Neural Stem Cell Aging and Neurodegeneration

Project Summary Perturbation of mitochondrial proteostasis, a form of mitochondrial stress, activates the mitochondrial unfolded protein response (UPRmt), a retrograde signaling pathway leading to transcriptional up-regulation of mitochondrial chaperones and stress relief. Recent advances in mitochondrial biology link UPRmt to lifespan extension independently of oxidative stress and damage in model organisms. These observations beg the questions of whether mitochondrial protein folding stress and the UPRmt regulate healthspan and lifespan in mammals. We have recently identified a novel regulatory branch of the UPRmt. We will elucidate the physiological significance of this pathway in regulating stem cell aging, tissue degeneration, and degenerative diseases, such as Alzheimer’s disease. Using a gain-of-function approach, we will test the feasibility of activating these molecules to extend healthspan during natural aging and ameliorate Alzheimer’s disease. Collectively, these studies highlight a novel defense program that improves mitochondrial integrity and tissue homeostasis. Successful completion of the proposed studies will provide a critical mechanistic understanding of how mitochondria and metabolism regulate tissue homeostasis. In addition to generating important basic knowledge, these studies will provide new targets for developing potential interventions for aging and aging- associated diseases, including Alzheimer’s disease.