UPDATE ON THE ROAD TO THE CURE - AUGUST 2021Category:
ICBII UPDATE ON THE ROAD TO THE CURE
Ram S. Bhatt, PhD., Chief Science Officer
Effect of Aging on the Blood-Brain Barrier (BBB)
Advances in modern medicine, nutrition, hygiene, and safety standards have doubled the life expectancy of humans worldwide over the last century. It has been estimated that in the next 50 years, the elderly will comprise approximately 20% of the world population.
With the aging population living longer, age-associated neurological and neurodegenerative diseases have become a global epidemic and are especially debilitating to the afflicted and their families, creating tremendous emotional and socioeconomic conditions. The reason for the surge in neurodegenerative diseases is that the blood–brain barrier (BBB) that protected our central nervous system (CNS) from unregulated leakage of blood-borne materials such as viruses, bacteria, parasites, medicines, and cancer cells when we were young is no longer working optimally upon aging. 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.
Changes in Brain Barrier Function with Aging A challenge in the assessment of BBB dysfunction in healthy human aging is that many parameters can only be assessed in post-mortem tissues, and so it is difficult to distinguish changes at the BBB in humans that occur as a result of aging versus disease. However, measurements of BBB dysfunction in living human subjects using imaging techniques such as PET, SPECT, and MRI have become robust with advances in instrumentation and analysis techniques and have suggested that pathological changes at the BBB do occur progressively with aging and predict clinical symptoms such as cognitive impairment. Findings in rodent models also corroborate general aging-associated phenotypes of the BBB and have elucidated possible mechanisms by which BBB functions are altered with age. These details are further described below.
i. BBB Disruption Advanced imaging technologies that can visualize leakage of intravenously injected tracers such as gadolinium via dynamic contrast MRI have indicated that BBB disruption does occur in the aging human brain, albeit at low levels. Further evidence comes from animal studies.
In healthy aged mice (24 mo.), leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice (3 mo.), suggesting that there is BBB disruption in animals. Increased immunoglobulin (IgG) leakage in aged mice was associated with astrogliosis, which is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from CNS trauma. Increased levels of TNF-alpha have been detected in aged rodents that suggest inflammatory changes in these animals. Neuro-inflammation is implicated in numerous CNS diseases including Alzheimer’s and Parkinson’s.
ii. White Matter Loss the Effect of leaky BBB on white matter loss has been studied by comparative brain imaging of a younger (52 years old) participant and an older (83 years old) participant [Gero Science, 42, 1183 (2020)]. The authors observed significantly more loss of white matter in the brain region that controls cognition in 83 years old participant than the younger participant. This may explain why cognition declines with age.
The BBB in Age-Associated Neurological Diseases Aging increases the risk of developing disease, and many neurological conditions such as Alzheimer’s and Parkinson’s in which the BBB has been implicated are also associated with aging. Age-associated BBB dysfunction may predispose or exacerbate the molecular mechanisms of CNS diseases. Promoting neurovascular health and identification of methods to maintain BBB integrity could be a promising venue to promote healthy aging. Until such methods are identified all of us need to be diligent to rigorously adhere to cardiovascular exercise program that may help promote neurovascular health.
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