Transcriptional Landscape of Cellular Senescence in the Human Brain in Healthy Aging and in Neurodegenerative Diseases
Aging is the primary risk factor for neurodegenerative diseases such as Alzheimer’s disease and Frontotemporal dementia. Nevertheless, the biological processes associated with aging that are responsible for greater neurodegenerative disease risk in the human brain remain unknown.
Cellular senescence is a cell state characterized by replicative arrest accompanied by a distinctive proinflammatory secretory phenotype. Senescent cells accumulate in multiple body tissues with aging, have been found to actively drive naturally occurring age-related tissue deterioration and contribute to multiple aging-associated diseases. There is emerging evidence in animal models that timely targeted elimination of senescent cells can prevent neurodegenerative diseases and development of drugs that target and eliminate these deleterious senescent cells (‘senolytics’) is already underway. However, our limited knowledge regarding the role of senescent cells in human brain aging and neurodegenerative diseases is a key barrier to implementing this novel therapeutic strategy in humans. This project aims to address this critical knowledge gap. I will use state-of-the-art genomics techniques to characterize gene expression data from postmortem human tissue to address several fundamental questions in the field regarding the regional and cell-specific contributions of cellular senescence to neurodegenerative diseases. These insights may open the door for future effective treatments.