Fisetin as a treatment for community-acquired pathogen susceptibility during aging, obesity and neurodegenerative diseases

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Aging and the chronic diseases associated with aging, such as obesity and neurodegeneration, combined with military service (trauma, burn pit exposure etc.) make old age Veterans more vulnerable to community-acquired viral pathogens. This reduces quality of life for Veterans and places a tremendous burden on our healthcare system. As the Veteran population ages, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rational strategies for minimizing the vulnerability of aged Veterans to viral and bacterial pathogens. The Geroscience hypothesis posits that therapeutically targeting fundamental mechanisms of aging would yield a larger dividend in terms of improving the health of the aged population, than would treating individual age-related diseases, and would confer resistance against stressors such as viral infections. During aging, senescent cells accumulate and can prove toxic to many organismal functions. Elimination of senescent cells using senolytic drugs have already fostered clinical trials, and in mice, senolytics improve physical function, tissue health and suppress all-cause mortality. The current pandemic has identified those who are particularly vulnerable to adverse outcomes when exposed to a new pathogen, and community acquired viral infection has emerged as an urgent threat to our aged population, including Veterans. Little is known about the effects of community-acquired infections in vulnerable populations, including those with obesity and neurodegeneration. The goal of the present project is to determine if fisetin (a senolytic compound derived from fruits and vegetables) and other senolytics such as dasatinib and quercetin, can reduce morbidity and mortality in mice with obesity and mice with neurodegeneration, that are exposed to normal microbial experience (NME), as a model of community acquired viral infection. We will also use the knowledge and resources we have to study the role of cellular senescence in driving adverse outcomes in aged, obese and Parkinson's mouse models acutely exposed to NME. Preliminary data indicate that mice with a substantial senescent cell burden respond much worse to inflammatory challenges than mice without senescent cells. Furthermore, exposure to normal pathogens carried by wild or pet store mice is sufficient to kill old experimental mice housed in specified pathogen-free conditions, but it does not kill young mice. Here, we propose to use this experimental paradigm to determine if senolytics, drugs that specifically kill senescent cells, suppress mortality in NME exposed aged obese mice, and in a mouse model of Parkinson's disease. The immediate goal is to generate sufficient preclinical data to support clinical trials using nutraceuticals with senolytic activity to prevent adverse outcomes in Veterans at high risk of infection or grave illness after infection.