Concerted Enhancement Of Core And Output Rhythms To Promote Healthy Aging

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PROJECT SUMMARY / ABSTRACT During aging, the circadian clock and clock-controlled rhythms display attenuated oscillatory amplitude, concomitant with physiological and behavioral decline. The circadian dysregulation is more pronounced in Alzheimer's Disease (AD), where disrupted sleep and circadian cycles are increasingly appreciated as a potential disease-driving factor. Importantly, intervention studies support a positive modifiable function of the clock to promote healthy aging. We previously identified a natural compound Nobiletin (NOB) as a clock- enhancing molecule which activates the ROR nuclear receptors in the cellular oscillator to increase circadian amplitude, improve metabolic health and promote healthy aging. Likewise, several dietary interventions that prolong healthy lifespan and/or longevity, including caloric restriction and time-restricted feeding in the active phase (TRF), were also found to enhance circadian gene oscillation and output metabolism. Preliminary studies support beneficial roles of NOB and TRF against AD; however, their synergistic function and mechanism remain unknown. In the parent R01 grant (R01AG065984) entitled “Concerted enhancement of core and output rhythms to promote healthy aging”, we investigate a concerted function of NOB and TRF to strengthen the clock and delay peripheral age-related decline. The current administrative supplement proposal is in response to NOT-AG-20- 034. Building on our recent preliminary results showing beneficial effects of NOB to improve pathology and behavior in an AD mouse model, we hypothesize that TRF synergizes with NOB to coordinately activate circadian functions to decelerate AD-related decline. In Aim 1, we will determine the role of TRF.NOB against pathological and behavioral decline in APP/PS1 mice. In Aim 2, we will investigate circadian physiological cycles, and determine changes in circadian and AD gene expression in the hippocampus and the cortex. This project is well aligns with the parent project in experimental design and methodologies, and importantly will begin to address a key knowledge gap regarding a role of NOB and TRF against neurodegeneration in AD mice. The ultimate goal is to determine whether and how the clock can be activated by this powerful dual- modality intervention to delay AD progression. Based on our serial studies on NOB and the promising and readily translatable TRF strategy, these studies will reveal a candidate therapeutic strategy against AD pathology/behavior. The innovations include a conceptual paradigm of the NOB.TRF regimen for AD, and novel circadian mechanisms in key brain regions for AD gene expression. Given the pressing needs to counter the rapidly aging population, the 24/7 ad libitum lifestyle that disrupts natural circadian rhythms, and the imminent crisis of AD, such a versatile and feasible intervention will have an immediate and long-lasting impact on the quality of life in the elderly and AD patients.