The Daily Populous Friday July 25th, 2025 morning edition
Authored by nature.com and submitted by Edm_vanhalen1981

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.

Fig. 1: Psilocin treatment extends cellular lifespan. Human lung fibroblasts were treated continuously with vehicle (DMSO 0.02%) or 10 µM psilocin until they reached replicative senescence. A Cumulative population doubling curves; arrows indicate time point when cells reach replicative senescence (n = 4 technical replicates). B The area under the curve (AUC) was calculated using the sum of trapeze areas for each time point intervals (n = 4 technical replicates). C Cumulative population doublings at the onset of senescence (n = 4 technical replicates). D Population doubling time comparing young cells (0–4 days) vs. aged cells (60–63 days) post-treatment. Groups were compared using 2-way ANOVA (n = 4 technical replicates). E Cumulative cell number over cellular lifespan. F Table showcasing cellular lifespan population doublings and lifespan extension. Extension refers to the number of additional population doublings of psilocin-treated cells vs. vehicle, which is also shown as a percent increase relative to vehicle-treated cells. G, H Senescence was assessed at 42 days post-treatment by senescence-associated β-galactosidase (β-gal) staining; scale bar = 70 µm (G) and quantitative assessment of β-gal activity (n = 5 technical replicates) (H). I Western blot demonstrating dose-dependent alterations in protein expression of age-associated markers. J Reactive oxygen species (ROS) production was evaluated by Amplex Red assay (n = 3 technical replicates). K Average telomere length was assessed by RT-PCR (n = 4 technical replicates) and is expressed as kilobase pairs per chromosomal end. All values are shown as mean ± SD. Unless otherwise stated, comparisons were made using two-sided unpaired t-tests with unequal variance.; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns not significant. Full size image

To evaluate the impact of psilocybin on longevity in vivo, aged (19 month) female mice were treated with vehicle or psilocybin once/month for 10 months (Fig. 2A); mice were initially given a low-dose (5 mg/kg) for the first treatment followed monthly high-dose (15 mg/kg) treatment for a total of 10 treatments. We elected to utilize 19-month old mice, which is roughly equivalent to 60–65 human years, in order to evaluate its therapeutic potential as a clinically-relevant anti-aging intervention. Within 30 min post-treatment, mice exhibited increased head-twitch response (data not shown), which is a well-established behavioral indicator of hallucinogenic impacts of psilocybin in mice15. Both psilocybin and vehicle groups exhibited some loss in body weight from the start to end of the treatment protocol, however weight loss was not significantly different in vehicle- vs. psilocybin-treated mice (Supplementary Fig. 3). Notably, psilocybin treated mice demonstrated significantly higher survival (80%), compared to vehicle (50%) (Fig. 2B). Although not quantitatively measured, psilocybin-treated mice exhibited phenotypic improvements in overall fur quality, including hair growth and reductions in white hair compared to vehicle-treated mice (Fig. 2C). In summary, we provide the first experimental evidence demonstrating that psilocybin treatment can enhance survival in aged mice.

Fig. 2: Psilocybin treatment in aged mice extends lifespan. C57BL/6J aged (19 month) female mice were treated with vehicle (n = 28) or psilocybin (n = 30) by oral gavage. Mice were given a lower dose (5 mg/kg) of psilocybin in month 1, followed by monthly dosing with high dose (15 mg/kg). At 10 months post-initial treatment, when the first group of mice reached median survival, all were euthanized. A Schematic diagram of treatment protocol. B Kaplan–Meier survival curve over the 10-month treatment duration, showing vehicle-treated (n = 14 out of 28) vs. psilocybin-treated (n = 24 out of 30) mice; *p = 0.014 using the Log-rank Mantel–Cox test. C Representative images of mice prior to treatment (19 month) and after the final treatment (28 month) with vehicle or psilocybin. Red arrows indicate regions where hair growth and/or hair color changes were observed. Full size image

Psilocybin is a potent serotonergic agonist that interacts with the serotonin receptor (5-HT 2A ) and other 5-HT receptor subtypes. Notably, the 5-HT 2A receptor is expressed in multiple organs and cell types (including fibroblasts, neurons, cardiomyocytes, endothelial, epithelial, macrophages, and T-cells)16. A recent study demonstrated that 5-HT 2A stimulation in cortical neurons induced SIRT1-dependent expression of antioxidant enzymes, which led to reduced oxidative stress and neuroprotection17. SIRT1 is a key regulator of senescence, and overexpression of SIRT1 has been shown to extend organismal lifespan in C. elegans and mice18. Here, we demonstrate that psilocin increased SIRT1 expression in cells, suggesting a potential mechanism by which psilocybin delays senescence and promotes longevity. This study provides the first experimental evidence suggesting that psilocybin may impact multiple hallmarks of aging, including delayed senescence, preservation of telomere length, enhanced DNA stability (via increased DNA-damage responses such as GADD45a), and/or it could reduce aberrant intercellular communication (via decreased oxidative stress and subsequent signaling). Future studies are warranted to further elucidate the impacts of psilocybin on age-related pathways and the molecular mechanisms responsible for its systemic effects (including 5-HT-dependent and/or -independent mechanisms). Prior studies have demonstrated that the long-lasting impacts of psychedelic treatments may be due to epigenomic-driven alterations, including chromatin remodeling and DNA methylation19,20,21. It is possible that psilocybin may also mediate epigenetic changes which contribute to the observed geroprotective effects; such studies warrant investigation. However, regulatory barriers imposed by its schedule I designation along with the limited availability of federal funding for psilocybin research remain significant obstacles that have hindered research progress22,23; thus, the mechanisms underlying its potential therapeutic benefits remain poorly understood.

Our study provides the first experimental evidence demonstrating that psilocybin impacts hallmarks of aging, supporting the previously proposed “psilocybin-telomere hypothesis”6. We demonstrate that psilocin/psilocybin treatment extends both cellular and animal lifespan (even when treatment is initiated late in life). An effective anti-aging treatment that could be administered to adults during late life could have significant clinical potential. The dose utilized in mice was modeled based on a clinical trial in patients ranging from 29 and 70 years (three patients were >65 years), where no serious adverse events were reported at the study endpoint or the post-study follow-up (98 days)24; These findings support the feasibility of psilocybin treatment in older adults. Further, the FDA’s designation of psilocybin as a “breakthrough therapy” underscores its safety profile, as minimal adverse effects have been reported25,26,27,28. However, additional studies are warranted to identify optimized protocols for therapeutic efficacy, including the age of treatment initiation, frequency and dose of treatments, and to determine if treatment impacts maximal lifespan. Would earlier intervention yield greater therapeutic benefits, and/or is there a threshold in older age beyond which psilocybin fails to provide efficacy? Although some studies have reported sex-specific effects of psilocybin in rodents, the existing literature offers limited and inconsistent evidence regarding sex-based pharmacodynamic differences29,30,31. Accordingly, we employed a single-sex design to minimize potential confounding variables associated with sex-based biological differences and to ensure reproducibility in this initial in vivo investigation. Future studies are warranted to evaluate sex-specific therapeutic and mechanistic effects of psilocybin. Our in vitro studies suggest that psilocin-mediated cellular lifespan extension did not result in oncogenic transformation, as psilocin-treated cells did reach replicative senescence and exhaustion of proliferative potential. However, it could be argued that delayed exhaustion of proliferative potential and/or senescence could impact oncogenesis or cancer progression. Future research should rigorously assess the potential impacts of long-term psilocybin treatment in vivo on cancer incidence and/or progression. Few studies have evaluated the impacts of long-term prolonged dosing.

Beyond its neurological and psychological benefits, our findings suggest that psilocybin influences systemic aging processes, potentially explaining its long-lasting therapeutic effects across multiple disease indications. Although the impact of psilocybin on peripheral organs remains largely unexplored, these studies implicate untapped therapeutic potential for psilocybin’s systemic impacts. Psilocybin may represent a “disruptive” pharmacotherapy as a novel geroprotective agent to promote healthy aging and/or as a potential therapeutic intervention for age-related diseases.

goda90 on July 25th, 2025 at 04:23 UTC »

Crossing my fingers that longevity obsessed billionaires have a trip that makes them more empathetic.

BobaButt4508 on July 25th, 2025 at 03:52 UTC »

Stg, they’re going to find that this stuff cures diseases of the brain too

naturist_rune on July 24th, 2025 at 21:09 UTC »

Tl;dr a little bit of mushroom goodness is good for you, huh?