The Paleo Diet has become hugely popular. It encourages dieters to eat whole foods, such as meat and seafood, leafy green and starchy root vegetables, fruit, nuts, and seeds. While a paleo diet need not be low in carbohydrates, a significant proportion of its advocates follow a low-carb/high-fat (LCHF) version of the diet. But a new study claims that the LCHF version of the diet may not be as effective as was believed. The study, looking at the health effects of a LCHF diet in mice1, showed that the diet “increases weight gain and does not improve glucose tolerance, insulin secretion or β-cell mass in NZO mice.” Sof Andrikopoulos, associate professor at the University of Melbourne the senior author of the paper, interpreted the results as suggesting that, “there is no scientific evidence that these low-carbohydrate, high-fat diets work. In fact, if you put an inactive individual on this type of diet, the chances are that person will gain weight.” according to the press release.It has received a lot of media attention with headlines such as:

“New study says Paleo diet ‘unhealthy and fattening’ angering ardent devotees” – The Telegraph

“Health Buzz: Paleo Diet May Cause Weight Gain and Boost Blood Sugar, Study Suggests” --US News & World Report

And “Paleo diets = weight gain” --Brisbane Times

Andrikopoulos concludes that this type of diet, exemplified in many forms of the popular Paleo diet, is not recommended.These are bold statements to make, especially with the rising popularity of the Paleo diet. But does his study support the claims made by Professor Andrikopoulos and the media? Before we dig into the study, let’s examine what a paleo-style diet (PSD) is and the theory behind it.The first academic article to investigate human nutrition from the perspective of human evolution was published in 1985 in the prestigious New England Journal of Medicine2. The article was titled “Paleolithic nutrition. A consideration of its nature and current implications.” Its authors were S. Boyd Eaton, a medical doctor based in Atlanta, and Melvin Konner, Professor of Anthropology and of Neuroscience and Behavioral Biology at Emory University. Their paper reviewed the evidence for what the likely dietary and nutritional requirements for humans are based on contemporary knowledge from paleoanthropological (i.e., fossil and archeological) record and studying modern hunter-gathers. Based especially on the review of the nutritional components of modern hunter gatherer diets, they concluded that humans across the globe living in an ancestral state of Paleolithic tool technology and subsistence patterns ate a wide range of macronutrient ratios and food types both animal and plant. Nevertheless, they drew some basic principles common to all natural human diets: they were composed of real foods with minimal processing, and were much higher in micronutrients than most foods produced by agricultural and industrial food systems. They ended by acknowledging that evidence on ancestral human diets is not in and of itself proof of its healthiness, but that it should serve as the default model for what is healthy for humans. They recommended their hypothesis should be tested in experimental and clinical settings for evidence of its value in treating and preventing chronic disease, or what they termed the “diseases of civilization.”Additional research has lent strong support to the idea that Homo sapiens living in their most natural conditions, such as contemporary hunter-gatherer and foraging groups appear to thrive on animals and starchy plants, supplementing their diet with leaves, fruits, nuts, and seeds3.Since the publication of this seminal article, the PSD movement has become increasingly popular, with many advocates (and detractors) in the academe, clinical medicine, and in the general public. So, just what is the PSD? First, it is not one single diet. Rather, it is a framework for recognizing and categorizing what foods are likely the most appropriate for optimal human health based on anthropological and evolutionary evidence. As a popular diet, what all PSDs have in common is the exclusion of the foods that weren’t available as staples until the agricultural revolution, namely grains, legumes, and dairy. It includes foods that would have been attainable using Paleolithic (old stone age) technology, such as meat, seafood, most vegetables including starchy tubers, mushrooms, and fruit, nuts and seeds. Basically, it is a whole-foods diet that eschews foods that are processed using Neolithic, and especially industrial, processes. Thus, no flours, refined sugars, or refined oils.Let’s pause and consider whether a mouse would serve as a good model for tests of a human PSD diet. Mice and rats are adapted to quite a different dietary niche than are humans. They are granivorous (seed predators), and in captivity are healthiest on a diet of seeds, nuts, and grain, supplemented with other plant material and occasionally invertebrates4, 5.Rats and mice have lived in situ with humans since the dawn of agriculture in the North Africa, Central Asia, and East Asia approximately 10kya. The agricultural revolution in Europe and Asia was not about farming so much as it was about discovering how to grow and harvest the seeds of annual grasses such as wheat, barley, rice, and legumes. That is, on harvesting and storing rat and mouse food. Given that grains and legumes are the natural diet of rats and mice, they have many adaptations to grain and legume consumption. These adaptations include the ability to digest many types of lectins6,7, which are proteins found in high concentrations in grains and legumes, and to digest phytates8,9,10 which bind minerals to the bran of the seed so that they are not bioavailable.Humans, however, lack these physiological adaptations, and thus are actually quite poor at digesting grains and legumes11,12. Anthologists have long noted that the first farmers that adopted a grain-based agriculture showed remarkable nutritional deficiencies, including short stature, bone deformities and hypoplasias (deformities in the bone due to interruption of proper growth—usually as a result of stress or nutritional deficiencies), and dental cavities13,14.Traditional cultures that include these foods as staples reduce the seeds’ toxicity through soaking, sprouting, and fermenting them. Production of grain-based foods in the modern industrial system typically skips these critical steps. Thus, it should come as no surprise that most people who remove grains from their diet experience dramatic improvements in their health.This raises the suggestion that laboratory research on foods that are healthy for rats and mice should not be used as a basis for what foods are healthy for a human to consume. Doing so results in the misleading recommendation that human diets ought to be based on those that are found to be healthy for a lab rat or mouse!Likewise, the optimal human diet is not likely to be optimal for a rat or a mouse. Indeed, diets such as the HFLC whole foods diet that have been shown to lead to weight loss in human clinical research, has been found to have the opposite effect in mice15. They summarize in their abstract: “In sum, the response of mice to a carbohydrate-free diet was greater weight gain and metabolic disruptions in distinction to the response in humans where low carbohydrate diets cause greater weight loss than isocaloric controls. The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans.”Beyond the issue with using a mouse model to study human nutrition, many mouse models used in such research are either selectively bred or genetically engineered to manifest specific symptoms approximating human disease. The hope is to mimic the mechanism of the disease in the mouse model so that the findings may be used to understand and better treat the disease in humans. Unfortunately, the mechanism of the disease in the animal model often does not accurately mimic the disease as it occurs in humans (e.g.,[16]). Thus, the generalities of the findings from such mouse studies can be either very limited or even misleading.For example, Andrikopoulos and his coauthors selected an unusual strain of mouse (NZO) that had been selectively bred to be prone to obesity and diabetes17. Thus, it is questionable how well the results from this mouse model translate to normal humans, or even humans with adult-onset diabetes (type 2 diabetes mellitus (T2DM)). The NZO mouse develops obesity and diabetes early in development and there appears to be a distinct autoimmune component to the disease18. Thus, this mouse may turn out not to be a good model for the mechanisms of the disease in most humans.Returning to the mouse study in question, what exactly was the diet composed of that supposedly served as a model of a human-style LCHF PSD?It is true that the LCHF diet was indeed low carb—only 6% carbohydrate. Thirteen percent of the diet was from protein, and a whopping 81% was fat. But when you look at the actual ingredients that composed the diet, it turns out to be entirely made from highly processed and refined ingredients. The entire carbohydrate content was sucrose, a highly refined ingredient! The protein consisted only of casein. Casein is refined from dairy and is never consumed in isolation on a whole-foods diet. The majority of the diet was composed of a mixture of fats, many of them from refined sources, such as cocoa butter, canola oil, and clarified butter. See here for a complete list of the dietary ingredients.This diet contrasts markedly from a typical PSD, even a LCHF PSD like the one promoted by the low-carb Paleo-diet community. A PSD minimizes natural or added sugars, especially from refined sources like sucrose. The relatively small portion of carbohydrates typically included in a LCHF PSD are from whole-food sources and high in complex starch, such as tubers, plantains, root vegetables (beets, carrots, etc.), and some fruit (in moderation). That is, PSD adherents follow a whole foods diet composed of foods that receive relatively low amounts of processing, and are relatively high in fiber and resistant starch (which promote a healthy microbiome).Given my own positive health changes from adopting a LCHF PSD (see below), and the positive health changes many of my family and friends have experienced, I became interested in studying the common factors that make a diet healthy or unhealthy in a rat model. I hypothesized based on an evolutionary/ancestral framework that a healthy diet for both rodents and people would be composed primarily of whole foods (species-appropriate, of course), while a diet composed primarily of highly processed and refined ingredients would be unhealthy.My own research using an outbred rat model has shown that it is the degree of processing, and not macronutrient ratio (carb:protein:fat), that seems to be the significant factor in determining how healthy a diet is. A diet made from highly refined and purified ingredients was obesogenic and led to cognitive impairments19.Thus, it comes as no surprise that the diet used by the researchers, which was made of very highly processed ingredients, caused weight gain and health markers to change towards those associated with diabetes and metabolic syndrome. In fact, the control diet fed to mice in the control group was made of more whole foods and less refined ingredients, and those mice remained lean and healthy. Thus, the control diet could be considered the more ancestral or paleo (for a mouse) of the two, and by this perspective the outcome of their study actually supports a PSD! This is quite contrary to the interpretation presented by the media and the lead author himself.Why would the lead author, a scientist of reputable standing in the Australian academe, have been so misled? I don’t know Professor Andrikopoulos personally, and haven’t asked him why he decided to use such a highly processed diet to emulate a PSD in mice. Dr. Andrikopoulos is an Associate Professor and Head of the Islet Biology and Metabolism Research Group at the University of Melbourne, Department of Medicine (Austin Health) which investigates the genetic susceptibility of islet dysfunction using animal models of diabetes. He is also currently president of the Australian Diabetes Society. It stands to reason that he should be very knowledgeable about the large number of human clinical trials showing that LCHF diets work to reduce obesity, type-two diabetes, and metabolic syndrome (for a list of high quality random control trials (RCT) in humans see here), as well as the use of ketogenic (i.e., very high fat, very low carb) diets to successfully manage cancer20,21,22, degenerative neurological disorders23,24,25,26, neural repair after injury (in a mouse model!27), and psychopathologies and developmental disorders 28,29,30,31. Veech et al.32 provide a nice review of the therapeutic benefits of ketone bodies, the primary fuel source for generating ATP for cellular metabolism when on a ketogenic diet. Yet, in the mouse paper the authors say that there is “no scientific evidence” that LCHF diets work.Regardless of the source of such disconnect from the clinical literature, clinical and scientific reports that use a mouse model to make generalizations about a healthy versus unhealthy diet for humans fail to understand the theory behind ancestral diets. That is, they fail to recognize the unique and divergent ecologies and evolutionary histories that shape a species-typical diet, leading to quite different ancestral diets for a mouse than a man.So, what is the current evidence for whether or not a PSD is healthy for humans? The emerging evidence from the clinical literature shows that emulating a PSD with foods available in modern society results in improved health.A recent review and meta-analysis by Manheimer et al.33, found that a PSD resulted in greater short-term improvements in symptoms of metabolic syndrome, which typically occur together as predispositions towards type-2 diabetes and cardiovascular disease, than did control diets based on current US guidelines. [See [34], for a recent short-term study supporting the health promoting effects of a PSD and lifestyle.]Published studies along with the many individual reports of health improvements that ensue with the adoption of a PSD, together support the idea that, so long as an individual is eating its species-appropriate diet, then the major factor in metabolic health is determined by how processed the ingredients that compose the diet are. There may be evolutionary and mechanistic reasons why processed foods lead to poor health and disease in humans35. A HFLC diet composed of whole foods that are ancestrally-appropriate for humans, such as vertebrate and invertebrate animals, starchy tubers, vegetables, fruit, seeds, and nuts (i.e., a PSD) has been found to be health-promoting for many individuals. Likewise, a high-carb, low-fat (HCLF) PSD diet, composed of whole foods that are ancestrally-appropriate for humans, has also been found to be health-promoting for many people36. The common factor is not the ratio of macronutrients but the quality of those macronutrients (processed versus whole foods) and whether they are species appropriate.This should not be contentious when viewed from an evolutionary and ecological perspective. Diets that mimic ancestrally-appropriate diets for humans, such as paleo and primal diets are only contentious when looked at through the modern lens of human epidemiology and the industrial food economy. Unfortunately, epidemiological and observational studies are fraught with confounding factors, and their data tend to be notoriously inaccurate because they typically depend on self-report questionnaires and surveys37,38. Thus, they cannot serve as a reliable source of guidance towards a healthy human diet, but instead should only be used to offer hypotheses to be tested with experimental research.One of the most effective ways to test the hypothetical benefits (or detriments) of a particular diet or lifestyle is to try it out on oneself. In 2008 after having read Gary Taubes’ book Good Calories, Bad Calories about the science behind the LCHF diet39 and the blogs of many leading PSD advocates, I decided to adopt the LCHF PSD. The results were amazing, coming just short of miraculous.The first thing I noticed was that I lost some weight on the diet. That wasn’t my intention because I was always skinny. But, I noticed my midsection becoming leaner, going down from a 34” waist to a 30” waist. Moreover, my face became leaner and my eyelids became less “droopy”.Even more profound were the changes to my cognition and health. Up until then, I had been plagued by frequent bouts of “brain fog”, intense irritability when I was hungry (what folks in the paleo and low-carb communities refer to as “hangry”), and low energy. These symptoms completely vanished and were replaced by a new vitality and clarity of thought. Continual gut inflammation (bloating) disappeared as well.Perhaps the most amazing result, however, was that after a year on the diet, a heritable genetic condition called erythropoietic protoporphyria (EPP) went into complete remission! Sufferers of EPP experience painful and burning skin when exposed to sunlight. I had always avoided the sun as a result. But, I discovered that not only did my tolerance to sun exposure increase dramatically, the EPP symptoms completely vanished no matter how much sun exposure I received!It was these dramatic changes that led me to start the Ancestral Health Society with its annual symposium, an academic conference for the discussion of human health and disease from the framework of evolutionary mismatch. I also started the Journal of Evolution and Health (, of which I’m currently editor-in-chief, for publishing academic, clinical, and popular work on these topics. It also was my motivation to test in a rat model the hypothesis that the processing of foods leads to impairments in mood and cognition.Of course the news stories everywhere are claiming “Paleo diet shown to be harmful!” Such dramatic statements grab attention, but do more harm than good for improving our scientific knowledge. Adopting an evolutionary framework, based on sound scientific empirical work, is our best way forward to understand human health in the modern world. Evolutionary mismatch theory provides the most powerful framework from which to understand and address the multitude of diseases of civilization that plague us today; not only diet, but other lifestyle factors such as activity, sleep, sunlight exposure and circadian rhythm entrainment, social connections, chronic stress, and access to nature and free play. By adopting the evolutionary mismatch framework, perhaps we can begin to improve our future by recognizing the power of our past.References

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