Regulation of mTOR receptor by rapamincin in senescence accelerated mice: the role of autophagy in aging process

• Grant number: 20/05439-4
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2022
• Effective date (End): September 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal researcher: Joilson de Oliveira Martins
• Grantee: Luiz Adriano Damasceno de Queiroz
• Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 22/05928-0 - Regulation of the mTOR receptor by rapamycin in accelerated senescence mice: the role of autophagy in the aging process, BE.EP.DR

Abstract

Aging is a natural and multifactorial process obtained by the gradual loss of physiological integrity. In this context, autophagy, a process of intracellular content degradation, naturally regulated by the rapamycin target nutrient sensing receptor (mTOR) or chemically by the drug rapamycin (RAPA), has a direct relationship with cellular homeostasis and maintenance of the senescent phenotype. Senescence is a cellular state that contributes to the aging process, altering the metabolism and functions of the cell, causing local and systemic damage over time, both at the level of tissues and organs, as well as at the level of the immune and endocrine system. This project goal is investigate and identify which changes in glucose metabolism are caused by RAPA-stimulated autophagy, and how this impacts the expression of the senescent phenotype in cells of the immune system and in tissues and organs of high metabolic activity, from Senescence-Accelerated mice Prone 8 (SAM-P8) and Accelerated Senescence Resistant 1 (SAM-R1). For this, the following will be taken: I) molecular and cellular mechanism of senescence, such as: changes in the metabolic profile associated with blood by photometry, genetic markers by qPCR, cytokine profile by ELISA, presence of apoptosis by histology, in muscle, pancreas, spleen and liver, and changes in the blood and spleen lymphocyte population by flow cytometry; II) the relationship between the modulation of autophagy and the senescence phenotype, through the evaluation of the signaling pathway of proteins involved in autophagy activation by western blot; III) changes in glucose sensitivity and metabolism, such as: changes in glucose metabolism in vivo by Insulin Tolerance Test (ITT) and glucose (GTT), and in vitro by metabolomics, respiratory capacity per seahorse, number of mitochondria by qPCR, membrane potential by confocal microscopy, and ROS production by flow cytometry. (AU)