The Glymphatic System and Waste Clearance with Brain Aging: A Review
Open accessAbstract
The glymphatic system is a glial-dependent waste clearance pathway in the brain, in place of lymphatic vessels, dedicated to drain away soluble waste proteins and metabolic products. Specifically, the glymphatic network serves as a “front end” for waste clearance, and is connected downstream to an authentic lymphatic network, associated with dura covering the brain as well as cranial nerves and large vessels at the skull exits. The anatomical and functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control glymphatic transport function and waste clearance from brain. In this review, we aim to provide an overview and discussion of the concept behind the glymphatic system, current evidence, and controversies, while specifically focusing on the consequences of aging and evidence of its existence in human brain. Discovering novel strategies for optimizing and maintaining efficient brain waste clearance across the lifespan may in the future prove to be important for preventing cognitive decline and sustaining healthy aging.
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Aging is associated with a steep fall in glymphatic flow in rodent and human brains.
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [53]
CSF inflow of larger tracers is reduced by up to 85% in aged wild-type mice.
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [53]
Contrast clearance in human brain tissue is inversely correlated with age in all subjects studied.
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [53]
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- [36]Iliff JJ Lee H Yu M Feng T Logan J Nedergaard M Benveniste H Brain-wide pathway for waste clearance captured by contrast-enhanced MRI J Clin Invest 2013 123 1299 1309 23434588 PMC3582150
- [62]Benveniste H Lee H Ding F Sun Q Al-Bizri E Makaryus R Probst S Nedergaard M Stein EA Lu H Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane Anesthesiology 2017 127 976 988 28938276 PMC5685871
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Wardlaw, J. M., Benveniste, H., Nedergaard, M., Zlokovic, B. V., Mestre, H., Lee, H., Doubal, F. N., Brown, R., Ramirez, J., MacIntosh, B. J., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0312-z · Cited by 870 · see citing works
Self-citationImpairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human
Zhou, Y., Cai, J., Zhang, W., Gong, X., Yan, S., Zhang, K., Luo, Z., Sun, J., Jiang, Q., & Lou, M. (2020) · Annals of Neurology · doi:10.1002/ana.25670 · Cited by 305 · see citing works
Glymphatics visualization after focused ultrasound-induced blood-brain barrier opening in humans
Meng, Y., Abrahao, A., Heyn, C. C., Bethune, A. J., Huang, Y., Pople, C. B., Aubert, I., Hamani, C., Zinman, L., Hynynen, K., et al. (2019) · Annals of Neurology · doi:10.1002/ana.25604 · Cited by 114 · see citing works
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.02.006 · Cited by 87 · see citing works
How Do Cognitively Stimulating Activities Affect Cognition and the Brain Throughout Life?
Mather, M. (2020) · Psychological Science in the Public Interest · doi:10.1177/1529100620941808 · Cited by 36 · see citing works
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22 · see citing works
- Authors
- Benveniste, H., Liu, X., Koundal, S., Sanggaard, S., Lee, H., & Wardlaw, J.
- Affiliations
- Yale University (US)
- University of Edinburgh (GB)
- Venue
- Gerontology
- Publisher
- S. Karger AG
- Published
- 2018-07-11
- Volume
- 65
- Issue
- 2
- Pages
- 106-119
- ISSN
- 0304-324X (ISSN-L)
- 1423-0003
- PMC
- PMC6329683
- OpenAlex
- W2851624943
- Cited by
- 517
- References
- 84
- Citations by year
- 2026: 64 · 2025: 89 · 2024: 65 · 2023: 88 · 2022: 76 · 2021: 55 · 2020: 54 · 2019: 16 · 2018: 8
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Fondation Leducq (16CVD05)
- National Institutes of Health
- Medical Research Council (MR/J006971/1)
- National Institute on Aging (RF1AG057705, RF1AG053991, R01AG048769)
- National Institute of Neurological Disorders and Stroke (R01NS100366)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- glymphatic system, brain waste clearance, brain aging, cognitive decline, human brain
- MeSH terms
- Glymphatic System, Aging, Animals, Brain, Humans
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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