Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Chronic diseases are a significant problem in aging population causing immense economic burden to healthcare systems around the world. Alzheimer’s disease (AD) is the most common form of dementia, affecting as many as 5.8 million Americans who are aged 65 and older and is the sixth leading cause of death in the United States. As age is the greatest risk factor in developing AD, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Calorie restriction (CR) can slow or prevent AD in animal models, but reduced calorie diets are notoriously difficult to sustain. In this proposal, I will examine if dietary regimens and drugs that mimic aspects of a traditional CR diet, but which are easier to adhere to, can slow or prevent the development and progression of AD. Studies from the Lamming lab and others have shown that protein restriction (PR) improves many aspects of metabolic health in both humans and mice, and extends mouse lifespan, likely in part through reducing the activity of the amino acid sensitive kinase mechanistic Target Of Rapamycin complex 1 (mTORC1), which is a key regulator of autophagy. In preliminary studies, I have found that PR reduces brain mTORC1 activity and activates autophagy, and slows or prevents cognitive decline and the progression of AD pathology in the 3xTg mouse model of AD. Our lab has shown that restriction of the branched chain amino acids (BCAAs; leucine, isoleucine, valine) recapitulates the metabolic benefits of PR and extends lifespan. Defects in BCAA catabolism, or excess dietary BCAAs, may drive the pathogenesis of AD by increasing BCAA levels in the brain, activating mTORC1, and inhibiting autophagy. However, the role of individual BCAAs in these effects are unknown. I will determine the effects of restricting protein or leucine, the essential amino acid that most strong agonizes mTORC1, on metabolic health, cognition, AD pathology, and autophagy in the APP/PS1 mouse model of AD, which develops cognitive deficits later in life than the 3xTg mice. I will also test if reducing levels of BCAAs via pharmacological stimulation of BCAA catabolism reduces brain levels of BCAAs, inhibiting brain mTORC1 signaling and boost autophagy, recapitulating the beneficial effects of restrictive diets. Finally, utilizing distinct feeding regimens I will determine if prolonged daily fasting, which CR animals are subjected to in laboratory experiments, can recapitulate the beneficial effects of a CR diet on the development and progression of AD. Together, these proposed aims will address long-standing questions about how dietary interventions can affect the development and progression of AD. I will be completing this fellowship under the mentorship of my sponsor, Dr. Dudley Lamming, an expert in aging biology, metabolism, and mTOR signaling, and my co-sponsor, Dr. Luigi Puglielli, a world-leading expert in Alzheimer’s disease. Completing these aims and the accompanying individualized training plan will help me develop the skills necessary to become a successful tenure track faculty member focused on the biology of aging and Alzheimer’s disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
