Access Type
Open Access Embargo
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
First Advisor
Dr. Marianna Sadagurski
Abstract
ABSTRACTEXPLORING CANAGLIFLOZIN, AN SGLT2i, AS A GEROTHERAPEUTIC FOR COGNITIVE DECLINE AND BRAIN AGING by HASHAN S.M. JAYARATHNE May 2025 Advisor: Dr. Marianna Sadagurski Major: Biological Sciences (Cellular, developmental & neurobiology) Degree: Doctor of Philosophy
Aging is a significant risk factor for chronic diseases, particularly neurodegenerative conditions such as Alzheimer’s disease (AD). Recent evidence suggests that pharmacological interventions targeting aging-related molecular pathways may delay disease progression and alleviate late-life illnesses. In this study, we examined the effects of Canagliflozin (Cana), an FDA-approved SGLT2 inhibitor, which extended the lifespan of genetically diverse male UM-HET3 mice by 14% without affecting female mice. Cana exhibited notable neuroprotective effects in Cana diet-fed males in both the hypothalamus and the hippocampus regions. Cana also improved locomotor activity and reduced anxiety-like behavior in aged nondiabetic males. In female mice, improvements were limited to decreased neuroinflammation in the hypothalamus. Additionally, Cana showed early and sustained benefits in body composition and energy metabolism in males, while females showed metabolic improvements later in life. Hypothalamic transcriptomic analysis indicated that Cana activated genes in a sex-specific fashion, with males displaying more pronounced beneficial metabolic alterations with age. Moreover, cognitive enhancements were also observed in middle-aged males on the Cana diet. Utilizing a multi-omics approach, we demonstrated that Cana promotes cognitive function and cellular metabolism by regulating key pathways at the transcriptomic and proteomic levels, including the negative regulation of β-amyloid formation. Our findings highlightCana's sex-specific and regional neuroprotective benefits, suggesting its potential as a therapeutic strategy for neurodegenerative diseases and advancing our understanding of gerotherapeutic approaches.
Recommended Citation
Jayarathne, Hashan Sri Madhubhashana, "Exploring Canagliflozin An Sglt2i As A Gerotherapeutic For Cognitive Decline And Brain Aging" (2025). Wayne State University Dissertations. 4256.
https://digitalcommons.wayne.edu/oa_dissertations/4256