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

• Grant number: 19/01587-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2019
• End date: December 25, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Carlos Alberto Vergani Junior
• 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
• Associated scholarship(s): 21/13222-8 - Unveiling the tissue-specific contribution of ALG-1 for oxidative stress response of C. elegans, BE.EP.DD

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 argonaute ALG-1, are important elements controlling healthspan. In a previous study, our group observed that ALG-1 is required for the 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 argonaute in healthspan 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. (AU)