Targeting Aging-Related Delays in Cognitive Recovery After Anesthesia by Attenuating Oxidative Stress: Implications for Alzheimer's Disease
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PROJECT SUMMARY The geriatric population is increasingly at risk for anesthetic complications, with postoperative delirium a common and disruptive outcome. Postoperative delirium impairs cognitive recovery, reduces quality of life, and disproportionately affects older adults and patients with Alzheimer’s disease. Despite the high prevalence of postoperative delirium, there are no targeted treatments to mitigate its effects, and the precise underlying mechanisms—especially those involving oxidative stress and aldehyde metabolism—remain poorly understood. Therefore, this basic science project will fill this critical knowledge gap by determining how aldehyde dehydrogenase 2 (ALDH2) is central to regulating oxidative stress during anesthesia, with a particular emphasis on the role of ALDH2 in the context of Alzheimer’s disease. The central hypothesis for this R03 proposal is that reduced ALDH2 activity associated with aging causes impaired handling of oxidative stress and leads to delayed neurologic recovery from anesthesia. By leveraging cutting-edge tools including a humanized ALDH2*2 mouse and a small-molecule ALDH2 activator, this research will elucidate the mechanism by which aging-related oxidative stress contributes to prolonged neurologic recovery after anesthesia, particularly in models with impaired ALDH2 activity and Alzheimer’s disease pathology. Aim 1 will show that anesthesia induces higher oxidative stress in aged ALDH2*2 and APOE4 mice. Aim 2 will determine if increasing ALDH2 activity during anesthesia in aged wild-type, ALDH2*2 and APOE4 mice will improve anesthetic neurocognitive recovery. Through comprehensive research training in geriatrics, neuroenergetics, and biochemical approaches, this project will serve as a foundation for aging-related anesthetic research and includes a comprehensive research training and professional development plan. This grant will be mentored under the guidance of Dr. Eric Gross, and my cross-disciplinary group of advisors including Drs. John Newman, Miles Berger, Daria Mochly-Rosen, and Charles Brown. This research proposal aligns closely with the mission of the National Institute on Aging by addressing a crucial issue related to understanding the aging process in the context of general anesthesia. This research holds the potential to shed light on new strategies for enhancing post-anesthetic neurologic recovery in vulnerable geriatric populations, especially in patients with Alzheimer’s disease, ultimately reducing the burden of post-operative delirium. By elucidating mechanisms and potential interventions, this study offers significant promise for improving perioperative neurologic outcomes in older adults, representing a high-value investment in the health-span and improved perioperative outcomes for the aging population.
