An omic-based Drug Repurposing approach to modulate Immunosenescence and Inflammaging

Immunosenescence is the gradual decline of the immune system in older people characterized by a reduced response to neo-antigens, vaccines and pathogens, due to an increased dysregulation of the innate and adaptive immune system. Key hallmarks of systemic immunosenescence are a reduction of naïve T and B cells, causing antigen-responsiveness deficiency, and by a chronic pro-inflammatory environment that contributes to the dysregulation and disorganization of the entire immune system called inflammaging. In order to evaluate drugs ability to revert immunosenescence, we set up an in vitro stimulation study using peripheral blood mononuclear cells (PBMCs) from healthy donors (age 20-30), and analyzed cell response to drugs at the transcriptional level via bulk RNAseq analysis. The bioinformatic analysis elucidated the mechanisms underlying the immunomodulatory properties of the drugs and their ability to affect the regulation of immunosenescence signatures. In the end literature-selected drugs demonstrated to be able to revert the regulation of the upregulated signature of immunosenescence and in particular Spermidine 10μM, Dexamethasone 100nM and Rapamycin 10nM were declared as the most interesting drugs. Overall, this work offered a primary evaluation of the potential of the literature-selected drugs to prevent or improve immunosenescence, paving the way to new possible therapies for the treatment of immune system dysfunction in the elderly.