DESCRIPTION (provided by applicant): Age-related decline in the physiological and cognitive functions in humans is of great concern to society and there is an urgent need to identify biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the circadian system is important for maintaining health during aging. The circadian system comprises of a central pacemaker regulating behavior and peripheral oscillators in most body organs that coordinate daily oscillations in gene expression, small metabolites, and tissue-specific physiological processes. Multiple observational studies in humans linked disruption of circadian clocks with accelerated aging symptoms, such as neurodegenerative diseases, but the underlying mechanisms are not understood. We recently reported that a mutation in one of the clock genes leads to premature aging and impaired neuronal homeostasis in the model organism Drosophila melanogaster. We also determined that the circadian mechanism decays in peripheral clocks of aging flies due to reduced expression of clock genes. Our preliminary data suggest that specific genetic interventions can improve molecular and behavioral rhythms in the aging organism. We hypothesize that increasing the strength of circadian peripheral clocks may retard aging and promote health span. We will test this hypothesis as a collaborative team between three labs with complementary expertise focusing on three aims: 1) Identify molecular causes of age- related decay of clock gene expression in different tissues; 2) Test whether improvement in clock genes oscillations avert functional decay in aging flies and extend health span and lifespan; and 3) Identify pathways controlled by peripheral clocks that mediate health span benefits in aging flies. Our results should yield critical information regarding functional links between strong peripheral circadian clocks and aging rate. Insights obtained from this in vivo research may have clinical relevance by uncovering novel ways to maintain optimal health during aging in humans by enhancement of the circadian systems.

Age-related decline in various life functions in humans is of great concern for society, and there is an urgent need to identify the biological mechanisms that support healthy aging and longevity. Our recent work suggests that the biological (circadian) clocks play important roles in maintaining health of the nervous system during aging. The proposed studies will uncover the molecular mechanisms that cause age related decay of circadian rhythms, such as sleep- activity cycles, and explore ways to rejuvenate circadian rhythms in aging individuals. Insights obtained from this work performed on a model organism may lead to novel ways of increasing healthspan in humans by enhancing the circadian system in aging individuals. DISCLAIMER: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.