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Dicer, miRNAs and the control of mitochondrial function in the context of aging and caloric restriction

Grant number: 15/01316-7
Support Opportunities:Regular Research Grants
Duration: September 01, 2015 - August 31, 2017
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
Associated researchers:Fernanda Marques da Cunha ; William Tadeu Lara Festuccia


Aging is one of the main risk factors for chronic diseases and has been increasing in prevalence worldwide in the past few decades. Advances in the understanding of the mechanisms involved in the aging process and how interventions can delay or prevent its deleterious consequences are thus becoming urgent. Health span can be increased in different species, including in primates, by metabolic interventions such as caloric restriction and exercise. The mechanisms through which these interventions slow down age-related functional decline are not yet clear but appear to involve metabolic processes that have the mitochondria as their main regent. Our data show that there is a coordinated reduction in the expression of components of the miRNA processing pathway, particularly the enzyme Dicer, and several miRNAs in adipose tissue of mice, in human preadipocytes and in the nematode C. elegans with aging, and this reduction is prevented in mice and C. elegans by caloric restriction. In C. elegans, overexpression of Dicer in the intestine of the worm, the functional analogue of the adipose tissue of mammals, results in increased life span and increased resistance to oxidative and metabolic stress. In recent data from our group, we observed that Dicer knockdown reduces respiration in nematodes and significantly decreases the expression of genes involved in mitochondrial biogenesis and function in adipose tissue of mice. In addition, worms that do not express Dicer have blocked the effects of increased life span promoted by calorie restriction or treatment with Metformin, which depend on an adaptive mitochondrial response. According to these data, we propose a more detailed study of these mechanisms, using different genetically modified animal models to assess whether Dicer and certain miRNAs are capable of regulating life span and/or determine some of the beneficial effects of caloric restriction by controlling essential metabolic functions involving the mitochondria. (AU)

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Scientific publications (12)
(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)
BRANDAO, BRUNA B.; MADSEN, SOREN; RABIEE, ATEFEH; OLIVERIO, MATTEO; RUIZ, GABRIEL P.; FERRUCCI, DANILO L.; BRANQUINHO, JESSICA L.; RAZOLLI, DANIELA; PINTO, SILAS; NIELSEN, THOMAS S.; et al. Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 117, n. 38, p. 23932-23941, . (17/03423-0, 15/01316-7, 17/04377-2, 12/06238-6, 15/03292-8, 17/01184-9, 12/04079-8, 18/21635-8, 17/07975-8)
DE-SOUZA, EVANDRO A.; CAMARA, HENRIQUE; SALGUEIRO, WILLIAN G.; MORO, RAISSA P.; KNITTEL, THIAGO L.; TONON, GUILHERME; PINTO, SILAS; PINCA, ANA PAULA F.; ANTEBI, ADAM; PASQUINELLI, AMY E.; et al. RNA interference may result in unexpected phenotypes in Caenorhabditis elegans. Nucleic Acids Research, v. 47, n. 8, p. 3957-3969, . (12/00195-3, 10/52557-0, 17/22057-5, 17/04377-2, 17/03423-0, 16/02207-0, 17/08829-5, 15/01316-7, 17/01339-2, 14/10814-8, 17/01184-9, 14/25068-0, 16/15958-3)
GUERRA, BEATRIZ A.; BRANDAO, BRUNA B.; PINTO, SILAS S.; SALGUEIRO, WILLIAN G.; DE-SOUZA, EVANDRO A.; REIS, FELIPE C. G.; BATISTA, THIAGO M.; CAVALCANTE-SILVA, VANESSA; D'ALMEIDA, VANIA; CASTILHO, BEATRIZ A.; et al. Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects. MOLECULAR METABOLISM, v. 29, p. 124-135, . (15/03292-8, 17/22057-5, 10/52557-0, 16/02207-0, 17/01184-9, 15/01316-7, 15/19530-5, 12/07259-7, 17/07975-8)
LUDWIG, RAISSA G.; ROCHA, ANDREA L.; MORI, MARCELO A.. Circulating molecules that control brown/beige adipocyte differentiation and thermogenic capacity. Cell Biology International, v. 42, n. 6, p. 10-pg., . (17/01184-9, 17/07975-8, 15/20822-0, 16/12294-7, 15/01316-7)
OTTON, ROSEMARI; BOLIN, ANAYSA PAOLA; FERREIRA, LETICIA TORRES; MARINOVIC, MARCELO PARADISO; SILVA ROCHA, ANDREA LIVIA; MORI, MARCELO ALVES. Polyphenol-rich green tea extract improves adipose tissue metabolism by down-regulating miR-335 expression and mitigating insulin resistance and inflammation. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 57, p. 170-179, . (13/22293-0, 15/01316-7)
LUDWIG, RAISSA G.; ROCHA, ANDREA L.; MORI, MARCELO A.. Circulating molecules that control brown/beige adipocyte differentiation and thermogenic capacity. Cell Biology International, v. 42, n. 6, SI, p. 701-710, . (16/12294-7, 15/01316-7, 17/01184-9, 17/07975-8, 15/20822-0)
REIS, FELIPE C. G.; BRANQUINHO, JESSICA L. O.; BRANDAO, BRUNA B.; GUERRA, BEATRIZ A.; SILVA, ISMAEL D.; FRONTINI, ANDREA; THOMOU, THOMAS; SARTINI, LORIS; CINTI, SAVERIO; KAHN, C. RONALD; et al. Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice. AGING-US, v. 8, n. 6, p. 1201-1222, . (10/52557-0, 15/01316-7, 11/24109-6)
BRANDAO, BRUNA B.; GUERRA, BEATRIZ A.; MORI, MARCELO A.. Shortcuts to a functional adipose tissue: The role of small non-coding RNAs. REDOX BIOLOGY, v. 12, p. 82-102, . (15/01316-7, 15/03292-8)
ROCHA, ANDREA LIVIA; DE LIMA, TANES IMAMURA; DE SOUZA, GERSON PROFETA; CORREA, RENAN OLIVEIRA; FERRUCCI, DANILO LOPES; RODRIGUES, BRUNO; LOPES-RAMOS, CAMILA; NILSSON, DANIEL; KNITTEL, THIAGO LEITE; CASTRO, POLLYANA RIBEIRO; et al. Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression. SCIENCE ADVANCES, v. 6, n. 49, . (10/52557-0, 17/01184-9, 18/15313-8, 16/23142-3, 17/07975-8, 16/24163-4, 15/01316-7, 16/12294-7)
PINTO, SILAS; SATO, VITOR N.; DE-SOUZA, EVANDRO A.; FERRAZ, RAFAEL C.; CAMARA, HENRIQUE; PINCA, ANA PAULA F.; MAZZOTTI, DIEGO R.; LOVCI, MICHAEL T.; TONON, GUILHERME; LOPES-RAMOS, CAMILA M.; et al. Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis. REDOX BIOLOGY, v. 18, p. 84-92, . (12/04064-0, 15/04264-8, 17/04377-2, 15/01316-7, 14/10814-8, 17/01184-9, 12/24490-4, 10/52557-0, 14/25270-3, 14/25068-0)
FERRAZ, RAFAEL C.; CAMARA, HENRIQUE; DE-SOUZA, EVANDRO A.; PINTO, SILAS; PINCA, ANA PAULA F.; SILVA, RICHARD C.; SATO, VITOR N.; CASTILHO, BEATRIZ A.; MORI, MARCELO A.. IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans. BMC Biology, v. 14, . (10/52557-0, 15/01316-7, 12/24490-4, 14/25270-3, 14/10814-8, 14/17145-4, 09/52047-5, 15/04264-8, 12/04064-0, 14/25068-0)
THOMOU, THOMAS; MORI, MARCELO A.; DREYFUSS, JONATHAN M.; KONISHI, MASAHIRO; SAKAGUCHI, MASAJI; WOLFRUM, CHRISTIAN; RAO, TATA NAGESWARA; WINNAY, JONATHON N.; GARCIA-MARTIN, RUBEN; GRINSPOON, STEVEN K.; et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature, v. 542, n. 7642, p. 450+, . (10/52557-0, 15/01316-7)

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