Translational analysis of cerebrovascular dysfunction in aging

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ABSTRACT Age-related vascular cognitive impairment (VCI) and gait abnormalities are the two most common causes of disability in older adults that lead to loss of independence and severely reduce quality of life. Recent studies have concluded that cerebromicrovascular pathologies play an important role in the manifestation of VCI and gait abnormalities. One of the fundamental roles of the cerebrovasculature is to match cerebral blood flow (CBF) with energetic demands of neurons through a process known as neurovascular coupling (NVC). NVC maintains an optimal cerebral tissue microenvironment and requires microvascular dilation induced by nitric oxide (NO) released from cerebromicrovascular endothelial cells (CMVECs) in response to neuronal/astrocytic activation. Recent studies demonstrate that inhibition of NO-mediated NVC responses in mice results in impaired cognitive performance and gait abnormalities. Importantly, one of the factors that regulates NVC and cognition in animal models is the vasoprotective hormone insulin-like growth factor-1 (IGF-1) that has been shown to decrease with age and influences many cell-types in brain. Recent findings suggest that age-related decline of circulating IGF- 1 promotes stress and DNA damage and is associated with increased expression of markers of cellular senescence in brain and aorta. Despite recent advances, there is a critical gap in our understanding related to specific molecular mechanisms that promote cerebromicrovascular endothelial dysfunction in aging, and whether the age-dependent deficiency of circulating IGF-1 is associated with impairments in NVC and higher brain functions (including cognition and gait) in humans. Our overall hypothesis is that age-associated IGF-1 deficiency promotes endothelial dysfunction and impairments in NVC by inducing endothelial cell senescence, which contribute to cognitive impairment and gait abnormalities in older animals and humans. The following aims are proposed: Aim 1) Assess whether dysfunction of NVC is mediated through a specific effect of IGF-1 deficiency on CMVECs and whether endothelial cell senescence contributes to this impairment. In this aim we will use novel model ofdisruption of IGF-1 signaling specifically in endothelial cells and a novel mouse model (p16-3MR) which allows to specifically eliminate senescent cells. Aim 2) Determine the relationship between age, circulating IGF-1 status, endothelial function, NVC responses, cognition and gait in human subjects.