C29-12 Psilocybin Treatment Could Improve Outcomes for Age-associated Lung Diseases

Abstract Rationale The elderly population is rapidly growing. Overwhelming epidemiologic data has demonstrated worse health outcomes with increasing age for a multitude of lung diseases (COVID being one of numerous examples). There is an increasingly urgent need for a more complete understanding of the molecular pathways and biological processes underlying aging to improve outcomes for age-associated lung diseases. Psilocybin is the psychoactive substance in psychedelic mushrooms, which has been used in > 150 clinical studies for numerous disease indications. However, the overwhelming majority of psilocybin studies have focused on its neuro/psych impacts or clinical outcomes; Few studies have evaluated its systemic impacts. It has been hypothesized that psilocybin may exert beneficial effects on aging; however, no prior studies have experimentally evaluated this. Methods Human lung fibroblasts were treated with psilocin (the active metabolite of psilocybin) throughout their replicative life span, and hallmarks of aging were evaluated. To evaluate the impact of psilocybin on aging in vivo, aged (19 month) female mice (∼60-65 human years) were treated with vehicle or psychedelic-dose psilocybin via oral gavage once/month for 10 months. Survival was evaluated and bulk RNA-seq, proteomic profiling, and bioinformatic analyses were used to evaluate organ-specific function. Results Psilocin treatment led to a dose-dependent increase in cellular life extension in human lung fibroblasts (10μM - 29%; 100μM - 57%). These results were consistent with dose-dependent impacts multiple hallmarks of aging, including delayed senescence, preservation of telomere length, enhanced DNA stability, and decreased oxidative stress (associated with decreased Nox4 and increased Nrf2). In mice, psilocybin treatment led to significantly increased survival (80%), compared to vehicle (50%). Bulk RNA-seq data and bioinformatic analyses demonstrated that the lung exhibited the greatest number of rescued hallmark pathways (32 out of 50), compared to any other organ, including the brain. Further, inflammatory response was the most significantly downregulated pathway across all organs. Conclusions Our studies support the untapped potential of psilocybin beyond its neurological/psychological benefits, as we demonstrate that psilocybin influences systemic aging processes. Psilocybin may represent a “disruptive” geroprotective agent that could be used as a novel therapeutic intervention to improve age-related lung disease outcomes. This abstract is funded by: Imagine, Innovate and Impact (I3) Award from the Emory School of Medicine. This work was also funded by a grant from the Emory Woodruff Health Sciences Center for Health in Aging