Rejuvenating sleep to enhance brain resilience with age

Sleep is a critical behavioral state that fulfills essential needs for health, including clearing waste products (e.g., protein aggregates) from the brain. But sleep is not everlasting. As humans age, sleep quality strikingly deteriorates, and this decline is associated with dementias (e.g., Alzheimer’s disease). While the occurrence of sleep disruption during aging is well documented, a key question remains: can we manipulate sleep to improve brain resilience with age? I hypothesize that sleep is a key modulator of animal health that can be manipulated to rejuvenate brain function and improve brain resilience in the context of aging and Alzheimer’s 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) modulate 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 amyloid beta 1–42 overexpression. 

The age dependence of sleep deterioration and neurodegeneration is difficult to study due to the time-consuming challenge of aging vertebrates. To overcome this challenge, achieve my experimental Aims, and tackle this question, I will use the African killifish, a model with an extremely short lifespan of only 4-7 months. The killifish has conserved vertebrate brain structures and exhibits the hallmarks of aging, including progressive cognitive decline and neurodegeneration. It also possesses practical advantages such as low husbandry costs, a short generation time, and genetic tractability. These traits make the killifish a suitable model system to investigate how sleep is a key modulator of brain resilience with age. Findings from these experiments will change the way we think about