PAST TIME - Repurposing of PPAR modulators: a novel STrategy to awaken T-cell IMmunity in the Elderly

Infections and cancers account for more than 25% of total deaths among elderly subjects worldwide (Global burden of disease 2019), and age-related deficits of the immune system are thought to greatly contribute to this phenomenon. The aim of PAST TIME is to reverse immunosenescence and improve the control of pathogens and malignancies in old subjects by repurposing molecules already in use for metabolic disorders.
Our published and unpublished observations suggest that T cells form elderly subjects are characterized by several dysfunctions, partly due by a dysregulated lipid metabolism. Notably, we demonstrated that the treatment of old naïve CD8+ T cells with two lipid lowering molecules (fenofibrate, a PPAR-alfa agonist, and rosiglitazone, a PPAR-gamma agonist) improves their functionality. In this project we will extend these findings and validate in vivo the use of PPAR agonists to reverse T-cell senescence.
We will assess the activity of the two lead candidates (fenofibrate and rosiglitazone) and of other analogues belonging to the same drug classes (fibrates and thiazolidinediones) on the restoration of functional and metabolic properties of naïve and memory CD4+ and CD8+ T cells from elderly subjects (WP1). The two molecules showing the strongest activity in vitro and with the best pharmacokinetic, pharmacodynamic and safety profile will be selected for further in vivo validation.
The selected molecules will be administered to naïve young and old mice to define immune cell functional, transcriptional and metabolic profiles (WP2). Next, their capability to foster the control of infectious diseases (WP3) and malignancies (WP4) will be assessed in old mice. Infection models will include both viral and bacterial infective agents toward which pathogen-specific immune responses will be measured. Tumor models will include breast and lung cancer, against which the PPAR agonists will be also assessed in combination with currently used therapies.
In parallel, a pharmaco-epidemiological analysis will be conducted, to assess the risk of occurrence of infections and tumors in adult and elderly subjects using fibrates or thiazolidinediones (WP5).
The consortium brings together research groups with complementary expertise and belonging to the Universities of Ferrara (UNIFE, as coordinator), Milan (UNIMI) and Siena (UNISI).
Expected results will provide new strategies to be rapidly transferred into the clinic to correct immune dysfunctions in the elderly. Drug repurposing is considered a faster approach for the introduction of new therapeutic agents and the use, in this project, of drugs already approved for humans will foster the translational potential of the findings.
Economical and societal benefits derived from the development of immune restoration strategies may be relevant considering the constant increase of the aged population.