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

> **NIH NIH K99** · STANFORD UNIVERSITY · 2023 · $128,331

## Abstract

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, neurodegenera...

## Key facts

- **NIH application ID:** 10740068
- **Project number:** 1K99AG076879-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ravi Nath
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $128,331
- **Award type:** 1
- **Project period:** 2023-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740068

## Citation

> US National Institutes of Health, RePORTER application 10740068, Investigating the role of sleep in brain resilience during aging using a scalable and short-lived vertebrate model (1K99AG076879-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10740068. Licensed CC0.

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