Metabolism

Underlying Mechanisms

Aims

Discovery of metabolic biomarkers and innovative therapeutic strategies aimed at improving age-related diseases due to altered metabolism.

Leader name(s)

Pr L. Yvan-Charvet
Pr E. Van Obberghen

General description

Increased risk for metabolic syndrome (MS) and cancer manifest late in life as a consequence of deterioration and decline in the maintenance of homeostatic processes over time due to selective pressure to meet cellular metabolic needs. Studies from model systems and humans have built a consensus that 2 main metabolic pathways are involved in these age-related metabolic deteriorations,

  • alterations of the Insulin/IGF-1/FOXO cascade and
  • the sterol biosynthesis pathway.

The modulation of these pathways is multifactorial including malnutrition, smoking or alteration of the intrauterine environment (IE) of the fetus, which are all influential actors in long-term health. However, how corruption of these pathways in age-related diseases are associated with declines in key cellular and organismal longevity functions such as cell survival, autophagy, protein synthesis, extracellular matrix (ECM) remodelling, stress defence or detoxification is ill-defined. The Aims of our WP are to:

1) Decode how nutritional alterations of the IE of the foetus predispose to age-dependent appearance of the MS by:

  • Determining the consequences of maternal protein restriction or hypercholesterolemia on the metabolic and immune phenotype of progeny at birth and later in life (‘Metabolic Age’)
  • Identifying & validating altered plasma metabolites and misexpressed miRNAs from birth to adulthood in the progeny
  • Establishing causal relationships between biological variables to allow a Mendelian randomization approach

2) Develop strategies to improve age-dependent deterioration of metabolism by:

  • Establishing the relevance of insulin and cholesterol-dependent metabolic pathways to key organismal longevity functions
  • Restoring a normal plasma metabolite and miRNA profile by nutritional balancing
  • Developing targeted strategies to prevent specific plasma metabolite alterations and/or misexpression of miRNAs

3) Validate metabolic and miRNA biomarker discovery and application in human cohorts by:

  • Facilitating translational research
  • Performing epidemiology and Mendelian randomization approaches in normoglycemic and diabetic cohorts
  • Assessing the relevance of cellular and molecular mechanisms using peripheral leukocytes as surrogates

4) Prevent age-related cancer development by:

  • Determining alterations of insulin and cholesterol-dependent metabolic pathways in preclinical models of lung cancer
  • Applying targeted strategies to prevent age-dependent appearance of the metabolic syndrome in lung cancer
  • Favouring studies on human tumours from the LCPE bio bank as a proof-of-concept (POC) testing
Task Title
Innovative discovery of environmental and genetic factors of ‘Metabolic Age’
Task Description
  1. Elucidating the environmental and genetic factors at the origin of the MS in established preclinical models: a focus on the IE of the foetus
  2. Studying maternal nutritional modulation of 2 main metabolic signalling pathways involved in age-related metabolic alterations
  3. Defining in progeny tissue specific and time-dependent modulation of the Insulin/FOXO pathway induced by maternal protein restriction, and sterol synthesis pathway induced by maternal hypercholesterolemia
  4. Decoding the impact of maternal nutritional modulation on the redox status of immune system and stress defence
  5. Identifying novel metabolic and miRNA biomarkers
  6. Testing association between key variables to explore causality
Task Improvement
  • Establish the existence of a developmental memory in metabolic tissues that registers intrauterine protein restriction and maternal hypercholesterolemia
  • Discover and evaluate the preclinical use of novel biomarkers for age-dependent appearance of the metabolic syndrome.
  • Reachable in 3 years
Task Title
Fighting age-related diseases due to altered metabolism
Task Description
  1. Investigating how the decline in the insulin and cholesterol-dependent metabolic pathways affect molecular responses of metabolic tissues (cell survival, autophagy, ECM remodelling, stress defence…) with age.
  2. Testing whether age associated defective amino acid transport is responsible for altered Insulin/mTor/FOXO signalling in metabolic tissues
  3. Investigating whether autophagy perturbs insulin and cholesterol-dependent metabolic pathways with age
  4. Developing antimiR strategies against age-related metabolic dysfunction
  5. Integrating novel discoveries to develop a nutritional balancing program
Task Improvement
  • Expand the understanding of altered homeostatic processes over time due to selective pressure to meet cellular metabolic needs
  • Test novel metabolic therapeutic strategies
  • Develop nutritional balancing program
  • Reachable in 4 years
Task Title
Metabolic biomarkers validation in human cohorts
Task Description
  1. Testing the clinical significance and confidence of preclinical data-driven hypotheses in normoglycemic and diabetic cohorts
  2. Validating metabolic & miRNA biomarkers
  3. Investigating cardiovascular complications and key cellular functions of peripheral leukocytes as surrogates of decline in key homeostatic processes
Task Improvement
  • Support preclinical data-driven hypothesis
  • Facilitate rapid testing of therapeutic interventions in humans
  • Reachable in 2 years
Task Title
Accelerating metabolic therapeutic opportunities
Task Description
  1. Testing the relevance of metabolic alterations observed with ageing for lung cancer risk and progression
  2. Applying therapeutic opportunities described in Task2 to prevent lung cancer progression in preclinical models
  3. POC for metabolic alterations in bio samples from the LCPE bio bank
Task Improvement
  • Discovery of clinical criteria to patient populations with relevant pathogenic trajectories
  • Lipid modulation & patient need for cancer risk reduction
  • Reachable in 2 years