**Abstract**

Brain function is supported by the cerebrovascular system, and changes in vascular phenotype and function through aging process make the brain more susceptible to neurodegenerative diseases, particularly cognitive decline. Correspondingly, the incidence of dementia and the prevalence of neurodegenerative diseases have also increased. In aging, the vessels have been exposed to the inflammatory state by harmful factors referred to as the senescence-associated secretory phenotype (SASP). Aging is a complex process that is associated with accumulated cellular stresses and an increased stress response. The aging in the brain includes structural and functional changes, which cause brain pathologies in the elderly. Particularly, damaged neurovascular event can be a consequent trigger in the pathology of vascular cognitive impairment. This chapter introduces the current knowledge on cognitive decline according to cerebrovascular aging relevant to endothelial senescence and the changes in the SASPs.

**Keywords:** aging, cerebrovascular, cognitive impairment, senescence-associated secretory phenotype, endothelial cells

## **1. Introduction**

Aging is a complex process that is associated with an accumulation of the effects of cellular stresses and an increased stress response. The aging in the brain includes structural and functional changes, which together cause brain pathologies in the elderly. These changes are also thought to be critical risk factors in the development of cognitive disorders [1, 2]. It is well known that the cerebrovascular system supports brain function [3]. Vascular phenotypic and functional changes caused by aging make the brain more susceptible to neurodegenerative diseases, particularly to cognitive decline [4]. Dysregulation of cerebral blood flow (CBF) is one factor in the pathogenesis of vascular cognitive impairment (VCI) [5]. However, definition, diagnostic criteria, and treatments for VCI have not been firmly established. Thus, strategies in translational medicine and the clinical approach to VCI patients and the current aged society need to be established. This is because according to the World Alzheimer Report 2015, it was estimated that 46.8 million people worldwide suffer from dementia, and this number is expected to increase to 74.7 million by 2030 and 131.5 million by 2050 [6]. The report also stated that the incidence of dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), will increase by 45%. As a result of the increase in the size of the aging population, the incidence of dementia and the onset or prevalence of neurodegenerative diseases

are increasing. These diseases have become important social concerns and represent both a current and a future social and economic burden.

In the aging process, age-related cerebrovascular dysfunction results from multiple pathophysiological changes. The first of them is oxidative stress and inflammation. Excessive oxidative stress is well known to contribute to vascular aging in both animals [4, 7–10] and humans [11, 12]. It is an overproduction of reactive oxygen species (ROS) rather than accumulation of ROS. In cellular senescence, inflammatory mediators such as chemokines and cytokines are secreted in an autocrine or paracrine manner. This is often referred to as the senescence-associated secretory phenotype (SASP) [13–15]. The second is the narrowing of the vascular lumen caused by atherosclerotic plaques, which is referred to as atherosclerosis in large vessels or arteriosclerosis in small vessels [16–18]. Technically a further factor is endothelial cell senescence induced by the SASP in the aging process. This arises as a result of the action of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 [19]. Under aging, atherosclerotic plaques are prone to arise in the human aorta and coronary arteries, which contain senescent endothelial cells [20]. The senescent phenotypes of endothelial cells can be physiologically classified as having either an anti-inflammatory phenotype or a pro-inflammatory senescent phenotype [21]. Recently, numerous studies have focused on the status of the immune system during aging [22–24]. This chapter introduces the current knowledge about cognitive decline according to cerebrovascular aging relevant to cellular senescence and the changes in the SASPs. It also provides approaches on how senescent vessels exposed to the SASP enhance age-related cerebrovascular degeneration and vascular damage-derived cognitive impairment.
