Fight Aging!

The hippocampus in the brain is vital to cognitive functions involving learning and memory. In today's open access paper, researchers review the evidence for the hippocampus to be particularly vulnerable to damaging mechanisms, including those involved in aging. It is tentatively suggested that physiological and biochemical differences in the hippocampus point to a greater fragility of the hippocampal blood-brain barrier as a common thread underlying pathological changes observed in aging and Alzheimer's disease. The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system. Its purpose is to restrict traffic of molecules and cells between the bloodstream and the brain, to maintain the brain's comparative isolation from much of the biochemistry of the rest of the body.

It is well established that the blood-brain barrier becomes dysfunctional in later life, as is the case for all other complex structures in the body. It leaks, allowing cells and molecules into the brain to cause local inflammatory reactions and other damage. The causes of this leakage are a complex web of interactions stretching from fundamental mechanisms of aging through changes in gene expression and altered cell behavior. As for the rest of aging, there is no good map to link what is known of the root causes of aging to what is known of the way in which cells in the blood-brain barrier become dysfunctional. This is why many in the community argue for a greater focus on addressing the root causes rather than on continued efforts to understand how exactly those root causes produce degenerative aging, in detail. If so much time and funding is going to be expended on the problem of aging, let it be on projects that have the hope of producing rejuvenation therapies rather than merely greater understanding.

Vulnerability of the Hippocampus to Insults: Links to Blood-Brain Barrier Dysfunction

The hippocampus, a medial temporal lobe structure that is a critical substrate (i.e., central nervous system component) that underlies learning and memory functions, can be adversely affected by a wide range of pathogens, neurotoxins, diseases, injuries, and environmental insults. It has often been suggested that the harmful effects of these insults may be greater on the hippocampus compared to other brain areas. However, there has been no systematic examination of this claim. An important reason to conduct this examination is that Alzheimer's disease and the severe dementia it causes are characterized by extensive hippocampal pathophysiology. It may be that insults that impair hippocampal functioning earlier in life may accelerate the emergence of more extensive hippocampal pathologies that could increase the risk of serious late-life cognitive decline.

One purpose of this review is to assess the vulnerability of the hippocampus to the most prevalent types of insults in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired brain injury, mental health conditions, endocrine disorders, developmental disabilities, nutrition) and to evaluate whether these insults affect the hippocampus first and more prominently compared to other brain loci. A second purpose is to consider the role of hippocampal blood-brain barrier (BBB) breakdown in either causing or worsening the harmful effects of each insult. Recent research suggests that the hippocampal BBB is more fragile compared to other brain areas and may also be more prone to the disruption of the transport mechanisms that act to maintain the internal milieu. Moreover, a compromised BBB could be a factor that is common to many different types of insults.

Our analysis indicates that the hippocampus is more vulnerable to insults compared to other parts of the brain. Our findings also indicate that hippocampal vulnerability to many of these insults is accompanied by a loss of BBB integrity in this region. For some of these insults, there was evidence that weakening of the hippocampal BBB occurred before and was more pronounced compared to the BBBs of other brain areas. These conclusions are limited, especially when considering the hippocampal BBB, by a lack of relevant data or by equivocal findings, with respect to the effects of some insults. In addition to the need to more rigorously test the notion of unique hippocampal vulnerability, we conclude that addressing the questions of how the protections afforded by the hippocampal BBB are compromised and how that weakening impairs hippocampal functioning are research goals of major significance, given the wide range of insults to which the hippocampus is vulnerable.