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

• Grant number: 21/08354-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2022
• End date: September 30, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Marcelo Alves da Silva Mori
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Alessandro dos Santos Farias
• Associated researchers: Ana de Medeiros Arnt ; Andrei Carvalho Sposito ; Bruno Geloneze Neto ; Carl Ronald Kahn ; Celso Darío Ramos ; Clarissa Lin Yasuda ; Daniel Martins-de-Souza ; Elinton Adami Chaim ; Gabriela Placoná Diniz ; José Luiz Proença Módena ; Licio Augusto Velloso ; Marco Aurélio Ramirez Vinolo ; Mariana Boroni ; Rogério Martins Amorim ; Vanderlan da Silva Bolzani
• Associated research grant(s): 24/20515-0 - Studying the role of m6A methylation in miRNA sorting in extracellular vesicles during obesity and type 2 diabetes, AV.EXT; 24/22135-0 - Uncovering Adipose-Brain Crosstalk in Alzheimer's Disease, AV.BR; 24/02285-7 - Dissecting the role of microRNAs in the adipose tissue - brain crosstalk in early onset Alzheimer's Disease, AP.R; 22/16724-7 - Multi-user Equipment approved in grant 2021/08354-2: AXIO Imager M2 Motorized Microscope with Apotome, AP.EMU
• Associated scholarship(s): 24/20995-1 - Uncovering The Mechanisms Of Caloric Restriction- Induced Insulin Sensitivity: The Potential Role Of Adipose Tissue-Derived miRNAs, BP.PD; 24/18680-2 - Characterization of the Tissue-Specific Role of the Argonaute ALG-1 in Aging, Stress Response, and Cuticle Integrity in C. elegans., BP.DR; 24/17122-6 - Therapeutic effects of fisetin in Canine Cognitive Dysfunction Syndrome., BP.IC; + associated scholarships 24/09705-1 - ANTITUMORAL MECHANISMS OF EXERCISE-INDUCED EXTRACELLULAR VESICLES IN BREAST CANCER: POTENTIAL ROLE OF miRNAS FROM THE ADIPOSE TISSUE, BP.PD; 24/07895-8 - Assessment of the influences of the microbiome and histidine metabolism on the effects of nicotinamide riboside on glycemic control in the context of obesity, BP.MS; 23/16423-0 - Assessment of the Interaction Between Thymic Involution, Immunosenescence, and Metabolic Dysfunction in an Animal Model of Lipodystrophy, BP.DR; 24/02090-1 - Investigation of the association between physical exercise and treatment with fluoroquinolone compounds in the prevention of obesity and its comorbidities, BP.MS; 24/02384-5 - CHARACTERIZATION OF CD4+ T CELL AND CYTOTOXIC CD4+ T CELL PROFILES IN METABOLIC AND AUTOIMMUNITY DISORDERS, BP.PD; 23/16404-5 - Investigation of mechanisms related to the development of partial lipodystrophy in a murine model, BP.DD; 23/07882-0 - Exploring the role of adipose tissue-derived microRNAs in obesity- and lipodystrophy-induced non-alcoholic fatty liver disease, BP.PD; 23/18100-3 - Functional validation of candidate genes as mediators of adipocyte hypertrophy, BP.DD; 23/09705-9 - Evaluation of Novel Mechanisms Mediating Innate Immunity of C. elegans in Response to Metformin, BP.IC; 23/07881-4 - Screening and characterization of new senolytics isolated from the Brazilian biodiversity, BP.PD; 23/01703-7 - Characterization of thymic involution and how it contributes to immunosenescence in mice, BP.PD; 23/01389-0 - Technical training on single-cell analysis, BP.TT - associated scholarships

Abstract

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)

Scientific publications

(9)

(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)

VERGANI-JUNIOR, CARLOS A.; MORO, RAISSA DE P.; PINTO, SILAS; DE-SOUZA, EVANDRO A.; CAMARA, HENRIQUE; BRAGA, DEISI L.; TONON-DA-SILVA, GUILHERME; KNITTEL, THIAGO L.; RUIZ, GABRIEL P.; LUDWIG, RAISSA G.; et al. An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress. NATURE COMMUNICATIONS, v. 15, n. 1, p. 15-pg., 2024-04-09. (17/01339-2, 19/25958-9, 21/08354-2, 17/01184-9, 14/50897-0, 19/04726-2, 22/05851-8, 17/23920-9, 19/01587-1, 23/08316-9, 14/10814-8, 18/11792-9, 18/21635-8, 16/15958-3, 17/04377-2)

CAMARA, HENRIQUE; INAN, MEHMET DINCER; VERGANI JR, CARLOS A.; PINTO, SILAS; KNITTEL, THIAGO L.; SALGUEIRO, WILLIAN G.; TONON-DA-SILVA, GUILHERME; RAMIREZ, JULIANA; DE MORAES, DIOGO; BRAGA, DEISI L.; et al. Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans. Gene, v. 895, p. 11-pg., 2023-11-25. (17/01339-2, 19/25958-9, 21/08354-2, 17/01184-9, 15/04264-8, 19/01587-1, 14/10814-8)

SANTORO, ADRIANA LEANDRA; VENDRAMINI, PEDRO H.; BRAGA, DEISI L.; MARTINS, LUCAS GELAIN; DOS SANTOS, GABRIEL F.; LIMA, GESIANE S.; TASIC, LJUBICA; MORI, MARCELO A.. Caenorhabditis elegans (C. elegans) sample preparation for metabolomics and lipidomics analysis - A review. TRAC-TRENDS IN ANALYTICAL CHEMISTRY, v. 169, p. 11-pg., 2023-10-25. (13/07607-8, 21/08354-2, 17/01184-9, 20/06057-8, 18/11792-9)

ALVES-SILVA, THAIS; HUNGARO, TALITA G. R.; FREITAS-LIMA, LEANDRO C.; ARTHUR, GABRIEL DE MELO; ARRUDA, ADRIANO C.; SANTOS, RAISA B.; OYAMA, LILA M.; MORI, MARCELO A. S.; BADER, MICHAEL; ARAUJO, RONALDO C.. Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain. ISCIENCE, v. 26, n. 12, p. 19-pg., 2023-11-18. (15/20082-7, 21/08354-2, 17/21368-7)

FERREIRA, SANDRA ROBERTA G.; MACOTELA, YAZMIN; VELLOSO, LICIO A.; MORI, MARCELO A.. Determinants of obesity in Latin America. NATURE METABOLISM, v. 6, n. 3, p. 24-pg., 2024-03-04. (21/08354-2, 13/07607-8)

BRUNETTA, HENVER S.; JUNG, ANNA S.; VALDIVIESO-RIVERA, FERNANDO; ZANI, STEPHENY C. DE CAMPOS; GUERRA, JOEL; FURINO, VANESSA O.; FRANCISCO, ANNELISE; BERCOT, MARCELO; MORAES-VIEIRA, PEDRO M.; KEIPERT, SUSANNE; et al. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. EMBO Journal, v. 43, n. 21, p. 22-pg., 2024-09-16. (21/08354-2, 17/17728-8, 13/07607-8, 19/21852-1, 22/00358-1, 23/07882-0, 20/14725-0, 22/13145-6, 23/00229-0)

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., 2023-07-31. (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)

TONET, NATALIA STINGHEN; MARCAL, DANILO FRANCISCO DA SILVA; DA SILVA, FLAVIA NATIVIDADE; BRUNETTA, HENVER SIMIONATO; MORI, MARCELO ALVES DA SILVA; DOS SANTOS, GUSTAVO JORGE; MOREIRA, EDUARDO LUIZ GASNHAR; RAFACHO, ALEX. Moderate chronic sleep perturbation impairs glucose and lipid homeostasis in rats. Sleep, v. 47, n. 7, p. 15-pg., 2024-05-24. (22/00358-1, 19/21852-1, 21/08354-2)

MCDONALD, J. TYSON; KIM, JANGKEUN; FARMERIE, LILY; JOHNSON, MEGHAN L.; TROVAO, NIDIA S.; ARIF, SHEHBEEL; SIEW, KEITH; TSOY, SERGEY; BRAM, YARON; PARK, JIWOON; et al. Space radiation damage rescued by inhibition of key spaceflight associated miRNAs. NATURE COMMUNICATIONS, v. 15, n. 1, p. 23-pg., 2024-06-11. (21/08354-2)