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Principal Investigator: CATHERINE M KOTZ
Organization: MINNEAPOLIS VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <2-Phenyl-Benzopyrans><2-Phenyl-Chromenes><21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><Acute><Adult><Adult Human><Affect><Age><Aged 65 and Over><Aging><Automobile Driving><Bacterial Infections><Beds><Behavior><Body Tissues><Brain><Brain Nervous System><Cell Aging><Cell Body><Cell Senescence><Cells><Cellular Aging><Cellular Senescence><Chronic Disease><Chronic Illness><Clinical Trials><Cognition><Cognitive><Cognitive deficits><Communities><Community-Acquired Infections><Coronaviridae><Coronavirus><Dasatinib><Data><Degenerative Neurologic Disorders><Drugs><Elderly><Encephalon><Exposure to><Flavonoids><Fostering><Geroscience><Goals><Health><Health Care Systems><Healthcare Systems><Histopathology><House mice><Human><In Vitro><Individual><Infection><Inflammatory><Inflammatory Response><Knowledge><Laboratory mice><Link><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Mus musculus><NAC precursor><Natural Products><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Nutraceutical><Obese Mice><Obesity><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Patients><Pattern><Persons><Pharmaceutical Preparations><Physical Function><Physical activity><Physiologic><Physiological><Predisposition><Primary Parkinsonism><QOL><Quality of life><Quercetin><Replicative Senescence><Reproducibility><Research Resources><Resistance><Resources><Risk><Role><SNCA><SNCA protein><Specific qualifier value><Specified><Susceptibility><Testing><Tissues><Transgenic Model><Transmission><Trauma><Veterans><Viral Diseases><Virus Diseases><Vulnerable Populations><a-syn><a-synuclein><above age 65><adiposity><adulthood><advanced age><adverse consequence><adverse outcome><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated chronic condition><age associated chronic disease><age associated chronic disorder><age associated chronic health condition><age associated chronic illness><age associated disease><age associated disorder><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age of 65 years onward><age related><age related chronic condition><age related chronic disease><age related chronic disorder><age related chronic health condition><age related chronic illness><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><aged><aged 65 and greater><aged 65+><aged animal><aged animals><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><aged ≥65><ages><aging associated><aging associated mechanism><aging mechanism><aging pathway><aging population><aging related><aging related mechanism><alpha synuclein><alpha synuclein gene><alphaSP22><animal old age><asyn><bacteria infection><bacteria pathogen><bacterial disease><bacterial pathogen><biological mechanism of age><biological pathways of age><brain cell><build resilience><build resiliency><burn pit><cell age><cellular age><chronic disorder><cognitive ability><cognitive defects><corona virus><corpulence><current pandemic><cytokine release syndrome><cytokine storm><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><develop resilience><develop resiliency><drivers of aging><driving><drug/agent><elderly animal><elderly mice><emerging pathogen><enhance resilience><enhance resiliency><experience><fisetin><frailty><fruits and vegetables><geriatric><germ free condition><gerodriver><geroscientific><high risk><human old age (65+)><improve resilience><improve resiliency><improved><in vivo><increase resilience><increase resiliency><infection risk><life span><lifespan><microbial><military service><military veteran><mortality><mouse model><murine model><mutant><naturally occurring product><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal degeneration><new pathogen><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><novel pathogen><ob/ob mouse><old age><old animals><old mice><over 65 years><pandemic><pandemic disease><pathogen><pathogen exposure><pathogenic bacteria><pathogenic virus><population aging><pre-clinical><preclinical><present pandemic><prevent><preventing><promote resilience><promote resiliency><resilience><resilience development><resilient><resistant><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senior citizen><senolytics><social role><specific pathogen free><stressor><synucleinopathy><therapeutic target><transgenic trait><transmission process><veteran population><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people><α synuclein gene><α-syn><α-synuclein><≥65 years>