Characterization in mice of novel genes involved in the evolutionarily conserved mechanisms of dietary restriction and its mimetics

• Grant number: 18/11672-3
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2018
• Effective date (End): August 31, 2021
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Acordo de Cooperação: Innovation Fund Denmark
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Felippe Mousovich Neto
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/01184-9 - CAMeLEOm: cross-species analysis of metabolic, lifespan effects and omics of dietary restriction mimetics, AP.TEM

Abstract

Dietary restriction extends lifespan across species from yeast to primates. It is well established that dietary restricted mice live longer than ad libitum fed mice and are protected from metabolic diseases like diabetes and obesity, as well as cancer, cardiovascular disease and other age-related complications. In mammals, part of the beneficial effect of dietary restriction is thought to be mediated through decreased fat mass and the ability to maintain mitochondrial function in adipose tissue. Dietary interventions seeking to reduce energy intake are generally challenged by low compliance. This has motivated the search for novel treatment regimens that extend life and promote health without necessarily compromising energy intake. Dietary methionine restriction has emerged as a promising alternative to calorie restriction and has equal beneficial effects across the evolutionary spectrum, which include lifespan extension in many model organisms. In rodents, methionine restriction also increases insulin sensitivity and reduces adiposity by increasing energy expenditure, in part due to stimulation of brown/beige adipocyte recruitment to the white adipose tissue, a phenomenon often referred to as "browning". Similarly, boosting nicotinamide adenine dinucleotide (NAD) levels by dietary supplementation of NAD precursors such as nicotinamide riboside, a recently identified member of the vitamin B3 family, has been shown to increase lifespan in C. elegans and was found in rodents to improve metabolic health by reducing adiposity of high-fat diet fed animals. Nicotinamide riboside is found in whey fractions of cow milk thereby constituting a dietary source for NAD production. However, comprehensive analyses of the effects of nicotinamide riboside supplementation on aging and the pathogenesis of age-related complications as well as metabolic function of the adipose tissue are currently lacking. We have previously shown a downregulation of the microRNA (miRNA) processing protein, Dicer, with age in adipose tissue of mice and in the nematode C. elegans. This can be prevented in both species by dietary restriction. Knockdown of Dicer in cells results in premature senescence, and adipose tissue-specific knockout of Dicer promotes insulin resistance in mice. Our published data also reveal that Dicer in adipose tissue is required for proper mitochondrial function in mice, and lack of Dicer in adipose tissue abrogates dietary restriction effects on insulin sensitivity. More importantly, we found that lifespan extension exerted by dietary restriction, methionine restriction or increased NAD levels requires functionally active Dicer in C. elegans, thus indicating that these dietary interventions interact in a Dicer dependent manner to confer their beneficial effects. Dicer is also required for dietary or methionine restriction induction of "browning" in adipose tissue of mice. We therefore propose that dietary restriction can be mimicked by modifications of specific nutrient components in the diet. Like dietary restriction, these interventions depend on Dicer function to exert their beneficial effects. Understanding how these interventions work and interact in higher vertebrates will be henceforth necessary to envision applying these regimens in people or finding alternatives that act in a similar fashion.

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. (18/11672-3, 17/22057-5, 18/11792-9, 17/08829-5, 19/14391-8, 17/01184-9)