Short-term rapamycin treatment of an older human cohort alters immune and inflammatory markers but fails to re-set the epigenetic biological clock 2259884

Abstract

Abstract Introduction Pharmacological inhibition of the mTOR pathway with rapamycin (RAPA) extends lifespan and improves aspects of healthspan in mice. Enhanced longevity was achieved even when treatment was initiated later in life, suggesting that RAPA could be used to slow progression of age-associated pathologies in older humans. Moreover, in some animal models, intermittent treatment with mTOR inhibitors elicited long-term beneficial outcomes while obviating adverse effects. Methods To determine whether short-term RAPA treatment was able to reverse age-associated deficits in humans, we undertook a placebo-controlled study of 1mg/d RAPA in older human subjects (PMID: 29408453). Using specimens available from this pilot trial, we have now characterized potential changes in immune, epigenetic, and microbiome parameters known to be negatively impacted by aging. Results RAPA effects on immune cells were observed, including increases in a unique CD11b+ myeloid subset which shares some features with MDSCs and in foxp3+ TREGS. An increase in suppressive cell subsets may be beneficial in preventing autoimmunity. Indeed, the 8-week RAPA treatment slightly decreased autoantibody levels in subjects with detectable titers. Treatment was also associated with concomitant decreases in sICAM-I and increases in sRAGE. Given the interplay between the microbiome, inflammation, and aging, it was of interest that the gut microbiota became more diverse within the first 6 weeks of RAPA treatment. On the other hand, short-term RAPA treatment did not alter the “epigenetic age” in PBMCs. Conclusion Although many RAPA effects could be elicited by short-term inhibition of mTOR, other parameters will likely require a longer treatment. To explore this possibility, we were recently funded for a PK/PD analysis of mTOR inhibition in older humans. The goal is to identify the optimal drug (RAPA vs. Everolimus), dose, and dosing frequency (daily vs. intermittent) that can be administered safely, tolerably, and long-term in humans (ages 65-90 yrs). Funding Source NIA [Pepper Center pilot grants; NIA/NIH R21; and NIA/NIH U01] Topic Categories Immune Mechanisms of Human Disease (HUM)