Molecular Regulation of Stem Cell Aging

SUMMARY The overall goal of this project is to identify functional metabolic changes in adult neural stem cells during aging, with the objective of `reprogramming' chromatin and transcriptional states in old stem cells and rejuvenate their function. The adult brain contains regenerative neurogenic niches that comprise neural stem cells (NSCs). NSCs can give rise to new neurons, astrocytes, and oligodendrocytes and contribute to aspects of learning and memory as well as injury repair. During aging, the ability of NSCs to generate new neurons decline dramatically. Interestingly, neurogenic decline can be reversed at least in part by `rejuvenating interventions' (e.g. diet and exercise), raising the exciting possibility that specific mechanisms can boost regenerative niches to counter aging. While some mechanisms underlying NSC decline have been identified, a systematic characterization of the program that regulate regenerative neurogenic regions during aging has been elusive. Identifying how metabolic changes impacts neurogenic niche aging and how metabolic interventions `reprogram' chromatin and transcriptional states will be critical to design efficient molecular strategies to slow the functional deterioration of regenerative niches and enhance the repair potential of the nervous system during aging. We have recently performed large scale CRISPR-Cas9 functional screens in vitro and in vivo in old NSCs, which unbiasedly identified glucose metabolism as a critical way to boost old NSC function during aging. In parallel, our lab has embarked on a systematic effort to identify the reversible changes in the epigenome, transcriptome and metabolome in neurogenic regions during aging, at both single cell and spatial resolution. Our central hypothesis is that boosting the metabolic states of old NSCs could reprogram chromatin and transcriptional states to rejuvenate the function of old neurogenic region. We propose the following experiments: 1. To identify the mechanisms by which manipulating glucose metabolism boosts old neural stem cells by impacting their chromatin and transcriptional states in collaboration with Project 1, Core B, and Core C; 2. To use `aging clocks' based on single cell RNA-seq to test in a scalable manner the impact of metabolic interventions on specific cell types in old stem cell niches in synergy with Projects 1 and 3 and Core C; 3. To examine the spatial relationship between metabolic and chromatin/transcription states in cells from the neurogenic niche in young, old, and rejuvenated individuals in collaboration with Core B. This project has major implications for countering brain aging and diseases such as Alzheimer's disease.