Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Healthy aging and the blood–brain barrier

Nature Aging volume 1, pages 243–254 (2021)Cite this article

Subjects

Abstract

The blood–brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the ApoE4 allele leads to an acceleration of most of the BBB’s age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Properties of the peripheral endothelial cell versus the vBBB or brain endothelial cell.
Fig. 2: Movement of brain fluids via diffusion and convection.
Fig. 3: Impact of ApoE4 on the vBBB.

Similar content being viewed by others

References

  1. Biedl, A. & Kraus, R. Uber einer bisher unbekannte toxische Wirking der Gallensauren auf das zentralnervensystem. Zentralblatt Inn. Med. 19, 1185–1200 (1898).

    Google Scholar 

  2. Goldmann, E. E. Vitalfarbung am zentral-nervensystem. Abh. Preuss. Akad. Wiss., Phys.-Math. KL I, 1–60 (1913).

    Google Scholar 

  3. Neuwelt, E. et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 7, 84–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Reese, T. S. & Karnovsky, M. J. Fine structural localization of a blood-brain barrier to endogenous peroxidase. J. Cell Biol. 34, 207–217 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brightman, M. W. & Reese, T. S. Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40, 648–677 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Erickson, M. A. & Banks, W. A. Neuroimmune axes of the blood–brain barriers and blood–brain interfaces: bases for physiological regulation, disease states, and pharmacological interventions. Pharmacol. Rev. 70, 278–314 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hawkins, B. T. & Davis, T. P. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bell, R. D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Montagne, A. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stewart, P. A. et al. A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc. Res. 33, 270–282 (1987).

    Article  CAS  PubMed  Google Scholar 

  12. Banks, W. A. The blood–brain barrier as an endocrine tissue. Nat. Rev. Endocrinol. 15, 444–455 (2019).

  13. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kiss, T. et al. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience 42, 429–444 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stamatovic, S. M. et al. Decline in sirtuin-1 expression and activity plays a critical role in blood–brain barrier permeability in aging. Neurobiol. Dis. 126, 105–116 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Le Couteur, D. G. & Simpson, S. J. Adaptive senectitude: the prolongevity effects of aging. J. Gerontol. A Biol. Sci. Med Sci. 66, 179–182 (2011).

    Article  PubMed  Google Scholar 

  18. Cornford, E. M., Braun, L. D. & Oldendorf, W. H. Developmental modulations of blood–brain barrier permeability as an indicator of changing nutritional requirements in the brain. Pediatr. Res. 16, 324–328 (1982).

  19. Mooradian, A. D. & Smith, T. L. The effect of age on lipid composition and order of rat cerebral microvessels. Neurochem. Res. 17, 233–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Kalaria, R. N. Cerebral vessels in ageing and Alzheimer’s disease. Pharmacol. Ther. 72, 193–214 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Sonntag, W. E., Eckman, D. M., Ingraham, J. & Riddle, D. R. in Brain Aging: Models, Methods, and Mechanisms (Ed. Riddle, D. R.) (CRC Press/Taylor & Francis, 2007).

  22. Sonnen, J. A. et al. Ecology of the aging human brain. Arch. Neurol. 68, 1049–1056 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Besser, L. M. et al. The revised national Alzheimer’s Coordinating Center’s Neuropathology Form — available data and new analyses. J. Neuropathol. Exp. Neurol. 77, 717–726 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rapoport, S. I., Ohno, K. & Pettigrew, K. D. Blood–brain barrier permeability in senescent rats. J. Gerontol. 34, 162–169 (1979).

    Article  CAS  PubMed  Google Scholar 

  25. Erickson, M. A. & Banks, W. A. Age-associated changes in the immune system and blood–brain barrier functions. Int. J. Mol. Sci. 20, 1632 (2019).

  26. Erickson, M. A. & Banks, W. A. Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J. Cereb. Blood Flow. Metab. 33, 1500–1513 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vorbrodt, A. W. & Dobrogowska, D. H. Immunocytochemical evaluation of blood–brain barrier to endogenous albumin in adult, newborn, and aged mice. Folia Histochem. Cytobiol. 32, 63–70 (1994).

    CAS  PubMed  Google Scholar 

  28. Saunders, N. R., Dziegielewska, K. M., Mollgard, K. & Habgood, M. D. Markers for blood–brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? Front. Neurosci. 9, 1–15 (2015).

    Google Scholar 

  29. Garg, A. & Balthasar, J. P. Investigation of the influence of FcRn on the distribution of IgG to the brain. AAPS J. 11, 553–557 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Parrado-Fernandez, C. et al. Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers. J. Cell. Mol. Med. 22, 5151–5154 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen, R. L. Is it appropriate to use albumin CSF/plasma ratio to assess blood brain barrier permeability? Neurobiol. Aging 32, 1338–1339 (2011).

    Article  PubMed  Google Scholar 

  32. Elahy, M. et al. Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immun. Ageing 12, 2 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Zhao, L. et al. Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain. Nat. Commun. 11, 4413 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Yang, A. C. et al. Physiological blood–brain transport is impaired with age by a shift in transcytosis. Nature 583, 425–430 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ivanov, A. I. Pharmacological inhibition of endocytic pathways: is it specific enough to be useful? Methods Mol. Biol. 440, 15–33 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Montagne, A. et al. Blood–brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Verheggen, I. C. M. et al. Increase in blood–brain barrier leakage in healthy, older adults. Geroscience 42, 1183–1193 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Verheggen, I. C. M. et al. Imaging the role of blood-brain barrier disruption in normal cognitive ageing. Geroscience 42, 1751–1764 (2020).

  40. Varatharaj, A. et al. Blood–brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: a validation study. J. Physiol. 597, 699–709 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Moinuddin, A., Morley, J. E. & Banks, W. A. Regional variations in the transport of interleukin-1α across the blood–brain barrier in ICR and aging SAMP8 mice. Neuroimmunomodulation 8, 165–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Mooradian, A. D., Morin, A. M., Cipp, L. J. & Haspel, H. C. Glucose transport is reduced in the blood–brain barrier of aged rats. Brain Res. 551, 145–149 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Banks, W. A., Moinuddin, A. & Morley, J. E. Regional transport of TNF-α across the blood–brain barrier in young ICR and young and aged SAMP8 mice. Neurobiol. Aging 22, 671–676 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Banks, W. A. & Kastin, A. J. Aging and the blood–brain barrier: changes in the carrier-mediated transport of peptides in rats. Neurosci. Lett. 61, 171–175 (1985).

    Article  CAS  PubMed  Google Scholar 

  45. Daniel, P. M., Love, E. R. & Pratt, O. E. The effect of age upon the influx of glucose into the brain. J. Physiol. 274, 141–148 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mooradian, A. D. Blood–brain barrier choline transport is reduced in diabetic rats. Diabetes 36, 1094–1097 (1987).

    Article  CAS  PubMed  Google Scholar 

  47. Jaeger, L. B. et al. Testing the neurovascular hypothesis of Alzheimer’s disease: LRP-1 antisense reduces blood–brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition. J. Alzheimers Dis. 17, 553–570 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohata, M., Sundaram, U., Fredericks, W. R., London, E. D. & Rapoport, S. I. Regional cerebral blood flow during development and ageing of the rat brain. Brain 104, 319–332 (1981).

    Article  CAS  PubMed  Google Scholar 

  49. Ibáñez, V. et al. Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy. Brain Res. Bull. 63, 147–154 (2004).

    Article  PubMed  CAS  Google Scholar 

  50. Qato, D. M., Wilder, J., Schumm, L. P., Gillet, V. & Alexander, G. C. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern. Med. 176, 473–482 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  51. ElDesoky, E. S. Pharmacokinetic–pharmacodynamic crisis in the elderly. Am. J. Ther. 14, 488–498 (2007).

    Article  PubMed  Google Scholar 

  52. Jansen, P. A. & Brouwers, J. R. Clinical pharmacology in old persons. Scientifica (Cairo) 2012, 723678 (2012).

    Google Scholar 

  53. Toornvliet, R. et al. Effect of age on functional P-glycoprotein in the blood–brain barrier measured by use of (R)-[11C]verapamil and positron emission tomography. Clin. Pharmacol. Ther. 79, 540–548 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. van Assema, D. M. et al. P-glycoprotein function at the blood–brain barrier: effects of age and gender. Mol. Imaging Biol. 14, 771–776 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Pan, Y. & Nicolazzo, J. A. Impact of aging, Alzheimer’s disease and Parkinson’s disease on the blood–brain barrier transport of therapeutics. Adv. Drug Deliv. Rev. 135, 62–74 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Chiu, C. et al. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer’s disease: preliminary observations. Neurobiol. Aging 36, 2475–2482 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Yu, C. et al. Neuroinflammation activates Mdr1b efflux transport through NFκB: promoter analysis in BBB endothelia. Cell. Physiol. Biochem. 22, 745–756 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Salkeni, M. A., Lynch, J. L., Price, T. O. & Banks, W. A. Lipopolysaccharide impairs blood–brain barrier P-glycoprotein function in mice through prostaglandin- and nitric oxide-independent pathways and nitric oxide-independent pathways. J. Neuroimmune Pharmacol. 4, 276–282 (2009).

    Article  PubMed  Google Scholar 

  59. Pollak, T. A. et al. The blood–brain barrier in psychosis. Lancet Psychiatry 5, 79–92 (2018).

    Article  PubMed  Google Scholar 

  60. Xie, R., Hammarlund-Udenaes, M., de Boer, A. G. & de Lange, E. C. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (–/–) and mdr1a (+/+) mice. Br. J. Pharmacol. 128, 563–568 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Storck, S. E. et al. The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood–brain barrier is linked by PICALM. Brain Behav. Immun. 73, 21–33 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hartz, A. M., Miller, D. S. & Bauer, B. Restoring blood–brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease. Mol. Pharmacol. 77, 715–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pardridge, W. M. Drug transport across the blood–brain barrier. J. Cereb. Blood Flow. Metab. 32, 1959–1972 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cserr, H. F. & Knopf, P. M. Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view. Immunol. Today 13, 507–512 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Kida, S., Pantazis, A. & Weller, R. O. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19, 480–488 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Davson, H. & Segal, M. B. in Physiology of the CSF and Blood-Brain Barriers 489–523 (CRC Press, 1996).

  67. Cserr, H. F. in Hydrocephalus (eds K. Shapiro, A. Marmarou, & H. Portnoy) 59–68 (Raven Press, 1984).

  68. Cserr, H. F. & Berman, B. J. Iodide and thiocyanate efflux from brain following injection into rat caudate nucleus. Am. J. Physiol. 4, F331–F337 (1978).

    Google Scholar 

  69. Ray, L., Iliff, J. J. & Heys, J. J. Analysis of convective and diffusive transport in the brain interstitium. Fluids Barriers CNS 16, 6 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4, 147ra111 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wright, E. M. Transport processes in the formation of the cerebrospinal fluid. Rev. Physiol. Biochem. Pharmacol. 83, 1–34 (1978).

    CAS  Google Scholar 

  73. Johanson, C. E. in Neuromethods; The Neuronal Microenvironment (eds Boulton, A. A., Baker, G. B. & Walz, W.) 33–104 (The Humana Press, 1988).

  74. Ichimura, T., Fraser, P. A. & Cserr, H. F. Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res. 545, 103–113 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Preston, J. E. Aging choroid plexus–cerebrospinal fluid system. Microsc. Res. Tech. 52, 31–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Ma, Q., Ineichen, B. V., Detmar, M. & Proulx, S. T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun. 8, 1434 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Avolio, A. P. et al. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 68, 50–58 (1983).

    Article  CAS  PubMed  Google Scholar 

  80. Tsao, C. W. et al. Relations of arterial stiffness and endothelial function to brain aging in the community. Neurology 81, 984–991 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Lee, H. Y. & Oh, B. H. Aging and arterial stiffness. Circ. J. 74, 2257–2262 (2010).

    Article  PubMed  Google Scholar 

  82. Iliff, J. J. et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34, 16180–16193 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Palmer, A. L. & Ousman, S. S. Astrocytes and aging. Front. Aging Neurosci. 10, 337 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li, Y. et al. Aging neurovascular unit and potential role of DNA damage and repair in combating vascular and neurodegenerative disorders. Front. Neurosci. 13, 778 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kubotera, H. et al. Astrocytic endfeet re-cover blood vessels after removal by laser ablation. Sci. Rep. 9, 1263 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Alvarez, J. I. et al. The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Allahyari, R. V., Clark, K. L., Shepard, K. A. & Garcia, A. D. R. Sonic hedgehog signaling is negatively regulated in reactive astrocytes after forebrain stab injury. Sci. Rep. 9, 565 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Scheibel, A. & Fried, I. in Aging of the Brain Vol. 22 (eds Alger, D. et al.) (Raven Press, 1983).

  89. Jamieson, J. J., Linville, R. M., Ding, Y. Y., Gerecht, S. & Searson, P. C. Role of iPSC-derived pericytes on barrier function of iPSC-derived brain microvascular endothelial cells in 2D and 3D. Fluids Barriers CNS 16, 15 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Nikolakopoulou, A. M. et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat. Neurosci. 22, 1089–1098 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R. & Zlokovic, B. V. Blood–brain barrier: from physiology to disease and back. Physiol. Rev. 99, 21–78 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Goodall, E. F. et al. Age-associated mRNA and miRNA expression changes in the blood–brain barrier. Int. J. Mol. Sci. 20, 3097 (2019).

  93. He, L. et al. Analysis of the brain mural cell transcriptome. Sci. Rep. 6, 35108 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fjorder, A. S. et al. Haploinsufficiency of ARHGAP42 is associated with hypertension. Eur. J. Hum. Genet. 27, 1296–1303 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Reed, M. J., Damodarasamy, M. & Banks, W. A. The extracellular matrix of the blood–brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease. Tissue Barriers 7, 1651157 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Xu, L., Nirwane, A. & Yao, Y. Basement membrane and blood–brain barrier. Stroke Vasc. Neurol. 4, 78–82 (2019).

    Article  PubMed  Google Scholar 

  97. Gastfriend, B. D., Palecek, S. P. & Shusta, E. V. Modeling the blood–brain barrier: beyond the endothelial cells. Curr. Opin. Biomed. Eng. 5, 6–12 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Liu, S., Agalliu, D., Yu, C. & Fisher, M. The role of pericytes in blood-brain barrier function and stroke. Curr. Pharm. Des. 18, 3653–3662 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Mitchell, G. F. et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 43, 1239–1245 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Rizzoni, D. et al. Vascular aging and disease of the small vessels. High. Blood Press. Cardiovasc. Prev. 26, 183–189 (2019).

    Article  PubMed  Google Scholar 

  101. Kurtz, A. & Oh, S. J. Age related changes of the extracellular matrix and stem cell maintenance. Prev. Med. 54, S50–S56 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Scioli, M. G., Bielli, A., Arcuri, G., Ferlosio, A. & Orlandi, A. Ageing and microvasculature. Vasc. Cell 6, 19 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Xi, Y. P., Nette, E. G., King, D. W. & Rosen, M. Age-related changes in normal human basement membrane. Mech. Ageing Dev. 19, 315–324 (1982).

    Article  CAS  PubMed  Google Scholar 

  104. Hawkes, C. A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).

    Article  PubMed  Google Scholar 

  105. Hawkes, C. A. et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-beta from the mouse brain. Aging Cell 12, 224–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Keable, A. et al. Deposition of amyloid beta in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim. Biophys. Acta 1862, 1037–1046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Uspenskaia, O., Liebetrau, M., Herms, J., Danek, A. & Hamann, G. F. Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci. 5, 37 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Vasudevan, A. et al. Basement membrane protein nidogen-1 shapes hippocampal synaptic plasticity and excitability. Hippocampus 20, 608–620 (2010).

    CAS  PubMed  Google Scholar 

  109. Candiello, J., Cole, G. J. & Halfter, W. Age-dependent changes in the structure, composition and biophysical properties of a human basement membrane. Matrix Biol. 29, 402–410 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Sykova, E., Mazel, T. & Simonova, Z. Diffusion constraints and neuron-glia interaction during aging. Exp. Gerontol. 33, 837–851 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Ceafalan, L. C. et al. Age-related ultrastructural changes of the basement membrane in the mouse blood–brain barrier. J. Cell. Mol. Med. 23, 819–827 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Kutuzov, N., Flyvbjerg, H. & Lauritzen, M. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood–brain barrier. Proc. Natl Acad. Sci. USA 115, E9429–e9438 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ando, Y. et al. Brain-specific ultrastructure of capillary endothelial glycocalyx and its possible contribution for blood brain barrier. Sci. Rep. 8, 17523 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Iozzo, R. V. & Schaefer, L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol. 42, 11–55 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wight, T. N. A role for proteoglycans in vascular disease. Matrix Biol. 71-72, 396–420 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A. & oude Egbrink, M. G. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 454, 345–359 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wight, T. N. Vessel proteoglycans and thrombogenesis. Prog. Hemost. Thromb. 5, 1–39 (1980).

    CAS  PubMed  Google Scholar 

  118. Gao, L. & Lipowsky, H. H. Composition of the endothelial glycocalyx and its relation to its thickness and diffusion of small solutes. Microvasc. Res. 80, 394–401 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Luft, J. H. Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed. Proc. 25, 1773–1783 (1966).

    CAS  PubMed  Google Scholar 

  120. McClatchey, P. M., Schafer, M., Hunter, K. S. & Reusch, J. E. The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature. Am. J. Physiol. Heart Circ. Physiol. 311, H168–H176 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Mulivor, A. W. & Lipowsky, H. H. Role of glycocalyx in leukocyte–endothelial cell adhesion. Am. J. Physiol. Heart Circ. Physiol. 283, H1282–H1291 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Yao, Y., Rabodzey, A. & Dewey, C. F. Jr. Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. Am. J. Physiol. Heart Circ. Physiol. 293, H1023–H1030 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Danielli, J. F. Capillary permeability and oedema in the perfused frog. J. Physiol. 98, 109–129 (1940).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Vink, H. & Duling, B. R. Capillary endothelial surface layer selectively reduces plasma solute distribution volume. Am. J. Physiol. Heart Circ. Physiol. 278, H285–H289 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Henry, C. B. & Duling, B. R. TNF-α increases entry of macromolecules into luminal endothelial cell glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 279, H2815–H2823 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Martens, R. J., Vink, H., van Oostenbrugge, R. J. & Staals, J. Sublingual microvascular glycocalyx dimensions in lacunar stroke patients. Cerebrovasc. Dis. 35, 451–454 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Hempel, C., Hyttel, P. & Kurtzhals, J. A. Endothelial glycocalyx on brain endothelial cells is lost in experimental cerebral malaria. J. Cereb. Blood Flow. Metab. 34, 1107–1110 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Haeren, R. H. et al. Assessment and imaging of the cerebrovascular glycocalyx. Curr. Neurovasc. Res. 13, 249–260 (2016).

    Article  PubMed  Google Scholar 

  129. Yoon, J. H., Lee, E. S. & Jeong, Y. In vivo imaging of the cerebral endothelial glycocalyx in mice. J. Vasc. Res. 54, 59–67 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Zuurbier, C. J., Demirci, C., Koeman, A., Vink, H. & Ince, C. Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells. J. Appl. Physiol. 99, 1471–1476 (2005).

    Article  PubMed  Google Scholar 

  131. Nieuwdorp, M. et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55, 1127–1132 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Machin, D. R. et al. Advanced age results in a diminished endothelial glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 315, H531–H539 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Methia, N. et al. ApoE deficiency compromises the blood brain barrier especially after injury. Mol. Med. 7, 810–815 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hafezi-Moghadam, A., Thomas, K. L. & Wagner, D. D. ApoE deficiency leads to a progressive age-dependent blood–brain barrier leakage. Am. J. Physiol. Cell Physiol. 292, C1256–C1262 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Donahue, J. E. & Johanson, C. E. Apolipoprotein E, amyloid-beta, and blood–brain barrier permeability in Alzheimer disease. J. Neuropathol. Exp. Neurol. 67, 261–270 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Kulminski, A. M. et al. Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan. PLoS Genet. 10, e1004141 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Halliday, M. R. et al. Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood–brain barrier breakdown. JAMA Neurol. 70, 1198–1200 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Montagne, A., Zhao, Z. & Zlokovic, B. V. Alzheimer’s disease: a matter of blood–brain barrier dysfunction? J. Exp. Med. 214, 3151–3169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G. & Michikawa, M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood–brain barrier model. J. Biol. Chem. 286, 17536–17542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Alata, W., Ye, Y., St-Amour, I., Vandal, M. & Calon, F. Human apolipoprotein E ε4 expression impairs cerebral vascularization and blood–brain barrier function in mice. J. Cereb. Blood Flow. Metab. 35, 86–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Johnson, L. A. et al. Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response. J. Cereb. Blood Flow. Metab. 39, 770–781 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Rhea, E. M., Torres, E. R. S., Raber, J. & Banks, W. A. Insulin BBB pharmacokinetics in young ApoE male and female transgenic mice. PLoS ONE 15, e0228455 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Yamazaki, Y. et al. ApoE (Apolipoprotein E) in brain pericytes regulates endothelial function in an isoform-dependent manner by modulating basement membrane components. Arterioscler. Thromb. Vasc. Biol. 40, 128–144 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Nahirney, P. C., Reeson, P. & Brown, C. E. Ultrastructural analysis of blood–brain barrier breakdown in the peri-infarct zone in young adult and aged mice. J. Cereb. Blood Flow. Metab. 36, 413–425 (2016).

    Article  PubMed  Google Scholar 

  146. Bors, L. et al. Age-dependent changes at the blood–brain barrier. A comparative structural and functional study in young adult and middle aged rats. Brain Res. Bull. 139, 269–277 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Zipser, B. D. et al. Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol. Aging 28, 977–986 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Zlokovic, B. V. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol. 70, 440–444 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Salloway, S. et al. Effect of APOE genotype on microvascular basement membrane in Alzheimer’s disease. J. Neurol. Sci. 203-204, 183–187 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Bachmeier, C. et al. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. Neuromolecular Med. 16, 686–696 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Deane, R. et al. ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J. Clin. Investig. 118, 4002–4013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vandal, M. et al. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J. Neurochem. 129, 516–526 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Tachibana, M., Yamazaki, Y., Liu, C. C., Bu, G. & Kanekiyo, T. Pericyte implantation in the brain enhances cerebral blood flow and reduces amyloid-beta pathology in amyloid model mice. Exp. Neurol. 300, 13–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  154. Paul, G. et al. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients. J. Clin. Investig. 125, 1339–1346 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Shimizu, F. et al. Pericyte-derived glial cell line-derived neurotrophic factor increase the expression of claudin-5 in the blood–brain barrier and the blood–nerve barrier. Neurochem. Res. 37, 401–409 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Salameh, T. S., Shah, G. N., Price, T. O., Hayden, M. R. & Banks, W. A. Blood–brain barrier disruption and neurovascular unit dysfunction in diabetic mice: protection with the mitochondrial carbonic anhydrase inhibitor topiramate. J. Pharmacol. Exp. Ther. 359, 452–459 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. May, J. M., Jayagopal, A., Qu, Z. C. & Parker, W. H. Ascorbic acid prevents high glucose-induced apoptosis in human brain pericytes. Biochem. Biophys. Res. Commun. 452, 112–117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Soto, I. et al. APOE stabilization by exercise prevents aging neurovascular dysfunction and complement induction. PLoS Biol. 13, e1002279 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Latimer, C. S. et al. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice. PLoS ONE 6, e26812 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bok, E. et al. Dietary restriction and neuroinflammation: a potential mechanistic link. Int. J. Mol. Sci. 20, 464 (2019).

  161. McCullough, M. J., Gyorkos, A. M. & Spitsbergen, J. M. Short-term exercise increases GDNF protein levels in the spinal cord of young and old rats. Neuroscience 240, 258–268 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Belaya, I. et al. Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease. J. Neuroinflammation 17, 271 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lundquist, A. J., Parizher, J., Petzinger, G. M. & Jakowec, M. W. Exercise induces region-specific remodeling of astrocyte morphology and reactive astrocyte gene expression patterns in male mice. J. Neurosci. Res. 97, 1081–1094 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Berthiaume, A. A., Hartmann, D. A., Majesky, M. W., Bhat, N. R. & Shih, A. Y. Pericyte structural remodeling in cerebrovascular health and homeostasis. Front. Aging Neurosci. 10, 210 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Rhea, E. M., Raber, J. & Banks, W. A. ApoE and cerebral insulin: trafficking, receptors, and resistance. Neurobiol. Dis. 137, 104755 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhao, N. et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron 96, 115–129 (2017).

    Google Scholar 

  167. Wilhelmus, M. M. et al. Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. J. Neurosci. 25, 3621–3627 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sweeney, M. D., Ayyadurai, S. & Zlokovic, B. V. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat. Neurosci. 19, 771–783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Blanchard, J. W. et al. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat. Med. 26, 952–963 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Department of Veterans Affairs and NIH R01 AG046619.

Author information

Authors and Affiliations

  1. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA

    William A. Banks, May J. Reed, Aric F. Logsdon, Elizabeth M. Rhea & Michelle A. Erickson

  2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    William A. Banks, May J. Reed, Aric F. Logsdon, Elizabeth M. Rhea & Michelle A. Erickson

Authors
  1. William A. Banks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. May J. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aric F. Logsdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth M. Rhea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michelle A. Erickson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the ideas, literature reviews, and writing and editing of the manuscript.

Corresponding author

Correspondence to William A. Banks.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Aging thanks Jeffrey Iliff, Patric Turowski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Banks, W.A., Reed, M.J., Logsdon, A.F. et al. Healthy aging and the blood–brain barrier. Nat Aging 1, 243–254 (2021). https://doi.org/10.1038/s43587-021-00043-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43587-021-00043-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing