ESR2: “Novel interactions between genes and nutrition in aged ”

EPFL (J. Auwerx group): Novel interactions between genes and nutrition in aged C. elegans

i. Objective of research: To Identify novel interactions between genes and nutrition in aged C. elegans.

ii. Current state of the art: Despite major advances in our understanding of the signaling pathways involved in energy homeostasis, our knowledge is limited with respect to their functional links to age-related metabolic alterations.

iii. Research methodology and approach: We propose to use C. elegans to elucidate how the genetic composition of the nematode renders it susceptible to dietary and pharmacological interventions. The training objective is to use molecular, biochemical, and in vivo techniques to determine how genes and environment interact, and how this affects ageing. Our ESR will use dietary and pharmacological interventions in C. elegans, using either mutant strains or worms that have been fed with specific RNAi, for prototypical genes known to be involved in lifespan and ageing e.g. daf-2, daf-16, nuo-1, pme-1 and sir-2-1. Dietary interventions will consist in changing fat and carbohydrate content of the plates or liquid culture medium, caloric restriction, whereas the pharmacological interventions will be selected from benchmark compounds that are known to affect worm lifespan, e.g. resveratrol, rapamycin, nicotinamide riboside, PARP inhibitors. Our ESR will explore the effect of these genetic and environmental factors on worm movement as a proxy for ageing. In follow-up experiments, the candidate will learn a variety of phenotypic and molecular/biochemical techniques, including highly specialized techniques of worm imaging e.g. using reporter strains, automated movement tracking, targeted metabolomics analysis e.g. NAD measurements, characterization of mitochondrial function (citrate synthase assays, mtDNA/nuDNA ratio, mtDNA mutation), proteomic analysis, and study of worm respiration using the Seahorse flux analyzer. Our ESR will also perform lifespan studies, including Kaplan-Meier statistics, hazard ratio calculations as well as integrate the information on ageing studies in the worm with comparable information obtained in other model organisms (e.g. fly, mouse) and humans.

iv. Originality and innovative aspects of the ESR project: it is widely accepted that various metabolic syndromes represent diet-induced diseases that account for one of the largest global health problems. Our proposed research aims at unravelling key molecular interaction between longevity assurance pathways and dietary intervention strategies.

v. Integration of the ESR project to the overall research programme: Our ESR will work with the Tavernarakis group on mitochondrial dysfunction, with the Schumacher group on the role of genome stability in nutrient-sensing pathways and with Genevia on the analysis of proteomics profiles.