Accelerating maturation of 3D human brain organoid models to study human aging mechanisms.

Preclinical drug discovery studies for neurodegenerative diseases done in mice hold very low predictability for the success of such compounds in human clinical trials. These repeated failures highlight the need for better preclinical models, ideally on human-derived tissue models. In the few years since they were first described, brain organoids have already shown a remarkable ability to recapitulate aspects of human brain development and function, and to model various early childhood neurological and neuropsychiatric disorders. However, a major limitation of studying aging mechanisms in human brain organoids is that neurons remain at an immature state, resembling an equivalent of a human developing brain. I believe that a multidisciplinary effort, combining knowledge and expertise from the aging and brain development fields holds the potential to push brain organoids to a mature state that will enable to model human brain aging and neurodegenerative diseases. In this study I will use brain intrinsic and systemic regulators of aging discovered by our lab, and others, in an attempt to accelerate maturation of human-derived brain organoids. This has the potential to produce the first ever aged human brain 3D cultures and identify factors which accelerate brain aging. I will use this model to gain insights to mechanisms driving human brain aging and how to effectively target these processes for a variety of aging-related diseases.