Periodic Reporting for period 4 - NutrientSensingVivo (The Physiology of Nutrient Sensing by mTOR)
Reporting period: 2020-07-01 to 2021-12-31
The alarming increase in nutrient intake, sedentarism and obesity calls for a better understanding of the molecular underpinnings of the cellular and organismal responses to such energetic perturbations. This would allow prevention and treatment strategies targeting the aberrant signaling of nutrients in human diseases such as cancer and diabetes.
Our objectives include the understanding of how are the intracellular and extracellular nutrient levels sensed and how are the responses orchestrated. Our focus is centered on type 2 diabetes, cancer, and the process of aging. We combine signal transduction information with physiology learned by the means of mouse genetics to provide a complete vision from the molecule to the organismal coordinated responses.
We have generated new tools to study how and why deregulated nutrient signaling drives B-cell lymphomas and established the reasons by which nutrient signaling exquisitely affects B lymphocytes in particular (Figure A). In addition, these novel tools revealed that an increase in nutrient signaling corrupts the internal control of B lymphocytes that prevent autoimmunity.
More recently, we have determined that a partial inhibition of nutrient signaling in B cells, by using genetic tools in mice, is a safe and efficacious interventions against B cell lymphomas, and with minimal, if any, side effect (Figure C). We anticipate that a stronger inhibition of nutrient signaling may mimic the beneficial effects of dietary restriction (DR) and complete inhibition of nutrient signaling would result deleterious and toxic for rapidly proliferating cells (Figure C).
We have also established that increased nutrient signaling drives a premature aging phenotype by increasing the overall inflammatory state of peripheral organs, a pathogenic situation that can be corrected pharmacologically and that feeds the disruptive concept of extending healthy aging in mammals, of compressing aging-related conditions toward the very last end of our lives.
We have also to establish a proof-of-concept scenario for targeting the nutrient signaling cascade as an anti B-cell lymphoma strategy.
Our results have also fostered our interest in determining the connection between nutrient levels and the onset of autoimmune pathologies, amenable of control by targeting nutrient signaling.
We have taken solid steps in the understanding of the metabolic perturbations associated with elevated nutrient signaling in the absence of an actual perturbations in nutrient intake or levels.
We have established that the sole activation of nutrient signaling in the liver abrogates the adaptation of the systemic metabolism to fasting conditions.
We have also established for the first time in mice the pro-aging effect of a moderate increase in nutrient signaling.