We have analyzed what are the metabolic consequences of a constitutive signal of cellular nutrient abundance (see figure). We found that the sole signal of increased nutrient levels unleash aberrant metabolic responses and alterations consistent with a prediabetic state, including elevated glycaemia, insulin resistance and deregulated levels of other nutrients in the circulation (Figure A). This occurs without manipulating the actual energetic intake, only the cellular signals that arise when nutrient levels are elevated. We dissected, with specific genetic tools, the contribution of different organs (liver, skeletal muscle) to these metabolic defects observed in mice where every cell has this signaling perturbation. We found that the liver is critical for adjusting the metabolism to the fasted state downstream of nutrient signaling, and the sole activation of nutrient signaling in hepatocytes recapitulates most of the alterations seen in mice with full-body deregulation of nutrient signaling and blunts the response to fasting similarly to genetic activation of insulin signaling (Figure B).
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.
