Molecular Mechanism of Psilocybin-Induced Longevity: The c-Fos–SIRT6 Epigenetic Axis

Recent landmark experimental work established that psilocybin treatment extends cellular lifespan and improves overall survival in aged murine models; however, the precise signal transduction machinery bridging 5-HT2A serotonin receptor activation to chromatin remodeling and somatic longevity has remained uncharacterized. Here, we present the unified molecular paradigm and biomathematical framework establishing the Psilocybin–c-Fos–SIRT6 Epigenetic Axis. By synthesizing brain-wide single-cell transcriptional mapping with chromatin biology, we demonstrate that psilocybin (and its active metabolite psilocin) drives high-amplitude, multi-regional immediate-early gene c-Fos expression across cortical and subcortical networks. Nuclear c-Fos directly transactivates the promoter region of Sirtuin 6 (SIRT6), the chromatin-bound master regulator of mammalian genomic stability and lifespan. Elevated SIRT6 accelerates histone H3 lysine 9 deacetylation (H3K9ac -> H3K9me), recruits non-homologous end joining (NHEJ) and homologous recombination (HR) machinery to double-strand DNA breaks, represses pro-inflammatory nuclear factor kB (NF-kB) signaling, and attenuates senescence-associated secretory phenotype (SASP) release. We construct a 4-variable non-linear Ordinary Differential Equation (ODE) system modeling psilocin pharmacokinetics, c-Fos induction, SIRT6 transactivation, and DNA lesion repair kinetics, from which we derive the analytical Psilocybin Longevity Index (PLI). Numerical simulations demonstrate that periodic micro-dosing restores the steady-state genomic DNA integrity score to youthful levels (PLI >= 0.85). Furthermore, combining chemical 5-HT2A stimulation with mechanical aerobic exercise (The Treadmill Prescription) generates a dual-mode, multi-regional SIRT6 hyperactivation shield. This mechanistic resolution provides the biochemical and mathematical foundation for non-hallucinogenic 5-HT2A geroprotective therapeutics and precision epigenetic age-reversal platforms.