Uncovering the effects of exercise on senescence in brain aging
Description: Given the growing aging population and increasing prevalence of age-related cognitive impairment (CI), there is a critical need to identify novel strategies for prevention and intervention. CI may be driven in part by cellular senescence, specifically within microglia. Physical exercise protects against aging and age-related CI but the mechanisms underlying these benefits remain poorly characterized. One mechanism involves the production of exerkines, signaling molecules released during exercise. Exerkines exert paracrine and endocrine effects, influencing signaling pathways within a tissue or across organ systems. Emerging evidence also indicates exerkines may mitigate the effects of senescence. However, the origins and mechanisms of exerkines, as well as their role in microglial-specific senescence and CI, remain significant gaps in knowledge. This project will assess exerkines derived from multiple tissues, relate their expression to CI, and explore their roles as novel mediators of microglial senescence in the brain. Our central hypothesis is that exerkines reduce microglial senescence and improve cognitive function in aging brain. Our long-term goal is to identify novel therapeutic targets that enable prevention and treatment of age-related CI. Our rationale is that defining exerkines linked to reduced microglial senescence and improved cognitive function will inform the development of translatable therapies for the aging population. In Aim 1, we will exercise young and old mice and characterize cognitive function and physical fitness, assess markers of neurogenesis and microglial senescence, relate exerkine expression to learning and memory, and evaluate the effects of candidate exerkines associated with CI on senescent microglia in vitro. In Aim 2, I will use old p21-dTomato reporter mice and assess the impact of exercise on senescent cell accumulation in the brain, characterize exercise-specific effects on senescence and exerkine expression and identify the most affected cell types via single-cell RNA-seq (scRNA-seq), and compare scRNA-seq senescence and exerkine expression patterns to human brain aging datasets. Overall, this study will have a significant impact by informing the use of healthy aging interventions (i.e., exercise) as preventative strategies against aging-related complications and support my goal of becoming an independent investigator studying brain health and CI linked to aging and age-related diseases, such as dementia.
Funder: American Heart Association
Amount: $150,000
Funding type: fellowship
Funder scheme: Ralph L. Sacco Scholars Postdoctoral Fellowship
Start date: 2026-07-01
End date: 2028-06-30
Investigators: Cali McEntee, Cali McEntee
Institution: The Regents of the University of Michigan
Funded outputs count: 0
Funder award ID: 26RSSPOST1643261
OpenAlex ID: G3240584128