terms were selected to capture both anatomical structures and disease-relevant processes linked to lymphatic clearance, immune regulation, and aging. Boolean operators (“OR” and “AND”) were used to combine the following key terms spanning anatomy and mechanism: (“meningeal lymphatics” OR “deep cervical lymph nodes” OR “glymphatic clearance” OR “CSF-ISF drainage” OR “cranial lymphatics” OR “CNS lymphatics” OR “perineural drainage”) AND (“aging” OR “MRI” OR “lymphovenous anastomosis” OR “Alzheimer’s disease” OR “neurocognitive decline” OR “Parkinson’s disease” OR “immune regulation” OR “immunity”). No language filters were applied during the initial search; however, only English-language publications were retained for full-text review. Articles published between January 2003 and December 2025 were eligible for inclusion. Reference lists of included studies were manually screened to identify relevant articles not captured by the database queries. The full search syntax, including database-specific filters and query structure, is provided in the Review Protocol (Supplementary Material S1). This process was conducted independently by two reviewers, with discrepancies resolved by discussion until consensus was achieved.

1.2. Inclusion Parameters and Data Extraction

We conducted a focused and methodologically structured literature review spanning January 2003 to December 2025. Studies were deemed eligible if they met the following predefined criteria outlined in our review protocol (Supplementary Material S1): 1. Publication type: Original articles published in peer-reviewed scientific journals. 2. Language: English. 3. Topical relevance: Investigated meningeal lymphatics, dCLNs, glymphatic clearance, CSF–ISF drainage, age-related changes in peripheral or central lymphatic structures, or lymphatic-mediated immunity. 4. Biological domain: Addressed structural and/or functional characteristics of brain-draining lymphatic circuits. 5. Experimental evidence: Included human imaging studies, animal or human histopathological analyses, or relevant mechanistic models. Eligible methodologies encompassed immunohistochemistry, histological reconstruction, and CE-MRI and NC-MRI protocols. Studies focused exclusively on peripheral lymphatics without central relevance were excluded. Full eligibility criteria and justification for inclusion/exclusion decisions are detailed in the review protocol (Supplementary Material S1).

Data extraction was performed independently by two reviewers in accordance with the predefined framework outlined in our review protocol (see Supplementary Material S1). Initial screening included titles and abstracts, followed by full-text evaluation of eligible articles. Any disagreements regarding inclusion or data interpretation were resolved through discussion and finalized by consensus. For each included study, the following variables were extracted and recorded using structured templates: 1. Bibliographic information, including first author, year of publication, journal name, and DOI. 2. Study type and design, classified as human, animal, or in vitro, with specification of experimental model and aging context. 3. Methodological characteristics – such as imaging modalities (e.g., CE-MRI, NC-MRI 3D-FLAIR), histopathological techniques (e.g., immunohistochemistry, light-sheet microscopy), or molecular assays. 4. Lymphatic-related outcomes, including anatomical features, drainage patterns, and markers of meningeal or cervical lymphatic structure and function. 5. Aging relevance, key findings were extracted with an emphasis on age-dependent alterations in lymphatic integrity, clearance efficiency, or immune modulation. 6. Clinical or translational implications, where applicable, particularly studies proposing diagnostic, surgical, or therapeutic relevance to neurodegeneration or perioperative outcomes. All references and extracted data were systematically managed using EndNote21 for citation organization and Microsoft Excel for tabulation and quality control. Extraction tables were reviewed iteratively to ensure consistency with the aims of the review and alignment with eligibility criteria.

1.3. Study Quality and Relevance Assessment

Given the heterogeneity of included studies, spanning imaging, histopathology, mechanistic models, and therapeutic interventions, quality assessment was adapted to the methodological context of each article. Evaluation criteria were derived from prior literature and specified in the registered review protocol (Supplementary Material S1), with the aim of contextualizing findings rather than excluding studies based on rigid scoring. For imaging studies, quality appraisal focused on technical rigor, including spatial resolution, validation of contrast or non-contrast protocols, and reproducibility of acquisition parameters. Particular attention was given to studies employing high-resolution MRI or dynamic tracer-based techniques capable of resolving meningeal and cervical lymphatic structures. The presence of control groups, standardized imaging sequences, and quantifiable signal metrics further informed our assessment. For histopathological and mechanistic studies, criteria included methodological standardization (e.g., validated antibodies, imaging platforms), use of appropriate controls, sample size sufficiency, and the extent to which findings were translatable to human aging or neurodegenerative conditions. We also considered whether inclusion and exclusion criteria were explicitly defined and whether sources of potential bias were addressed. All studies were reviewed independently by two investigators, and discrepancies were resolved by consensus through collaborative discussion. This process mirrored the procedures used for study selection and data extraction, ensuring methodological consistency throughout the review. Rather than applying a numerical scoring system, this quality assessment sought to inform the strength and relevance of the evidence base across diverse study types, while highlighting areas of methodological strength and ongoing uncertainty.

2. Findings and Thematic Analysis

2.1. Overview of Included Studies and Models

A total of 610 records were identified through systematic database searches, including 460 from PubMed and 150 from Scopus. After removing 107 duplicates, 503 unique articles remained for initial title and abstract screening. Of these, 330 were excluded based on predefined criteria. Full-text evaluation of 173 articles led to the removal of 36 additional studies: 32 lacked age-related model systems, 4 did not address the meningeal lymphatic system, and 5 were deemed out of scope. In total, 96 studies met all inclusion criteria and were incorporated into this review. The study selection workflow is outlined in Figure 1.

Figure 1: PRISMA 2020 flow diagram of study selection.

This diagram shows the number of records identified through database searches (PubMed and Scopus, December 2025) using terms related to meningeal lymphatics, deep cervical lymph nodes, glymphatic clearance, CSF-ISF drainage, cranial lymphatics, CNS lymphatics, perineural drainage, aging, MRI, lymphovenous anastomosis, Alzheimer’s disease, neurocognitive decline, Parkinson’s disease, immune regulation, immunity, followed by duplicate removal, title/abstract screening, full-text assessment, and final inclusion of studies that met eligibility criteria. Eligibility decisions were made by two independent reviewers, with disagreements resolved by discussion. The process enabled a focused synthesis of cross-species data on aging-related meningeal–cervical lymphatic structure and function.

These 96 studies were categorized into three major groups reflecting the translational continuum of current knowledge. Table 1 summarizes 15 original clinical or surgical investigations in humans, including imaging, histology, and patient outcomes relevant to meningeal lymphatic anatomy and aging. Table 2 compiles 52 experimental studies using murine or non-human primate models that explore meningeal lymphatic function, aging-related clearance dynamics, neuroimmune interfaces, and mechanistic interventions. Finally, Table 3 presents 29 scholarly contributions, comprising 25 reviews, 2 commentaries, 1 methods paper, and 1 book chapter, which collectively provide critical context and conceptual synthesis on aging, CSF clearance, and lymphatic biology.

Table 1: Human Imaging and Clinical Studies Characterizing Meningeal and Cervical Lymphatic Pathways.

This table presents original human studies investigating the anatomy, function, and clinical relevance of meningeal and cervical lymphatic structures. Included methodologies span noninvasive imaging (e.g., contrast and non-contrast MRI, 3D-FLAIR), cadaveric anatomical dissection, and early therapeutic interventions such as lymphovenous anastomosis. Reported findings contribute to structural mapping, functional assessment, and exploratory modulation of brain-draining lymphatic pathways in health, aging, and disease.

Author(s), Year	Title	DOI	Study Type	Model	Aging/Lymphatic Focus	Key Findings
Bajenoff M, Egen JG, Qi H, Huang AY, Castellino F, Germain RN (2007)	Highways, byways and breadcrumbs: directing lymphocyte traffic in the lymph node	https://doi.org/10.1016/j.it.2007.06.005	Review		Lymphocyte trafficking and lymph node microarchitecture	Summarizes mechanisms that guide lymphocyte movement in lymph nodes.
Barker RB, Karakaya E, Baran D, et al (2025)	The glymphatic and meningeal lymphatic systems may converge, connecting traumatic brain injury progression with chronic traumatic encephalopathy onset	https://doi.org/10.1016/j.mcn.2025.104031	Review		Glymphatic and meningeal lymphatic dysfunction in TBI/CTE	Converging glymphatic and meningeal dysfunction may link TBI to chronic neurodegeneration.
Chavda VP, Dyawanapelly S, Dawre S, et al (2023)	Lyotropic liquid crystalline phases: Drug delivery and biomedical applications	https://doi.org/10.1016/j.ijpharm.2023.123546	Review			Overview and uses of LLC drug delivery methods
Hinson C, Sink M, Henn D, et al (2025)	Preventing Secondary Lymphedema: A Systematic Review and Meta-Analysis on the Efficacy of Immediate Lymphovenous Anastomosis	https://doi.org/10.1002/jso.70046	Review		Prevention of secondary lymphedema via immediate LVA post-cancer surgery	Immediate LVA lowers lymphedema risk after oncologic lymphadenectomy
Hladky SB, Barrand MA (2014)	Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence	https://doi.org/10.1186/2045-8118-11-26	Review		CNS fluid flow and lymphatic/glymphatic concepts	Evidence-based review of brain fluid entry, circulation, and drainage via perivascular and lymphatic routes.
Hong JP, Chen WF, Nguyen DH, Xie Q (2025)	A Proposed Role for Lymphatic Supermicrosurgery in the Management of Alzheimer’s Disease: A Primer for Reconstructive Microsurgeons	https://doi.org/10.1055/a-2513-4313	Review		Conceptual role of lymphatic supermicrosurgery in Alzheimer’s disease clearance	Proposes that relieving lymphatic obstruction may enhance amyloid clearance in Alzheimer’s disease.
Jessen NA, et al., (2015)	The Glymphatic System – A Beginner’s Guide	https://doi.org/10.1007/s11064-015-1581-6	Review		Overview of glymphatic structure, function, and relevance to CNS waste clearance.	Glymphatic system is a glial-dependent CSF-ISF clearance pathway with implications for protein waste elimination and neurological disease.
Jiang-Xie LF, Drieu A, Kipnis J (2025)	Waste clearance shapes aging brain health	https://doi.org/10.1016/j.neuron.2024.09.017	Review		Conceptual synthesis on lymphatics, aging, disease	Integrated waste clearance declines with age, linking to Alzheimer’s and Parkinson’s pathology.
Liang Z, Dong X, Zhang Z, Zhang Q, Zhao Y (2022)	Age-related thymic involution: Mechanisms and functional impact	https://doi.org/10.1111/acel.13671	Review		Age-related thymic involution and immune decline	Thymic involution with age disrupts stromal microenvironment and T-cell development, contributing to immunosenescence.
Lins MP, Dos Santos Reis MD (2025)	Age-Related Thymic Involution	https://doi.org/10.1007/978-3-031-77921-3_11	Review		Mechanisms of age-related thymic involution	Summary of age-driven thymic decline mechanisms and consequences for immune aging.
Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J (2017)	Understanding the functions and relationships of the glymphatic system and meningeal lymphatics	https://doi.org/10.1172/JCI90603	Review		Overview of meningeal lymphatic anatomy, drainage, and neuroimmune roles	Meningeal lymphatic pathways link CNS with peripheral immunity and contribute to CSF drainage and immune regulation.
Margetis K, Weisbrod LJ, Launico MV (2025)	StatPearls (Neuroanatomy, Cerebrospinal Fluid)	https://www.ncbi.nlm.nih.gov/pubmed/29262203	Book Chapter		Background context.	Summarizes core CSF physiology and canonical outflow concepts used to contextualize clearance discussions
Masters AR, Haynes L, Su DM, Palmer DB (2017)	Immune senescence: significance of the stromal microenvironment	https://doi.org/10.1111/cei.12851	Review		Conceptual synthesis on lymphatics, aging, disease	Lymphatic/immune interaction
Miyajima M, et al., (2015)	Evaluation of the Production and Absorption of Cerebrospinal Fluid	https://doi.org/10.2176/nmc.ra.2015-0003	Review		Provides CSF clearance framework that includes lymphatic associated outflow concepts, without age stratified data.	Summarizes evolving CSF circulation and absorption models and discusses non venous outflow concepts that intersect with meningeal and lymphatic related pathways, but does not provide quantitative aging effects.
Naganawa S. (2015)	The technical and clinical features of 3D-FLAIR in neuroimaging	https://doi.org/10.2463/mrms.2014-0132	Review		Non-invasive human brain lymphatic imaging	3D-FLAIR offers and accessible imaging modality which decreases artifact signal from CSF and harbors increases sensitivity for fluid changes
Oliver G, Kipnis J, Randolph GJ, Harvey NL (2020)	The Lymphatic Vasculature in the 21(st) Century: Novel Functional Roles in Homeostasis and Disease	https://doi.org/10.1016/j.cell.2020.06.039	Review		Conceptual synthesis on lymphatics, aging, disease	Integrative perspective on clearance and neuroimmune interfaces.
Page MJ, McKenzie JE, Bossuyt PM, et al (2020)	The PRISMA 2020 statement: an updated guideline for reporting systematic reviews	https://doi.org/10.1136/bmj.n71	Methods/Reporting		Systematic review reporting	PRISMA 2020 guideline for transparent reporting.
Palmer DB (2013)	The effect of age on thymic function	https://doi.org/10.3389/fimmu.2013.00316	Review		Conceptual synthesis on lymphatics, aging, disease	Lymphatic/immune interaction
Pinho-Correia LM, Ghanizada H, Nedergaard M, Da Mesquita S (2025)	CSF transport at the brain-meningeal border: effects on neurological health and disease	https://doi.org/10.1016/S1474-4422(25)00115-2	Review		Conceptual synthesis on lymphatics, aging, disease	Integrative perspective on clearance and neuroimmune interfaces.
Pollay M (2010)	The function and structure of the cerebrospinal fluid outflow system	https://doi.org/10.1186/1743-8454-7-9	Review		CSF outflow / transport mechanisms	Foundational overviews of brain fluid movement.
Proulx ST et al., (2021)	Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics	https://doi.org/10.1007/s00018-020-03706-5	Review		Provides mechanistic and anatomical context for interpreting lymphatic contributions to CSF clearance, including limitations in assigning dominance to a single route	Summarizes converging evidence that CSF tracers can reach lymphatic drainage via dural lymphatics and perineural routes, and emphasizes ongoing debate regarding relative pathway contributions
Rego S, Sanchez G, Da Mesquita S (2023)	Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease	https://doi.org/10.1186/s13024-023-00645-0	Review		Conceptual synthesis on lymphatics, aging, disease	Integrative perspective on clearance and neuroimmune interfaces.
Salvador AFM, Abduljawad N, Kipnis J (2024)	Meningeal Lymphatics in Central Nervous System Diseases	https://doi.org/10.1146/annurev-neuro-113023-103045	Review		Conceptual synthesis on lymphatics, aging, disease	Integrative perspective on clearance and neuroimmune interfaces.
Tamir J.I., Blumenthal M., Wang J., (2025)	MRI acquisition and reconstruction cookbook: recipes for reproducibility, served with real-world flavour	https://doi.org/10.1007/s10334-025-01236-4	Review		Indirectly relevant via imaging reproducibility guidance.	Discusses reproducible MRI acquisition and reconstruction practices and proposes standard guidelines.
Thomas JL, et al., (2022)	CSF-to-dura gateways	https://doi.org/10.1084/jem.20221719	Commentary		CSF pathways and meningeal interfaces relevant to drainage.	Highlights arachnoid granulations as porous CSF gateways to dura and outlines models linking these structures to dural lymphatic interfaces.
Thompson HL, Smithey MJ, Surh CD, Nikolich-Zugich J (2017)	Functional and Homeostatic Impact of Age-Related Changes in Lymph Node Stroma	https://doi.org/10.3389/fimmu.2017.00706	Review		Conceptual synthesis on lymphatics, aging, disease	Lymphatic/immune interaction
van der Thiel MM, Backes WH, Ramakers I, Jansen JFA (2023)	Novel developments in non-contrast enhanced MRI of the perivascular clearance system: What are the possibilities for Alzheimer’s disease research?	https://doi.org/10.1016/j.neubiorev.2022.104999	Review		Advancements in non-contrast MRI to study perivascular and clearance systems in aging/AD.	Summarizes non-contrast MRI advances for perivascular clearance, highlights potential for Alzheimer’s research
Xie Q, Louveau A, Pandey S, Zeng W, Chen WF (2024)	Rewiring the Brain: The Next Frontier in Supermicrosurgery	https://doi.org/10.1097/PRS.0000000000010933	Commentary		Discussion of lymphatic reconstruction in neurological disease.	Proposes expanding lymphatic microsurgery to brain and clearance pathways.
Zhao MY, Ye CY, Liu YC, et al (2025)	Role of meningeal lymphatic vessels in brain homeostasis	https://doi.org/10.3389/fimmu.2025.1593630	Review		Aging and functional roles of meningeal lymphatic vessels in brain homeostasis.	Meningeal lymphatics support CSF drainage and brain homeostasis; dysfunction links to aging and CNS disease.

Table 2: Animal Model Studies Investigating Brain-Draining Lymphatic Pathways.

This table summarizes experimental studies in rodent and non-human primate models examining the structure, function, and regulation of meningeal, cervical, and associated lymphatic drainage pathways. Studies address diverse biological questions, including lymphatic development, drainage dynamics, immune interactions, age-related decline, and responses to brain injury. Findings elucidate mechanisms of cerebrospinal and interstitial fluid handling, neuroimmune communication, and clearance in the context of health and disease.

Author(s), Year	Title	DOI	Study Type	Model	Aging/Lymphatic Focus	Key Findings
Antila S, Chilov D, Nurmi H, et al (2024)	Sustained meningeal lymphatic vessel atrophy or expansion does not alter Alzheimer’s disease-related amyloid pathology	https://doi.org/10.1038/s44161-024-00445-9	Original Research Article	AD mouse models (APdE9, 5xFAD)	Menigeal lymphatic manipulation and CSF clearance	Modulating lymphatic size altered clearance but did not change AD pathology
Antila S., Karaman S., Nurmi H., (2017)	Development and plasticity of meningeal lymphatic vessels	https://doi.org/10.1084/jem.20170391	Original Research Article	Mouse	Meningeal lymphatic formation and VEGF-C/VEGFR3 signaling	Meningeal lymphatics develop postnatally and are plastic via VEGF-C/VEGFR3
Aspelund A, Antila S, Proulx ST, et al (2015)	A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules	https://doi.org/10.1084/jem.20142290	Original Research Article	Mouse	Meningeal lymphatic anatomy and CSF drainage	Dural lymphatics drain CSF/ISF to dCLNs; ablation impairs clearance
Da Mesquita S, Herz J, Wall M, et al (2021)	Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and beta-amyloid pathology	https://doi.org/10.1126/sciadv.abe4601	Original Research Article	Aged mice; CCR7-deficient and 5xFAD transgenic mice	Aging-linked meningeal lymphatic/glymphatic dysfunction	Aging and CCR7 loss worsen meningeal lymphatic decline, glymphatic flow, and cognition.
Da Mesquita S, Louveau A, Vaccari A, et al (2018)	Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease	https://doi.org/10.1038/s41586-018-0368-8	Original Research Article	Aged and transgenic Alzheimer’s model mice	Effects of aging on meningeal lymphatic drainage and Alzheimer pathology	Meningeal lymphatic dysfunction worsens amyloid pathology and cognitive decline; VEGF-C improves drainage and cognition.
Debes G.F., Arnold C.N., Young A.J., (2005)	Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues	https://doi.org/10.1038/ni1238	Original Research Article	Mouse	CCR7-mediated immune cell egress via lymphatics	CCR7 expression on T Lymphocytes regulates migration and accumulation
Drieu A, Du S, Storck E, (2022)	Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid	https://doi.org/10.1038/s41586-022-05397-3	Original Research Article	Mouse + human transcriptomic support	CSF flow modulation by border macrophages in aging and Alzheimer’s	Border macrophages control CSF flow; depletion impairs clearance, restored by stimulation.
Fang R, Jin L, Lu H, Xie Q, Yang X, Kueckelhaus M (2025)	A Novel Microsurgical Model of Cervical Lymph Node-to-Vein Anastomosis (LNVA) for Studying Brain Lymphatic Outflow	https://doi.org/10.1097/SCS.0000000000011535	Original Research Article	Rat	Cervical lymphatic venous anastomosis model for brain lymphatic outflow	Rat LNVA model shows stable node-to-vein drainage confirmed by ICG imaging.
Han M, Han Y, Jiang Z, (2025)	Ultrasmall inorganic nanoparticles repair damaged meningeal lymphatic vessels to boost Parkinson’s disease therapy	https://doi.org/10.1073/pnas.2503434122	Original Research Article	Mouse	Meningeal lymphatic vessel damage and repair via nanoparticle intervention	Nanoparticles restored meningeal lymphatic drainage and improved Parkinson’s-like pathology in mice.
Hitpass Romero K, Stevenson TJ, Smyth LCD, et al (2025)	Age-related meningeal extracellular matrix remodeling compromises CNS lymphatic function	https://doi.org/10.1186/s12974-025-03436-0	Original Research Article	Aged mice + human dural fibroblasts	Age-related ECM remodeling impairing meningeal lymphatic drainage	ECM/fibrosis around meningeal lymphatics disrupts lymphatic flow and CSF clearance in aged mice.
Hu X, Deng Q, Ma L, (2020)	Meningeal lymphatic vessels regulate brain tumor drainage and immunity	https://doi.org/10.1038/s41422-020-0287-8	Original Research Article	Mouse	Meningeal lymphatics modulate immune response and tumor drainage	Disruption of dorsal MLVs impairs tumor drainage and immune cell trafficking, reducing checkpoint therapy efficacy.
Iliff JJ et al., (2012)	A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β	https://doi.org/10.1126/scitranslmed.3003748	Original Research Article	Mouse	Paravascular (glymphatic) CSF–ISF transport mechanisms that resemble lymphatic clearance pathways.	Identified a para-arterial CSF influx and paravenous ISF clearance route that supports removal of interstitial solutes, including amyloid-β.
Iliff JJ et al., (2013)	Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain	https://doi.org/10.1523/JNEUROSCI.1592-13.2013	Original Research Article	Mouse	CSF–ISF exchange via arterial pulsation.	Identifies arterial pulsatility as a key determinant of paravascular CSF–ISF exchange and solute clearance.
Jacob L, de Brito Neto J, Lenck S, et al (2022)	Conserved meningeal lymphatic drainage circuits in mice and humans	https://doi.org/10.1084/jem.20220035	Original Research Article	Animal models, Human	Characterization of conserved meningeal lymphatic drainage pathways in mice and humans	Conserved 3D meningeal lymphatic anatomy links dura to extracranial routes in mice and humans, supporting translational imaging relevance.
Jin H., Yoon J.H., Hong S.P., (2025)	Increased CSF drainage by non-invasive manipulation of cervical lymphatics	https://doi.org/10.1038/s41586-025-09052-5	Original Research Article	Mouse	Cervical lymphatic modulation and CSF outflow in aging	Mechanical stimulation enhanced CSF drainage and ameliorated age-related outflow impairment
Kataru R.P., Park H. J. Shin J., (2022)	Structural and functional changes in aged skin lymphatic vessels	https://doi.org/10.3389/fragi.2022.864860	Original Research Article	Mouse	Age-related structural and functional lymphatic changes	Aged lymphatic vessels show reduced density and impaired function.
Kimura T, Hamazaki TS, Sugaya M, et al (2014)	Cilostazol improves lymphatic function by inducing proliferation and stabilization of lymphatic endothelial cells	https://doi.org/10.1016/j.jdermsci.2014.01.001	Original Research Article	Mouse	Enhancement of lymphatic endothelial proliferation and lymphatic function	Cilostazol stimulated lymphatic endothelial growth and improved lymphatic transport in mouse lymphedema models.
Kwok T.S., Medovich S.C., Sila-Junior A., (2022)	Age-associated changes to lymph node fibroblastic reticular cells	https://doi.org/10.3389/fragi.2022.838943	Original Research Article	Mouse	Age-related lymph node stromal (FRC) changes and fibrosis	Aged lymph nodes show increased fibrosis, impaired fibretic reticular cell differentiation, and decreased naïve T-cell motility within the stromal microenvironment.
Link A, Vogt TK, Favre S, et al (2007)	Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells	https://doi.org/10.1038/ni1513	Original Research Article	Mouse	Lymph node stromal cell control of immune cell homeostasis	Lymphatic/immune interaction
Louveau A, Herz J, Alme M.N., (2018)	CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature	https://doi.org/10.1038/s41593-018-0227-9	Original Research Article	Mouse	Meningeal lymphatic drainage of CSF & immune cell trafficking	Meningeal lymphatics contribute to CSF drainage and immune cell entry into lymph nodes; their ablation modifies neuroinflammation.
Louveau A, Smirnov I, Keyes TJ, et al (2015)	Structural and functional features of central nervous system lymphatic vessels	https://doi.org/10.1038/nature14432	Original Research Article	Mouse	Discovery of meningeal lymphatic vessels and their structural/functional connectivity to deep cervical lymph nodes.	Functional lymphatic vessels exist in dura; they express lymphatic markers, carry CSF and immune cells, and connect to cervical nodes.
Ma Q et al., (2017)	Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice	https://doi.org/10.1038/s41467-017-01484-6	Original Research Article	Mouse	Age associated reduction in lymphatic mediated CSF outflow	Lymphatic vessels constituted a major CSF outflow route for small and large tracers, and CSF lymphatic outflow was reduced in aged mice compared with young mice
Ocskay Z, Balint L, Christ C, Kahn ML, Jakus Z (2024)	CCBE1 regulates the development and prevents the age-dependent regression of meningeal lymphatics	https://doi.org/10.1016/j.biopha.2023.116032	Original Research Article	Mouse	CCBE1 role in meningeal lymphatic development and age-dependent regression	CCBE1 deletion impairs meningeal lymphatic formation and accelerates age-associated regression
Patel T.K., Habimana-Griffin L., GaoX., (2019)	Dural lymphatics regulate clearance of extracellular tau from the CNS	https://doi.org/10.1186/s13024-019-0312-x	Original Research Article	Mouse	Conceptual synthesis on lymphatics and disease	Meningeal lymphatic integrity is critical for tau removal in otherwise healthy mice
Richner JM, Gmyrek GB, Govero J, et al (2015)	Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection	https://doi.org/10.1371/journal.ppat.1005027	Original Research Article	Mouse	Age-dependent trafficking defects in draining lymph nodes	Aged mice show impaired immune cell trafficking and delayed lymph node responses, reducing WNV control
Royo Marco A., Bruch K.R., Cowan M.N. (2025)	Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis	https://doi.org/10.1016/j.celrep.2025.116521	Original Research Article	Mouse	VEGFC-mediated restoration of lymphatic drainage after injury.	Post-TBI VEGFC treatment reduced tauopathy, improved neuropathology, and supported lymphatic-mediated clearance.
Rustenhoven J., Drieu A., Mamuladze T., (2021)	Functional characterization of the dural sinuses as a neuroimmune interface	https://doi.org/10.1016/j.cell.2020.12.040	Original Research Article	Mouse	Meningeal immune interface and antigen capture at dural sinuses.	Dural sinuses support CSF antigen capture and T cell surveillance at CNS boundaries.
Rustenhoven J., Pavlou G., Storck S. E., (2023)	Age-related alteration in meningeal immunity drive impaired CNS lymphatic drainage	https://doi.org/10.1084/jem.20221929	Original Research Article	Mouse	Age-related meningeal immune signaling impairing lymphatic drainage	Elevated IFNγ in aged meninges impairs lymphatic CSF drainage; neutralizing IFNγ improves function.
Shan X, Lu Y, Luo Z, et al (2024)	A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer’s Disease	https://doi.org/10.1021/acsnano.4c01206	Original Research Article	Mouse	LLC implant targeting lymphatic drainage in AD mice	Implant enhances drainage, reduces Aβ burden, improves cognition.
Song E., Mao T., Dong H., (2020)	VEGF-C-Driven lymphatic drainage enables immunosurveillance of brain tumors	https://doi.org/10.1038/s41586-019-1912-x	Original Research Article	Mouse	Interventions for oncology-related lymphatics	VEGF-C treatment facilitates CD8 T Cell priming and migration from dCLNs and promotes an anti-tumor immune response in the setting of GBM
Thompson H.L., Smithey M.J., Uhrlaub J.L., (2019)	Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates	https://doi.org/10.3389/fimmu.2017.00706	Original Research Article	Mouse and Nonhuman primates	Age-related structural and functional changes in lymph nodes.	Aging alters LN stroma, disrupting architecture and immune homeostasis.
Weber M., Hauschild R. Schwarz J., (2013)	Interstitial dendritic cell guidance by haptotactic chemokine gradients	https://doi.org/10.1126/science.1228456	Original Research Article	Mouse	Peripheral lymphatic endothelial chemokine gradients.	Endogenous CCL21 gradients guide dendritic cells toward lymphatic vessels.
Wen Y.R., Yang H.J., Wang X. (2018)	Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease	https://doi.org/10.4103/1673-5374.230299	Original Research Article	Mouse	Effect of dural lymphangiogenesis on amyloid clearance.	VEGF-C-driven dural lymphangiogenesis increases amyloid-β drainage and improves cognition in AD mice.
Yoon JH, Jin H, Kim HJ, et al (2024)	Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage	https://doi.org/10.1038/s41586-023-06899-4	Original Research Article	Mouse	Nasopharyngeal plexus as CSF drainage hub.	Identifies anterior lymphatic route to dCLNs.
Zakharov A, et al., (2003)	Lymphatic cerebrospinal fluid absorption pathways in neonatal sheep revealed by subarachnoid injection of Microfil	https://doi.org/10.1046/j.0305-1846.2003.00508.x	Original Research Article	Sheep	Not age focused; foundational cerebrospinal fluid lymphatic drainage anatomy	Demonstrates cerebrospinal fluid absorption along extracranial lymphatic pathways following subarachnoid tracer administration
Zhu X, Lin J, Yang P, et al (2024)	Surgery induces neurocognitive disorder via neuroinflammation and glymphatic dysfunction in middle-aged mice with brain lymphatic drainage impairment	https://doi.org/10.3389/fnins.2024.1426718	Original Research Article	Mouse	Brain lymphatic impairment exacerbates glymphatic dysfunction post-surgery.	Lymphatic ligation worsens surgery-induced inflammation, neuronal damage, and cognitive decline in mice.
Zou W., Pu T., Feng M., (2019)	Blocking meningeal lymphatic drainage aggravates Parkinson/s disease-like pathology in mice overexpressing mutated alpha-synuclein	https://doi.org/10.1186/s40035-019-0147-y	Original Research Article	Mouse	Conceptual synthesis on lymphatics and disease.	Ligation of cervical lymphatic vessels worsens alpha-synuclein accumulation, inflammation, dopaminergic neuron loss, and motor deficits in PD mice.

Table 3: Summary of Reviews and Commentaries on Brain Lymphatic and Immune Interfaces.

This table compiles selected review articles and expert commentaries covering core conceptual domains in brain lymphatic biology. Topics include glymphatic–lymphatic integration, immune–meningeal interfaces, age-related dysfunction, and emerging translational strategies. Publications are organized by thematic focus and contribute interpretive frameworks for understanding the structural and functional role of lymphatic drainage in neurological health and disease.

Author(s), Year	Title	DOI	Study Type	Model	Aging/Lymphatic Focus	Key Findings
Absinta M, Ha SK, Nair G, et al (2017)	Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI	https://doi.org/10.7554/eLife.29738	Original Research Article	Humans and non-human primates	In vivo detection of meningeal lymphatics	Demonstrated meningeal lymphatic vessels in living humans using MRI, supported by histology.
Al-Diwani A, Provine NM, Murchison A, et al (2025)	Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes	https://doi.org/10.1093/brain/awae329	Original Clinical Research	Human	Age-linked biomarker clearance via cervical lymphatics	CNS biomarkers (e.g., pTau181) enriched in dCLNs; decline with age.
Albayram M, Richmond S.B., Yagmurlu I.S., (2025)	Meningeal lymphatic architecture and drainage dynamics surrounding the human middle meningeal artery	https://doi.org/10.1016/j.isci.2025.113693	Original Research Article	Human (dynamic MRI; tissue analysis)	Human ventral meningeal lymphatic architecture	Identified delayed drainage dynamics and lymphatic-like structures near the MMA in humans.
Albayram MS, Smith G, Tufan F, et al (2022)	Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes	https://doi.org/10.1038/s41467-021-27887-0	Original Research Article	Human participants (MRI)	Human meningeal lymphatic drainage patterns	MRI depicts dural lymphatic channels and connections to cervical nodes, with age-related changes
Brierley J.B, Field E.J. (1948)	The connexions of the spinal sub-arachnoid space with the lymphatic system	https://www.ncbi.nlm.nih.gov/pubmed/18873158	Original Research Article	Human cadaver	Spinal subarachnoid–lymphatic connections	Anatomical connection of CSF to lymphatic pathways
Chen WF, Jou C, Pandey SK, Lo SL (2024)	Primary Lymphedema: Anatomically Isolated or a Pervasive Systemic Disorder?	https://doi.org/10.1097/GOX.0000000000006328	Clinical study	Human	Systemic lymphatic dysfunction in primary lymphedema	ICG lymphography shows widespread lymphatic impairment beyond clinical symptoms
Ding X.B., Wang X.X., Xia D.H. (2021)	Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease	https://doi.org/10.1038/s41591-020-01198-1	Clinical Study	Human	Meningeal lymphatic flow and dCLN perfusion in PD	Reduced meningeal lymphatic flow and delayed dCLN perfusion in PD
Figenschau S.L, Kunutsen E, Urbarova I, (2018)	ICAM1 expression is induced by proinflammatory cytokines and associated with TLS formation in aggressive breast cancer subtypes	https://doi.org/10.1038/s41598-018-29604-2	Original Research Article	Human		Cytokines upregulate ICAM1 expression linked to TLS formation in aggressive breast cancer.
Goodman J.R., Adham Z. O., Woltjer R.L., (2018)	Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer’s dementia subjects	https://doi.org/10.1016/j.bbi.2018.07.020	Original Research Article	Human	Age-related changes in dural sinus–associated lymphatic vasculature	Dural sinus–associated lymphatic vessels are visualized and morphologically altered in Alzheimer’s dementia.
Hadamitzky C, Spohr H, Debertin AS, Guddat S, Tsokos M, Pabst R (2010)	Age-dependent histoarchitectural changes in human lymph nodes: an underestimated process with clinical relevance?	https://doi.org/10.1111/j.1469-7580.2010.01213.x	Clinical Study	Human	Age-related structural degeneration of lymph node histoarchitecture	Human lymph nodes show age-dependent structural changes, including altered architecture and fibrosis.
Herlihy A.H., Hajnal J.V, Curati W.L, (2001)	Reduction of CSF and blood flow artifacts on FLAIR images of the brain with k-space reordered by inversion time at each slice position (KRISP)	https://www.ncbi.nlm.nih.gov/pubmed/11337335	Human MRI methodology	Human		Describes artifact-reducing FLAIR MRI technique (KRISP) for better imaging of CSF/blood flow
Ihara M, Nishino M, Taguchi A, et al (2014)	Cilostazol add-on therapy in patients with mild dementia receiving donepezil: a retrospective study	https://doi.org/10.1371/journal.pone.0089516	Clinical Study	Human	Cognitive outcome in elderly dementia patients.	Cilostazol add-on therapy was associated with slower cognitive decline in mild dementia patients.
Imholz C, Schaller C, Watson JA, Zurfluh CE, Grigorean A, Lindenblatt N (2025)	Robotic-assisted lymphovenous anastomosis to treat periorbital lymphedema and systematic review of lymphatic reconstruction of face and neck lymphedema	https://doi.org/10.1007/s11701-025-02552-6	Clinical Study	Human	Robotic LVA for clinical management of lymphedema in head and neck patients.	Robotic LVA in periorbital lymphedema.
Inatomi Y, Yoshida S, Kamizono K, Hanada M, Yasumatsu R, Kadota H (2018)	Successful treatment of severe facial lymphedema by lymphovenous anastomosis	https://doi.org/10.1002/hed.25206	Clinical Study	Human	LVA to treat severe post-surgical facial lymphedema	LVA rapidly reduced persistent facial edema and restored function
Johnston M.A., Zakharov A., Papaiconomou C., (2004)	Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species	https://doi.org/10.1186/1743-8454-1-2	Original Research Article	Human, non-human primates, and other mammals including mouse, rat, rabbit, and sheep	Connections between CSF and nasal lymphatics across species.	Demonstrates direct anatomical links between CSF spaces and nasal lymphatic vessels in humans and animals
Kaciulyte J, Giacomini G, Garutti L, et al (2025)	Facial Lymphedema Following Head and Neck Tumor Resection: Preliminary Experience of Supermicrosurgical Treatment With LVA-Report of Three Cases	https://doi.org/10.1002/micr.70012	Clinical Study	Human	Surgical restoration of lymphatic drainage after head/neck cancer lymphatic injury.	Supermicrosurgical LVA reduced facial lymphedema and improved quality of life in three cases, with minimal complications.
Li X, Zhang C, Fang Y, et al (2024)	Promising outcomes 5 weeks after a surgical cervical shunting procedure to unclog cerebral lymphatic systems in a patient with Alzheimer’s disease	https://doi.org/10.1136/gpsych-2024-101641	Clinical Study	Human	Surgical cervical shunting to augment cerebral lymphatic outflow	Cervical shunting was safe and showed early signs of improved brain drainage and Alzheimer’s metrics.
Lin YS, Liu CJ, Chou CH (2024)	Lymphovenous Anastomosis for the External and Internal Types of Head and Neck Lymphedema: A Case Series and Preliminary Clinical Results	https://doi.org/10.1097/GOX.0000000000005872	Clinical Study	Human	LVA application to symptomatic head and neck lymphedema	LVA improved symptom scores and function in external/internal head-neck lymphedema.
Mihara M, Uchida G, Hara H, et al (2011)	Lymphaticovenous anastomosis for facial lymphoedema after multiple courses of therapy for head-and-neck cancer	https://doi.org/10.1016/j.bjps.2011.01.006	Clinical Study	Human	Lymphovenous anastomosis outcomes/prevention	Clinical efficacy/safety in lymphedema (head/neck or systemic).
Murakami G, Taniguchi I (2004)	Histologic heterogeneity and intranodal shunt flow in lymph nodes from elderly subjects: a cadaveric study	https://doi.org/10.1007/BF02523646	Original Research Article	Human	Conceptual synthesis on lymphatics, aging, disease	Age-related histologic changes in lymphatics
Ringstad G, Eide PK (2020)	Cerebrospinal fluid tracer efflux to parasagittal dura in humans	https://doi.org/10.1038/s41467-019-14195-x	Original Research Article	Human	CSF outflow / transport mechanisms	Foundational overviews of brain fluid movement.
Ringstad G, Vatnehol SAS, Eide PK (2017)	Glymphatic MRI in idiopathic normal pressure hydrocephalus	https://doi.org/10.1093/brain/awx191	Clinical Study	Human	Glymphatic MRI in iNPH	Human evidence for impaired glymphatic outflow.
Shah T, et al., (2022)	Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma	https://doi.org/10.1084/jem.20220618	Original Research Article	Human	Age-linked structural changes in human arachnoid granulations.	Arachnoid granulations show porous CSF pathways, immune cells, and age-related shifts at lymphatic interfaces.
Taniguchi I, Murakami G, Sato A, et al (2003)	Lymph node hyalinization in elderly Japanese	https://doi.org/10.14670/HH-18.1169	Clinical Study	Human	Conceptual synthesis on lymphatics, aging, disease	Age-related histologic changes in lymphatics
Thomas M, Pike C, Humphreys I, Bragg T, Ghattaura A (2023)	Impact and outcomes after lymphaticovenous anastomosis for 150 cases of lymphoedema followed up over 24 months	https://doi.org/10.1016/j.bjps.2023.06.068	Clinical Study	Human	Lymphovenous anastomosis outcomes/prevention	Clinical efficacy/safety in lymphedema (head/neck or systemic).
Vera Quesada C.L., Rao S.B. Torp R., (2023)	Widespread distribution of lymphatic vessels in human dura mater remote from sinus veins	https://doi.org/10.3389/fcell.2023.1228344	Original Research Article	Human	Distribution of lymphatic vessels in human dura	Meningeal lymphatic endothelial cells were observed in proximity to blood vessels, but more frequently showed significant distribution distant from vasculature and were most abundant at the skull base.
Wittens M.M.J., Allemeersch G.J., Sima D.M., (2021)	Inter- and intra-scanner variability of automated brain volumetry on three magnetic resonance imaging systems in Alzheimer’s disease and controls	https://doi.org/10.3389/fnagi.2021.746982	Original Research Article	Human	Aging and volumetric brain changes; no direct lymphatic analysis.	Demonstrates variability of automated brain volumetry across MRI scanners; implications for neurodegeneration assessment.
Zeltzer A, Nistor A, Adriaenssens N, Deleuze J, Giunta G, Hamdi M (2025)	Outcomes of Lymphovenous Anastomoses and Vascularized Lymph Node Transplant in the Combined Surgical Treatment of Lymphedema: A Prospective Cohort Study	https://doi.org/10.1097/PRS.0000000000012326	Clinical Study	Human	Lymphovenous anastomosis outcomes/prevention	Clinical efficacy/safety in lymphedema (head/neck or systemic).

Collectively, these categories encompass a diverse but integrative body of literature that spans molecular, cellular, anatomical, imaging, and translational perspectives on the aging meningeal lymphatic system. This curated evidence base enables a multi-layered thematic analysis, structured to highlight both foundational mechanisms and emerging clinical implications.

2.2. Systemic Lymphatic Aging: Peripheral to Central Shifts

Immune senescence in aging is closely linked to structural and functional decline of the lymphatic system. A prominent example is thymic involution, a conserved hallmark of aging across species (Liang et al., 2022; Lins & Dos Santos Reis, 2025). Once thought to result primarily from hematopoietic attrition, this involution is now understood to reflect degeneration of the non-hematopoietic stromal cell niche. These stromal networks form the essential scaffolding of lymphoid organs, organizing proliferative zones and maintaining chemokine gradients that direct immune cell trafficking (Masters et al., 2017; Palmer, 2013).

Stromal networks serve as both the structural backbone and functional organizer of primary and secondary lymphoid tissues, orchestrating the cellular milieu required for effective adaptive immunity. Aging disrupts this scaffolding, weakening the microenvironmental support essential for B- and T-cell maturation, survival, and signaling (Anderson & Jenkinson, 2001; Bajenoff et al., 2007; Link et al., 2007). Functionally, this decline manifests in impaired immune responses, as demonstrated by delayed germinal center formation and attenuated antibody production in aged mice following West Nile virus infection, hallmarks of diminished adaptive competence (Richner et al., 2015).

Although thymic involution has traditionally exemplified age-associated lymphoid regression, emerging evidence indicates that similar stromal deterioration also undermines secondary lymphoid tissues, particularly lymph nodes (LNs) (Anderson and Jenkinson 2001, Bajenoff, Egen et al. 2007). In aged LNs, progressive loss of stromal integrity impairs antigen presentation, lymphocyte maturation, and peripheral immune surveillance—functions once attributed predominantly to hematopoietic decline. Recent studies have reframed this paradigm, implicating stromal collapse within LNs as a parallel driver of immunosenescence (Thompson, Smithey et al. 2017). This evolving view expands the scope of lymphatic aging from peripheral immune organs toward central interfaces, linking systemic stromal vulnerability with compromised brain–immune communication (Anderson & Jenkinson, 2001; Bajenoff et al., 2007).

Histopathological studies of cadaveric lymph nodes provide robust anatomical evidence of age-associated degeneration, particularly in individuals over 60. Common findings include loss of high endothelial venules (HEVs), increased stromal fibrosis, and adipose infiltration, especially within inguinal and axillary basins, collectively undermining the structural framework essential for immune cell trafficking and antigen capture (Hadamitzky et al., 2010). Across both American and Japanese cohorts, nodal hyalinization and arterial obliteration have been consistently observed, implicating compromised perfusion and matrix remodeling as core features of aging LNs (Taniguchi et al., 2003). These pathological signatures are often more pronounced in individuals with metabolic comorbidities, suggesting that adiposity may exacerbate lymphatic decline. Additional reports of fatty degeneration in the medullary sinus, cortical hypertrophy, and focal macrophage accumulation across cervical, thoracic, and abdominal nodal regions further underscore the widespread and heterogeneous nature of lymphatic dysfunction in aging (Murakami & Taniguchi, 2004).

At the vessel level, aging induces widespread structural and molecular deterioration within peripheral lymphatic networks, particularly in the skin. Disruption of endothelial junctional organization, loss of chemotactic signaling, and diminished vessel integrity collectively impair immune cell trafficking. Mechanistically, age-related downregulation of vascular endothelial growth factor receptor 3 (VEGFR3) and reduced Akt phosphorylation promote endothelial apoptosis and senescence, contributing to lymphatic atrophy (Kataru et al., 2022). Concurrently, CCL21 expression declines by nearly 50%, weakening C-C motif chemokine receptor 7 (CCR7)/C-C Motif Chemokine Ligand 21 (CCL21)–mediated chemotaxis essential for lymphocyte migration (Debes et al., 2005; Weber et al., 2013). Junctional proteins such as VE-cadherin and ZO-1 become disorganized, compromising barrier function and transendothelial migration. In contrast, adhesion molecules,1 including intercellular adhesion molecule 1 (ICAM 1) and P-selectin, are upregulated, potentially favoring perilymphatic leukocyte clustering under low-flow states (Figenschau et al., 2018; Kataru et al., 2022). These alterations sharply reduce dendritic cell migration to draining lymph nodes, thereby weakening peripheral antigen delivery and adaptive immune responses. Notably, recent work suggests that several of these degenerative features, junctional disorganization, impaired trafficking, and chemokine imbalance, may also emerge within aging meningeal lymphatics, linking peripheral lymphatic senescence to central neuroimmune decline (Da Mesquita et al., 2021; Louveau et al., 2018; Rustenhoven et al., 2021; Rustenhoven et al., 2023).

In addition to structural and immunologic deterioration, lymphatic aging increasingly manifests as clinically relevant fluid clearance failure. Functional imaging studies challenge the assumption that lymphedema is confined to visibly affected areas. In patients with primary lymphedema, a congenital disorder of lymphatic vessel development, noninvasive lymphoscintigraphy has revealed that more than 80 percent exhibit widespread lymphatic impairment, even in anatomically unaffected regions (Chen et al., 2024). These findings suggest that lymphatic insufficiency may be systemic, with focal symptoms arising only when local compensatory mechanisms are exhausted. Although age-related lymphatic decline is generally classified as secondary lymphedema, it may similarly reflect a diffuse and progressive breakdown of lymphatic integrity. Taken together, these data reinforce the concept that aging imposes a global lymphatic burden that can disrupt both localized immune competence and broader processes of interstitial fluid regulation and antigen clearance. This broader view supports a conceptual shift from organ-specific models of immune decline toward integrated frameworks that account for peripheral-to-central lymphatic vulnerability across the lifespan.

2.3. Meningeal Lymphatics and Cervical Drainage Architecture

For much of the modern era, the brain was believed to lack conventional lymphatic vasculature. Clearance and immune surveillance were thought to rely solely on arachnoid granulations and passive solute exchange along perivascular spaces (Hladky & Barrand, 2014; Pollay, 2010). However, advances in whole tissue imaging and molecular profiling have revealed a distinct lymphatic network within the meninges (Barker et al., 2025; Pinho-Correia et al., 2025; Zhao et al., 2025). These meningeal lymphatic vessels express classical lymphatic markers, including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE 1), podoplanin (PDPN), prospero homeobox 1 (PROX1), and VEGFR3, and share structural features with peripheral lymphatic vessels. Anatomically, they course alongside major dural sinuses and arteries (Louveau et al., 2015). I In rodent models, meningeal lymphatics have been identified along the transverse and sigmoid sinuses, the rostral rhinal and retroglenoid veins, and in proximity to the middle and anterior meningeal arteries. Several efflux routes have been described, including drainage along the pterygopalatine artery, veins of the sigmoid sinus, and cranial nerves I, II, V, VII, IX, X, and XI as they exit through the skull base (Aspelund et al., 2015; Ma et al., 2017). In parallel, CSF drainage along spinal nerve roots into the epidural lymphatic plexus of the spinal column has been documented (Brierley & Field, 1948; Zakharov et al., 2003).

Meningeal lymphatic vessels further distinguish themselves from peripheral counterparts through their structural and functional organization. Rodent meningeal lymphatics lack classic valves along much of their cranial course; direct evidence for human meningeal collecting-segment valves and active pumping remains limited. Nevertheless, collecting lymphatics in this region exhibit intrinsic contractile activity that facilitates directional flow toward extracranial drainage routes (Ma et al., 2017). A recently characterized nasopharyngeal lymphatic plexus further expands this anatomical framework by interconnecting anterior and middle cranial compartments, including the subarachnoid space, pituitary, cavernous sinus, and cribriform region, with both superficial and deep cervical lymph nodes (Louveau et al., 2018; Yoon et al., 2024). Together, these observations position the meningeal lymphatic system not only as a conduit for fluid outflow, but as a structural interface bridging intracranial compartments and peripheral immune organs, prompting a revision of classical models of brain–immune communication.

Subsequent CE-MRI studies have expanded our understanding of CSF clearance beyond the parasagittal dura. Work by Ringstad and Eide demonstrated that tracers injected into the subarachnoid space reach parasagittal dural compartments, refining dorsal efflux models by emphasizing dural tissue interfaces rather than direct transfer to venous sinuses (Ringstad & Eide, 2020). More recently, Jacob et al. and Ding et al. described conserved drainage circuits linking intracranial lymphatic structures to extracranial lymphatic vessels and dCLNs in both healthy individuals and patients with Parkinson’s disease (PD) (Ding et al., 2021; Jacob et al., 2022). These studies support a broader framework of brain-to-lymphatic connectivity that extends beyond dorsal convexity routes. However, they also highlight significant regional heterogeneity and the lack of a single dominant outflow tract. Importantly, these findings suggest anatomical continuity but not uniform functional coupling, cautioning against overinterpretation of CE-MRI results. Differences in spatial resolution, tracer kinetics, and study design require careful distinction between local visualization, proximal efflux, and downstream drainage. Together, CE-MRI studies offer valuable anatomical insight into human meningeal lymphatic organization, while underscoring the need for careful experimental and interpretive boundaries (Absinta et al., 2017; Jacob et al., 2022; Ringstad & Eide, 2020).

Beyond fluid clearance, the meningeal lymphatic system has emerged as a dynamic site of immunological interaction. Under homeostatic conditions, the dura contains enriched populations of CD4-positive and CD8-positive T cells, as well as major histocompatibility complex class II (MHC II)-positive antigen-presenting cells (APCs), which cluster within perisinusoidal niches (Rustenhoven et al., 2021). Associated dural vasculature expresses adhesion molecules such as vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), and selectin P (Selp), facilitating immune cell extravasation into the dural space. In parallel, stromal cells within the dura express structural and immune ligands, including collagen type I alpha 1 (Col1a1) and myosin light chain 9 (Myl9), which support T-cell residency via interactions with CD44 and CD69 (Rustenhoven et al., 2021). Together, these features suggest that immune cell positioning and activation in the meninges are tightly integrated with lymphatic architecture and function. In inflammatory contexts, this coupling becomes functionally significant: for example, in experimental autoimmune encephalitis, surgical interruption of meningeal lymphatic drainage to deep cervical lymph nodes attenuates disease severity, implicating these nodes in antigen presentation and adaptive response coordination (Louveau et al., 2018). Moreover, antigen uptake from the cerebrospinal fluid appears to occur at localized hotspots along dural sinuses, where T cells and MHCII-positive cells reside in proximity to both lymphatic and blood vessels (Rustenhoven et al., 2021).

Extending these insights to brain tumors, preclinical glioblastoma models highlight a dual role for meningeal lymphatics in both fluid drainage and immune priming. In murine glioblastoma, tumor growth promotes lymphangiogenesis along dorsal meningeal territories, expanding the network of LYVE1-positive vessels and enhancing dendritic cell trafficking to deep cervical lymph nodes (Hu et al., 2020). Disruption of this pathway worsens cerebral edema and impairs antigen clearance, while treatment with VEGFC restores lymphatic structure and facilitates dendritic cell migration via CCR7 and CCL21 signaling. Complementary studies by Song et al. show that VEGFC-induced lymphangiogenesis can enhance T cell priming: preconditioning with VEGFC before tumor inoculation leads to near complete tumor rejection, an effect lost upon depletion of CD4 or CD8 T cells, but not B cells, or upon ligation of deep cervical lymph nodes (Song et al., 2020). These findings position meningeal lymphatics as a functional bridge between intracranial antigen drainage and peripheral adaptive immunity. Importantly, this immune interface is not restricted to tumor models. In aging, reduced CCR7 expression on regulatory T cells and interferon gamma (IFNγ)-driven remodeling of lymphatic endothelial cells impair meningeal lymphatic surveillance (Da Mesquita et al., 2021; Louveau et al., 2018; Rustenhoven et al., 2023). Taken together, these observations establish the brain meninges as an active immunological frontier where drainage and immune regulation converge. Disruption of this interface may compromise both fluid clearance and adaptive immune coordination across diverse neuropathological contexts, and may become more pronounced with aging or in the setting of chronic neuroinflammation.

2.4. Aging-Related Structural Decline and Brain Homeostasis Disruption

Degenerative changes in lymphatic architecture, well established in peripheral tissues, have now been identified within the cranial compartment, implicating both meningeal lymphatic vessels and dCLNs in aging-related vulnerability. In aged mice, whole-mount imaging reveals a significant reduction in the caliber and density of meningeal lymphatic vessels, which is accompanied by decreased CSF influx into the brain parenchyma (Da Mesquita et al., 2018). Serial imaging with fluorescent tracers further demonstrates reduced tracer efflux through meningeal lymphatics and diminished accumulation in cervical lymph nodes when compared with young controls (Ma et al., 2017). Importantly, these alterations are not merely passive. Structural remodeling has been observed within the ventral meningeal lymphatic plexus, including valve disruption and altered vessel morphology, which may reflect maladaptive adaptations to impaired flow dynamics (Ahn et al., 2019).

Within this framework, VEGF-C therapy has demonstrated partial efficacy in restoring lymphatic integrity in aged mice. VEGF-C delivery enhances CSF distribution and promotes clearance of intracranial tracers to the dCLNs, supporting at least partial recovery of the drainage axis connecting brain and neck (Da Mesquita et al., 2018; Louveau et al., 2015). Regression of the nasopharyngeal lymphatic plexus, an anterior drainage route affected by aging, is also mitigated by VEGF-C, which reduces endothelial apoptosis and preserves structural volume in this region (Yoon et al., 2024). In addition, VEGF-C treatment has been shown to confer immune benefits in brain tumor models by improving meningeal lymphatic function (Hu et al., 2020; Song et al., 2020). Collectively, these findings support the concept that lymphangiogenic augmentation can improve certain structural and functional parameters, although the extent to which these effects influence disease outcomes remain context-dependent.

In transgenic models of Alzheimer’s disease (AD), augmentation of meningeal lymphatic structure and function using VEGF-C has yielded variable results. Antila et al. reported that adeno–associated virus–mediated VEGF-C delivery improved drainage measures and partially restored lymphatic architecture, but did not lead to measurable improvements in behavioral performance or amyloid pathology in their model (Antila et al., 2024). In contrast, other studies using VEGF C strategies or implant-based drainage enhancement approaches have reported improved macromolecule clearance and, in some cases, functional benefits in aged AD contexts (Shan et al., 2024; Wen et al., 2018). Complementary mechanistic work shows that intact meningeal lymphatics contribute to extracellular tau clearance (Patel et al., 2019), and VEGF-C therapy has demonstrated protective effects in tauopathy models following injury, supporting the broader relevance of lymphatic modulation across protein aggregation settings (Royo Marco et al., 2025). Altogether, these findings support a plausible therapeutic benefit, while also emphasizing that efficacy is likely shaped by disease stage, model system, and the specific means by which lymphatic pathways are targeted (Antila et al., 2024).

Human postmortem studies provide further nuance by revealing meningeal lymphatic atrophy alongside amyloid beta (Aβ) accumulation within the dura, but not within the lymphatic vessel walls (Goodman et al., 2018). Experimental ablation of meningeal lymphatics in mice is sufficient to increase hippocampal Aβ deposition, reinforcing the functional importance of these vessels even in the absence of spontaneous meningeal amyloidosis (Da Mesquita et al., 2018). These findings highlight the complexity of meningeal lymphatic contributions to disease, where both structural integrity and regional context influence pathological outcomes.

Recent work has extended the investigation of VEGF-C-related pathways to Parkinson’s disease (PD). In preclinical models, meningeal lymphatic dysfunction exacerbates alpha synuclein accumulation and correlates with worsening motor and memory impairments (Zou et al., 2019). Human imaging studies have also identified reduced meningeal lymphatic flow in idiopathic PD (iPD) compared to atypical Parkinsonian disorders and healthy controls (Ding et al., 2021), offering a clinical parallel. More recently, Han et al. demonstrated that treatment with chiral substituted polyvinylpyrrolidone (CSPVP) nanoparticles enhanced meningeal lymphatic vessel structure and drainage. This was accompanied by upregulation of VEGF-C and VEGFR3 signaling, activation of calcium-dependent transcriptional programs, and functional recovery in a preformed fibril-induced PD model, including improved motor and cognitive performance and reduced alpha-synuclein burden (Han et al., 2025). Together, these findings support VEGF-C signaling as a potential therapeutic target in PD-related contexts, while emphasizing the need for further mechanistic and translational investigation.

Additional studies support a broader role for cervical lymphatic drainage in maintaining cognitive function, even in the absence of overt neurodegenerative disease. In healthy mice, surgical ligation of deep cervical lymph nodes under systemic inflammatory conditions caused hippocampal neuronal injury and impaired spatial memory (Zhu et al., 2024). These findings underscore the importance of intact brain-draining lymphatic pathways for cognitive resilience, particularly under inflammatory stress that may become more prevalent with age.

Age-related degeneration of meningeal lymphatic pathways also remodels the local immune niche in ways that may reinforce progressive dysfunction. In aged mice, regulatory T cells show reduced CCR7 expression, resulting in impaired retention in dCLNs and accumulation of CD4-positive FOXP3-positive regulatory T cells and NK1.1-negative TCR beta-positive T cells within the meninges, alongside a decline in CD4-positive FOXP3-negative effector T cells (Da Mesquita et al., 2021; Louveau et al., 2018). This CCR7 deficiency is associated with impaired glymphatic influx and reduced aquaporin 4 vascular coverage, linking altered immune trafficking to reduced clearance capacity (Da Mesquita et al., 2021). Over time, T cells infiltrate beyond perisinusoidal regions, indicating disruption of spatial containment (Da Mesquita et al., 2021; Louveau et al., 2018; Rustenhoven et al., 2021).

Functional consequences of this immune redistribution have been shown in Alzheimer disease models. In contrast to Antila et al., Da Mesquita and Kipnis demonstrated that meningeal lymphatic dysfunction impairs spatial learning and memory, with or without CCR7 knockout, and differentially influences amyloid plaque burden (Da Mesquita et al., 2021; Da Mesquita et al., 2018). Importantly, accumulated T cells may exert pathophysiologic effects. IFNγ produced by these cells disrupts lymphatic endothelial barrier integrity by mislocalizing VE-cadherin and promoting vessel hyperpermeability. Neutralization of IFNγ restores drainage to dCLNs in aged mice, identifying a potentially reversible mechanism (Rustenhoven et al., 2021; Rustenhoven et al., 2023).

In parallel, depletion of parenchymal border macrophages has been shown to narrow perivascular spaces, increase extracellular matrix deposition, and blunt vasomotion through loss of metalloproteinase-driven matrix remodeling, ultimately restricting CSF outflow and exacerbating amyloid burden in transgenic mice (Drieu et al., 2022). The resulting fibroblast-driven matrix stiffening may further enhance T cell retention by amplifying stromal cues, including Col1a1 and Myl9 (Rustenhoven et al., 2021). Together, these observations support a convergent model in which aging impairs CCR7-dependent trafficking, promotes T cell accumulation, sensitizes lymphatic endothelium, and alters stromal architecture, changes that collectively compromise meningeal lymphatic drainage and cognitive resilience.

Overall, the evidence supports a model in which aging-related remodeling of meningeal and cervical lymphatic pathways reduces drainage capacity and reshapes immune architecture, with downstream consequences for solute clearance, neuroinflammatory tone, and cognitive stability. At the same time, variability across preclinical studies, including differences in disease model, timing, and method of lymphatic manipulation, indicates that functional benefits are not uniformly observed. These complexities reinforce the need for anatomically grounded, mechanism-based interpretations when assessing human data and underscore the importance of refining therapeutic strategies that target lymphatic dysfunction in age-related neurodegenerative disease.

2.5. Cross-Species Differences in Lymphatic Structure and Drainage

Rodent models have substantially advanced our understanding of meningeal lymphatic anatomy and function by enabling mechanistic manipulations, tracer-based clearance studies, and aging analyses under controlled experimental conditions that remain difficult to replicate in humans. These investigations were central in establishing that CSF-ISF exchange is coupled to perivascular transport pathways, contributing to the clearance of solutes that accumulate with age. They also demonstrated that lymphatic-linked CSF efflux declines over time (Iliff et al., 2012; Iliff et al., 2013; Jessen et al., 2015; Ma et al., 2017; Proulx, 2021). Together, this work provides a foundational mechanistic framework while emphasizing the importance of clearly delineating species-specific anatomical constraints when translating findings to the context of human brain aging.

Critical anatomical and physiological differences constrain the direct extrapolation of rodent lymphatic aging studies to humans, especially with regard to CSF absorption routes. In humans, CSF outflow has traditionally been attributed to arachnoid villi and granulations that drain into dural venous sinuses. However, more recent models support a multipathway system that includes perineural and dural lymphatic-associated routes (Johnston et al., 2004; Margetis et al., 2025; Proulx, 2021). Growing evidence also suggests that arachnoid granulations interface with dural stromal and immune compartments, indicating that CSF handling may involve immune exchange and filtration in addition to bulk venous transfer. The relative contributions of these components likely shift with physiological context and disease state (Miyajima & Arai, 2015; Shah et al., 2023; Thomas & Benveniste, 2023).

In rodents, arachnoid villi and granulations are comparatively underdeveloped, and quantitative tracer studies indicate that perineural and lymphatic pathways play a dominant role in CSF clearance (Johnston et al., 2004; Proulx, 2021; Zakharov et al., 2003). In mice, lymphatic associated outflow supports removal of both small and large solutes and declines with age, such that disruption of meningeal lymphatic function can cause substantial deficits in global CSF clearance (Ma et al., 2017). In contrast, humans possess additional absorptive capacity through arachnoid granulations and extracranial routes. As a result, similar manipulations may not produce equivalent effects across the whole brain, even if they remain locally significant for immune surveillance and regional solute handling (Proulx, 2021; Shah et al., 2023).

With respect to regional organization, dorsal meningeal lymphatics refer to vessels aligned with the superior sagittal and transverse sinuses along the cranial convexity, including regions adjacent to branches of the middle meningeal artery (MMA) (a dorsal compartment feature), whereas ventral pathways encompass skull-base-associated territories. Evidence for skull-base ventral lymphatics is emerging, although compartment-specific contributions remain unquantified. In mice, meningeal lymphatics are largely restricted to dorsal surfaces, where they parallel dural sinuses and support tractable experimental interrogation of lymphatic function (Antila et al., 2017; Louveau et al., 2017). This arrangement represents a simplified architecture compared to humans, in whom imaging and histological studies reveal a broader and regionally diverse network that includes ventral territories and MMA-adjacent structures (Ahn et al., 2019; Albayram et al., 2025; Albayram et al., 2022; Vera Quesada et al., 2023). These ventral lymphatic structures, rudimentary or absent in rodents, lie at anatomical intersections where CSF-ISF efflux converges with vascular and immune interfaces (Ringstad et al., 2017). However, the specific contribution of these compartments to global brain clearance remains incompletely defined, and dorsal-focused rodent models provide limited access to skull base-associated lymphatic function in aging (Ahn et al., 2019; Hadamitzky et al., 2010; Jacob et al., 2022).

Rodent studies have predominantly focused on dorsal dural lymphatics, with limited investigation into skull base or ventral drainage pathways. This emphasis reflects the simplified cranial architecture of mice, in which lymphatic vessels are largely confined to the dorsal surface. In contrast, human meningeal lymphatics extend into basal regions adjacent to the basal forebrain and hippocampus, areas that are disproportionately affected by aging and neurodegenerative disease (Pinho-Correia et al., 2025). Recent anatomical and imaging studies support the presence of lymphatic-associated structures within the skull base and MMA-adjacent dural compartments, suggesting potential relevance for CSF and ISF handling under specific anatomical or physiological conditions (Albayram et al., 2025; Jacob et al., 2022; Jiang-Xie et al., 2025; Vera Quesada et al., 2023). However, the proportional contributions of these compartments to total brain solute clearance remain undefined, and no functional hierarchy has been established between dorsal and ventral systems. Age-associated changes within these regions may influence vulnerable neural circuits, but current evidence remains hypothesis-generating. Accurate modeling of meningeal lymphatic aging, therefore, requires explicit incorporation of both dorsal and ventral components, along with recognition of unresolved questions regarding their functional partitioning.

Species-specific distinctions are also evident at the level of cervical lymphatic drainage. Human dCLNs are larger and structurally more complex than their rodent counterparts and represent plausible downstream endpoints for intracranial drainage, as supported by emerging but incomplete human evidence, whereas route-specific fractions from the dorsal and ventral meningeal compartments remain unknown. Although supportive evidence exists, direct demonstration of route-specific flow patterns in humans remains limited (Hadamitzky et al., 2010; Thompson et al., 2017). Age-related degenerative and fibrotic remodeling of these nodes could impose additional bottlenecks on CSF and ISF clearance, thereby compounding upstream drainage deficits (Jin et al., 2025; Kwok et al., 2022; Thompson et al., 2019). While this expanded nodal architecture may enhance clearance capacity earlier in life, its structural complexity could render it increasingly susceptible to failure under chronic inflammatory, metabolic, or vascular stress, particularly as compensatory reserve diminishes with age (Hadamitzky et al., 2010).

Taken together, these comparative observations underscore the need to recalibrate experimental frameworks when modeling meningeal lymphatic aging. Differences in CSF and ISF clearance routes, lymphatic vessel topology, extracellular matrix composition, and nodal complexity shape how aging-related dysfunction emerges across species (Ahn et al., 2019; Hitpass Romero et al., 2025; Proulx, 2021). The simplified dorsal lymphatic network in rodents, combined with limited skull base representation, limits direct extrapolation to human aging and disease. Critically, human meningeal lymphatics exhibit a broader anatomical distribution and greater structural heterogeneity, particularly in the ventral regions and the skull base, which remain understudied in preclinical models. These anatomical and functional disparities call for future models that better reflect the full extent of human lymphatic circuitry, regional context, and age-related vulnerability. By embracing species-aware designs and addressing current gaps in functional partitioning, the field can advance toward a more mechanistically grounded and translationally relevant understanding of how lymphatic decline shapes brain aging and cognitive resilience.

2.6. Imaging Advances Reveal Age-Linked Drainage Impairment

Magnetic resonance imaging (MRI) has become a powerful modality for examining brain drainage pathways in vivo, enabling indirect visualization of meningeal and cervical structures involved in cerebrospinal and interstitial fluid clearance. By offering region-specific and longitudinal insights across the aging spectrum, MRI provides a noninvasive platform to explore how anatomical or physiological alterations may relate to impaired clearance, neuroinflammation, and cognitive vulnerability. Although technical limitations persist, continued advances in MRI methodology have expanded its capacity to interrogate brain fluid dynamics in aging.

Initial studies of human meningeal lymphatic anatomy used contrast-enhanced MRI (CE-MRI) with gadolinium-based agents to visualize dural fluid compartments in vivo. A landmark investigation demonstrated contrast enhancement within linear and nodular structures along the parasagittal dura adjacent to the superior sagittal sinus, providing the first in vivo evidence of dorsal convexity meningeal lymphatic structures in humans (Absinta et al., 2017). Using high-resolution 3T MRI with vascular signal suppression, this work consistently detected dorsal dural lymphatic structures in all examined human participants and nonhuman primates. Notably, contrast enhancement was limited to parasagittal regions and absent from ventral skull base or cervical territories. The study was designed to characterize anatomical presence rather than functional drainage or cranial-to-cervical coupling, thereby defining dorsal meningeal lymphatic structures while avoiding conclusions about global clearance.

Building on these contrast-enhanced approaches, dynamic imaging studies have identified altered lymphatic-associated tracer clearance in idiopathic Parkinson’s disease compared with controls, suggesting that a cranial-to-cervical drainage pathway may be disrupted in human neurodegeneration (Ding et al., 2021). Although contrast-enhanced MRI provides only indirect evidence of drainage, these findings demonstrate the translational potential of lymphatic imaging to detect disease-related changes in brain fluid transport.

To enable repeated, physiology-sensitive measurements across time, non-contrast MRI (NC-MRI) techniques, such as 3D fluid-attenuated inversion recovery (3D-FLAIR) and motion-sensitized sequences, have increasingly been applied to study lymphatic-related signal dynamics. These methods allow indirect inference of regional fluid handling under physiological conditions and have revealed age-associated changes, including altered parasagittal dural signal and reduced visibility of deep cervical lymph nodes. However, NC-MRI is sensitive to motion, partial-volume effects, and susceptibility artifacts, particularly in the skull base and foraminal regions, where complex bone–air interfaces complicate interpretation. Consequently, parasagittal convexity regions are generally more suitable for reproducible sampling, while skull base territories require caution. Despite these limitations, optimization strategies, such as positional adjustments, multiplanar acquisitions, and protocol harmonization, can enhance sensitivity to relevant anatomical signals and extend the applicability of 3D-FLAIR approaches. As methods evolve, this technique may offer a valuable, noninvasive platform for probing human brain clearance physiology with increasing specificity and reliability. Across-site reproducibility hinges on consistent acquisition parameters, region definitions, and harmonized preprocessing, with MRI-based lymphatic markers best understood as hypothesis-generating tools rather than direct measures of lymphatic vessel flow.

High-resolution NC-MRI studies have provided quantitative context for age- and sex-associated alterations in brain-draining lymphatic-related signal behavior. In a whole-brain 3D T2-FLAIR cohort spanning adolescence to late adulthood, parasagittal dural signal intensity progressively increased with age, whereas signal and volume of deep cervical lymph nodes decreased, indicating a gradual decoupling along the dural–cervical axis (Albayram et al., 2022). This study initially screened 236 individuals with epilepsy or suspected epilepsy (ages 15–80 years), of whom 81 were retained after exclusion and quality control (45 females, 36 males; mean age 41.7 ± 20.4 years). Imaging was performed on a 3T Siemens Prisma system using an isotropic whole-brain 3D T2-FLAIR acquisition (0.9 mm section thickness; TR/TE/TI = 5000/387/1800 ms), enabling reliable assessment of dorsal dural and cervical nodal compartments. Regional heterogeneity was observed along cranial nerve–associated efflux territories, with signal intensity ratios of the CN IX–XII complex to central white matter markedly lower in regions inferior to the deep cervical lymph nodes compared to more superior regions (0.44 ± 0.08 vs. 1.40 ± 0.21), supporting anatomical coupling between cranial exit zones and cervical drainage. Receiver operating characteristic analysis yielded modest discrimination of dorsal dural metrics at age 50 (AUC 0.68, 95% CI 0.56–0.79), suggesting gradual rather than threshold-based age effects. Beyond aging, sex-specific patterns were evident: males exhibited greater signal intensity and thickness in both dorsal and ventral meningeal lymphatic. regions than females, differences that remained significant after adjusting for age and intracranial volume (Albayram et al., 2022). These findings highlight that 3D FLAIR readouts capture fluid-sensitive signal behavior reflecting physiological drainage dynamics, while also revealing consistent age- and sex-dependent divergence along the human meningeal–cervical clearance axis.

While NC-MRI findings do not confirm lymphatic dysfunction per se, they provide a valuable, indirect window into region-specific alterations in CSF–ISF dynamics that accompany aging and disease (Albayram et al., 2022; van der Thiel et al., 2023). By capturing fluid-sensitive signal changes without contrast administration, sequences such as 3D FLAIR provide a feasible and reproducible approach for longitudinal evaluation of brain fluid handling in clinical and research settings. However, interpretive precision depends on anatomical context and acquisition strategy. The parasagittal dura, located along the cranial convexity, provides a reliable region of interest owing to its relatively stable geometry and lower susceptibility to skull-base–associated artifacts (Absinta et al., 2017). In contrast, skull base–adjacent territories and foraminal exit zones are prone to partial volume effects, pulsation-induced blurring, and distortion from bone–air interfaces, complicating interpretation. Signal behavior in these regions is further influenced by sequence parameters, including inversion time, echo time, and refocusing design, and may benefit from positional optimization strategies such as multi-angle 3D FLAIR acquisition combined with anatomical modeling, which could extend reliable assessment beyond the dorsal convexity (Herlihy et al., 2001; Naganawa, 2015)

Recent integrative analyses of brain fluid transport in aging and AD have further clarified the interpretive boundaries of NC-MRI. In a comprehensive synthesis of human and animal imaging studies, van der Thiel et al. described consistent directional changes, such as reduced cardiac-pulsation–driven fluid movement and attenuated clearance-related modulation, that emerge across age and neurodegeneration, despite significant variability in imaging protocols and anatomical coverage (van der Thiel et al., 2023). Crucially, this framework reinforces that NC-MRI readouts reflect indirect physiological correlates, rather than direct measures of lymphatic vessel flow or CSF–ISF drainage. These signals are shaped by vascular compliance, tissue stiffness, sequence parameters, and acquisition geometry. Thus, NC-MRI metrics should be considered semi-quantitative, hypothesis-generating indicators that require transparent reporting, harmonized pipelines, and cross-modal validation before serving as robust markers of lymphatic dysfunction in aging or disease (Tamir et al., 2025; Wittens et al., 2021).

Taken together, CE- and NC-MRI approaches have markedly advanced in vivo investigation of brain fluid clearance pathways, each offering distinct yet complementary insights. CE-MRI has been particularly informative for visualizing dorsal and sinus-adjacent dural compartments, whereas NC-MRI provides repeatable, physiology-sensitive readouts that reflect region-specific fluid dynamics along the meningeal–cervical axis. At the same time, both modalities are constrained by the interpretation of indirect signals, anatomical variability, and protocol heterogeneity. Accordingly, MRI-based markers of brain drainage are best interpreted as hypothesis-generating tools, rather than direct surrogates of lymphatic flow, that require validation through tracer studies, histopathology, and longitudinal designs before supporting mechanistic conclusions in aging and neurodegeneration.

2.7. Targeting Lymphatic Decline: Emerging Therapeutic Pathways

Recent advances in neurovascular biology have positioned the meningeal lymphatic system as a promising target for therapeutic intervention and diagnostic innovation in the aging brain. Because current human imaging approaches provide only indirect insight into lymphatic drainage physiology, most strategies remain at the level of preclinical proof of concept or early-stage translational testing. Nevertheless, the progressive decline in lymphatic clearance with age, including fibrotic remodeling, nodal atrophy, and stagnation of cerebrospinal and interstitial fluid, offers a compelling mechanistic rationale for restoring drainage capacity in both healthy aging and neurodegenerative conditions.

Among the most extensively studied interventions is VEGF-C, which promotes lymphatic vessel formation, increases meningeal lymphatic caliber, and enhances CSF clearance in aged mice (Da Mesquita et al., 2018). In experimental models, these structural improvements are accompanied by partial restoration of glymphatic transport and attenuation of cognitive decline, supporting VEGF-C as a biologically plausible candidate for addressing age-related lymphatic insufficiency (Da Mesquita et al., 2018; Yoon et al., 2024).

Beyond growth factor delivery, recent work has identified Collagen and Calcium Binding EGF Domains 1 (CCBE1) as a molecular regulator of lymphatic development and maintenance that may be relevant to aging-associated lymphatic trajectories. While initially characterized in neonatal contexts, CCBE1 loss in young adult mice accelerates meningeal lymphatic degeneration, even in the absence of cerebrovascular injury (Ocskay et al., 2024). This phenotype may represent a model of molecular decline that precedes broader neurovascular remodeling, offering a tractable framework for identifying early determinants of lymphatic vulnerability. In this way, CCBE1-linked signaling pathways may serve as complementary mechanistic entry points for delaying or attenuating functional senescence in the brain-draining lymphatic network.

In addition to regenerative and molecular approaches, drug delivery technologies are beginning to offer practical strategies for modulating meningeal lymphatic function. Lyotropic liquid crystalline (LLC) nanoparticles enable co-delivery of hydrophilic and hydrophobic agents within a stable injectable matrix and have shown promise in experimental models. For example, an LLC-based co-formulation of cilostazol and donepezil hydrochloride, administered into the deep cervical lymph nodes, has been reported to enhance lymphatic drainage, reduce hippocampal amyloid beta burden, and restore spatial memory in mouse models of AD (Chavda et al., 2023; Shan et al., 2024). Cilostazol, a phosphodiesterase III inhibitor with vasoprotective and pro-lymphangiogenic properties, has also been associated with peripheral lymphatic repair and cognitive benefit when combined with donepezil in previous studies (Ihara et al., 2014; Kimura et al., 2014). In this setting, the observed benefits of LLC therapy occurred without measurable changes in cerebral blood flow, suggesting that its primary mechanism may involve modulation of the lymphatic axis rather than enhancement of vascular perfusion. Related nanotechnology platforms have also been proposed to engage the VEGF-C and VEGFR-3 pathway, including CSPVP nanoparticles as discussed in Section 2.4, with reported benefit in pre-formed fibril induced Parkinson’s disease models (Han et al., 2025).

On the diagnostic front, the anatomical role of dCLNs as terminal drainage hubs for meningeal lymphatics has created interest in their potential as biomarkers of upstream dysfunction. Recent work suggests that fine needle aspiration of these nodes yields higher concentrations of Alzheimer-associated biomarkers, including Aβ40, Aβ42, and phosphorylated tau (pTau181), compared with peripheral blood sampling (Al-Diwani et al., 2025). Because this sampling method is minimally invasive and repeatable, it may offer a practical avenue for earlier detection or longitudinal monitoring, particularly during preclinical or prodromal stages when therapeutic intervention could have the greatest impact.

Together, these therapeutic and diagnostic strategies, spanning regenerative growth factor signaling, molecular pathways that govern lymphatic maintenance, nanoparticle-based delivery systems, and nodal biomarker sampling, underscore the emerging translational relevance of meningeal lymphatic biology in the aging brain. Reconceptualizing the lymphatic system as an active and potentially modifiable determinant of brain homeostasis, rather than a passive drainage route, may broaden the landscape of actionable targets for preserving cognitive function and mitigating vulnerability to age-related neurodegeneration.

2.8. Microsurgical Repair of Brain Drainage: Toward Clinical Translation

Lymphovenous anastomosis (LVA) is an established microsurgical approach that redirects lymphatic flow into the venous system and has shown consistent clinical benefit in managing peripheral oncologic lymphedema. When performed at the time of axillary or inguinal lymph node dissection, LVA reduces limb swelling, lowers infection risk, and lessens long term dependence on compression therapy. Meta-analyses report a marked reduction in secondary lymphedema incidence when used prophylactically during nodal surgery (Hinson et al., 2025; Thomas et al., 2023; Zeltzer et al., 2025).

Building on this peripheral foundation, recent experimental studies have examined whether similar microsurgical techniques could be adapted to address age-related dysfunction in brain-draining lymphatic circuits. In a preclinical rat model, reconnection of the dCLNs to the external jugular vein successfully redirected lymphatic flow, as visualized by indocyanine green imaging, thereby establishing technical feasibility without evaluating cognitive outcomes (Fang et al., 2025). Additional tumor model studies demonstrate that disruption of dCLNs can alter immune surveillance and edema dynamics, reinforcing their sentinel function and highlighting the biological complexity of modulating cervical lymphatic drainage (Hu et al., 2020; Song et al., 2020).

Accordingly, restoring connectivity between deep cervical lymph nodes and the venous system via lymph node-to-vein bypass raises important clinical considerations. Aging is often accompanied by nodal atrophy, fibrotic remodeling, and diminished lymphatic structural integrity, suggesting that bypass strategies may help reinforce impaired drainage pathways. At present, however, these applications remain exploratory and will require longitudinal and interventional studies in humans to determine their safety, effectiveness, and clinical relevance.

In parallel, LVA has been applied clinically in the head and neck region to manage chronic lymphedema, including periorbital and facial swelling, with symptomatic improvement observed in small patient cohorts. These studies support the anatomical feasibility and procedural safety of cervical applications, yet are limited by modest sample sizes, variability in surgical technique, and short duration of follow-up. Importantly, none have assessed the impact of these procedures on intracranial lymphatic clearance or neurodegenerative processes (Imholz et al., 2025; Inatomi et al., 2018; Kaciulyte et al., 2025; Lin et al., 2024; Mihara et al., 2011).

A recent human proof-of-concept study described ultrasound-guided cervical lymphaticovenous anastomosis in an individual with Alzheimer-type dementia, assessed using multimodal imaging and short-interval clinical follow-up (Li et al., 2024). Although post-procedural changes in amyloid PET signal and bedside cognitive assessments showed modest numerical shifts, the absence of a control group, the single-subject design, and the limited follow-up duration preclude interpretation of durability or disease modification. Nonetheless, this report demonstrates procedural feasibility and offers an initial example of how imaging and clinical endpoints may be jointly employed in exploratory human studies.

Recent reviews and perspectives have contextualized these preliminary findings within a broader translational landscape, noting that application of lymphatic microsurgery to neurologic conditions is presently grounded in peripheral lymphedema outcomes, animal studies, and early human feasibility efforts (Hong et al., 2025; Xie et al., 2024). These sources identify deep cervical lymphatic structures as anatomically plausible extracranial targets, while underscoring that clinical translation in neurologic disease remains conceptual and will require rigorously designed prospective studies with standardized imaging, cognitive, and safety endpoints.

In sum, the application of lymphatic supermicrosurgery to brain drainage remains exploratory. While findings from peripheral lymphedema and early feasibility models support the rationale for targeting extracranial cervical structures, current evidence does not demonstrate that surgical augmentation enhances intracranial clearance or modifies the course of neurodegenerative disease. Advancing this approach will require unified operative criteria, well-controlled prospective trials, and outcome frameworks that integrate physiology-sensitive imaging with clinically relevant cognitive and safety measures.

3. Discussion

The intersection of lymphatic biology and aging neuroscience is beginning to reveal a previously underrecognized pathway through which the brain and body maintain physiological interaction across the lifespan. In particular, age-associated decline of meningeal and cervical lymphatic function is gaining recognition as a contributor to vulnerability in older adults, not only in the context of neurodegeneration, but also in immune regulation and perioperative outcomes. This relationship is currently supported primarily by preclinical studies and indirect observations from human imaging. While peripheral lymphatic aging has long been linked to impaired wound healing and diminished immune defense, the clinical relevance of brain-draining lymphatic pathways, especially meningeal vessels and their connections to the dCLNs, has only recently come into focus. Dysfunction of these vessels may hinder CSF-ISF clearance, amplify neuroinflammatory signaling, and disrupt antigen surveillance. Together, these alterations could increase susceptibility to cognitive decline, perioperative complications, and progression of neurodegenerative disorders (Oliver et al., 2020; Rego et al., 2023; Salvador et al., 2024).

Consistent with this framework, diminished meningeal lymphatic function in the aging brain has been linked to perivascular congestion, glial reactivity, and reduced solute clearance in both preclinical models and human imaging studies (Jiang-Xie et al., 2025; Rego et al., 2023). High-resolution NC-MRI in living humans has revealed regionally heterogeneous signal alterations suggestive of age-related changes in meningeal and cervical lymphatic anatomy, including parasagittal dural expansion and apparent involution of the dCLNs (Albayram et al., 2022; van der Thiel et al., 2023). This apparent disconnect between upstream dural pathways and downstream cervical nodes may reflect progressive fragmentation of drainage integration with advancing age. Such a model offers a conceptual bridge linking impaired fluid handling not only to AD and iPD, but also to broader neurological vulnerability across the aging spectrum. Beyond chronic neurodegeneration, emerging data suggest that lymphatic dysfunction may influence acute vulnerability following surgical or traumatic stress. In animal models, impaired meningeal or cervical drainage intensifies neuroinflammation and delays recovery after injury or anesthesia. In humans, age-related changes in lymphatic anatomy identified through imaging may provide a permissive substrate for postoperative delirium or prolonged recovery, although causal relationships have not yet been established (Barker et al., 2025; Jiang-Xie et al., 2025).

These central changes mirror broader patterns of lymphatic aging observed in peripheral tissues. In both brain and body, aging is associated with structural compromise, including reduced vessel density, valve dysfunction, perilymphatic fibrosis, and diminished immune responsiveness (Hadamitzky et al., 2010; Kataru et al., 2022; Murakami & Taniguchi, 2004; Palmer, 2013; Rustenhoven et al., 2021; Thompson et al., 2017). In the cervical region, dysfunction of the dCLNs impairs cerebrospinal fluid drainage and disrupts adaptive immune responses, as demonstrated in brain tumor models (Hu et al., 2020; Song et al., 2020). Deficits in lymphocyte homing, antigen presentation, and cytokine regulation may contribute to sustained neuroinflammation and inefficient amyloid clearance, two mechanisms central to neurodegenerative progression. Taken together, aging-related decline in both intracranial and peripheral lymphatic networks may jointly shape the trajectory of cognitive and immune vulnerability in later life.

Building on this mechanistic foundation, emerging therapeutic strategies aim to support or restore impaired brain-draining lymphatic pathways. Preclinical studies have demonstrated that promoting lymphangiogenesis, through agents such as VEGF-C or developmental regulators such as CCBE1, can enhance meningeal lymphatic function and improve cerebrospinal fluid outflow in aged animals (Da Mesquita et al., 2018; Ocskay et al., 2024; Yoon et al., 2024). In parallel, nanoparticle-based delivery platforms targeting meningeal vessels and dCLNs are under investigation as means of improving access to lymphatic structures. In experimental models of AD and PD, these strategies have been associated with reduced amyloid or α-synuclein burden and improved behavioral outcomes (Chavda et al., 2023; Han et al., 2025; Shan et al., 2024). Although still at an early stage, such approaches may offer translational value in older populations, where comorbidities and blood–brain barrier limitations often constrain conventional treatments. Together, these efforts represent an evolving framework for therapeutic engagement of the brain’s lymphatic interface in aging-related neurological disorders.

In the surgical domain, supermicrosurgical LVA, originally developed to alleviate peripheral oncologic lymphedema, is now being considered as a potential strategy to augment extracranial lymphatic drainage in the aging brain. A recent preclinical study demonstrated the technical feasibility of reconnecting the dCLNs to the external jugular vein, successfully rerouting lymphatic outflow as visualized by indocyanine green imaging (ICG) (Fang et al., 2025). Clinically, LVA has shown benefits in reducing periorbital and cervical lymphedema in selected patient groups (Imholz et al., 2025; Inatomi et al., 2018; Kaciulyte et al., 2025; Lin et al., 2024; Mihara et al., 2011). While most applications have targeted peripheral disease, the potential to adapt these techniques to support intracranial clearance in older adults remains largely conceptual. Compared with intrathecal interventions, extracranial lymphatic reconstruction may provide a less invasive alternative to enhance CSF and ISF outflow without directly manipulating central nervous system structures. With further refinement and integration of imaging tools for preoperative guidance, such approaches could eventually support individualized surgical strategies for patients at elevated risk of neuroimmune dysregulation or postoperative complications.

In parallel, advances in preoperative and intraoperative imaging are beginning to align with the broader aim of preserving and enhancing brain lymphatic clearance during surgery. High-resolution non-contrast 3D-FLAIR MRI has shown particular promise in visualizing lymphatic-associated structures under physiological conditions without the need for exogenous contrast agents (Albayram et al., 2022; van der Thiel et al., 2023). While these sequences do not directly image lymphatic vessels, they provide a valuable interpretive window into age-associated signal changes, such as parasagittal dural hyperintensity or diminished visibility of the dCLNs, that may reflect altered flow or stagnation within meningeal and cervical drainage pathways. These patterns, however, must be interpreted cautiously, given the method’s sensitivity to acquisition parameters and susceptibility to artifacts in anatomically complex regions. Nonetheless, when protocols are carefully optimized, 3D-FLAIR imaging may help identify regional vulnerabilities and inform future validation using tracer-based or postmortem studies. Notably, the integration of such imaging with intraoperative tools like ICG fluorescence offers a real-time anatomical framework that may assist surgical navigation near critical dural or cervical lymphatic structures. Looking forward, high-resolution lymphatic imaging could eventually support risk stratification, prehabilitation strategies, and lymphatic-sparing surgical planning tailored to aging patients.

Looking ahead, the field of translational lymphatic science must increasingly recognize aging as a central biological context. Retrospective analyses of individuals who have undergone radical neck dissections may provide an opportunity to examine whether long-term disruption of cervical lymphatic drainage contributes to cognitive vulnerability later in life, although such associations remain to be systematically examined. In parallel, future interventional studies aimed at enhancing lymphatic function, whether through pharmacologic, surgical, or imaging-guided approaches, will need to incorporate age as a critical determinant of both efficacy and safety, particularly in relation to brain clearance and immune resilience. While the integration of lymphatic assessment into perioperative care remains investigational, it may ultimately inform risk stratification and recovery planning for older adults undergoing neurosurgical or head and neck procedures. More broadly, there is growing recognition that aging-associated decline in brain-draining lymphatic pathways may represent not merely an epiphenomenon of neurodegeneration, but a modifiable physiological axis. Reframing these changes as potential therapeutic targets, rather than fixed consequences, could open new directions for preserving cognitive function and enhancing recovery in aging populations, contingent on rigorous validation in longitudinal and interventional studies.

In summary, age-related decline of the meningeal lymphatic system constitutes a critical but potentially modifiable axis of vulnerability in brain health. This gradual deterioration may contribute to impaired solute clearance, heightened neuroinflammatory tone, and increased susceptibility to neurodegenerative progression in later life. At the same time, it presents a tangible opportunity for therapeutic intervention, now increasingly accessible through advances in high-resolution imaging, microsurgical innovation, and targeted lymphatic modulation. By integrating anatomical insight with emerging strategies across pharmacology, surgery, and imaging, it may become possible to preserve or restore lymphatic function in the aging brain. These approaches offer promise not only for supporting cognitive resilience and slowing disease progression, but also for shifting the therapeutic paradigm from reactive symptom management toward proactive, clearance-oriented neuroprotection.