Background: The observation that the emergence of common Western diseases takes place with much greater prevalence as societies migrate from natural-living cultures to modernized societies, has been well documented. For approximately 84,000 generations humans lived under hunter-gatherer conditions but recently endured dramatic change from our native lifestyle with the occurrence of the agricultural, industrial, and digital revolutions. The massive technological advancement that occurred within a relatively recent timeframe enabled humans to live in manner that is remarkably different than our pre-agricultural past. Consequently, the shift from a natural to a modern lifestyle likely promotes a gene-environment mismatch which causes metabolic dysregulation which causes disease.Methods: Using a within-participant design, we examined whether, compared to baseline, changes in lifestyle towards a more Paleolithic-style pattern, for a four-day and four-night period related to changes in a variety of metabolic parameters. Two groups of 14 volunteers were isolated for a period of four days and four nights in the natural park Südeifel on the borders between Germany and Luxembourg. Participants lived outdoors without tents. The daily hiking performance was 16.4 km (≈ 24963 steps/day) and the daily activity time 5.49 h/day by a mean caloric intake of 1747 kcal/day.Results: After four days of simulated Paleolithic conditions, body weight (-2.9%), body mass index (-2.7%), body fat (-10.4%), visceral fat (-13.6%) and waist-hip-ratio (-2.2%) significantly decreased, while muscle mass significantly increased (+2,3%). Additionally, fasting glucose (-6.5%), basal insulin (-44.4%), homeostasis model assessment-index (-49.3%) and fatty liver index (-41%) significantly dropped. In contrast, C-reactive protein, significantly increased (+67.1%).Conclusion: Our study indicates that a short nature trip, where modern humans adjust their behavioral patterns to simulate a more Paleolithic-like condition, could serve as an effective strategy to help prevent or improve modern metabolic disease. Particularly, the major findings of an expeditious reduction of homeostasis model assessment-index and fatty liver index scores in only four days reveal the potential for meaningful benefits with such an intervention, even when compared to the effects of longer-term, single-intervention studies such as dietary or fitness programs on similar metabolic parameters.