Impacting Inflammation Through Mechanistic Target of Rapamycin (imTOR)

Inflammatory diseases limit healthspan, defined as the length of one’s life spent in good health. We propose an ancillary study to an NIA-funded trial U01AG076941 (EVERLAST) that we call Impacting inflammation through mechanistic Target Of Rapamycin (imTOR). The EVERLAST parent trial will test the ability of low/intermittent doses of the rapamycin analogue everolimus to selectively inhibit mTORC1 but not mTORC2, and thus improve multiple indicators of healthspan, while avoiding the undesirable side-effects of rapamycin. Analysis of immune cells as major sources of mTOR-regulated inflammation, coupled with analysis in the context of parent trial outcomes, would significantly enhance the value of EVERLAST without changing subject burden. imTOR thus responds to NOT-AG-23-020 “Maximizing the Scientific Value of Secondary Analysis of Existing Cohorts and Datasets in Order to Address Research Gaps and Foster Additional Opportunities in Aging Research”. EVERLAST is enrolling middle-aged to older adults who are generally healthy but are overweight/obese and insulin resistant to take placebo or everolimus daily (0.5mg), or everolimus once weekly (5mg) for 24 wks. EVERLAST will determine the impact of this intervention on fundamental hallmarks of aging including changes in metabolism, muscle function, brain health, senescence, and frailty. imTOR will expand the scope of EVERLAST beyond flu vaccine-generated immune responses by quantitating the impact of everolimus on chronic inflammation, a key cause of age-related health declines generated mainly by immune cells. imTOR will focus mainly on CD4+ T cells based on our data showing these cells are dominant sources of inflammation in healthy and obesity-associated aging. imTOR is designed to test the overall hypothesis that everolimus lowers the risk of age-related health problems by reducing chronic inflammation through mechanisms that include improved bioenergetics and redox balance in immune cells. We will complement primary focus on T cells with analyses of myeloid cells, the latter a secondary source of systemic inflammation. Mechanistic insights into everolimus action on immune cells will be analyzed relative to changes in hallmarks of aging collected for EVERLAST. We will compare mitochondrial outcomes between immune cells and skeletal muscle to challenge the assumption of similar everolimus impacts on distinct tissue types. Parallel ex vivo manipulations will establish cause/effect relationships amongst everolimus, mTORC1/2 function, cell physiology, cytokine profiles, and the frequency of polyfunctional T cells, a newly appreciated modulator of inflammatory disease. Success with the proposed project coupled with EVERLAST outcomes will determine safety and efficacy of everolimus for promoting healthspan in our ever-aging population.