During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic disease epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans' primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.

During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans’ primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.

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.

On their way from the Stone Age via the Agricultural Revolution to current high-tech conditions, humans lost their primal foraging behavior. Today, energy expenditure is not necessary anymore for gathering nor hunting, and metabolic diseases are epidemically arising wherever our original Paleolithic lifestyle is turning into a modern sedentary lifestyle. In this pilot study, we followed through the concept that a radical change towards a Paleolithic hunter-gatherer lifestyle could serve as therapy against any metaflammatory disease, even in the short term. Thirteen healthy adult volunteers were transferred to the DELUX National Park (Germany and Luxembourg) for four days and three nights, where Stone Age conditions where mimicked. Thirty-eight biochemical and bioelectrical parameters were measured from participants before and after this relocation. Body weight (-3,9%), body fat (-7,5%), body mass index (-3,8%), visceral fat area (-14,4%) and metaflammation-related parameters (fasting glucose = -18,2%; fasting insulin = -50,1%; HOMA = -57,8%) decreased significantly. C-reactive protein, as the main indicator for low-grade inflammation, increased up to an average of 169,6 %. Our data show that returning to our Paleolithic roots may have positive effects on risk factors commonly associated with metabolic disorders, such as obesity and type 2 diabetes. These findings may lead the way to further research to answer the question whether the already existing metabolic conditions and/or autoimmune and neuroinflammatory diseases could be influenced by a Paleolithic lifestyle. Introduction Along the way from stone age via agriculture revolution to modern high tech conditions, humans lost their primal foraging behavior. In western society, energy dense food is always available and human existance does not rely on exercise to survive anymore. More than 2,5 million years of mankind, abundant physical activity and fasting during the day as well as food intake after sunset (which serves as a reward for successful hunting and gathering) represented the general case. Therefore, humans developed an extraordinary flexible metabolic system, trained by daily and seasonal fluctuations of food and water supply, thermic and immunological challenges as well as hiking and hunting under fasting conditions.

Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben zum «Leuchtturmprojekt Demenz» im Themenfeld 1 «Therapie und Pflegemaßnahmen: Wirksamkeit unter Alltagsbedingungen». Hierbei handelt es sich um eine multizentrische randomisierte Interventionsstudie, die den Einfluss von Sport (multimodale sportliche Aktivität) unter kontrollierten Bedingungen auf die kognitive Entwicklung von Alzheimer-Patienten im frühen Stadium prüft. In einem zweiarmigen Design werden je 150 Patienten mit früher AD unter Verum- bzw. Kontroll-Bedingungen untersucht. Die Verum-Gruppe erhält ein spezifisches sportliches Trainingsprogramm. In der Kontrollgruppe werden lediglich Dehnungsübungen durchgeführt. Primäre Endpunkte der Studie sind die kognitive Leistung der Patienten sowie deren Alltagskompetenz im Verlauf. Die gesundheitsbezogene Lebensqualität der Patienten sowie etwaige Verhaltensstörungen und depressive Symptome werden als sekundäre Endpunkte erfasst. Darüber hinaus werden die Angehörigen zur krankheitsbezogenen Belastung befragt und auf depressive Symptome untersucht. Angelehnt an die Hypothesen der «Initiative Demenzversorgung in der Allgemeinmedizin» (IDA) sollen entsprechende nicht-medikamentöse Versorgungsangebote dazu beitragen, dass Patienten länger in ihrem gewohnten häuslichen Umfeld leben. Im Sinne der Nachhaltigkeit der zu erwartenden Ergebnisse wird ein «Do it yourself»-Manual erstellt, mit dem das Trainingsprogramm auch ohne professionelle Anleitung, z. B. im Rahmen von Selbsthilfegruppen durchgeführt werden kann. Die weitere Implementierung (z. B. in Internetforen und weiteren Medien) wird durch einen Beirat der lokalen Krankenkassen, Gesundheitsämter und der Deutschen Alzheimer-Gesellschaft unterstützt.

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We here describe two apparent paradoxes concerning high CRP levels and NCD risk. One has emerged from observational studies in the Amazon region showing that the indigenous Tsimane in Bolivia appear protected against non-communicable diseases (NCDs) such as obesity, type 2 diabetes, and cardiovascular diseases despite increased inflammatory markers. These findings stand in contrast to Western societies, where an increasing body of evidence demonstrates that low-grade-inflammation is the driver of NCDs. The second paradox has emerged from two field studies (Eifel studies) conducted in 2013 and 2014 with Westerners who returned to a simulated Palaeolithic lifestyle in a National park for 4 days. We had detected elevated inflammation markers, despite otherwise anti-inflammatory effects of these interventions as indicated by metabolic blood parameters. We here propose three hypotheses for this second inflammatory paradox. Keywords Amendments from Version 1In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do. Moreover, we have been more careful with our formulations in the revised manuscript, refraining from making any causal claims. We agree with the reviewers that our hypothesis concerning the forest bathing effect is currently only speculative until further measurements have been made. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Our future research is planned to more specifically address the forest bathing hypothesis.In context of our third hypothesis, we have included the additional mechanism proposed by the reviewers in our discussion and re-wrote a large part of the third hypothesis. Our revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies.We agree that there are no data showing that chronic inflammation in Tsimans protects them against NCD (correlation is not causation). We have erased this claim. Rather, we agree that the best explantion is probably the absence of typical NCD risk factors. We also state in the revision that the data are not able to provide evidence for one of our hypotheses over any other, so that future studies should particularly put these hypotheses to test. Finally, we agree that it is unclear if and when the elevated CRP levels found in the Eifel study participants would have decreased again. However, a similar study has found increased CRP levels after a 10-day trip through the wilderness. This is stated now in the last two sentences of the conclusions section. See referee reports REVISED Abbreviations

Recently, observational studies in the Amazon region showed that the indigenous Tsimane in Bolivia appear protected against non-communicable diseases (NCDs) such as obesity, type 2 diabetes, and cardiovascular diseases despite increased inflammatory markers. These findings stand in contrast to Western societies, where an increasing body of evidence demonstrates that low-grade-inflammation is the driver of NCDs. In 2013 and 2014, we carried out two field studies (Eifel studies) with Westerners who returned to a simulated Palaeolithic lifestyle in a National park for 4 days and detected elevated inflammation markers, analogous to the conditions of the Tsimane. We here propose three hypotheses for this inflammatory paradox.