LABE

DecAI: Aging Decoding Initiative

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Marcelo Alves da Silva Mori

Main researcher abroad: Adam Antebi

Associate Researchers: Claudia Regina Cavaglieri

Type: Regular

Duration: July 01, 2020 - June 30, 2023
 

Abstract

A number of pathways have been shown to regulate animal lifespan and organismal aging. The Antebi lab has recently discovered the nucleolus as a crucial focal point for these pathways. The nucleolus is a subnuclear organelle dedicated to rRNA production and ribogenesis, which also controls other key processes in the RNA metabolism of the cell, including small RNA processing and assembly of ribonucleoproteins. miRNAs are a class of small non-coding RNAs which regulate gene expression at the post-transcriptional level and have been implicated in development, disease, and aging. We and others have shown that miRNAs can influence lifespan, and that they can exert their effects in a cell-non-autonomous fashion. Our investigation of miRNA regulation in aging and cell-non-autonomy gave rise to the initiation of the DecAl cooperation in 2018, a project funded by CAPES and DAAD to allow human resource exchange. Early results from this collaboration have revealed that loss-of-function mutations in a miRNA/siRNA processing enzyme, DICER, affect nucleolar size, also potentially also placing the nucleolus as a link between small RNAs and aging. In addition, we found that incubation of human Jurkat cells with serum of exercised mice reduces nucleolus size and that this effect is dependent on the presence of DICER in adipocytes, suggesting that nucleolus size is cell non-autonomously controlled by adipose tissue small RNAs in response to exercise training. Despite the mounting evidence, the extent and mechanism of this regulation remains unclear. The focus of this proposal is therefore to (1) identify genes and circulating factors that affect miRNA and siRNA processing and RNA metabolism in aging, and (2) map the processes through which this regulation occurs, with a particular focus on the nucleolus.

​

Determination of Molecular Candidates Contributing to Increased Risk of COVID-19 in Elderly Individuals

Principal researcher Marcelo Alves da Silva Mori

Recipient:  Marcelo Alves da Silva Mori

Associate researchers: Lucia da Conceição Andrade; Robson Francisco Carvalho

Type: Regular

Duration: May 01, 2020 - April 30, 2022
 

Abstract

COVID-19 has recently emerged as an age-related disease whose mechanisms are still poorly understood. Using a combination of hypothesis-oriented and unsupervised, data-driven approaches, as well as patients and pre-clinical models, we expect to come up with candidate proteins and pathways which could not only predict the susceptibility to the disease, but also unveil the molecular mechanisms through which aging contributes to SARS-Cov-2 infection. We also expect to provide a candidate FDA and ANVISA approved drugs which could potentially target these pathways to prevent, mitigate or eliminate virus infection. Our overarching aim is to elucidate how aging constitutes the main risk factor for COVID-19, providing potential solutions to its pandemic.

CAMeLEOm: cross-species analysis of metabolic, shelf-life, and food restriction mimetic omics

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Marcelo Alves da Silva Mori

Main researcher abroad:  Jonas Thue Treebak; Markus Herrgard

Associate Researchers: Maria Cristina Foss de Freitas; Niels Jessen

Type: Thematic

Duration: September 01, 2017 - December 31, 2021

​

Abstract

The overarching aim of this proposal is to delineate the common molecular networks in adipose tissue involved in the lifespan and health promoting effects of dietary restriction and its mimetics such as dietary supplementation with Nicotinamide Riboside (NR) - a dairy constituent that maintains NAD metabolism. To achieve that, we designed a pipeline to sort out biologically relevant pathways affected by these interventions. Briefly, we will perform omics of samples obtained from C. elegans, and adipose tissue and serum of mice and humans (healthy and/or type 2 diabetic) subjected to DR or its mimetic interventions. We will correlate these findings with lifespan and/or metabolic profiling and use bioinformatics tools to identify evolutionary conserved pathways that are commonly affected by dietary interventions. The relevant pathways will then be scrutinized using gain-or loss-of-function models in C. elegans, mice and mammalian preadipocyte cell lines, providing new insights into how these dietary interventions affect health span in multiple organisms, including humans.

​

Investigation of activation mechanisms of miRNA biogenesis through the beta-adrenergic pathway

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Gerson Prophet de Souza

Overseas supervisor:  Yu-Hua Tseng

Associate Researchers: Maria Cristina Foss de Freitas; Niels Jessen

Type: Doctorate

Duration: May 01, 2021 - April 30, 2022

​

Abstract

Increased calorie intake and reduced energy expenditure are the main etiological factors in obesity. On the other hand, increased brown adipose tissue activity and recruitment of beige adipocytes are proposed to antagonize obesity-related complications. miRNAs are important regulators of metabolic processes. These small molecules are generated by a pathway that the rate limiting enzyme named DICER, which has been shown to play a key role in adipose tissue thermogenesis and brown/beige adipocyte differentiation and function. Activation of thermogenesis in adipose tissue is mediated by the beta-adrenergic receptors. The signaling cascade mediated by beta-adrenergic agonists occurs through the second messenger cAMP, which promotes a wide range of effector mechanisms to modify cell metabolism, thus promoting lipolysis, thermogenesis, and browning of white fat. Our current results demonstrate that beta-adrenergic signaling robustly induces miRNA/siRNA biogenesis and function, and this participates in the establishment of the oxidative and thermogenic profile induced by beta-adrenergic agonists in adipocytes. However, the underlying mechanisms how beta-adrenergic activation promotes miRNA/siRNA function is unclear. Through this application we propose to study the mechanisms and signaling events involved in the changes of miRNA biogenesis in response to adrenergic stimulation. We intend to do it by a combination of proteomic and functional analyses, which will allow us to identify partners and post-translational modifications in the components of the DICER complex, as well as to investigate the importance of these changes to miRNA biogenesis and adipocyte physiology in response to beta-adrenergic stimulation. This proposal will shed light on how beta-adrenergic activation contributes to induction of miRNA/siRNA function and promotes DICER activity, and how this mechanism participates in the pathways triggered by beta-adrenergic agonists in the adipocyte.

Using preclinical models to determine molecular candidates that contribute to the increased risk of COVID-19 during aging

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Felipe Mousovich Grandson

Type: Postdoctoral

Duration: October 01, 2021 - April 30, 2022

​

Abstract

COVID-19 has emerged as an age-related disease whose mechanisms are still poorly understood. Using a combination of hypothesis-oriented and unsupervised, data-driven approaches, as well as patients and pre-clinical models, we expect to come up with candidate proteins and pathways which could not only predict the susceptibility to the disease, but also unveil the molecular mechanisms through which aging contributes to SARS-Cov-2 infection. We also expect to provide a candidate FDA and ANVISA approved drugs which could potentially target these pathways to prevent, mitigate or eliminate virus infection. Our overarching aim is to elucidate how aging constitutes the main risk factor for COVID-19, providing potential solutions to its pandemic.

​

Search for new adipocyte size regulators

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Diogo de Moraes

Type: Doctorate

Duration: August 01, 2021 - June 30, 2024

​

Abstract

Cardiometabolic diseases are a public health issue, and they have high incidence in the elderly and obese individuals. Among the demographic, anthropometric and histopathological characteristics associated with cardiometabolic disease risk, adipocyte size is more associated with diabetes than age or fat percentage. Evidence suggests that large adipocytes may represent a consequence of the loss of preadipocyte differentiation. These hypertrophied adipocytes also cause hypoxia in the adipose tissue. Both of these characteristics are found in individuals with cardiometabolic diseases, the obese and the elderly. Hypoxia can also cause inflammation, which inhibits preadipocyte differentiation, possibly closing up a vicious cycle that leads to metabolic dysfunction. In this way, the better comprehension of adipocyte size regulation may help us to understand and treat these conditions. Therefore, the proposal of the current project is to identify genes that control human adipocyte size. To do this, we will use public databases that contain the transcriptome and adipose tissue slides from heterogeneous human populations to find genes that are associated with adipocyte size. Next, we will validate if these genes are also associated with adipocyte size in independent human and mouse samples. Finally, we will perform a functional validation, to determine if these genes can regulate adipocyte size in vitro.

​

​

Exploring new intercellular communication mechanisms in metabolic diseases

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Adriana Leandra Santoro

Type: Postdoctoral

Duration: September 01, 2020 - August 31, 2022

​

Abstract

Cells exchange information via secretion of molecules such as metabolites, proteins and miRNAs. Mechanisms of intercellular communication become disrupted during metabolic diseases, leading to changes in the circulating levels of these molecules. The main purpose of this project is to identify secreted molecules that exert relevant biological functions in the context of metabolic diseases. For that we will use plasma/serum samples of mice and humans understand interventions that promote weight loss and we will profile circulating molecules using omics approaches to identify the ones that associate with a healthy metabolic status. Once we identify these molecules, we will test them in a series of cell and animal models to characterize their potential to protect against metabolic diseases.

​

Contribution of adipose tissue miRNAs to cardiac function, metabolism and remodeling

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Henver Simionato Brunetta

Type: Postdoctoral

Duration: September 01, 2020 - August 31, 2022

​

Abstract

Obesity and overweight are risk factors for the development of cardiovascular diseases. Importantly, cardiovascular diseases are the main cause of death worldwide, being responsible for around 31% of all deaths. Although initially thought as an energy storage tissue, adipose tissue is now recognized as an important endocrine organ. Adipose tissue communicates with other organs via hormones called adipokines, and as more recently demonstrated, via microRNAs (miRNAs). Our group has shown that the expression of DICER, an important protein involved in miRNAs processing, in adipose tissue, is altered in Obesity and aging. Indeed, adipose tissue-specific Dicer deletion in mice leads to insulin resistance, metabolic alterations in non-adipose tissues and premature aging. These data strongly evidence the crosstalk between adipose tissue and other organs via miRNAs. Cardiac tissue is able to use several different substrates; indeed, metabolic flexibility is associated with heart function. In addition, cardiac remodeling, as observed in hypertension, leads to alteration in cardiomyocyte metabolism. However, even with the well-established relationship between adipose tissue function and cardiovascular diseases, it is still not clear if miRNAs from adipose tissue play a role in cardiac function, whether in physiologic or pathologic scenarios. The aim of the present study is to investigate the crosstalk between adipose tissue and heart via miRNAs using an adipocyte-specific Dicer knockout mouse. Our hypothesis is that miRNAs from adipose tissue play to role in cardiac metabolism and function. Moreover, adipose tissue miRNAs could participate in cardiac remodeling during hypertension.

​

Investigation of new tissue-specific aging control mechanisms by caloric restriction in C. elegans

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Thiago Leite Knittel

Type: Doctorate

Duration: November 01, 2019 - June 30, 2022

​

Abstract

There is a worldwide trend towards aging of the world's population, what gives rise to social, economic and public health issues. Caloric Restriction (CR) is an intervention that slows down the aging process in different species, resulting in a reduction in the risk of age-related diseases. Aging and CR affect the cells of the organism in an indiscriminate manner. However, some cells seem to act faster or differently while others act in a determinant manner to coordinate organismal aging. Studying the casual relationships between tissue-specific and aging is challenging in mammals and almost impossible in humans, what slows advances in this area of knowledge. Caenorhabditis elegans is a model that allows this kind of studies as it provides easy genetic manipulation, exhibits a short life span and acts in a pattern that is similar to humans. With that in mind, we intend to isolate the main somatic tissues of C. elegans subjected to ad libitum diet or CR and analyze gene expression via RNA sequencing. We will identify genes that exhibit changes with CR and select the ones that present similar changes in samples from mice and humans. We will then test their impact on the aging and CR phenotypes of C. elegans and their influence on the phenotypes of murine myoblasts and adipocytes. These trials will allow the identification of new mechanisms of communication between tissues in the context of aging. These discoveries have the potential to inspire new drug targets.

​

Study of the role of ALG-1 and its regulatory mechanisms in the health of Caenorhabditis elegans

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Carlos Alberto Vergani Junior

Type: Doctorate (Direct)

Duration: September 01, 2019 - February 28, 2023

​

Abstract

Population aging represents an important social problem in the 21st century and mobilizes the attention of public agencies for the elaboration of interventions aiming to preserve vitality and increase healthspan. miRNAs and the proteins involved in their biogenesis and function, such as the argonaut ALG-1, are important elements controlling healthspan. In a previous study, our group observed that ALG-1 is required for longevity promoted by a mutation in the glp-1 gene which results in loss of germline in C. elegans. In addition, it was observed that worms with ALG-1 overexpression presented greater oxidative stress resistance. Despite the evidence that shows the importance of this argonaut in health span maintenance, the pathways and mechanisms by which ALG-1 acts still need to be elucidated. Previous data indicate that the expression of ALG-1 is under an intricate mechanism of counter-regulation, where ALG-1 levels are controlled by miRNAs induced by ALG-1 itself. miR-71, for example, is a negative regulator of ALG-1 and is required for glp-1 mutant induced longevity. However, ALG-1 is increased in these mutants, suggesting a mechanism where upregulation of ALG-1 expression overcomes or is uncoupled of the negative regulation exerted by miR-71. Thus, finding a mechanism of regulation of ALG-1 independent of miR-71 may be the key to maintaining high miRNAs levels, including miR-71, during aging, which would promote longevity. Therefore, in this project we intend to elucidate the mechanisms by which ALG-1 acts to maintain healthspan in C. elegans, investigating upstream and downstream regulators and observing their influence over the aging process.  

​

Study of the role of miR-203-3p in adipose tissue metabolism and in the pathogenesis of metabolic diseases in mice

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Gabriel Palermo Ruiz

Type: Doctorate (Direct)

Duration: March 01, 2019 - February 28, 2023

​

Abstract

The Metabolic Syndrome affects 25% of the adult population, emerging as one of the largest public health concerns worldwide, being Obesity and insulin resistance extremely relevant in this context. Caloric restriction and physical exercise appear as important interventions to treat metabolic diseases, however, the cellular and molecular components that participate in the beneficial effects of these interventions are not completely elucidated. It is known that adipose tissue microRNAs (miRNAs) are regulated under these conditions and that miR-203-3p is articularly decreased in Obesity and increased in response to physical exercise and caloric restriction. Preliminary data from our group point to miR203-3p as a candidate to mediate metabolic adaptation under energetic stress conditions. However, this miRNA is barely explored in the context of metabolism and studies are required to characterize its functions in vivo. Thus, we propose to generate adipocyte-specific mir203 knockout mice seeking to understand the function of miR-203-3p in adipose tissue in vivo, its role in the metabolic adaptation to caloric restriction and physical exercise, as well as its possible therapeutic role in metabolic disorders. In parallel, we will evaluate, in vivo and in vitro, a possible role for adipose tissue miR-203-3p in intertissue communication.

​

Scanning and characterization of circulating molecules that affect energy expenditure

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Raissa Guimarães Ludwig

Type: Doctorate

Duration: July 01, 2018 - September 30, 2022

​

Abstract

The prevalence of obesity has been growing worldwide alongside its comorbidities. Current anti-obesity therapies appear to be poorly efficient, especially on the long-term, and are associated with significant side effects. There are two ways to lose weight: by decreasing energy intake or increasing energy expenditure. One way to increase energy expenditure in mammals is through the stimulation of brown/beige adipocytes and the increase in their function. This phenomenon correlates with high levels of UCP1 expression and activity. Some conditions capable of regulating UCP1 expression and function have already been described. Among them, there is chronic cold exposure, exercise, an enriched social environment, and cancer cachexia. These conditions act through cell autonomous mechanisms, such as by regulating transcription factors in preadipocytes or adipocytes, and cell non-autonomous mechanisms, such as by signaling through hormones and other circulating molecules. The study and understanding of the circulating molecules that act in adipose tissue to increase its brown/beige characteristics is essential for the development of more efficient and secure pharmacological strategies that could help to mitigate the global scenario of obesity. We observed, based on our preliminary results, that a serum subject to dietary restriction modulates the expression of Ucp1 in vitro in mouse adipocytes derived from brown adipose tissue. This seems to be due to one or more circulating molecules present in the serum of ad libitum-fed individuals that induce UCP1 in a dose-dependent manner. These molecules are absent or very low in serum of DR-subjected individuals. Interestingly, this effect can be reproduced using serum of rats or obese humans subjected to bariatric surgery. We aim to find these circulating molecules that are likely proteins or protein-dependent molecules. This/these molecule(s) may bring insights into the development of new drugs to combat obesity.

​

Intestinal effects of Nicotinamide Riboside and Pterostilbene: an investigation into permeability, mucus production and nutrient absorption.

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Raul Gobato da Costa

Type: Scientific Initiation

Duration: October 01, 2021 - September 30, 2022

​

Abstract

Our group has been studying oral supplementation of Nicotinamide Riboside (NR) and Pterostilbene (PT) in the context of aging (2017/01184-9). The results of this thematic study indicate that oral supplementation of NR, PT and NRPT modulates intestinal physiology aspects. We saw lower intestinal permeability and higher quantity of goblet cells in intestinal segments of male mice treated with NR, PT or NRPT. PT had the capacity to low the body weight gain in animals on chow diet and ad libtum. The changes of body weight induced by PT were not dependent on the ingestion and energy expenditure in mice. On the other hand, we observed higher energy loss in the mice's feces, indicating that PT oral supplementation induced different intestinal effects.

​

​

Translational models and identification of new therapeutic targets in the field of adipose tissue biology, type 2 diabetes and non-alcoholic steatohepatitis

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Jeremie Boucher, Eliton Adami Chaim, Everton Cazzo

Type: Regular

Duration: 2019 - Current

​

UNICAMP Task Force Against COVID-19

Main researcher: Marcelo Alves da Silva Mori

Recipient:  Henrique Marques Souza, Marco A. Vinolo, Alessandro dos Santos Farias, Pedro Manoel Mendes de Moraes Vieira, Daniel Martins-de-Souza, Andre Schwambach Vieira, José Luiz Proença Módena, Licio Augusto Velloso, Maria Luiza Moretti, Marcelo Menossi, Sávio Cavalcanti , Marisa Beppu, Ana Arnt, Munir Skaf, José Gontijo, Luiz Carlos Dias

Type: Extension

Duration: 2020 - Current

​