Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Jan 8;113(1):71-81.
doi: 10.1016/j.neuron.2024.09.017. Epub 2024 Oct 11.

Waste clearance shapes aging brain health

Li-Feng Jiang-Xie  1 , Antoine Drieu  2 , Jonathan Kipnis  3
Affiliations
Review

Waste clearance shapes aging brain health

Li-Feng Jiang-Xie et al. Neuron. .

Abstract

Brain health is intimately connected to fluid flow dynamics that cleanse the brain of potentially harmful waste material. This system is regulated by vascular dynamics, the maintenance of perivascular spaces, neural activity during sleep, and lymphatic drainage in the meningeal layers. However, aging can impinge on each of these layers of regulation, leading to impaired brain cleansing and the emergence of various age-associated neurological disorders, including Alzheimer's and Parkinson's diseases. Understanding the intricacies of fluid flow regulation in the brain and how this becomes altered with age could reveal new targets and therapeutic strategies to tackle age-associated neurological decline.

Keywords: brain borders; brain clearance; lymphatic; meningeal immunity; meningeal lymphatic; neuroimmunology; sleep.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors have patents and provisional patent applications related to the work discussed in this review.

Figures

Figure 1.
Figure 1.. Major anatomical pathways for brain cleansing
Fresh cerebrospinal fluid (CSF) travels along the peri-arterial space and infiltrates the brain parenchyma, carrying metabolic waste to the peri-venous spaces. This brain fluid transport system is commonly known as glymphatic system. Parenchyma border macrophages (PBM) modulate the resistance of peri-vascular flow. Neurons provide the driving force for CSF infiltration into brain parenchyma. The brain’s waste products dissolve in the CSF and are later transported to the periphery through the meningeal lymphatic vessels.
Figure 2.
Figure 2.. Parenchyma border macrophage (PBM) dysfunction in the aged brain obstructs brain fluid perfusion and impairs waste clearance
In the aged brain, dysfunctional PBM leads to the accumulation of extracellular matrix (ECM) proteins, which narrows the perivascular space and increases resistance to fresh cerebrospinal fluid (CSF) delivery. This reduction in CSF perfusion into the brain parenchyma results in the buildup of junk proteins in the aging brain.
Figure 3.
Figure 3.. Meningeal lymphatic dysfunction in the aged brain impairs waste clearance.
In the aged brain, reduced infiltration of fresh cerebrospinal fluid (CSF) into the brain parenchyma hinders the removal of metabolic waste. Additionally, dysfunction of the meningeal lymphatic vessels further impairs brain cleansing by obstructing the transport of waste-dissolving CSF into peripheral circulation.
See this image and copyright information in PMC

References

    1. Farkas E, and Luiten PG (2001). Cerebral microvascular pathology in aging and Alzheimer’s disease. Progress in Neurobiology 64, 575–611. 10.1016/s0301-0082(00)00068-x. - DOI - PubMed
    1. van der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, and Scheltens P (2018). Vascular cognitive impairment. Nat Rev Dis Primers 4, 18003. 10.1038/nrdp.2018.3. - DOI - PubMed
    1. Nedergaard M, and Goldman SA (2020). Glymphatic failure as a final common pathway to dementia. Science 370, 50–56. 10.1126/science.abb8739. - DOI - PMC - PubMed
    1. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, et al. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4, 147ra111. 10.1126/scitranslmed.3003748. - DOI - PMC - PubMed
    1. Rasmussen MK, Mestre H, and Nedergaard M (2022). Fluid transport in the brain. Physiol Rev 102, 1025–1151. 10.1152/physrev.00031.2020. - DOI - PMC - PubMed

LinkOut - more resources