With the increase in life expectancy, aging and age-related cognitive impairments arebecoming one of the most important issues for human health. At the same time, ithas been shown that epigenetic mechanisms are emerging as universally importantfactors in life expectancy. The Senescence Accelerated Mouse P8 (SAMP8) strainexhibits age-related deterioration evidenced in learning and memory abilities and is auseful model of neurodegenerative disease. In SAMP8, Environmental Enrichment (EE)increased DNA-methylation levels (5-mC) and reduced hydroxymethylation levels (5-hmC), as well as increased histone H3 and H4 acetylation levels. Likewise, we foundchanges in the hippocampal gene expression of some chromatin-modifying enzymegenes, such asDnmt3b,Hdac1,Hdac2,Sirt2, andSirt6.Subsequently, we assessedthe effects of EE on neuroprotection-related transcription factors, such as the Nuclearregulatory factor 2 (Nrf2)-Antioxidant Response Element pathway and Nuclear Factorkappa Beta (NF-κB), which play critical roles in inflammation. We found that EE producesan increased expression of antioxidant genes, such asHmox1,Aox1, andCox2, andreduced the expression of inflammatory genes such asIL-6andCxcl10, all of this withinthe epigenetic context modified by EE. In conclusion, EE prevents epigenetic changesthat promote or drive oxidative stress and inflammaging