Interplanetary human spaceflight represents a formidable medical challenge but also provides a unique platform for investigating human adaptation to extreme environmental changes. Understanding the long-term effects of isolation has relevance in a range of scenarios and it is well recognized that a better understanding of the relationship between environmental exposure and the epigenome can lead to more effective preventive measures. Here we conduct a longitudinal epigenetic mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles. Firstly we found that long-term isolation can induce global DNA methylation remodeling and this change seems to be an active adaptation (rather than a random process or a by-product of the isolation). This study is the first to demonstrate the dynamic relationship between global epigenetic remodeling and isolation-induced mood state and biochemical changes. Secondly by considering the location of methylation sites within the genome and using gene-pathway annotation we were able to identify pathways that were significantly enriched in methylation events and consider their association with specific function and the timeline of the mission. Thirdly via our definition of epi-entropy a measure of entropy adapted to methylation events we observed that the methylation remodeling produced a marked reduction in epi-entropy. Results suggest that DNA methylation change is an indicator of change rather than its by-product i.e. there is a psychology-epigenome-metabolism model of long-term depression; DNA methylation programs the environment signal into the epigenome which is subsequently transformed into the biochemical output and health outcome. Thus longitudinal epigenetic profiling could code the effect of isolation and act as early indicators of latent health outcome. A longitudinal epigenetic mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. 36 samples of blood cell DNA methylation profiling were obtained by Illumina HumanMethylation450 BeadChip across 6 sampling points during the 520 days mission for all of the 6 crew members.