Psilocybin reduces depressive-like behavior and improves cognition in healthy aging mice via epigenetic regulation of plasticity- and immune-related genes

For many, cognitive and affective health declines through typical aging. Although cognitive and affective symptoms are often studied in isolation, they share substantial overlap, and arise, in part, from common biological processes. Aging is accompanied by diminished neural plasticity, heightened neuroinflammation, and widespread alterations in the epigenome. These molecular changes mirror behavioral decline, linking the erosion of cellular adaptability to the decline of cognitive function and emotional well-being in aging. Here, we show that psilocybin reverses age-related behavioral and epigenetic alterations in aged mice. Male and female C57BL/6 mice (11 months old) received two intraperitoneal doses of psilocybin (1mg/kg) or saline one week apart and were evaluated for memory and affective behaviors. Psilocybin improved learning and memory in females and reduced depressive-like behavior across sexes. Genome-wide DNA methylation profiling in the prefrontal cortex and bilateral hippocampus revealed widespread, sex- and region-specific effects, with the right hippocampus of females showing the most extensive gene-level changes. Differentially methylated loci were enriched for pathways related to synaptic organization, axon guidance, and neuroimmune signaling. Notably, psilocybin reversed age-associated methylation at CpG sites linked to typical aging, including within the Tbr1 promoter, a transcription factor essential for excitatory neuron development and synapse formation. Moreover, methylation at Tbr1 mediated psilocybin’s pro-cognitive effects on Y-Maze performance in females. Together, these findings demonstrate that psilocybin induces coordinated behavioral and epigenetic remodeling in the aging brain, with lateralized and sex-dependent signatures implicating neuroimmune and neuroplasticity transcriptional networks. Psilocybin thus emerges as a candidate compound for promoting aging resilience.