Investigating the impact of peripheral senescent cells on the brain

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Abstract Ever since the discovery of the senescence-associated secretory phenotype (SASP) having potent autocrine and paracrine signaling effects, together with the demonstration of beneficial effects of reducing senescent cell burden in progeroid and chronologically aged mice, the role of senescent cells in the pathogenesis of many age-related chronic disorders has been extensively studied. As a result, it has now been established that senescent cells accumulate in tissues by promoting local inflammation, tissue aging and destruction, stem and progenitor cell dysfunction, and the spread of senescence to non-senescent cells. More recently, the detrimental effects of senescent glial cells, senescent brain ependymal cells, and senescent oligodendrocyte progenitor cells in various kinds of neurological disorders have attracted significant interest. However, neither of these studies discerns the effects of peripheral vs. central senescent cells. Indeed the impact of peripheral senescent cells on healthy brain aging and age-related cognitive impairment remain unexplored yet. Existing evidence demonstrates that a high burden of senescent cells in peripheral tissues plays a possible causal role in the pathogenesis of multiple age-related chronic diseases, which is the leading predictive factor for developing cognitive deficits later. We speculate that peripheral senescent cells link chronic diseases, brain aging, and cognitive impairment. Thus, we hypothesize that high senescent cell burden in peripheral tissues contributes to or accelerates age-related pathological changes in the hippocampus, predisposing the brain to cognitive dysfunction. We will use three different senescence-associated models to test our hypothesis. Aim1 is to test if increased peripheral senescent cell burden contributes to age-dependent cognitive deficits in chronologically aged mice. Aim2 is to test if obesity-driven peripheral senescent cells contribute to neuropsychiatric dysfunction and cognitive deficits. Aim3 is to test if peripheral senescent cells accelerate age-dependent neuropathological processes and cognitive deficits in Alzheimer’s disease model mice. We will apply our recently developed cell transplantation model to test whether peripherally transplanted senescent cells directly cause or exacerbate the cognitive decline in the context of aging, obesity, and Alzheimer’s diseases. To further investigate the possible mechanisms of how peripheral senescent cells affect brain microenvironments, we will examine cellular and molecular changes in the hippocampus resulting from high periphery senescent cell burden using the newly developed mass cytometry (CyTOF) approach and other complement methods. Overall, our studies will answer a critical question of whether reducing peripheral senescent cell burden is necessary for treating age- and disease-related neurological disorders and neurodegenerative diseases.