Reviewing What is Known of the Biochemistry of Blood-Brain Barrier Dysfunction in Aging

Blood vessels passing through the central nervous system are sheathed by specialized cells that form the blood-brain barrier. The barrier controls the passage of cells and molecules into the brain. This protection is essential to the normal function of the brain, which operates in a biological environment that is very different to that of the result of the body. Unfortunately, and like all systems in the body, the blood-brain barrier deteriorates with age. This allows harmful molecules and cells to leak into the brain, provoking a damaging state of chronic inflammation in brain tissue. Inflammation is thought to be an important component of age-related neurodegenerative conditions, and to the degree that blood-brain barrier dysfunction contributes to the overall state of inflammation in brain tissue, it can be considered one of the important causes of neurodegeneration.

What to do about this problem? There is the question. The blood-brain barrier is a complex system, and thus its failure is also complex, when considered in detail. As is the case for much of aging, it is presently somewhere between challenging and impossible to accurately assess the relative importance of the many changes, failures, and forms of damage that can be measured in the cells of the blood-brain barrier. Even determining the direction of cause and effect for a few of these line items can be a hard task, an undertaking of years for teams of scientists. This is why the easier path to knowledge is to start with what is known of the root causes of aging, attempt to repair those causes one by one, and then observe the results on the dysfunction of critical biological systems such as the blood-brain barrier.

For example, senescent cells that accumulate in old tissues can now be cleared to a sizable degree via the application of senolytic therapies. Will this help to restore lost blood-brain barrier integrity? If so, it is then possible to look at specific differences before and after treatment in order to ask why this outcome the case. That may then inform researchers about the arrangement and relationships of blood-brain barrier pathologies in a more general sense. A working, narrowly focused rejuvenation therapy is the best of tools with which to explore the details of the aging process.

Blood-Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Blood vessels are essential to transport oxygen and nutrients, remove CO2 and other waste products, and, thus, maintain homeostasis in the body. Blood vessels that vascularize the central nervous system (CNS) acquire specific anatomical and functional characteristics that collectively form the blood-brain barrier (BBB). At the cellular level, the BBB is developed by continuous non-fenestrated endothelial cells (ECs) encompassed by pericytes, smooth muscle cells, astrocytes, microglia, oligodendroglia, and neurons that are altogether called the neurovascular unit (NVU). At the molecular level, the BBB ECs are compacted by claudins, occludins, and ZO-1 [tight junction (TJ) proteins] and junction adhesion molecule (JAM) proteins to restrict the paracellular and transcellular diffusion of molecules in the CNS.

In addition, the BBB ECs mediate influx transporters to select metabolite uptake from the blood and efflux transporters to remove toxins and waste products from the brain into the blood. In BBB ECs, leukocyte adhesion molecules (LAMs) express very low to suppress immune surveillance in the brain. Thus, the BBB confines the access of neurotoxic compounds, blood cells, and pathogens to the brain. In addition, the BBB sustains the homeostasis of the brain through tight regulation of the transport of molecules between the brain parenchyma and peripheral circulation.

Hence, the BBB is a fundamental and crucial element of normal and healthy brain function. Any impairment in the cellular or molecular components causes BBB breakdown that results in BBB dysfunction. Aging is one of several factors involved in the breaking of the BBB and was first observed in aged patients reported in the 1970s. In dysfunctional BBBs, the possibility of permeability increases; thus, toxic and blood-borne inflammatory substances that infiltrate the brain could change the biochemical microenvironment of the neurons, thus leading to neurodegenerative diseases and dementia. It has been reported that BBB disruption in aged people is strongly related to Alzheimer's disease (AD) and cognitive impairment.

Although researchers have reported the contributions of BBB disruption to the pathogenesis of cognitive impairment associated with normal aging and dementia, more research is needed to elucidate the precisely causing factors and the cellular and molecular mechanisms of BBB maintenance, breakdown, and repair correlated with neurodegeneration and cognition decline. In the future, how aging and dementia affect BBB function in health and disease state, thus leading to neurodegeneration and cognitive impairment, should be explored in living organisms. Clinical research pertaining to this will boost our knowledge and help us better understand the association between BBB breakdown and cognitive decline. Such studies pave the way for the use of the BBB as a novel biomarker and therapeutic target to treat dementia and other neurological diseases associated with cognitive impairment.

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