Periodic Reporting for period 4 - EndoMitTalk (Endolysosomal-mitochondria crosstalk in cell and organism homeostasis)
Période du rapport: 2021-09-01 au 2023-02-28
Our group is interested in understanding how chronic inflammation may accelerate the aging process. Specifically, we want to study how immune cell metabolism may act as a therapeutic target in delaying aging and age-associated diseases.
The activation, expansion, differentiation and the regression to homeostasis of immune cells are processes associated with metabolic changes. Following antigen recognition, T cells are activated and initiate a proliferation phase characterized by a metabolic change similar to the Warburg effect described in tumoral cells. This metabolic reprogramming could be advantageous for cells that proliferate rapidly, such as cancerous or immune cells. T-cell differentiation and functional fate could be altered by modulating its metabolism. These results have opened up a new field of research, known as immunometabolism, that studies metabolic regulation in the immune response and is currently considered a promising therapeutic window in cancer and autoimmune disease research.
Our major scientific interest involves studying the role of metabolic regulation in the inflammatory response, and defining how immunometabolism may be used as a therapeutic tool in inflammatory diseases and pathologies associated with aging.
In summary, using a multidisciplinary approach we had explored immunometabolism as a new therapeutic target against chronic inflammation and aging.
1. Demonstration that mimicking age-associated mitochondrial dysfunction in T cells does not only recapitulate immunosenescence, but causes a general, body-wide deterioration of health with multiple aging-related features, including metabolic, musculoskeletal, cardiovascular and cognitive alterations, altogether resulting in premature death (Science, 2020). These results place the metabolism of T cells at the crossroad between inflammation, senescence and aging, highlighting that immunometabolism can be a therapeutic target to delay aging.
2. Decoding the molecular mechanisms by which aged T cells contribute to inflammaging and age-related diseases. (a) Th1-Cytokines induce cellular senescence (b) Loss of Self-tolerance mechanisms. (c) Defective immuno-surveillance of senescent cells. (d) Altered gut microbiota. (Cell Metabolism 2021; Nature Rev Immunol, 2022; Annual Rev Immunol, 2023).
3. The above studies in our laboratory have allowed them to propose new therapeutic targets (by targeting aged T cells, blocking Th1 Cytokines, improving mitochondrial respiration or nutritional intervention) to delay age-related multimorbidity (EMBO Mol Med, 2023) and to reverse aortic aneurysms and prevent sudden death due to aortic dissections (Circulation, 2021; Atherosclerosis, Thrombosis Vascular Biology, 2022)