Off topic but tangential and interesting:
"Psilocybin treatment extends cellular lifespan and improves survival of aged mice”
Aging volume 11, Article number: 55 (2025)
Abstract
Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.
Introduction
To date, >150 clinical studies with psilocybin have been completed or are ongoing for various clinical indications, including psychiatric (anxiety, depression, addiction), neurodegenerative (Alzheimer’s), pain, and more1,2,3. Human studies have demonstrated that a single-dose of psilocybin can improve debilitating physical and psychological symptoms—with durable effects (up to ~5 years)4,5. Despite considerable clinical evidence supporting the therapeutic benefits of psilocybin, the molecular mechanisms responsible for these impacts remain enigmatic. Studies with psilocybin have predominantly focused on neurological impacts and/or behavioral outcomes; few studies have evaluated alternative or systemic mechanisms which may also contribute to its beneficial effects. The “psilocybin-telomere hypothesis”6 postulates that psilocybin interventions may quantifiably impact telomere length, which offers a potential explanation for its efficacy across a wide range of clinical indications. This hypothesis is based on a large corpus of studies linking mental health biological aging markers6. Accumulating evidence indicate that clinical depression accelerates aging and telomere shortening7,8,9. Positive mental psychological states are associated with longer telomeres, whereas negative psychological conditions (e.g. chronic stress, anxiety, and depression) are associated with telomere attrition7,10,11,12,13. Given the clinical evidence supporting the efficacy of psilocybin for these conditions, it is plausible that psilocybin may impact telomere length. However, no prior studies have experimentally investigated the direct impact of psilocybin on biological aging.
To evaluate the impact of psilocybin on cellular aging, we employed a validated model of replicative senescence using human fetal lung fibroblasts14. For all in vitro studies, we used psilocin (the active metabolite of psilocybin), which is formed when psilocybin is broken down after ingestion. Cells were serially passaged with media containing psilocin or vehicle until they reached replicative senescence. Psilocin treatment (10 μM) resulted in a 29% extension of cellular lifespan, characterized by delayed exhaustion of proliferative potential, increased cumulative population doublings, and decreased population doubling time, compared to vehicle (Fig. 1A–F). Results were more striking using a higher dose of psilocin in the same cell type (100 μM treatment led to a 57% extension in cellular lifespan; Supplementary Fig. 1A–F). Induction of senescence occurred in both vehicle and psilocin-treated cells, as both groups reached exhaustion of their proliferative potential (no evidence of oncogenic transformation was observed), however the onset of senescence was delayed in psilocin-treated cells (Fig. 1A). Further, compared to vehicle, psilocin-treated cells exhibited decreased βgal activity (Fig. 1G–H). These results were consistent with dose-dependent reductions in markers of cell cycle arrest (p21, p16), and increased markers of proliferation (PCNA) and DNA replication (pRB) (Fig. 1I). Compared to vehicle, psilocin treatment also led to elevated sirtuin1 (SIRT1; a critical role in regulating cellular aging, metabolism, and stress-responses) and decreased Growth Arrest and DNA Damage-inducible 45 alpha (GADD45a) levels, suggesting reduced DNA damage (Fig. 1I). Psilocin treatment also reduced oxidative stress levels in a dose-dependent manner (Fig. 1J), which was associated with decreased levels of NADPH oxidase-4 (Nox4, a master regulator of oxidant production) and increased nuclear factor erythroid 2-related factor 2 (Nrf2, a master regulator of antioxidant responses) (Fig. 1I). Overall, these results suggest that the in vitro impacts of psilocin are dose-dependent, with higher dosing ultimately leading to greater cellular life extension. To further validate these findings, we repeated these studies with a different cell type (adult human skin fibroblasts); 100 μM psilocin treatment increased cellular lifespan by 51%, which was accompanied by reduced senescence and decreased oxidative stress levels (Supplementary Fig. 2). To investigate other potential mechanisms by which psilocin contributes to increased lifespan, we also evaluated the impact on telomere length (reductions in telomere length is a hallmark of cellular aging). As expected, senescent vehicle-treated cells exhibited reduced telomere length compared to young control cells (Fig. 1K). In contrast, telomere length was preserved in psilocin-treated age-matched cells (Fig. 1K). In summary, these data suggest that psilocin impacts signaling pathways associated with cellular aging, which ultimately delayed the onset of senescence and increased cellular lifespan.
Full paper:
https://www.nature.com/articles/s41514-025-00244-x