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The interplay between the immune system and metabolism as a key determinant of the aging process


What shapes the rate of aging of a given species or individual? Despite the recent advances in the field of biogerontology, this fundamental question remains without a comprehensive answer. Nutrition, reproduction and exposure to environmental threats (such as pathogens) are among the most important driving forces shaping life history. At the cornerstone of how these elements impact lifespan is metabolism and immunity. The ability of an organism to respond to changes in the environment without disrupting its homeostasis requires metabolic adaptation and robust defense mechanisms. Remarkably, events occurring early in life set how the organism adapts, learns and responds to environmental threats across its entire life. For example, the organism's lifetime capacity to store energy in adipose tissue is (epi)genetically determined and defined mostly pre-puberty, and it is one of the most accurate predictors of an individual's health span. Similarly, the maturation of the adaptive immune system occurs in the thymus during infancy. After puberty, the thymus starts involuting and this is associated with progressive impairment of adaptive immunity. Here we aim to investigate genetic and epigenetic factors that contribute to set, early in life, the individual's ability to handle excess energy and respond to threats to its homeostasis, ultimately contributing to determining the chance of the individual to survive and reproduce. We hope to achieve these goals by undertaking interdisciplinary approaches, applying cutting-edge technology and using a variety of models. One of these approaches will be directed to the discovery of genes and the ontogenic features that determine adipocyte size as a predictor of adipose tissue reservoir capacity. We also aim to identify what controls thymic involution and thus contribute to senescence of the immune system, paying particular attention to the metabolic features that underlie this phenomenon. In addition to these discovery-oriented approaches, we aim to further explore ongoing collaborative efforts. One of them is to further characterize a particular T lymphocyte - the cytotoxic CD4 T cell - given its predicted role in determining the tonus of immune responses and its ability to tip the balance from an efficient, pathogen-directed response to an exacerbated, autoaggressive response. We will also explore new therapeutic venues to mitigate the effects of immune or metabolic dysfunctions. For that we organized our proposal around a translational research platform to help us transfer basic knowledge into veterinary or human medicine applications. With this proposal, we expect not only to produce cutting-edge research, but also bring academia closer to society through scientific dissemination and potential for innovation. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BRUNETTI, NATALIA S.; DAVANZO, GUSTAVO G.; DE MORAES, DIOGO; FERRARI, ALLAN J. R.; SOUZA, GABRIELA F.; MURARO, STEFANIE PRIMON; KNITTEL, THIAGO L.; BOLDRINI, VINICIUS O.; MONTEIRO, LAUAR B.; VIRGILIO-DA-SILVA, JOO VICTOR; et al. SARS-CoV-2 uses CD4 to infect T helper lymphocytes. eLIFE, v. 12, p. 26-pg., . (20/04558-0, 15/15626-8, 19/06459-1, 19/04726-2, 19/16116-4, 19/05155-9, 19/13552-8, 16/18031-8, 19/00098-7, 20/04583-4, 16/00194-8, 21/08354-2, 19/17007-4, 19/22398-2, 17/01184-9, 19/14465-1, 20/04579-7, 13/08293-7, 18/14933-2, 17/23920-9, 19/06372-3, 16/24163-4, 16/23328-0, 20/04919-2, 20/04746-0)

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