Aging of immune system function, or immunosenescence, is poorly understood but is thought to underlie increased susceptibility to infection of the elderly. A major hallmark of immunosenescence is dysfunction of macrophages, a type of immune blood cell. Macrophages in elderly people exhibit decreased number and phagocytic activity (the ingestion of microbes), as well as abnormal inflammatory responses, which impact inflammatory pathologies of aging. The cause(s) of macrophage senescence remains unknown. Another classic sign of aging in animals from flies to humans is loss of circadian regulation. This proposal tests the hypothesis that aging causes defects in the circadian clock located in immune blood cells, which in turn causes defects in their cellular function and contributes to increased susceptibility to infection. We developed a model system to study circadian regulation of primitive macrophages in Drosophila, using genetic and immunological tools unavailable in other systems. We found that immunity against infection is circadian- regulated. Specifically, phagocytosis by macrophages (or phagocytes) is circadian-regulated and this circadian regulation has significant effects on survival of infection. Our current data show that aging of Drosophila causes dramatic susceptibility to infection-specifically, old flies lose circadian regulation of phagocytosis. Because we and others find that the clock in phagocytes regulates their function, these data suggest a model: aging causes circadian dysregulation in phagocytes, which causes defects in phagocytosis and increased susceptibility to infection. To test this model, we will: 1. Test the hypothesis that the clock in phagocytes undergoes aging-related senescence and identify the underlying molecular mechanism. 2. Determine the effect of the aging phagocyte clock on gene expression and cellular function. 3. Investigate the causal relationships between circadian healthspan, immunosenescence, and lifespan. Thus the proposed experiments will analyze the aging of circadian regulation of immune system function on molecular, cellular, and organismal levels. Phagocytosis is an ancient and crucial part of every animal's innate immune system, including humans. Because of the high evolutionary conservation of both innate immunity and circadian biology, defining these molecular mechanisms in Drosophila will provide insight into ways to ameliorate or prevent aging of human innate immune system function.
Two major hallmarks of aging are loss of circadian regulation and increased susceptibility to infection;both hallmarks are observed in aging Drosophila, a genetically tractable model organism ideal for study of evolutionarily conserved physiologies such as circadian regulation, innate immunity, and aging. We found that aging is associated with loss of a specific immune mechanism: circadian-regulated phagocytosis by immune blood cells, or phagocytes. This proposal investigates molecular mechanisms of aging of the circadian clock in phagocytes and the impact on cellular function, the organism's immunity, and its lifespan.
|O'Connor, Reed M; Stone, Elizabeth F; Wayne, Charlotte R et al. (2017) A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells. J Cell Biol 216:595-605|
|Zhuravlev, Yelena; Hirsch, Sophia M; Jordan, Shawn N et al. (2017) CYK-4 regulates Rac, but not Rho, during cytokinesis. Mol Biol Cell 28:1258-1270|
|Sundaramoorthy, Sriramkumar; Garcia Badaracco, Adrian; Hirsch, Sophia M et al. (2017) Low Efficiency Upconversion Nanoparticles for High-Resolution Coalignment of Near-Infrared and Visible Light Paths on a Light Microscope. ACS Appl Mater Interfaces 9:7929-7940|
|Ulgherait, Matt; Chen, Anna; Oliva, Miles K et al. (2016) Dietary Restriction Extends the Lifespan of Circadian Mutants tim and per. Cell Metab 24:763-764|
|Allen, Victoria W; O'Connor, Reed M; Ulgherait, Matthew et al. (2016) period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection. Curr Biol 26:184-94|
|Jordan, Shawn N; Davies, Tim; Zhuravlev, Yelena et al. (2016) Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division. J Cell Biol 212:39-49|
|Marcinkevicius, Emily V; Shirasu-Hiza, Mimi M (2015) Message in a biota: gut microbes signal to the circadian clock. Cell Host Microbe 17:541-3|