Age-Dependent Accumulation of Senescent Cells and Their Impact on Cerebralvascular Health and Cognition

• Main Author: DelFavero, Jordan Elizabeth
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2022
• Subjects: Aging; Gerontology; Neurosciences; Physiology
• ISBN: 9798368477206

Vascular cognitive impairment and dementia (VCID) continues to burden our rapidly growing elderly community. Despite efforts studying neuronal causes dementia, there is no effective treatment. Shifting our focus to the historically neglected role of the biology of aging in dementia may unveil novel mechanisms of dementia. Senescence is a major contributor to age-related pathologies and recent studies demonstrate that selective removal of senescence cells prevent/delay the development of age-related diseases. We hypothesized that accumulation of senescence cells in the brain play a role in vascular cognitive impairment and dementia. Using P16-3MR mice we can visualize and selectively eliminate senescent cells. The age-dependent timeline of senescent cell accumulation in the brain was determined with flow cytometry and revealed that cerebral endothelial cells withstand a high burden of senescence. In parallel, the age-dependent timeline of cognitive decline was established with a comprehensive battery of behavioral assays. Structural changes to the cerebral vasculature were determined with in-vivo, longitudinal optical coherence tomography through a chronic cranial window. We found that aging causes a reduction of cerebrovascular vessel density (microvascular rarefaction), which we restored with senescent cell elimination. Physiological changes to the cerebral vasculature were identified via in-vivo, longitudinal multiphoton measurements of blood brain barrier permeability, and neurovascular coupling measurements. Similarly, we found that the aging induced permeability of the blood brain barrier is ameliorated after removing senescent cells. Neurovascular coupling is also improved upon eliminating senescent cells. Here we show that senescent cells contribute to microvascular rarefaction, blood brain barrier permeability, neurovascular uncoupling, and cognitive decline. These data demonstrate the integral role of senescence cell accumulation in the development of VCID.