Chronic sleep disruption is a stressor for healthspan and lifespan - Project Summary. All animals, including humans, require sleep. Sleep deprivation or sleep disruption is a potent stressor. In animals, complete sleep deprivation for just a few days can be lethal. In humans, chronic sleep disruption (CSD) is associated with an increased risk of age-related diseases. CSD is more prevalent among working adults with irregular work schedules, and individuals of lower socioeconomic status (SES) are more likely to work outside regular daytime hours. Therefore, the health consequences of CSD can contribute to health disparities. However, chronic sleep disruption in humans also inadvertently leads to several lifestyle changes, including increased consumption of energy-dense diets, which are themselves associated with a higher risk of age-related diseases. Furthermore, some evidence suggests that CSD may elicit counter-regulatory mechanisms that attenuate its adverse effects. Consequently, it remains unknown whether CSD interacts with the biological mechanisms of aging to increase the risk of age-related diseases. Understanding the link between CSD and these biological mechanisms will reveal whether it contributes to reduced health span and lifespan associated with health disparities. Rodent models of acute sleep disruption lasting up to a few days replicate several key findings from comparable sleep disruption in humans under controlled conditions. However, after a few days of recovery sleep, these phenotypes revert to normal. Therefore, studies of longer-term chronic sleep disruption (CSD), different doses of CSD, sex-specific effects of CSD, and whether it affects disease-free lifespan (health span) or total lifespan are needed. Advances in the mechanisms of aging, leading to their synthesis into the hallmarks of aging, offer a mechanistic framework to evaluate whether long-term CSD affects one or more of these hallmarks. To circumvent the technical challenges of longer-term CSD in mice, this proposal will use a validated method of automated, programmable, gentle tactile perturbation of resting animals to deliver different levels of sleep disruption in adult male and female mice. In Specific Aim 1 (R61 phase), adult mice will be subjected to increasing doses of CSD for several weeks. A multidisciplinary team with complementary and project-relevant expertise will systematically assess the impact of CSD on specific hallmarks of aging in selected tissues and cell types to identify how different doses of CSD impact these hallmarks. Next, in Aim 2 (R33 phase), adult mice will be subjected to a selected dose of CSD for one year. Various validated markers of health and disease will be systematically evaluated at periodic intervals. Lifespan and cause of death will be determined in CSD and control mice. Completion of these experiments will offer a comprehensive framework of how CSD intersects with biological mechanisms of aging and can potentially offer testable hypotheses on which pro-longevity interventions can attenuate the adverse effects of CSD and thereby reduce health disparities.
