Abstract

Aging affects all of us. Among all the organs, brain aging is particularly challenging. This is because of the lack of options in tissue transplant and the unique biology and susceptibility of the brain to aging. Most neurons are born during development and must maintain their function throughout life. The brain aging effects ultimately lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Understanding the fundamental mechanisms in brain aging can be an important way to approach the root cause of multiple degenerative diseases. We propose leveraging our recently developed genomic technologies to tackle this question and to elucidate the molecular logic of brain aging with scalability. We will establish a technology based on the CRISPR-Cas9 gene-editing system to modulate cellular features in targeted ways in living brains. We will then use single-cell RNA sequencing to read out the consequences in distinct cell types. Overall, the proposed work will offer a new technology to dissect the molecular mechanisms of aging in living, intact tissues and to uncover the functional consequences and cell-type specificity of brain aging.