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July 12, 2011

The distinctive features of the human genome or genetic program evolved in an era of some two and one half million years known as the paleolithic era (early stone age).  This era ended about 10,000 B.C.E. During this period,  food was often scarce, unpredictable and also often not very diverse. There was no electricity and little interior lighting, so sleeping and waking was entrained to the sun/moon light/dark cycle. Obtaining food usually required a considerable expenditure of physical energy by hunting or foraging. Like other mammals, to guard against future shortages, we evolved the capacity to store excess calories when food was diverse and abundant. Today a vast diverse abundance of food is always readily available. For most of us, obtaining our food requires the expenditure of a modest amount of mental but little physical energy. Much of the modern diet is “pre-digested” in the form of powdered grains, refined sugars and liquified pre-frozen fruits so that we do not even have to expend energy to digest our food.  This mismatch between our hunter-gatherer genome and our modern sedentary processed food lifestyle is thought to have resulted in a worldwide epidemic in the diseases of civilization or metabolic syndrome diseases such as prolonged obesity/sarcopenia (fat gain and loss of lean body mass such as muscle and bone), cardiovascular disease,  type 2 diabetes, hypertension and dislipidemia (elevated serum triacyglycerols (triglycerides), small-dense LDL cholesterol and reduced HDL cholesterol). Hence to optimize our biology and health, it is thought that we must return to the rhythms and patterns of our pre-industrial, pre-agricultural ancestors without abandoning the spectacular advances that technology has brought about.

Another source of inspiration for those who are seeking to optimize their health and biology are  laboratory experiments that seek to maximize health and longevity in animals ranging from yeast cells to rhesus monkeys by restricting calories or specific nutrients.

Comparison of restricted and unrestricted rhesus monkeys

The above picture compares unrestricted rhesus monkeys (A-B) with restricted monkeys (C-D) at an average lifespan age.  Restricted animals, such as these monkeys, are often astoundingly robust, healthy and long-lived but also chronically hungry, a kind of blessed/wretched state that few humans have so far attempted to emulate.  To overcome this hunger obstacle,  scientists have proposed various strategies for tricking the hunger mechanism into requiring fewer calories.  On a similar front, others are seeking to identify small molecules that will activate the health and life-span promoting signaling pathways that are activated by calorie restriction. One such candidate calorie restriction memetic, resveratrol, has turned out to be mostly hot air and wishful thinking, but the search continues.

The picture represents the tradeoff between growth and longevity. At least one dwarf mouse of the type shown on the right lived nearly five years more than twice the lifespan of the species.

Another intriguing area of aging research involves the genetic engineering of test animals with modifications that typically reduce the production of growth promoting compounds such as insulin, insulin like growth factor or growth hormone or that downregulate the receptors to these hormones or the signaling pathways  that are downstream to these receptors. One such animal., the GHR-KO Dwarf Mouse 11C, very nearly lived 5 years or the human equivalent of 180 to 200 years. This mouse was born at the Southern Illinois University vivarium on January 15, 1998 and died about one week short of 5 years later. At the time of his death he weighed only 8 grams, small even for a dwarf mouse. Apparently there is a trade off between growth and longevity. The researchers hypothesized that the long life of the GHR-KO Dwarf mice is partly related to their low levels of glucose and insulin. At a deeper level the long life of these genetically modified mice as well as calorie restricted mice is apparently partly related to downregulation of  the mTOR gene/protein and the upregulation or activation of the SIRT1 signaling gene/protein.  mTOR suppression promotes autophagy, the breakdown and removal of old broken down mitochondria, oxidized proteins and AGE’s or advanced glycation end products. AGE’s are protein-sugar molecules that can build up in cells and tissues over time causing cell senescence and aging. Old broken down mitochondria can be a major source of DNA damaging free radicals. Oxidized proteins can disrupt the the cell signaling system of the cell. Sirt1 activation results in slower aging by decreasing oxidative damage to cellular DNA and by increasing DNA repair mechanisms.

On still another front, researchers hope to renew tissues and even entire organs using the technologies of genetic engineering and regenerative medicine. One fascinating possibility is that the immune system, red blood cells and the inner layer of blood vessels could be renewed by replacing the bone marrow stem cells that form these immune and blood/vascular tissues.

If you are searching for a way to apply these calorie restriction/genomic harmony ideals to your own wellness strategy, then the key concepts may be as follows:

(1) Adopt the lifestyle of your Paleolithic ancestors.  Eat the kind of food that they ate and mimic their patterns of food consumption. If you do this correctly you will most likely substantially reduce the total number of calories you consume relative to the calories you expend. In so doing  you will very likely not only lose a lot of weight, you will also improve a wide range of health parameters including the highly important aging parameters that are slowed by calorie restriction. You will very likely switch the signaling patterns in your body’s cells from growth/fat storage/reproduction mode to maintenance/repair mode. This latter pattern is synonymous with robust health and slowed aging.  On the negative side, it does not prepare you for future food shortages or famines!  In the 21st century, future food shortages associated with reduced income can be avoided by various economic measures. The body’s stone age “intelligence” or genome has not yet caught up with this, so it continues to pile on the pounds in anticipation of the coming famine. Over time there is a dramatic shift in the body’s physiology towards disease and disfunctionality.

(2) Sleep the way your ancestors slept and expend energy or exercise in a way that mimics their lifestyle.

(3) I am not suggesting that you need to eat the exact same foods that our ancestors ate. Rather the idea is to mimic the nutrient pattern of the paleolithic era as a first approximation to an ideal diet. A second approximation would be to follow a diet that matches the best cutting edge research. A third and probably even better approximation would be to select an individual diet that minimizes disease and maximizes your individual physiological measures of wellness. In other words what works best for you is the bottom line. The main drawback of this individualized approach is that it may be somewhat difficult to measure health parameters.

(4) In selecting an ancestor to emulate, do not select one who was living under conditions of great nutrient abundance and diversity. This ancestor was  no doubt in a kind of fat storage, cell growth and reproductive signaling mode. He/she was probably not exercising too much. Instead emulate the ancestor who had a real perpetual need to hunt or gather because food was always both scarce and often not too diverse. This hypothetical model ancestor was consuming a diet that was nutrient dense but calorically deficient. It was nutrient balanced and symmetric in the long term but unbalanced and asymmetric in the short term. This hypothetical ancestor was perpetually lean but very well nourished and was switched over into a maintenance/repair signaling pattern that is correlated with robust health and longevity.

(5) Do all of the above while also applying the best discoveries of modern medical science.

(6) Finally the above prescriptions for healthy living are in no way one-size-fits-all. If you are someone who experiences high uric acid levels and consequent activation of fat storage signaling pathways in response to excessive  purine rich protein/meat, then you may need to limit your consumption of purine rich meats.  If you are part of the 10% of the population that is fat-insensitive, meaning that your brain does not respond to fat by decreasing hunger, then a low fat version of this diet would be best for you.  If you are part of the 40% of the population that is grain sensitive, then you need to be zealous about restricting grains, especially the non-sprouted variety. If you are ethically opposed to the use of animals for food even if they are treated humanely, then you will want to put together a vegetarian version of the diet prescriptions of this blog. In the not too distant future maybe artificial intelligence expert systems (“health bots”) will be able to customize a diet, exercise and lifestyle regimen that will fit each person’s unique physiology, monitor that physiology over time, and make recommendations for changes.

Further reading:

Colman, R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009;325(5937): 201-204.

Cordain, L. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005; 81:341-354. (

Johnson, Richard J. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? J Comp Physiol. 2009 January; 179(1):67-76

Pinel, J. P. J. Hunger, Eating, and Ill Health. American Psychologist 2000; 55(10): 1105-1116.(

Stipp, David. A new path to longevity. Scientific American,  January 2012.

Varady, K.A. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am J Clin Nutr 2007;86:7-13.


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