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Investigation of the interaction between Dicer and the NAD+ signalling pathway in C. elegans metabolism and aging

Grant number: 17/08829-5
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2017
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Marcelo Alves da Silva Mori
Grantee:Guilherme Tonon da Silva
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The world's population is rapidly aging, leading to an increase in the prevalence of age-related diseases and hence increasing the economic burden. Caloric restriction (RC) is an evolutionarily conserved intervention shown to extend lifespan and delay the onset of age-related diseases across species. However, due to its side effects in humans, and because it consists of a strict diet, the search for RC mimetics and the understanding of their molecular effects becomes necessary. It is known that some beneficial effects of RC depend on an increase in NAD+ levels. In fact, interventions aiming to raise NAD+ such as nicotinamide riboside (NR), a vitamin B3 analogue, and inhibition of PARP-1/PME-1, a major NAD+-consuming enzyme, prevent age-associated metabolic decline, increase oxidative metabolism and promote longevity in mice and worms in a way depending on SIR-2.1, a NAD+-dependent deacetylase, and involving the activation of molecular pathways that lead to resistance against proteotoxic and oxidative stress, comprising a predominantly mitochondrial action. Interestingly, in C. elegans, lack of DCR-1, the rate-limiting enzyme in the miRNA processing pathway, is associated with impaired mitochondrial respiration and reduced oxidative stress resistance, as well as shorter lifespan. Also, the effects of RC in improving metabolism and extending lifespan rely on dcr-1 in both mice and worms. As a final line of evidence to link NAD+ and dcr-1 in the context of aging and metabolism, our unpublished data using RNAi shows that dcr-1 is fully required for the lifespan extension promoted by the pme-1 mutation. In this study, we will investigate the temporal requirement (larval and/or adult) of dcr-1 for the lifespan-extending effects of NAD+ boosters and if the increase in NAD+ can modulate DCR-1 protein levels. Furthermore, we will verify which molecular components previously implicated in NAD+ effects are impaired when dcr-1 is silenced. Finally, we will perform RNAseq in pme-1(ok988) long-lived worms as an attempt to find small RNAs that can mediate NAD+ effects, thus expanding the understanding about the molecular basis of life- and health-extending interventions. (AU)

Scientific publications
(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)
BRAGA, DEISI L.; MOUSOVICH-NETO, FELIPPE; TONON-DA-SILVA, GUILHERME; SALGUEIRO, WILLIAN G.; MORI, MARCELO A. Epigenetic changes during ageing and their underlying mechanisms. BIOGERONTOLOGY, v. 21, n. 4, SI APR 2020. Web of Science Citations: 1.
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.; MASSIRER, KATLIN B.; MORI, MARCELO A. RNA interference may result in unexpected phenotypes in Caenorhabditis elegans. Nucleic Acids Research, v. 47, n. 8, p. 3957-3969, MAY 7 2019. Web of Science Citations: 3.

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