Investigating the role of sleep in brain resilience during aging using a scalable and short-lived vertebrate model

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Project Summary Sleep is a critical behavioral state that fulfills essential needs for health, including clearing waste products (e.g., amyloid beta [Aβ]) from the brain. As humans age, sleep quality strikingly deteriorates, and this decline correlates with increased risk for neurodegeneration, vascular dementia, and Alzheimer’s disease. While the occurrence of sleep disruption during aging is well documented, the causative impact of sleep on brain resilience with age and disease remains unexplored. I hypothesize that sleep is a key modulator of animal health that can be manipulated to improve brain resilience in the context of aging and disease. To investigate the impact of sleep on brain resilience late in life, I will (Aim 1) characterize if age-associated sleep deterioration (e.g., circadian timing and amount of sleep) impacts cognitive health, (Aim 2) perturb sleep and test the impact on cognitive resilience late in life, and (Aim 3) determine if sleep improves brain resilience in the context of human Aβ1-42 overexpression. The age dependence of sleep deterioration and neurodegeneration is difficult to study at scale due to the time-consuming challenge of aging vertebrates. To overcome this challenge and tackle this question, I will use the African killifish, a model with an extremely short lifespan of only 4-7 months. The killifish exhibits key hallmarks of human aging (e.g., neurodegeneration, frailty) and has conserved brain structures and genes known to regulate sleep. Critically, killifish brains exhibit increases in neurofibrillary degeneration, oxidative stress, gliosis, and inflammation, as well as decreases in repair, as they age. The killifish also possesses practical advantages such as low husbandry costs, a short generation time (<1 month), and genetic tractability. These traits make the killifish a suitable model system to investigate how sleep may impact brain resilience with age. In preliminary efforts, I built a longitudinal tracking system to generate an unprecedented view into how sleep changes across the lifespan, and I found that killifish exhibit an age-associated sleep decline that parallels human sleep decline. I also genetically perturbed sleep and identified novel lifespan-extending genes. I used my new CRISPR knockin method to develop the first killifish model for Alzheimer’s disease. Using these tools and discoveries, I will determine how sleep impacts brain resilience with age and disease. I am pursuing this project at Stanford University with training from my mentor Dr. Anne Brunet, co-mentor Dr. Karl Deisseroth, and an exceptional scientific advisory team whose expertise spans brain aging, Alzheimer’s disease, neurodegeneration, and sleep. Through continued training with the K99/R00 award, I will learn new methods (killifish genetics, intact whole-mount brain staining, and advanced transcriptomic/behavioral data analysis) and concepts (the biology of aging, Alzheimer’s disease, protein aggregation, neurodegeneration). This work, my career development, and my technical training will provide me with the skills and knowledge required to be a successful leader of a laboratory at a top academic institution.