Elucidate the Molecular and Cellular Targets of Caloric Restriction in Rejuvenating Aged Mammalian Brain

2025 Seed Grant
Junyue Cao, Ph.D.
The Rockefeller University

As we age, the brain’s ability to function declines, increasing the risk of cognitive impairments and neurological diseases like Alzheimer’s and Parkinson’s. Our research investigates how caloric restriction (CR), a method of reducing food intake, promotes healthier brain aging in animals, potentially extending lifespan and improving brain function. Given the brain’s complexity, with hundreds of unique cell types, understanding CR’s effects is challenging. We are using advanced technologies, such as our newly developed IRISeq and EasySci platforms, to examine how CR impacts specific brain cells and regions in young and old mice. Our preliminary findings show that CR enhances the growth of new brain cells (neurogenesis), strengthens the protective coating around nerve fibers (myelination), and reduces “aging” genes linked to cellular senescence, particularly in areas like the ventricles and white matter. Our project has two goals: first, to map the effect of CR on over 300 brain cell types using EasySci to identify which cells benefit most; second, to explore whether CR counters brain aging by suppressing senescent cells, using drugs to remove them and analyzing the results with IRISeq and EasySci. We expect to confirm that CR rejuvenates the brain by targeting specific cells and reducing senescence, providing insights that could lead to new treatments mimicking CR’s benefits without dietary restrictions. These findings may help develop therapies to prevent or delay age-related cognitive decline and neurodegenerative disorders like Alzheimer’s and Parkinson’s, improving brain health in aging populations.

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