Project Portugal 2030

Summary

The UnFOXingAGE* project aims to bring mechanistic insight into the geroprotective role of FOXM1 transcription factor through its disclosure as a master regulator of DNA repair in immune cells capable of decelerating immunosenescence, a predominant problem within the current ageing population, associated with poor response to vaccinations, susceptibility to infection, and incidence of chronic diseases. By taking a thorough and multidisciplinary approach, the project aspires to advance the understanding of immune function decline with increasing age and to develop an innovative immunotherapy based on T cell reprogramming through FOXM1 genetic induction. In specific, the objectives of this project are (graphical abstract): 1. Establish FOXM1 as master regulator of DNA repair and chromatin structure in ageing. FOXM1 is a promising target to revert DNA damage in aged cells, as it transcriptionally drives the expression of many DNA repair genes. Since DNA damage affects most, if not all, aspects of the ageing phenotype, the effect of DNA repair boosting by FOXM1 in other senescence hallmarks will be investigated, with a focus on epigenetic remodelling of chromatin structure. 2. Establish FOXM1 as a rejuvenating reprogramming factor. The initiation phase of cellular reprogramming proceeds with changes in several biological processes including increased proliferation, improved DNA repair and epigenetic remodelling. FOXM1 genetic induction phenocopies these major aspects, and therefore, grades as novel rejuvenating strategy able to modulate gene regulatory networks towards decelerated age clocks. 3. Validate FOXM1 as a rejuvenation factor in immune cells. The immune system will ensue as the focal point since compelling evidence points to DNA damage induced by defective DNA repair in immune cells as a driver of organismal ageing. Thus, FOXM1 induction positions as potentially capable of rejuvenating the immune system by targeting DNA damage. 4. Validate the rejuvenating impact of an adoptive FOXM1 T cell therapy in organismal ageing. Infusion of T cells expressing a FOXM1 transgene will be tested as a novel immunotherapy to improve immune function, as well as to increase the efficacy of immunotherapies in the elderly. Through these objectives, UnFOXingAge aims to advance scientific knowledge on the mechanisms behind immunosenescence and chronic diseases, and to disclose the thus far missing genoprotective therapeutic strategy to improve immunity in older people. *PI note for the Acronym: Foxing is an age-related process of deterioration that causes spots and browning on old paper documents. The name may derive from the fox-like reddish-brown color of the stains.