Risk Factors: Aging

Introduction

Aging is the primary, nonmodifiable risk factor for cerebrovascular disease (CVD). Two of the most detrimental diseases related to aged cerebrovascular dysfunction are stroke and vascular dementia. Aging is associated with changes to the immune system, neural networks, and vascular regulation. Vascular compliance is impaired with aging, which may contribute to vascular dementia. Aging can produce numerous detrimental outcomes to multiple organ systems. Damaged organs can release a host of inflammatory factors that compromise the cerebrovasculature. Comorbid diseases associated with peripheral organ dysfunction enhance the inflammatory response to brain damage. The risk of functional and cognitive deficits due to cerebrovascular inflammation complicates outcome in CVD. In essence, the age-related comorbidities can both increase susceptibility to CVD and worsen patient outcome.

Both stroke and vascular dementia limit the brain’s blood supply. The brain requires 20% of the body’s consumed energy resources, which are distributed by normal vascular perfusion. Age-related complications include atherosclerosis (AS), cerebral amyloid angiopathy, and small vessel disease. Age-related comorbidities, such as cardiovascular disease, respiratory obstructive disease, and diabetes mellitus type 2, also prevent the adequate distribution of nutrients and energy into the brain. These conditions are known to occlude vessels, disrupt vascular function, and can lead to acute areas of infarct. Most importantly, these problems reduce glucose distribution to the brain. Here, we discuss how aging is a risk factor for CVD. We examine how age-related complications disrupt vascular function and integrity, thereby increasing the risk of ischemic stroke and vascular dementia. We also highlight mechanistic changes caused by aging, and therapeutic options that may benefit the elderly clinical population.

Aged Blood–Brain Barrier and Neuroinflammation-aging

The blood–brain barrier (BBB) maintains an optimal cellular milieu for normal brain function. In the aged human brain, BBB integrity is not lost but becomes more susceptible to immune and inflammatory mediators. Challenges to the BBB may account, in part, for vascular dementia often observed in the elderly . The aged BBB is more permeable than a young BBB, due to changes in glial, mitochondrial, and tight junction protein function . Aging also damages astrocyte podocytes and the basement membrane that comprise the neurovascular unit. Neurotoxic proteins and peripheral immune cells, typically excluded from the brain, in the aged brain, can now enter the parenchyma when BBB integrity is compromised ( Fig. 33.1 ). These brain xenobiotics trigger neuroinflammatory cascades and generate reactive oxygen species, which both contribute to a basal level of inflammation and increased risk of neuronal cell death ( Fig. 33.1 ). As such, it has been reported that aged animals exhibit worsened outcomes following experimental brain injury. Therefore, therapeutics designed to improve outcomes associated with CVD should focus on maintaining BBB integrity in aged animal models.

Neuroinflammation and oxidative stress are both enhanced in the aged brain. The elderly possess a chronic low-grade level of inflammation within the brain, termed inflamm-aging . Not surprisingly, the aged rat also exhibits higher basal levels of circulating proinflammatory cytokines and other markers of oxidative stress. Not only does the aged brain have higher basal levels of inflammation, but it also loses its ability to cope with the challenges of vascular dysfunction and ischemic insults. The infiltration of toxic proteins and peripheral immune cells is exacerbated in the aged animal following neural injury possibly due to a loss in BBB integrity. The infiltrating peripheral immune cells release proinflammatory signals into the brain parenchyma ( Fig. 33.1 ). These warning signs can activate neighboring microglia, the brain’s immune cell. Once a certain threshold is attained, microglia can aberrantly release additional inflammatory signals that damage neighboring neurons.

Stroke

Atherosclerosis

Atherosclerosis (AS) is common among the elderly and is known to contribute to cerebral infarction and hemorrhage. Atherosclerotic plaques build up in blood vessels over time and eventually break off and occlude smaller vessels in the brain ( Fig. 33.2 ). Researchers are investigating how AS develops to reduce plaque development and possible occlusion. These occlusions restrict blood flow and oxygen delivery to important brain regions. The lack of oxygen and nutrient delivery can trigger many detrimental effects including leukocyte diapedesis, neuroinflammation, and ROS generation ( Fig. 33.2 ). These effects are toxic to neuronal cells and may contribute to CVD. A limitation in stroke research is that aged rodents are highly resistant to AS development due to their limited exposure to a typical high-fat human diet . This preclinical limitation makes it difficult to model human plaque development; however, new genetic manipulation techniques have enabled for better AS modeling.

Inflammation, oxidative stress, and immune cell accumulation are common factors that contribute to AS pathology in the brains of elderly patients . Hypertension is another common risk factor for the development of AS, and may play a crucial role in vessel wall damage. High blood pressure is a common symptom associated with AS and is known to contribute to BBB breakdown. BBB breakdown allows toxic proteins and peripheral immune cells to enter the brain parenchyma causing damage to neuronal cells ( Fig. 33.2 ). Overall, AS treatments remain limited; however, a better understanding of AS development has helped to establish lifestyle changes as the most effective preventative strategy.