ISS: Mechanisms of microgravity accelerated aging on human brain organoids

This project will study brain aging and inflammation in microgravity. Long-term space exposure creates a series of physiological alterations including cognitive decline. Studying astronauts' brains before and after their mission can tell what goes wrong but provides little insight on the mechanisms responsible for the observed alterations.

This, this project will grow stem cell-derived human brain tissues at the International Space Station to accelerate our understanding of the mechanisms involved in brain aging. These studies will have profound implications for improved neurological pre-clinical models for applications on Earth. Educational benefits from this investigation include incorporating the results into the training of graduate students and high school students.

The work will also be disseminated to the broader community through a video channel and podcast episodes.

Microgravity has been shown to evoke alterations in cell growth, differentiation, cell communication, aging, and epigenetic/gene expression alterations in various cell types, including brain cells. Preliminary data, from a previous spaceflight, showed exposure to microgravity induced a series of molecular changes that mimic aging in human cells. Such alterations might accelerate or enhance cellular (telomerase dynamics) and molecular processes (activation of endogenous retroelements) that are important for neurological disorders.

Here, this study will mechanistically investigate this aging phenotype on human brain organoids infused with microglia. First, the brain organoids will be optimized for spaceflight compatibility. Second, the impact of re-activation of endogenous retroelements will be characterized.

And third, brain organoids will be generated with inducible TERT and modulate their activity at different developmental stages to determine how telomerase activity affects the development of brain organoids. The proposed work will advance understanding of 3D brain organoids enabling improved models of neurological disorders that represent significant health burdens.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.