CHRONOSPHERE

The Adventist Health Studies

Figure 1: Survival of California Adventist men (1980-1988) and other California men (1985) beyond the age of 30 years. The difference between the 2 groups was significant (P,.001). These were non-Hispanic white subjects. Hazards for 1989 are used for non-Adventist Californians older than 94 years (see the “Subjects and Methods” section of the text). AHS indicates Adventist Health Study; CI, confidence interval.

The Seventh-day Adventist Church (SDA) is a Christian denomination that was founded in 1963 as an offshoot of the Millerite movement in the US during the middle part of the 19th century. Ellen White, the principal founder of SDA, advocated a lifestyle incorporating the following five behaviors: not smoking, eating a plant based diet, eating nuts several times per week, engaging in regular exercise and maintaining normal body weight throughout the individual’s lifetime[1] Adventists also typically eschew alcohol (~8% drink), tobacco (~1.8% smoke), butter, strong seasonings (including pepper), caffeine (coffee, tea, cola) and consider the eating of pork, shellfish, and other foods proscribed as “unclean” in Leviticus as especially unwholesome.[2]

Beginning in 1960, two studies were conducted to determine the effects of the SDA lifestyle on all-cause mortality, as well as on disease-specific mortality and morbidity. The first study was conducted in the interval from 1960 to 1965. The Adventist Mortality Study, also known as the Adventist Health Study-1 (AHS-1) was comprised of 22,940 California Adventists and consisted of an intensive 5-year follow-up, and a more informal 25-year follow-up.[3] The AHS-1 found that the mean lifespan for California Adventist men was 6.2 years longer than for non-Adventist California men. The mean lifespan extension achieved by SDA women was more modest; a 3.7-year advantage over their non-SDA counterparts. These statistics were based on life table analyses.[4]

The reduction in disease specific mortality was impressive, with the overall death rate from neoplasms being 60% lower for SDA men and 76% lower for SDA women.[3, 5] The incidence of breast and colorectal cancer were dramatically lower than in the control population with SDA women experiencing 85% less breast cancer [6-8]and SDA men and women experiencing 62% less colorectal cancer.[3, 9, 10]The incidence of coronary heart disease (CHD) was 66% lower for SDA men and 98% lower for SDA women.[11-13] On average Adventist men live 7.3 years longer and Adventist women live 4.4 years longer than other Californians.

The second Adventist Health Study (AHS-2) took place in the time period between 1974 and 1988 and involved approximately 34,000 Californian Adventists over the age of 25. AHS-2 was designed to try to determine which components of the SDA lifestyle provided protection against specific types of disease. The AHS-2 found that the consumption of red and white meat was associated with an increase of colon cancer and that, independent of meat consumption, eating legumes was protective against the disease.[5, 10, 14] The consumption of nuts was found to be inversely related to the incidence of myocardial infarction, and regular consumption of nuts several times a week reduced the incidence of coronary heard disease CHD by ~50%.[15-17] A strong inverse relationship was found between the risk of CHD and the consumption whole grain wheat bread, as opposed to white bread (~45% reduction in CAD).[16] In men, the frequent consumption of tomatoes and of soy milk was associated with a ~60% reduction in the incidence of prostate cancer.[16, 18, 19]

Figure 2: Survival of California Adventist women (1980-1988) and other California women (1985) beyond the age of 30 years. The difference between the 2 groups was significant (P,.001). These were non-Hispanic white subjects. Hazards for 1989 are used for non-Adventist Californians older than 94 years (see the “Subjects and Methods” section of the text). AHS indicates Adventist Health Study; CI, confidence interval.

Unlike the Cretan diet, the dietary practices of the SDAs are less homogenous and typically incorporate foods commonly consumed by Americans (although with more moderation), including many associated with degenerative disease, such as refined sugar and snack foods. Similarly, the SDA diet typically strives to replace traditional American foods with healthier alternatives, while maintaining the flavor, texture and appearance of the original dishes.[20] One way this is done is by using a range of proprietary textured vegetable protein products (TVP) derived from wheat or soy (with corn or soy oil providing the calories from fat) as meat substitutes. There is also a heavy emphasis on the consumption of vegetables, nuts, whole grains and fruits.[21, 22]

Figure 3: Examples of textured vegetable protein products made to resemble commonly eaten meat dishes in the US.

These products have historically been manufactured by companies owned by or closely associated with the SDA church[23] and this was an added factor in their widespread use. Lentils are also often substituted for meat in traditional American recipes, such as meatloaf and soup. The use of TVP meat substitutes increase compliance by making products that allow for the preparation of foods that fill the cultural niche of beef, chicken and turkey. There are even faux-meat hot dogs available (Figure 3). Nuts are also commonly used as an ingredient in TVP dishes to provide added flavor and a more meat-like mouth feel.[20] Examples of commonly used SDA “meatless meat products” (Figure 3) along with their ingredients and nutritional content are available at http://fatsecret.com/calories-nutrition/worthington-loma-linda#Meatless_Foods.

The primary sources of lipids in the SDA diet have historically been from corn and soy oils, and to a lesser extent oils from nuts (corn oil has partly been replaced by canola oil in the contemporary SDA diet). In examining the commonalities between the SDA and the Cretan diet, the following components seem the most likely candidates to explain the reduction in morbidity and mortality observed in both populations:

• No or very low consumption of red meat
• No or low consumption of meat (excluding fish) in general
• Large consumption of fresh fruits and vegetables
• Use of free range hens’ eggs
• No or low consumption of butter
• No or low consumption of unfermented milk products
• Emphasis on legumes in the diet
• Emphasis on the regular consumption of nuts
• Fat intake primarily in the form of polyunsaturated or monounsaturated fats of vegetable origin
• Regular exercise
• Maintenance of near ideal body weight over the lifespan
• Abstention from smoking

Which Diet for a New Lifestyle?

Figure 4: The Greek Food Column and the three critically important lifestyle elements that accompany it; balance, proportionality and regular exercise.

The Lyon Heart Study clearly showed that the diet of Crete can be adhered to over a period of 5 years. Figure 4 is the Greek Column Food Guide based on the diet of Crete. The visualization of this food guide in the form of a Greek column includes the concepts of genetic variation and nutrition and balanced energy intake and energy expenditure; it is based on foods, not food groups. Although it excludes certain foods made with hydrogenated oils, it does not restrict the intake of naturally occurring foods. It also takes into consideration moderation, variety and proportionality. Dietary guidelines shown in Table 1 provide further information on how to implement the diet of Crete.

Table 1.
The seven dietary guidelines of The Cretan Diet
1. Eat foods rich in (n-3) fatty acids such as fatty fish (salmon, tuna,
trout, herring, mackerel), walnuts, canola oil, flaxseeds and green
leafy vegetables. Or, if you prefer, take (n-3) supplements.
2. Use monounsaturated oils such as olive oil and canola oil as your
primary fat.
3. Eat seven or more servings of fruits and vegetables every day.
4. Eat more vegetable protein, including peas, beans and nuts.
5. Avoid saturated fat by choosing lean meat over fatty meat (if you
eat meat) and low fat over full fat milk products.
6. Avoid oils that are high in (n-6) fatty acids, including corn,
safflower, sunflower, soybean, and cottonseed oils.
7. Reduce your intake of trans fatty acids by cutting back on
margarine; vegetable shortening; commercial pastries; deep-fat
fried food; and most prepared snacks, mixes and convenience
food.

Studies on the diets of hunter-gatherers suggest that (n-3) fatty acids were present in practically all foods that humans ate, and present in equal amounts with (n-6) fatty acids (i.e., 1:1 ratio). The depletion of the (n-3) fatty acids in Western diets is the result of the industrialization of farming, and to a lesser extent, the recent emergence of aquaculture. The high ratio of (n-6) to (n-3) fatty acids (16.74:1 instead of 1:1) is a consequence of the inexpensive mass production of vegetable oils and their substitution in much of the diet for saturated fats as a consequence of economic considerations, government policy (corn and soy subsidies) and erroneous health advice by the “experts.” The latter, led by Ancel Keyes,  recommended the indiscriminate substitution of saturated fat and butter with oils high in (n-6) fatty acids to lower serum cholesterol. This effort was successful in reducing the incidence of CVD, however it has not reduced the incidence of other pro-inflammatory diseases, and the mean lifespan has not increased fully commensurate with the decrease in CVD mortality.

The results of the Seven Countries Studies and the Lyon Heart Study based on a modified Cretan diet that is balanced in (n-6) and (n-3) fatty acids, rich in antioxidant micronutrients, and in chemoprotective trace minerals  from fruits, vegetables, wild growing herbs and greens is associated with decreased rates of heart disease and cancer; more so than any other diet, drug intervention, or technique. Indeed, all attempts to date to administer nutrients believed to be protective against disease as supplements have been unsuccessful. Attempts to reduce the incidence of CVD with vitamin C, vitamin E and with folic acid and vitamin B-6 (the latter to achieve reduction in elevated serum homocyeteine levels) have failed, suggesting that the biochemical protection these molecules provide in vitro, and in laboratory animal settings, requires the presence of other molecular species in order to act in vivo.

What appears to be unique about the Cretan (and to a lesser extent the SDA diet) is the content of bioprotective nutrients with a broad range of action, specifically the following: 1) a more balanced intake of essemtial fatty acids (EFAs) from vegetable, animal and marine sources; a ratio of (n-6) to (n-3) fatty acids of ;2:1 instead of the 15:1 in most Western diets (it is 16.74:1 in the US); and 2) a diet rich in antioxidants, i.e., high in vitamin C, vitamin E, b-carotene, glutathione, resveratrol, selenium, phytoestrogens, folate, and other phytochemicals from green leafy vegetables; phenolic compounds from wine and olive oil; high intakes of tomatoes, onions, garlic and herbs, especially oregano, mint, rosemary, parsley and dill, which contain  lycopene, allyl thiosulfinates, salicylates, carotenoids, indoles, onoterpenes, polyphenols, flavonoids and other phytochemicals used in cooking vegetables, meat and fish.

Some Serious Caveats Regarding the Applicability of Historical Data

In asking people about how long they expect to live, I’m often surprised by the high degree of confidence they exhibit based on the longevity of relatives. If you challenge the assumption that because their aunts, uncles or parents lived into their 80s or 90s that they will too, you will likely be met with the vehement assertion that this fact pretty much guarantees a similar outcome for the respondents. This assertion would be more credible if their long lived 1^st or 3^rd degree kin were reared under identical, or at least under similar conditions. And therein lies the rub, because this is usually not the case.

Figure 5: Average weekly hours spent on home production from 1900 to 2000 for two aggregates of the population; those in their productive prime, and those in their declining years.

It must be remembered in making historical comparisons with contemporary Westerners in terms of both life expectancy, and dietary or other interventional lifespan studies, that 20th century Cretans and Adventists were, of necessity, far less sedentary than is the average 21st century Westerner today. In this cohort of people housework (household production) involved a considerable amount of exercise, and often no small amount of hard physical labor. Until the middle of the 20th century in the US, laundry was done by hand, in whole or in part, and clothing was hung up to dry, taken down and ironed. Even operating automobiles involved clutching, shifting gears and manual operation of windows – small things by themselves, but cumulatively important.

Figure 6: Between 1950 and 2000 there was a ~ 20% reduction in the types of work classified as “high activity.” What is neither shown nor known is the degree to which both high and low activity jobs have become less strenuous. [24]

Meal preparation in 1965 required ~ 16.5 hours per week and the total numbers of hours spent in home production was on the order of 51.8 hours at that time. [25] As can be seen in Figure 5, time spent on home production decreased significantly beginning around 1960. Beyond the decrease in total hours spent on housework, there was a much larger decrease in the amount of physical effort required. Washing machines and clothes dryers, prepared meal components and entire prepared meals, as well as countless other “labor saving” devices, goods and services have markedly decreased fitness. The same has been true of strenuous physical activity in the work place where the overall number of high activity jobs have decreased by ~ 20% from 1970-2000.[26, 27]  There has also been a large shift in the workplace demographic since the mid-2oth century. Life expectancy increased from 47.3[28] years in 1900 to 77.8 years today, a consequence of which (in part) was the exodus of teens from the workforce. In 1920, ~20% of the US labor force was comprised of males aged 15 to 18 years of age.[28] Today, very few teenagers work full time jobs, and the number of teens employed in summer jobs has decreased from ~60% in 1994, to ~40% in 2008.[29] Of those teens who do find summer employment very few are in physically demanding (and consequently usually hazardous) areas of work, such as construction or agriculture. This change, coupled with increased TV viewing and other sedentary activities, translates into reduced fitness in the age 15-30 demographic.

Figure 7: The graph above shows the distribution of the Body Mass Index between the 1971–1975 and 1988–1994 surveys. Over this time, median BMI increased by 0.9; the 75th percentile increased by 1.5; and the 95th percentile increased by 2.7.[238]

In their article, “Why Have Americans Become More Obese?” Cutler, et al., take the contrary position and argue that it is not reduced energy expenditure (or fitness) in the the population, but rather, the reduced investment required in terms of time per calorie consumed, that has been the primary cause of the change in US, and increasingly Western European eating habits (and thus is responsible for the current epidemic of obesity and type II diabetes).[30] Superior food packaging and preservation have cut not just meal preparation time dramatically, but also cleanup time. The mess generated in the preparation of multiple elements of a meal is now confined to the factory and the cleanup is included in the price of the food. It is also no longer necessary to spend as much time cooking, or even heating food, because it can be rapidly prepared and be made ready to eat in a matter of minutes from refrigerator or cupboard by the use of the microwave oven. These technological changes have thus reduced the threshold for eating formerly time consuming and messy to prepare dishes to the point of almost no effort or expenditure of time at all. It is now almost as easy to eat a piece of cake or pie, a brownie, or complex entree as it once was to eat an apple. All the mess and time involved in baking a cake or a pie from scratch is gone.

Regardless of the cause, we are most certainly not our parents or our grandparents, and as the current epidemic of obesity and type II diabetes attests, we are not likely to age or die as they did, either. Any doubts about the difference between “us” and “them” (or even “us then” and “us now”) should be laid to rest by a careful perusal of Figure 7.

The generations who participated in the AHS and Seven Countries Study were also fed differently. In Europe, they were subjected to nearly a decade of reduced calorie consumption, and even in the US, the relatively high cost of calories (in time, if nothing else) combined with less leisure time and fewer options for sedentary work, no doubt acted to limit calorie consumption, compared to today. This reduced calorie consumption may have been protective, and might have served to add years to life even in the presence or the absence of a more optimal diet. These generations of people were also fed on agricultural products derived mostly from small farms where crops and livestock had the opportunity to acquire a broad range of micro-nutrients and phytochemicals that are now less abundant in the food supply.

How Square is Curve Already?

Figure 8: The death rate from cardiovascular disease in the US has plummeted since the turn of century in part due to the replacement of saturated fats with of polyunsaturated fats in the diet.[31]

It should also be pointed out that data from longitudinal studies like the AHS-1&2 and the Seven Countries Study reach us as light does from a distant star. When we point and look at the star in the crook of the handle of the Big Dipper we say, “Look, there’s Alcor!” But of course that isn’t the Alcors we are looking at, but rather the light that shows what they looked like 83 years ago. Similarly, all of the data in AHS-1&2 and Seven Countries Study is a generation or two (or three!) old by the time we have it. The participants in those studies are mostly dead now, as indeed they would have to be in order for us to be able to plot lifespan curves for them. Thus, it is easy to make the mistake of saying, “If I adopt this diet I can expect 7 additional years of life, or 10 additional years of life, because that’s what the study participants experienced.

At least one problem with that assumption is that some of the benefits from both studies have very likely already been realized in the form of the switch from saturated to poly- and monounsaturated fats in the diet, which began in the early 1960s and continues through the present. The most significant benefit from both the Seven Countries Cretan diet and the Adventist Vegetarian diet has been the reduction in mortality (and morbidity) from CVD that has been ongoing since ~1968 in the US. The death rate from CVD has been halved since 1960 when both of these studies were undertaken (Figure 8). To those who vilify Ancel Keys for not getting it just right, I can only say, “Look at (Figure 8) and try to tell me that you could have done better.” So, we’ve undoubtedly used up some of benefit from these dietary interventions in terms of mean lifespan extension.

Figure 9: These curves show the best case extension of mean lifespan that can be anticipated with the Adventist Vegetarian diet or the Cretan Diet.

Finally, it is critically important to understand that both the Cretan and the Adventist Vegetarian diets are really not “diets” at all, but rather lifestyles. Both lifestyles have in common a strong emphasis on low impact exercise and a non-sedentary way of life. Both lifestyles were a product of a time without televisions or computers, and both lifestyles required then, and will require now, considerably greater time for food preparation and cleanup. The upside of that is that we should also eat less, if Cutler et al., are correct. That is important to consider as well, because, leaving aside whether fats, carbohydrates or protein should comprise X- percentage of a given diet’s calories, one thing both these diets have in common is modest to moderate calorie restriction.  Five, or possibly even 10 extra years of healthy, productive life should hopefully make the practical costs worthwhile.

The Caveman Diet, or Just How Credulous Are You?

“There are races of people who are all slim, who are stronger and faster than us. They all have straight teeth and perfect eyesight. Arthritis, diabetes, hypertension, heart disease, stroke, depression, schizophrenia and cancer are absolute rarities for them. These people are the last 84 tribes of hunter-gatherers in the world. They share a secret that is over 2 million years old. Their secret is their diet- a diet that has changed little from that of the first humans 2 million years ago, and their predecessors up to 7 million years ago. Theirs is the diet that man evolved on, the diet that is coded for in our genes. It has some major differences to the diet of “civilization”. You are in for a few big surprises.

The basic principles of the Paleolithic Diet are so simple that most high school students can understand them. Within 15 minutes from now you will grasp the major elements. At the technical level, Paleolithic Diet Theory has a depth and breadth that is unmatched by all other dietary theories.” – Dr. Ben Balzer, M.D.

The ideas underlying the Cretan Diet and the SDA Vegetarian diet are complex and do not admit of easy reduction to a catchphrase. The actual foods permitted and consumed in both diets differ markedly – one proscribing all meat, the other urging fish consumption, one obtaining most of the dietary fat calories from PUFAs, and the other from monounsaturated olive oil… It is these differences in the face of the common outcome of greatly improved health and moderate extension of the mean lifespan that are, in fact, key, because they tell us about the likely underlying common mechanisms and thus possibly of their action. They also offer us the opportunity for more choice, and therefore for more flexibility and the likelihood of greater compliance.

The Paleo Diet: A diet so unscientific, only a caveman would do it.

That is not, however, how people make a quick buck. Neither diet is particularly ‘sexy.’ And both diets require an understanding of the underlying biology that makes them work in order to be credible. It’s not possible, or at least not as easy to offer up a one sentence explanation for the feeble minded, such as, “This is a healthy diet that will extend lifespan because it is the natural human diet that our ancestors were evolved to eat.”[32-34] That sounds great because it is simple, easy to understand and “seems right” to a lot of uninformed, ignorant and fearful people. It also speaks to that deep and abiding suspicion that our health (and our other woes) is an artifact of our having lost our way – either from the primordial Garden of Eden, or from our biologically appropriate evolutionary ground state (i.e., before we embarked on agriculture). In fact, the emphasis on a 1:1 or 2:1 ratio of (n-6) to (n-3) fatty acids was derived from observations of contemporary hunter gatherer populations who have a low incidence of inflammatory and age-associated degenerative disease compared to that seen in post-agricultural populations. That was a useful insight that was subsequently validated in many human studies, the best of which extended over a period of decades. That’s the heart and soul of Level 1, Evidence Based Medicine.

In 1988, S. Boyd Eaton, Marjorie Shostak and Melvin Konner published a book entitled The Paleolithic Prescription: A Program of Diet & Exercise and a Design for Living[32] advocating a diet based on what the authors hypothesized the primordial pre-agricultural human diet was like. Subsequently, well over a dozen books have been published advocating variations on this diet based on arm chair hypothesizing from findings in the scientific and ethnographic literature.  The diet (depending upon the version you come across) is low (10-15% energy) or moderate in fat , low in carbohydrate (20–40% energy), and  high in protein diet (19–35% energy) which provides 55–65% of total calories from meat, 35–45% of calories from non-grain and low glycemic index vegetable sources with a primarily saturated fat intake (10%–58% energy) similar to or higher than that found in Western diets.[35-37]

The first problem with this approach is that the diet is not validated; the AHS and the Seven Counties studies had the considerable advantage of being able to study actual, living human beings under real world conditions, and then apply those insights to other populations, including populations already suffering from CVD. Indeed, that is where so many of the insights, as well as so many of the unresolved questions regarding these diets/lifestyles come from (i.e., the data are complex and robust). Late Paleolithic people are not only long dead and gone, they are really long dead and gone, and contemporary hunter gatherers – the few that remain – cannot be considered equivalent. Ironically, most of the data cited on the relationship between CVD and diet by the originators of the Paleolithic diet are from the Seven Countries Study![32, 37]

Even more to the point, there is present in the hypothesis of Eaton, Konner et al.,[32, 33] the notion that 10,000 years of agriculture is evolutionarily insignificant. In essence, they posit that human evolution with respect to diet stopped 10,000 years ago.[32, 35] At first glance this might seem to be credible, because human evolution has occurred over a period of millions years and it would seem that any changes that would occur in population genetics over a mere 10,000 years must be trivial. However, this is not the case for several reasons. First, the rate of evolution is a function of a complex interplay of multiple factors, including environmental change and selection pressure. It is only necessary to look at the various breeds of dogs, or pigeons created by artificial selection to understand that evolutionary change can be swift.

The introduction of agriculture was a watershed event and it would be astonishing if it was not accompanied by significant evolutionary adaptations to the dietary changes that resulted.  To understand that this is so it is only necessary to examine the strong natural selection for the gene that controls lactase production.[38] Human populations with a long history of cattle herding and milk consumption can metabolize lactose present in cow’s milk throughout adulthood, whereas populations that did not domesticate cattle cannot. Natural selection for the heterozygous carriers of the sickle-cell gene to maintain sickle-cell trait in populations exposed to malaria is another post-advent of agriculture evolutionary adaptation. This adaptation was selected for as a direct result of an agriculture-induced alteration to the environment; the clearance of the tropical forests in central Africa, which in turn led to the explosion in the population of the Anopheles mosquitoes that are the vectors for the Plasmodium parasite that causes malaria.

Recently developed techniques for measuring genetic variability now allow for the determination of selection operating in the human genome.[39] Directional selection has been identified in the glucose-6-phosphate dehydrogenase (G6PD) gene, which confers resistance to malaria.[40] What is more, G6PD resistance has evolved not once, but twice in humans, in both Africa and in the Americas.[41] Similarly, the genes expressing chemokine receptor 5 (CCR5) among Europeans, which confers resistance to the human immunodeficiency virus (HIV) are likely to have been selected for within this population over a period of several hundred years in response to Yersinia pestis (bubonic plague) and tuberculosis, both of which use the CCR5 receptor as an entry portal into the host.[42]  Numerous other studies have also provided evidence for the recent operation of natural selection on the human genome as a result of very recently developed techniques that allow for comparisons over long sections of DNA.[43-46]

In addition to the conservation of lactase production into adulthood, there is substantial evidence of evolutionary adaptation to the high carbohydrate diet that was a product of agriculture. The incidence of obesity that occurs upon exposure to high calorie “affluence diets” is known to vary greatly by ethnicity. The Pima people (or Akimel O’odham) are a racial group of Amerindians living in central and southern Arizona. One-half of adult Pima Indians have diabetes and 95% of those with diabetes are overweight or obese.

Obesity is thought to be 50-90% heritable. Genome scans in obesity studies are highly reproducible and, despite ethnic and environmental differences, the loci at chromosomes 2 and 10 are generally confirmed as the source of the phenotype. Obesity is “oligogenic,” with expression modulated by “polygenic modifier genes” interacting with the environment in food choices, physical activity, and smoking.[38] Prior to their introduction to the “American” diet after WWII the Pima were not obese and diabetes was extremely rare.[39-41] The diet of the Pima was a very low fat, high carbohydrate diet consistent with the subsistence agriculture of the desert southwest.[42, 43]  Some variations in the ectonucleotide pyrophosphatase phosphodiesterase gene-1 (ENPP1) are associated with a 50% increase in the risk of morbid obesity in adults and a 69% increased risk of childhood obesity. An ENPP1 mutation, for example, which is known to protect against obesity and type II diabetes, is present in about 90 percent of non-Africans, but nearly absent in Africans and, not coincidentally, in the Pima. Human evolution in response to environmental change and in response to dietary change is both ongoing and dynamic.[47][44]

Of course, the Paleolithic diet may be the best diet yet conceived. I could give many reasons why I believe this is not so, but absent hard data gleaned from human trials, I can’t prove much. And that is my final and most important point. I did a Pubmed search using the keywords “Paleolithic diet” and I got 67 hits. Of those 67 hits only 9 were papers that involved actual human or animal application of the diet, or even discussion of same. I’ve copied all of the cites for these studies below:

1: Konner M, Eaton SB. Paleolithic nutrition: twenty-five years later. Nutr Clin Pract. 2010 Dec;25(6):594-602. PubMed PMID: 21139123.

2: Jönsson T, Granfeldt Y, Erlanson-Albertsson C, Ahrén B, Lindeberg S. Apaleolithic diet is more satiating per calorie than a Mediterranean-like diet in  individuals with ischemic heart disease. Nutr Metab (Lond). 2010 Nov 30;7:85. PubMed PMID: 21118562; PubMed Central PMCID: PMC3009971.

3: Klonoff DC. The beneficial effects of a Paleolithic diet on type 2 diabetes and other risk factors for cardiovascular disease. J Diabetes Sci Technol. 2009 Nov 1;3(6):1229-32. PubMed PMID: 20144375; PubMed Central PMCID: PMC2787021.

4: Eaton SB, Konner MJ, Cordain L. Diet-dependent acid load, Paleolithic[corrected] nutrition, and evolutionary health promotion. Am J Clin Nutr. 2010 Feb;91(2):295-7. Epub 2009 Dec 30. Erratum in: Am J Clin Nutr. 2010 Apr;91(4):1072. PubMed PMID: 20042522.

5: Jönsson T, Granfeldt Y, Ahrén B, Branell UC, Pålsson G, Hansson A, Söderström  M, Lindeberg S. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009 Jul 16;8:35. PubMed PMID: 19604407; PubMed Central PMCID: PMC2724493.

6: Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009 Aug;63(8):947-55. Epub 2009 Feb  11. PubMed PMID: 19209185.

7: Osterdahl M, Kocturk T, Koochek A, Wändell PE. Effects of a short-term intervention with a paleolithic diet in healthy volunteers. Eur J Clin Nutr. 2008 May;62(5):682-5. Epub 2007 May 16. PubMed PMID: 17522610.

8: Jönsson T, Ahrén B, Pacini G, Sundler F, Wierup N, Steen S, Sjöberg T, Ugander M, Frostegård J, Göransson L, Lindeberg S. A Paleolithic diet confers higher insulin sensitivity, lower C-reactive protein and lower blood pressure than a cereal-based diet in domestic pigs. Nutr Metab (Lond). 2006 Nov 2;3:39. PubMed PMID: 17081292; PubMed Central PMCID: PMC1635051.

9: Eaton SB, Eaton SB 3rd. Paleolithic vs. modern diets—selected pathophysiological implications. Eur J Nutr. 2000 Apr;39(2):67-70. PubMed PMID: 10918987.

If I enter the keywords “Mediterranean diet” I get 2,269 hits, of which 225 are reports of clinical trials. I will not copy those here!

That’s it. Nine papers of poor quality and not a single clinical trial demonstrating reduced morbidity or mortality – even in CHD or type II diabetes.  Sixty-seven papers of hypothesizing 25 years after this diet was put forth. That is dismal science and it is inexcusable to take a position advocating such an intervention in the complete absence of any evidence that it will actually extend the human (or the laboratory animal) lifespan when there is a large body of high quality data that supports far less extreme, and far more practical dietary and lifestyle interventions that will accomplish those ends.

I have no problem with people coming up with a hypothesis, however kooky or sane, and then proceeding to try it out – even on people – as long as those people have informed consent and the data they are given is accurate. In looking over the various books and the countless media articles on the Paleolithic diet, I was struck by how much the Paleolithic Diet’s hype reminded me of the Pritikin diet hype, and even more so of the Pearson & Shaw Life Extension Revolution circus from 30 years ago. “Live to be 100!” “Feel great! Experience all day energy every day!” “Lose Weight!” Well, at least one of those is very likely true, and that is that most people who undertake any version of the Paleo diets I’ve reviewed will likely lose weight. But as to the other claims? Right now they are preposterous. The sad thing is that for first the time in history we have one diet/lifestyle choice that satisfies EBM-1 criteria, and another that satisfies EBM-2 criteria. Both are “proven” to reduce morbidity from a range of degenerative diseases, and both have been proven to significantly extend mean lifespan…

Max More, CEO Alcor Life Extension Foundation

As I so often say, “You pays your money and you takes your chances.” Still,  it is embarrassing to see cryonicists buy into yet another quick fix cure all, with no appropriate science to back it up. In his article “The Cryo-Paelo Solution”[48] Alcor President Max More advocates the Paleolithic Diet as a life extending add-on to cryonics. This recommendation is supplemented by a web interview.[49] His citations consist these of these popular books on the subject: Loren Cordain, The Paleo Diet; Nora T. Gedgaudas, Primal Body, Primal Mind; Mark Sisson, The Primal Blueprint; Gary Taubes, Why We Get Fat;Gary Taubes, Good Calories, Bad Calories; Arthur de Vany, The New Evolution Diet. The expert More cites as the one to consult for an introduction to Paleo-dieting is Loren Cordain, author of  The Paleo Diet. The quote that open this section on the Paleolithic diet is by Dr. Ben Balzer, M.D., and is from the “Introduction” to Cordrain’s book. Need I say more?

End of Part 3

References

1.            White E: Ministry of Healing: http://books.google.com/books/about/The_Ministry_of_Healing.html?id=2bu2ry223JAC: Kessinger Publishing, LLC; 1905.

2.            Rucker C: The Seventh-Day Diet: A Practical Plan to Apply the Adventist Lifestyle to Live Longer, Healthier, and Slimmer in the 21st Century: Pacific Press Publishing Association 2002.

3.            Mills PK, Beeson WL, Phillips RL, Fraser GE: Cancer incidence among California Seventh-Day Adventists, 1976-1982. Am J Clin Nutr 1994, 59(5 Suppl):1136S-1142S.

4.            Kahn HA, Phillips RL, Snowdon DA, Choi W: Association between reported diet and all-cause mortality. Twenty-one-year follow-up on 27,530 adult Seventh-Day Adventists. Am J Epidemiol 1984, 119(5):775-787.

5.            Grundmann E: Cancer morbidity and mortality in USA Mormons and Seventh-day Adventists. Arch Anat Cytol Pathol 1992, 40(2-3):73-78.

6.            Zollinger TW, Phillips RL, Kuzma JW: Breast cancer survival rates among Seventh-day Adventists and non-Seventh-day Adventists. Am J Epidemiol 1984, 119(4):503-509.

7.            Fraser GE: Diet as primordial prevention in Seventh-Day Adventists. Prev Med 1999, 29(6 Pt 2):S18-23.

8.            Mills PK, Annegers JF, Phillips RL: Animal product consumption and subsequent fatal breast cancer risk among Seventh-day Adventists. Am J Epidemiol 1988, 127(3):440-453.

9.            Mills PK, Beeson WL, Phillips RL, Fraser GE: Bladder cancer in a low risk population: results from the Adventist Health Study. Am J Epidemiol 1991, 133(3):230-239.

10.          Phillips RL, Snowdon DA: Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst 1985, 74(2):307-317.

11.          Fraser GE, Dysinger W, Best C, Chan R: Ischemic heart disease risk factors in middle-aged Seventh-day Adventist men and their neighbors. Am J Epidemiol 1987, 126(4):638-646.

12.          Fraser GE, Lindsted KD, Beeson WL: Effect of risk factor values on lifetime risk of and age at first coronary event. The Adventist Health Study. Am J Epidemiol 1995, 142(7):746-758.

13.          Fraser GE, Shavlik DJ: Risk factors for all-cause and coronary heart disease mortality in the oldest-old. The Adventist Health Study. Arch Intern Med 1997, 157(19):2249-2258.

14.          Giem P, Beeson WL, Fraser GE: The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology 1993, 12(1):28-36.

15.          Fraser GE, Sabate J, Beeson WL, Strahan TM: A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern Med 1992, 152(7):1416-1424.

16.          Fraser GE: Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-day Adventists. Am J Clin Nutr 1999, 70(3 Suppl):532S-538S.

17.          Sabate J: Nut consumption, vegetarian diets, ischemic heart disease risk, and all-cause mortality: evidence from epidemiologic studies. Am J Clin Nutr 1999, 70(3 Suppl):500S-503S.

18.          Willett W: Lessons from dietary studies in Adventists and questions for the future. Am J Clin Nutr 2003, 78(3 Suppl):539S-543S.

19.          Phillips RL, Snowdon DA: Association of meat and coffee use with cancers of the large bowel, breast, and prostate among Seventh-Day Adventists: preliminary results. Cancer Res 1983, 43(5 Suppl):2403s-2408s.

20.          Beck J, Beck, JJ, Jarnes, K.: Adventist Sabbath Dinner Cookbook: Pacific Press Publishing Association; 2001.

21.          Council GCoS-dAN: The Seventh-day Adventist Position Statement on Vegetarian Diets: http://www.sdada.org/position.htm. In.; 2010.

22.          Health LLUSoP: The Vegetarian Food Pyramid: http://www.vegetariannutrition.org/food-pyramid.pdf. In. Loma Linda: Loma Linda University; 2008.

23.          Center S: History of Loma Linda Foods: http://www.soyinfocenter.com/HSS/loma_linda_foods.php. In. Lafayette: Soyinfo Center; 2004.

24.          King G, Fitzhugh, EC, Bassett, DR Jr, McLaughlin, JE, Strath SJ, et al.: Relationship of leisure-time physical activity and occupational activity to the prevalence of obesity. Int J Obes Relat Metab Disord 2001, 25:606-612.

25.          Ramey V: Time Spent in Home Production in the Twentieth-Century United States: New Estimates from Old Data :http://weber.ucsd.edu/~vramey/research/Home_Production_published.pdf. The Journal of Economic History 2009, 59(1).

26.          Borodulin K, Laatikainen, T, Juolevi, A, Jousilahti, P. : Thirty-year trends of physical activity in relation to age, calendar time and birth cohort in Finnish adults. Eur J Public Health 2008, 18(3):339-344.

27.          Brownson R, Boehmer, TK, Luke, DA.: Declining rates of physical activity in the United States: what are the contributors. Annu Rev Public Health 2005, 26(421-43).

28.          Census USBot: U.S. Bureau of the Census, Historical Statistics of the United States, Colonial Times to 1970. 1971.

29.          Camarota S, Jensenius, K. : A Drought of Summer Jobs: Immigration and the Long-Term Decline in Employment Among U.S.-Born Teenagers: http://www.cis.org/articles/2010/teen-study.pdf. In: Backgrounder. Center for Immigration Studies; 2010.

30.          Cutler D, Glaeser, EL, Shapiro, JM.: Why have americans become more obese? Journal of Economic Perspectives 2003 17(3):93-118.

31.          National Heart LaBI: Morbidity & mortality: 1998 chartbook on cardiovascular, lung, and blood diseases. In. Edited by Health UDoHaHSNIo. Rockville, Maryland: US Government Printing Office; 1998.

32.          Eaton S, Shostak, M, Konner, M.: The Paleolithic Prescription: A Program of Diet & Exercise and a Design for Living. New York:: Harper & Row; 1988.

33.          Konner M, Eaton SB: Paleolithic nutrition: twenty-five years later. Nutr Clin Pract, 25(6):594-602.

34.          Lindeberg S: [Paleolithic diet and evolution medicine: the key to diseases of the western world]. Lakartidningen 2005, 102(26-27):1976-1978.

35.          O’Keefe J, Cordain L.: Cardiovascular Disease Resulting From a Diet and Lifestyle at Odds With Our Paleolithic Genome: How to Become a 21st-Century Hunter-Gatherer. Mayo Clin Proc 2004;, 79:101-108.

36.          Cordain L, Eaton SB, Miller JB, Mann N, Hill K: The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr 2002, 56 Suppl 1:S42-52.

37.          Marlowe F: Hunter-gatherers and human evolution. Evolutionary Anthropology 2005, 14:54 -67.

38.          Froguel P, Boutin P: Genetics of pathways regulating body weight in the development of obesity in humans. Exp Biol Med (Maywood) 2001, 226(11):991-996.

39.          Bennett PH, Burch TA, Miller M: Diabetes mellitus in American (Pima) Indians. Lancet 1971, 2(7716):125-128.

40.          Bennett PH, Rushforth NB, Miller M, LeCompte PM: Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res 1976, 32:333-376.

41.          Zimmet P, Arblaster M, Thoma K: The effect of westernization on native populations. Studies on a Micronesian community with a high diabetes prevalence. Aust N Z J Med 1978, 8(2):141-146.

42.          Ravussin E, Valencia ME, Esparza J, Bennett PH, Schulz LO: Effects of a traditional lifestyle on obesity in Pima Indians. Diabetes Care 1994, 17(9):1067-1074.

43.          Boyce VL, Swinburn BA: The traditional Pima Indian diet. Composition and adaptation for use in a dietary intervention study. Diabetes Care 1993, 16(1):369-371.

44.          Malhotra A, Kobes S, Knowler WC, Baier LJ, Bogardus C, Hanson RL: A Genome-Wide Association Study of BMI in American Indians. Obesity (Silver Spring).

45.          More M: The cryo-paelo solution: http://www.alcor.org/magazine/2011/03/07/the-cryo-paleo-solution/. Cryonics (on line edition) 2011.

46.          Snyder S: Alcor CEO Max More and the paleo diet: http://samsnyder.com/2011/05/22/alcor-ceo-max-more-and-the-paleo-diet/. In: A Blog by Sam Snyder. Sam Snyder; 2011.

Figure 1: Ancel Keys (January 26, 1904 – November 20, 2004) was the American physiologist and epidemiology of cardiovascular disease (CVD). He was responsible for two famous diets: K-rations formulated as balanced meals with a long shelf life for combat soldiers in World War II and the Mediterranean (Cretan) diet. Keys is shown (at right, above) two months before his 101st birthday.

The Seven Countries and Adventist Health Studies

Nathan Pritikin drew his initial conclusions about the effect of dietary change from classified data he was privy to during World War II (WWII) on the patterns of age-associated disease in Europe as a consequence wartime calorie restriction and severe reduction of fat intake due to the severely reduced availability of meat and dairy products.  He also observed that the incidence of age-associated degenerative diseases was  very low in human populations where the diet was very low in fat (~10% of the total caloric intake), contained no refined sugars and consisted mostly of fresh vegetables and fruits  with very little meat being consumed. Similarly, the physiologist Ancel Keys (Figure 1), who was working with the Army Quartermaster Corps in developing K-Rations,[1] became involved in the Army’s program to create scientifically informed re-feeding programs for POWs and civilians suffering from starvation, saw the same kind of data. Unlike Pritikin, Keys had the opportunity to do human experimentation afforded by wartime conditions.[2, 3] Keys working hypothesis was different than Pritkin’s, namely that it was primarily saturated fats in the diet that were responsible for the high incidence of cardiovascular disease (CVD) in the affluent and well-fed West.

This epidemiological approach to identifying patterns of food consumption associated with increased or reduced risk of degenerative disease was also being pursued around this time in the US, by physicians at the Loma Linda Medical Center in Loma Linda, CA. Loma Linda was an almost exclusively Seventh Day Adventist community at that time, and these physicians believed that their patients, who practiced a vegetarian diet in conjunction with abstention from tobacco and alcohol, were considerably healthier than the non-Adventist population in California. They began a study of diet, lifestyle and the incidence of disease and all-cause mortality in 1958; the Adventist Health Study-1 (AHS-1) [4-26]

Keys returned to Europe after the war and began a study of six European countries, which later became the Seven Countries Study. [27-72] The dietary recommendations which emerged from the Seven Countries Study are commonly referred to as the “Mediterranean diet.” However, the use of the words “Mediterranean diet” to describe these recommendations is a misnomer. The countries of the Mediterranean basin have large differences in diet, lifestyle and in their corresponding rates of morbidly and mortality. The country with the lowest death rate  (14.0 – 18.0 per 1000 persons), is Crete, whose death rate has been at this level since at least 1930. [73] The diet of Crete is archetypical of the ‘traditional’ Greek diet before the introduction of continental European and American foods into Greece after ~ 1960.

The Seven Countries Study was the first to generate robust data on the incidence of cardiovascular disease in a range of populations (US, Finland, The Netherlands, Italy, the former Yugoslavia, Japan and Greece) with a fairly broad spectrum of dietary patterns. The study showed differences on the order of 5 to 10-fold in coronary artery disease (CAD) between the populations studied. [36, 50, 74]

Figure 2: The Cretan diet food pyramid.

Both the Seven Countries Study and the AHS-1 demonstrated large reductions in disease-specific morbidly and mortality, as well as in all-cause mortality; primarily as a result of diet and lifestyle differences. In the case of the Seven Countries Study, extensive follow-on research using well designed prospective studies, resulted in the development of a set of dietary guidelines which became known as the “Mediterranean” or more correctly, the “Cretan diet.” The guidelines which constitute the Cretan diet satisfy Level-1 EBM criteria for extension of the mean lifespan by ~10 years, reduction in all cause mortality, high levels of compliance, and very importantly, titratability. In other words, the degree of compliance with the diet is roughly commensurate with the benefit that results. [75-77]

What About Cholesterol?

For thirty years an acrimonious debate has raged in the scientific and medical communities over whether cholesterol, or any molecular species of lipoprotein, “causes heart disease” or other CVD. The causes of the inflammatory events that underlie the start of arterial plaque formations are complex, possibly multifactorial (e.g., genetic, viral, microbial, environmental, etc.) and by no means fully elucidated. Keys, Pritikin and many others mistakenly believed that “elevated” serum cholesterol was the primary cause of CVD. This hypothesis is well supported by the epidemiological data. However, there are many people who have normal or even slightly low levels of total cholesterol, or of the low density lipoprotein (LDL) species whose oxidation is usually cited as the motor of atherogenesis.

However, the observations of Keys and Pritkin extended beyond a cause and effect relationship between cholesterol and CVD. In different ways, both men demonstrated that altering the total serum cholesterol level and/or the ratio between the LDL and high density lipoprotein (HDL) species, they could reduce the incidence of the disease. In Pritkin’s case, he even demonstrated that the disease could be reversed by the expedient of a very low fat diet.[78-80] Pritkin demonstrated his theory on a very small population of people; principally those who read his book, or otherwise followed his dietary advice. Keys, on the other hand, conducted an experiment on a grand scale.

Throughout the 1960s Keys campaigned relentlessly to persuade physicians, public health authorities and the public themselves (directly) to replace the bulk of the calories they consumed in (saturated) fat with polyunsaturated fat. The purpose of this international dietary intervention was to reduce the serum cholesterol of the population, and thus the incidence of CVD. This effort enjoyed unprecedented success and it has resulted a doubling of the proportion of the unsaturated fatty acid, linoleic acid, in the tissues of Americans between 1960 and 1975.[81]  The mortality rate from coronary heart disease (CAD) in the US began to fall, starting in 1968, and it has continued to decline since then. It has been estimated that approximately 50% of the decline in CVD is as a result of dietary and lifestyle changes, exclusive of the reduction in tobacco abuse.[82]

As a scientist, I am acutely interested to understand the details of the pathophysiology of atherosclerosis. As someone who wants to avoid CVD, I am much more concerned with what works, even if the biomechanics are incomplete, or even contradictory. In this case, what works is that on a population basis, blood lipids are highly predictive of the risk of disease. Similarly, for most patients, raising HDL and lowering LDL are protective against both the onset of CVD, and to a lesser extent, its progression. Lipid status is thus a useful screening tool, as well as an instructive guide to the individual patient’s likely response to treatment. It is not necessary to believe that “cholesterol,” or any particular species of lipoprotein “causes” CVD. It is only necessary to understand that they are, at the least, useful biomarkers on a population wide basis and that they are often useful in the intelligent management of individual patients.

 Table 1: Fatty Acids Ratios in Different Diets

From the inception of the AHS-1 in 1958, and the Six Countries Study around the same time,[68, 83] the primary focus of the research, as was the case with Pritikin, was on the possible relationship of the diet to the etiology of CVD, with special emphasis on the fatty acid composition of the diet. The 5-year follow-up in the Seven Countries Study found favorable all-cause death rates in Greece, Italy and Japan, as compared with the other countries, including dramatically lower rates of CVD in Crete, and to a lesser extent in Japan.[84]The diet of Crete has in common with the diet of hunter-gatherers similar quantities of antioxidants, saturated fat, fiber, monounsaturated fat and, very importantly, the ratio of (n-6) to (n-3) fatty acids. [75-77]

One the basis of insights gained from the Seven Countries Study a wide range of epidemiologic investigations,  controlled clinical trials and relevant animal experiments have confirmed the hypotriglyceridemic, anti-inflammatory and antithrombotic aspects of (n-3) fatty acids (28 –35) as well as the criticality of (n-3) fatty acids, particularly Docosahexaenoic (n-3) (DHA) acid in the diet for the normal development of the retina and brain in the human infant. As a consequence of these insights, a study of the (n-3) fatty acid composition of diets that were known to be associated with reduced rates of CVD and cancer was undertaken.[75] The initial conclusion was that the high olive oil intake, which accounts for ~35% of the calories consumed in the Cretan diet, was likely responsible for the low rates of CVD and cancer. However, the Japanese have a similarly low incidence of these diseases and yet only ~11% of their calorie intake is from fat, none of which is from olive oil.

Figure 3: Mortality and morbidity difference between populations of patients with coronary artery disease (CAD) eating the Cretan diet and those on the low fat American Heart Association Step 1 diet[151]

The common factors between the populations of Crete and Japan were that they both consumed large amounts of vegetables (including wild plants), fruits, nuts and legumes, all of which are rich sources of folic acid, glutathione and vitamins E, C and other antioxidants. Wild plants are rich sources of (n-3) fatty acids and antioxidants and their consumption is not confined to humans. Both in Crete and in rural Japan, chickens and other livestock, such as goats and cows, are free ranging and consume wild vegetation in abundance (and in the case of chickens, insects, arachnids and worms) which are rich in (n-3) fatty acids and antioxidants, as well as cytoprotective and vasculoprotective trace minerals which are concentrated in the food chain. The result is poultry, eggs and milk which contain radically different ratios of (n-3) to (n-6) fatty acids and are enriched with selenium. For example, eggs from Crete have a ratio of (n-6) to (n-3) of 1:3, whereas the US ‘battery egg’ has a ratio of 19:4. Of course, the presence of this favorable ratio of lipids in eggs is also reflected in prepared foods which contain eggs (such as noodles, some breads and soups, etc.) and in the flesh of the animals that are slaughtered and eaten.

Analysis of the serum (n-3) fatty acid levels of the populations in Crete and Japan demonstrated that they had had higher concentrations of (n-3) fatty acids than did the other populations in the study, all of whom had a far high incidences of age associated degenerative diseases. The two populations with the lowest CAD in the Seven Countries Study consumed the highest amount of α-linoleic acid (α-LNA) the major sources of which were the wild herb purslane, walnuts and figs. By contrast, the Japanese obtained their α-LNA from canola and soybean oils. Interestingly, the Seventh Day Adventists, who experience an increase in mean lifespan of 7.28 years (95% confidence interval, 6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88 years) in women over that of their non-Adventist cohorts in the US[10], consume a vegetarian diet that is rich in nuts and oils containing α-LNA. The SDAs, like the people of Crete, have not only higher levels of α-LNA, but also lower levels of linoleic acid[9, 85, 86]

Figure 4: The Lyon Diet Heart Study demonstrated a 50 to 70% reduction of the risk of recurrence of myocardial infarction (MI) after four years of follow-up in coronary heart disease (CHD patients. The Lyon diet employed α-LNA as 0.6 to 1% of total daily energy or about 2 g per day in patients who follow a traditional Mediterranean diet. Supplementation with very long chain omega-3 fatty acids (c.1g per day) in patients following a Mediterranean type of diet was shown to decrease the risk of cardiac death by 30% and of sudden cardiac death by 45% in the GISSI trial. [87]

In 1994 de Lorgeril and Renaud published the results of a prospective study to evaluate a diet which contained the types and ratios of essential fatty acids (EFAs) found to be effective at reducing CVD in the Seven Countries Studies. The Lyon Heart Study (LHS), as it came to be known, was a randomized, single-blind secondary prevention trial that combined a modified Cretan diet enriched with α-LNA with that of the Step I American Heart Association diet.[87] The LHS demonstrated a reduction in all-cause mortality of 70% in the experimental population which consumed a diet low in butter and processed meats, but high in fish, nuts, fruits and vegetables (Figure 5).[87] The LHS followed subjects for 5 years after the start of the intervention and examined the reduction of risk for coronary artery disease (CAD) as well as in mortality from all cancers. The reduction in CAD was 56% (P 5 0.03) over that of control subjects, and in cancer mortality it was 61% (P 5 0.05)!

Figure 5: Cardiac morbidity and mortality in the Lyon Diet Heart Study. Of particular importance to cryonicists is the reduction in mortality from sudden cardiac death (SCD). [87]

Olive Oil, or Something Else?

Figure 6: The author has serious questions about whether experiments conducted using industrially prepared laboratory animal chows (right) are representative of the results obtained when fresh fruits and vegetable as well as foods consumed in their native state are used (left).

An initial and obvious conclusion from The Seven Countries Study was that a significant part of the reduction in morbidity and the extension of lifespan due to the Cretan diet was a consequence of the consumption of a large fraction of the calories in the diet in the form of monounsaturated  fats (MUFAs), principally as a result of olive oil consumption. However, recent animal studies have yielded paradoxical results. For instance, experiments in green monkeys have shown that a diet high in MUFAs (olive oil source) causes atherosclerosis equivalent to that observed in animals fed a diet high in saturated fats (SFAs).[88] This effect appears to result from an increased secretion of cholesteryl oleate enriched lipoproteins, as well as due to an increase in the circulating blood levels of chylomicron remnants, which are highly atherogenic lipoproteins. [89-91]

These paradoxical animal results have raised questions amongst epidemiologists and nutritionists about whether MUFAs really have beneficial effects in humans. Green monkeys are metabolically and genetically different than humans and the human data indicate that dietary MUFAs have favorable effects on CHD risk. There is also a significant amount of mechanistic data that indicate that there are molecular species in olive oil that have potent antioxidant and anti-inflammatory properties. In particular, the polyphenolic compounds hydroxytyrosol and oleuropein have been shown to possess these properties both in vitro and in vivo.[92-96] There is also the issue of the way in which olive oil is incorporated into the chow for experimental animals (Figure 6). Olive oil incorporated into a manufactured chow along with other dietary ingredients is not the way in which humans consume it, and this factor should be taken into consideration in future studies.

Figure 7: The titratability of the beneficial effects of the Cretan diet are nicely illustrated in this series of graphs showing all cause mortality over a ten year period with three variations of the Cretan diet; the world Health Organization recommended diet base on the Seven Countries Study, a broadly similar diet, and a carbohydrate restricted version of the Cretan Diet. Kaplan-Meier survival curves for individuals considered adequate reporters of dietary intake, grouped as low-, medium-, or high-adherent individuals to the dietary patterns investigated. Crude hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression analyses with the use of low-adherent individuals as the reference group for each dietary pattern. A: World Health Organization (WHO) dietary guidelines, according to the Healthy Diet Indicator: medium adherent (HR: 0.70; 95% CI: 0.43, 1.15), high adherent (HR: 0.97; 95% CI: 0.45, 2.07). B: Mediterranean-like diet, according to the Mediterranean Diet Score: medium adherent (HR: 0.68; 95% CI: 0.44, 1.04), high adherent (HR: 0.29; 95% CI: 0.12, 0.70. C: Carbohydrate-restricted (CR) diet, according to the CR diet score: medium adherent (HR: 1.92; 95% CI: 1.02, 3.62), high adherent (HR: 2.17; 95% CI: 1.05, 4.45).[148]

Anti-inflammatory and Cytoregulatory Lipids in the Cretan Diet

One proposed resolution to the paradoxical animal findings regarding the atherogenicity of olive oil in the laboratory is the observation that both the high fat MFA diet of the Cretans, and the low fat PFA diet of the Japanese, are rich in (n-3) fatty acids and antioxidants, in particular resveratrol, glutathione, vitamin C, vitamin E, lycopene, b-carotene, polyphenols and polyamines obtained from fruits, vegetables, wild plants, and olive oil. [97] [98-101] Additionally, both diets are enriched in α-LNA and eicosapentaenoic acid [EPA, 20:5 (n-3)] from the consumption of large amounts of fish, relative to the control countries.[159, 171, 174] Because olive oil is high in the monounsaturated fatty acid oleic acid [18:1, (n-9)] and low in saturated (n-6) fatty acids it cannot compete with the endogenous desaturation and elongation of α-LNA, or with the incorporation of α-LNA into the constituent phospholipids of cell membranes. This is particularly important in the case of red blood cell (RBC) and platelet membranes, where they act to increase the deformability of RBCs and decrease the aggreability and adhesions of platelets. [102-108]

The ratio of (n-6) to (n-3) lipids in the Cretan diet is between 2:1 and 1:1, which is very close to the dietary ratio of the Japanese, as that of hunter-gatherer societies. The beneficial effects of such a ratio and their importance in normal growth and development [109, 110] as well as in the reduction of risk for CVD, hypertension, type II diabetes, osteoarthritis and, to a lesser extent cancer, are voluminously documented in the literature.[111] [112-116] The traditional Greek diet is very low in animal fat and thus the saturated fat content is quite low (7–8%). This low intake of SFAs is complemented by the high intake of  (n-6) and (n-3) EFAs which are also rich in phytoestrogens and other phytochemicals  as well α-LNA, vitamin C, vitamin E and glutathione.[117, 118] These molecules have been shown to have hypoglycemic, hypocholesterolemic and antitumor properties in animal experiments.[119-124] Consistent with these findings is the fact that the mortality from breast, prostate, bladder and colorectal cancer is lower in both the Cretan and the AHS populations than is the case for controls. [14, 20, 86, 125-129]

The principal EFA in the US diet is LA, an (n-6) fatty acid which is the precursor to the eicosanoids – molecules which have proinflammatory and cytoproliferative effects. The EFAs are converted to prostaglandins by the cyclooxygenases and to leukotrienes (LT) by the lipoxygenases. Arachidonicacid [(AA); 20:4(n-6)] and EPA, an (n-3) fatty acid, compete for cyclooxygenases and lipoxygenases, resulting in the production of eicosanoids with opposing effects. In general, AA-derived eicosanoids, such as the 2-series prostanoids and 4-series LTs, have pro-inflammatory effects, whereas EPA-derived eicosanoids, such as the 3-series prostanoids and5-series LTs, have anti-inflammatory effects. A focus of recent research has been to understand the importance of the (n-6) to (n-3) ratio, rather than the absolute level of either species of PUFA in cancer prevention.[102, 130]

Figure 8: The major active product of the omega-6 fatty acids is arachadonic acid which is converted to the 2-series prostaglandins and 4-series leukotrienes by the action of cyclooxygenase. The 2-series prostaglandins are pro-inflammatory.  In addition to the AA produced endogenously there are vast supplies available from the diet, most notably in meat, eggs and peanut oil.  In the Western diet there are comparatively few products of omega-3 metabolism to moderate the pro-inflammatory action of excessive dietary omega-6consumption. If the amount of omega-3 fatty acids in the diet is increased, their metabolites (primarily EPA and DHA) compete with arachidonic acid for access to cyclooxygenase resulting increased production of anti-inflammatory mediators as well as a decrease in the pro-inflammatory mediators, thereby significantly reducing the ratio of pro-inflammatory to anti-inflammatory mediators.

In animal studies (rats) LA increases the size and number of tumors, whereas fish oil [containing the (n-3) fatty acids EPA and DHA] decreases the incidence of tumor formation, as well as tumor size.[131] This finding is consistent with other studies in rats that indicate that the potent inhibitors of prostaglandin synthesis, the NSAIDs indomethacin and flurbiprofen are effective at reducing the incidence of spontaneously occurring breast cancer. Epidemiological studies in humans have also indicated a potentially chemoprotective effect as result of long term consumption of NSAID drugs.[132-136] Fish oils have been used to adjust systemic levels of  (n-3) fatty acids in animals models of colon, lung, breast, pancreatic and prostate cancers to reduce prostaglandin synthesis, with resulting chemoprevrention and/or slowed growth and metastases in neoplastic disease in the laboratory setting.[131]

These studies, together with the epidemiologic evidence, appear to confirm the importance of a (n-6) to (n-3) ratio of 2:1 as being chemoprotective in cancer, and raise the possibility that (n-3) fatty acids might be used as adjuvant therapy to reduce the risk of recurrence and metastases of breast cancer in humans following surgery and chemotherapy.[132-136] Epidemiological studies have also consistently shown that fish oil consumption protects against the development of a broad range of cancers, but especially breast and prostate cancer. [137-144] Thus, it is not the absolute level of either (n-3) or (n-6) lipids, but rather their presence in a ratio of 1:1 or 2:1 that chemoprotective against a number of cancers[128, 129, 145, 146] Western diets have a ratio of 10–20:1.[147]

Figure 9: The Cretan diet provides significant protection against Alzheimer’s disease (AD) in patients who have been diagnosed with mild cognitive impairment (MCI). Survival curves based on Cox analysis comparing cumulative AD incidence in subjects with MCI at the first evaluation by Mediterranean diet (MeDi) adherence tertile (P for trend = .02). The figure is derived from a model that is adjusted for cohort, age, sex, ethnicity, education, APOE genotype, caloric intake, body mass index, and time between the first dietary assessment and the first cognitive assessment. Duration of follow-up is truncated at 10 years. Results of log-rank tests for pairwise comparisons are as follows: middle vs low tertile, ² = 4.26, P = .03; low vs high tertile, ² = 1.39, P = .23; and middle vs high tertile, ² = 0.12, P = .72.[148, 149]

Both the Cretan and the Adventist vegetarian diets confer substantial protection against the mild cognitive impairment (MCI) of aging and against Alzheimer’s disease (AD)(Figure 9)[148, 149] Interestingly, the AHS-2 results demonstrate a link between the incidence of dementia and the consumption of all meat products, including fish and poultry. This may account for added benefit of Adventist Vegetarian diet over what would be expected on the basis of its lipid constituents and the presence of some adverse foodstuffs, such as refined sugar. Perhaps meat consumption is associated with adverse effects, per se? The literature is open to interpretation on this point.[150, 151]

The two highest quality studies examining the effect of vegetarian diets on lifespan, as well as morbidity were conducted by Key, et al., and were published in 2009.[152, 153] These studies found no significant difference in lifespan between the control and the vegetarian populations in the study. However, as so often happens in studies of this kind, both the control and the vegetarian group experienced statistically significant lower rates of mortality than the general population (UK). This kind of confounding result may be due to self-selection of on average healthier people within the general population to serve as controls. Another limitation on these studies is that they were barely powered adequately to detect small to moderate differences in mortality. The vegetarian group in this study had a lower body mass index (BMI) and consequently less obesity. The incidence of CVD and cancer were not statistically significant between the groups.

End of Part 2

References

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134.        Ge Y, Chen Z, Kang ZB, Cluette-Brown J, Laposata M, Kang JX: Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells. Anticancer Res 2002, 22(2A):537-543.

135.        Bardon S, Le MT, Alessandri JM: Metabolic conversion and growth effects of n-6 and n-3 polyunsaturated fatty acids in the T47D breast cancer cell line. Cancer Lett 1996, 99(1):51-58.

136.        Chajes V, Sattler W, Stranzl A, Kostner GM: Influence of n-3 fatty acids on the growth of human breast cancer cells in vitro: relationship to peroxides and vitamin-E. Breast Cancer Res Treat 1995, 34(3):199-212.

137.        Nielsen N, Hansen, JPH.: Breast cancer in Greenland-selected epidemiological, clinical and histological features. J Cancer Res Clin Oncol 1980, 98:287-299.

138.        Terry P, Lichtenstein, P, Feychting, M, Ahlbom, A, Wolk, A.: Fatty fish consumption and risk of prostate cancer. Lancet 2001, 357:1764-1766.

139.        Wargovich MJ: Fish oil and colon cancer. Gastroenterology 1992, 103(3):1096-1098.

140.        Caygill CP, Charlett A, Hill MJ: Fat, fish, fish oil and cancer. Br J Cancer 1996, 74(1):159-164.

141.        Lindner MA: A fish oil diet inhibits colon cancer in mice. Nutr Cancer 1991, 15(1):1-11.

142.        Mandal CC, Ghosh-Choudhury T, Yoneda T, Choudhury GG, Ghosh-Choudhury N: Fish oil prevents breast cancer cell metastasis to bone. Biochem Biophys Res Commun, 402(4):602-607.

143.        Moreira AP, Sabarense CM, Dias CM, Lunz W, Natali AJ, Gloria MB, Peluzio MC: Fish oil ingestion reduces the number of aberrant crypt foci and adenoma in 1,2-dimethylhydrazine-induced colon cancer in rats. Braz J Med Biol Res 2009, 42(12):1167-1172.

144.        Chiang KC, Persons KS, Istfan NW, Holick MF, Chen TC: Fish oil enhances the antiproliferative effect of 1alpha,25-dihydroxyvitamin D3 on liver cancer cells. Anticancer Res 2009, 29(9):3591-3596.

145.        Miano L: [Mediterranean diet, micronutrients and prostate carcinoma: a rationale approach to primary prevention of prostate cancer]. Arch Ital Urol Androl 2003, 75(3):166-178.

146.        Yee LD, Young DC, Rosol TJ, Vanbuskirk AM, Clinton SK: Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. J Nutr 2005, 135(5):983-988.

147.        Simopoulos A: Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet 2001, 88:18-27.

148.        Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA: Mediterranean diet and mild cognitive impairment. Arch Neurol 2009, 66(2):216-225.

149.        Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA: Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006, 59(6):912-921.

150.        Appleby PN, Thorogood M, Mann JI, Key TJ: The Oxford Vegetarian Study: an overview. Am J Clin Nutr 1999, 70(3 Suppl):525S-531S.

151.        Key TJ, Appleby PN, Rosell MS: Health effects of vegetarian and vegan diets. Proc Nutr Soc 2006, 65(1):35-41.

152.        Key TJ, Appleby PN, Spencer EA, Travis RC, Roddam AW, Allen NE: Mortality in British vegetarians: results from the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr 2009, 89(5):1613S-1619S.

153.        Key TJ, Appleby PN, Spencer EA, Travis RC, Roddam AW, Allen NE: Cancer incidence in vegetarians: results from the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr 2009, 89(5):1620S-1626S.

Calorie Restriction: First You Starve and Then You Die (Horribly)

Figure 1: Supercentenarians in “extreme old age”:  Jeane Calmette, 121; Ingeborg Mestad, 110; Walter Breuning, 114; Marie-Louise Meilleur, 117.

There’s a proven technique in animals for reaching the maximum lifespan; the longest time that animals of a given species have the inherent capacity to survive. It’s called calorie restriction, and there is a large body of animal data in an impressive range of species that says it works. There is even an ongoing project being conducted by the National Institutes of Aging (NIA) to evaluate calorie restriction in primates and it seems to be working in them, too. The calorie restricted Rhesus macaque monkeys have lower death rates, lower rates of age-associated degenerative diseases, and their overall health and activity level are dramatically better than is the case for the control animals, who are fed a diet that simulates the ad lib calorie intake by humans in the Developed World.

There’s just one catch, and that is that calorie restriction, to the extent necessary to get the individual to the maximum end of the lifespan envelope is, for most humans, a miserable experience. It is also one fraught with the potential for malnutrition and the development of eating disorders, such as anorexia nervosa and bulimia. But there’s another problem with calorie restriction in humans, and that’s that the end results are that you end up a blind, debilitated old crone or codger, and then you die.

Having said that, I don’t want to minimize or dismiss the probable very real advantages of calorie restriction in humans and they are that there is likely to be, on average, a 15-25 year extension of the healthy and reasonably productive lifespan, with a large decrease in most of quality of life eroding (and costly) degenerative diseases, such as diabetes, cardiovascular disease, osteoarthritis, dementia and very likely, tooth decay and gum disease. That’s impressive, even if it isn’t very practical for most people without some kind of pharmacological assistance.

There is also ongoing research to discover drugs that mimic the effects of calorie restriction on gene expression so that the benefits of the technique can be had without the attendant suffering and the very real risks of adverse effects on psychology and nutrition.[1] This is a promising area of research, and it will be covered here in considerable detail on an ongoing basis. However, this is not the time to start any discussion of  specific ‘evidence based’ technologies for extending healthy lifespan. Indeed, before we go any further, it is necessary to become familiar with the concept of evidence based medicine (EBM) (Figure 2).

Evidence Based Medicine

Figure 2:  Detailed Diagrammatic representation of the levels of evidence used in Evidence Based Medicine.

Evidence-based medicine (EBM), also called evidence-based practice (EBP) aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments, including the lack of treatment, and diagnostic tests.Evidence quality can range from meta-analyses and systematic reviews of double-blind, placebo-controlled clinical trials at the top of the pyramid (above), to conventional wisdom at the bottom.

The discrete types or levels of evidence I will be using in all my discussions here on Chronosphere are those of the Centre for Evidence Based Medicine (CEBM),  as set out in their “’Levels of Evidence’ Document” which is reproduced, below.

1. A summary of how evidence can be graded.

In simple terms, one way of looking at levels of evidence is as follows (the higher the level, the better the quality; the lower, the greater the bias):

or…

• Category I:  Evidence from at least one properly randomized controlled trial.
• Category II-1: Evidence from well-designed controlled trials without randomization.
• Category II-2: Evidence from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
• Category II-3: Evidence from multiple times series with or without intervention or dramatic results in uncontrolled experiments such as the results of the introduction of penicillin treatment in the 1940s.
• Category III: Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

[Source: Harris, R.P. et al. (2001). Current methods of the U.S. Preventive Services Task Force: a review of the process. American Journal of Preventive Medicine. April 20 (3 Supplement): 21-35.]

Not surprisingly, the place to start in looking for any reliable method(s) of life extension is at the top of the evidence pyramid, which consists of Systematic Reviews (including well designed meta-analyses) and Randomized Double Blind Clinical Studies.

Figure 3: The EBM pyramid made simple.

The majority of “amateur interventive gerontologists,” or active “life extensionists” who are pursuing lifespan extending therapies on themselves are usually both surprised and dismayed when looking at this pyramid (Figure 3). The first reason for this is that either all, or almost all, of the interventions they are using are at the very bottom of the pyramid. The second reason for the shock and dismay (and often disbelief) is that animal and in in vitro research rank below the ideas, editorializing and opinions of medical professionals, instead of at the top of the pyramid, where most activist life extensionists typically feel they should belong.

However, the fact is that very little animal, or in vitro research has any direct clinical applicability to humans.[2-4] This is not because government regulations or “greedy” pharmaceutical companies don’t want people to benefit from disease-curing or life extending drugs, but rather, because the vast majority of that research is either bad (junk) science or it fails to translate to humans.[4-10] Even when animal studies are well designed and carried out in relevant animal models of disease and show strongly positive results, mostly these findings fail to translate to humans. There are many reasons for this, but chief amongst them is that animals, despite their high ‘percentage’ of genetic overlap with humans, are really biochemically sufficiently different that the findings aren’t applicable to humans. The public are bombarded with numbers, such as chimpanzees are 96% to 98% genetically homologous with humans; cats: 90%, dogs: 82%, cows: 80%, rats: 69% and mice: 67% (http://www.ncbi.nlm.nih.gov/homologene).  These numbers get even more impressive when it is noted that 75% of mouse genes have equivalents in humans and 90% of the mouse genome can be matched to a comparable region on the human genome. In fact, recent research indicates that ~ 99% of mouse genes turn out to have analogs in humans.

Figure 4: If we were mice, most cancers would be treatable or cured, there would be effective drugs for stroke and cerebral ischemia, and a wide range of other conditions would have effective therapies. However, we are not mice.

So what’s the problem with the applicability of animal research to humans? Well, consider that at in 3 out of ten patients the drug prescribed for them fails to work. It’s not that the patient is non-compliant or just doesn’t get better; it is that the drug failed to have the anticipated therapeutic effect. Thus, in those patients, the drug was a waste of money and time; and to the extent that it may have adverse effects, a real danger. In fact, there are 2.2 million serious cases of adverse drug reactions (ADRs) and over 100,000 deaths each year in the US. That makes (ADRs) one of the leading causes of hospitalization and death in the US! Most people take ADRs and lack of therapeutic effect in the drugs they are prescribed (or purchase over the counter (OTC)) for granted. “Oh, that doesn’t work for me,” or “I can’t take that because…” are commonplace remarks. And they apply to people who use only “natural” or herbal remedies as much or more as they do those who use “synthetic” drugs.

The reason for these phenomena is very instructive about why animal research turns out to have so little applicability to humans. The cause of the huge variation in responsiveness to drugs in humans is genetic variation between individuals; even identical twins are not genetically identical, due to mutations and to variations in gene activation (epigenetic factors).[11] There are two types of genetic variations known to impact drug metabolism; copy number variation, which results from deletions, inversions, insertions and duplications in genes, and nucleotide variations, or single nucleotide polymorphisms (SNPs). It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to gene copy number. The nucleotide diversity (SNPs) between humans is about 0.1%, which is 1 difference per 1,000 DNA base pairs! Combine these two numbers and human genetic variation is estimated to be at least 0.5% or, if you prefer, 99.5% similarity between individuals.[11-13]

That seemingly trivial amount of genetic variation is responsible for the observed and well documented large disparity in response to therapeutic drugs observed within the human species. Even the SNPs (pronounced “snips”) have a profound effect on the response (or lack thereof) to therapeutic drugs and they are the sources of a major research effort to develop a catalog of SNPs that can be used as a diagnostic tool to predict and individual person’s drug response. This rapidly developing area of research is called pharmacogenomics and it has already seen clinical application in cancer chemotherapy, anticoagulant dosing, the treatment of Hepatitis C and psoriasis, and in seizure disorders.[14-20]

New Drug Development: May I Suggest Roulette, Instead?

A few more words need to be said about the drug development research and success. Leaving animal data aside, most human clinical trials to evaluate refinements of existing (and proven) drugs or therapies either fail, or result in active harm.[2, 21-23] The chances of a novel molecule making it from in vitro or animal testing to clinical use in humans are ~ 1,000 to 1. You’d be much, much better off playing straight-up roulette, where the odds against you are only 37 to 1. Even in studies or clinical trials where there are ample existing theory and prior in vitro, animal research and clinical trials data that were positive and point compellingly to a favorable outcome, trials often fail.

A good example of this with direct relevance to life extensionists is the saga of vitamin E in the treatment and prevention of atherosclerosis, and in particular, coronary artery disease.There are many animal experiments showing that vitamin E reduces or inhibits the development of atherosclerosis. Epidemiological studies in humans provided robust support to these data, since consumption of vitamin E in the diet was inversely associated with mortality from cardiovascular disease.[24, 25] And to the theoreticians and mechanists, there was the perhaps even more compelling fact that the free radical biochemistry implicated as being a primary factor underlying atherogenesis (oxidized low density lipoprotein (LDL)) is favorably impacted by the addition of vitamin E and similar chain breaking antioxidants to the diet in supraphysiological amounts.[26] The free radical theory of aging also supports the idea that vitamin E and other antioxidant molecules might reduce the incidence of degenerative disease, and perhaps retard aging. Further, in accordance with both theory and the animal data, administration of vitamin E to human volunteers reduced the level of lipid peroxidation, and in particular reduced the level of oxidized LDL.[27]

Figure 5:*NHS indicates Nurses’ Health Study; HPS, Health Professionals’ Follow-up Study; EPESE, Established Populations for Epidemiologic Studies of the Elderly; IWHS, Iowa Women’s Health Study; MI, myocardial infarction; and ellipses, none.

Several prospective studies in which vitamin E was given as a supplement, including the US Nurses’ Health Study[28] and the US Health Professionals’ Follow-up Study, found a 34% and 39% reduction (respectively), in the incidence of myocardial infarction, [29] More impressively still, the  Iowa Women’s Health Study found a 47% reduction in cardiac mortality.[30] These were not small studies published in obscure journals. They were very large trials (Figure 5) and they were published in the New England Journal of Medicine. So what’s the problem? The problem was that other researchers could not duplicate the results and so subsequent, carefully designed trials were conducted.

The largest and best designed of these was the a randomized, placebo-controlled Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study in which antioxidant vitamin supplementation was examined in 20,536 individuals with coronary disease, other occlusive arterial disease, or diabetes mellitus. The study participants were randomized to receive vitamin E (600 mg), vitamin C (250 mg), and beta carotene (20 mg) daily or matching placebo. Intention-to-treat comparisons of outcome were conducted among all participants. An advantage to this study was that critics of earlier failed trials pointed out that vitamin E can act as a pro-oxidant in the absence of vitamin C and that it has in vitro pro-oxidant activity in cell membrane lipids under some conditions. In vivo, vitamin C is the molecule which disposes of the water soluble radical species that can be generated by vitamin E and beta carotene was added to scavenge lipid soluble radicals.

The MRC/BHF study found no significant differences between the vitamin and placebo groups in all-cause mortality, or in deaths caused by vascular or nonvascular conditions. Nor were there any significant differences between groups in the incidence of nonfatal myocardial infarction or sudden cardiac death, nonfatal or fatal stroke, or coronary or non-coronary re-vascularization. In fact, the study found that the use of antioxidant vitamins did not produce any significant reductions in 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome, compared with placebo.[31]

Other studies also showed no benefit [32-34] and there was even some suggestion of harm in the form of an apparent increase in mortality and morbidity from gastrointestinal and intracranial bleeding. In 2009, a metanalysis of vitamin E supplementation trials by Dotan, et al., using Markov model analysis showed that the vitamin E supplemented “virtual cohort” had 0.30 decrease in their quality-adjusted life year (QALY) (95%CI 0.21 to 0.39) compared to the non-treated “virtual cohort.”[35] QALY is a statistical measurement tool used to evaluate not just death or discrete injurious events, such as heart attack or hemorrhagic stroke, but rather measure these events, along with all deaths or debilities as a single entity, and report them in terms of how much loss or gain of functional life occurs in a given group. This work supports an earlier metanalysis showing increased all-cause mortality associated with vitamin E doses ~500 mg/day or more. When a metanalysis was done to look specifically for the effects of vitamin E on stroke it was found that vitamin E increased the risk for hemorrhagic stroke by 22% and reduced the risk of ischemic stroke by 10%.[1]

The metanalysis indicating that vitamin E supplementation (≥500 mg q.d.) is associated with an increase in morbidity and mortality is consistent with the known effect of vitamin E in such doses on bleeding time. Supraphysiologic vitamin E antagonizes vitamin K and causes platelet dysfunction resulting in an increased prothrombin time. It is almost axiomatic in medicine that any increase in bleeding time (anticoagulation) is associated with an increased incidence of clinically significant gastrointestinal (GI) and intracranial bleeding. For vitamin E to show benefit, it would be necessary for any increase in adverse effects to be offset by the benefits it conferred. For vitamin E, this was not the case, whereas for aspirin, which also increases bleeding time and causes an increased incidence of GI and intracranial bleeding, shows such strong benefit in the reduction of myocardial infarction that it is worth the associated risk in the appropriate patient population (i.e., those 50 or over and those with known cardiovascular disease).

This kind of “reversal of fortune” happens over and over again in medicine with respect to drugs as as to other treatment interventions and it is one of the well justified reasons why the astute clinician is very skeptical about putative therapies to treat disease that have not been scientifically vetted – preferably repeatedly, internationally and in well designed and executed trials. It is thus an unfortunate reality that no matter how compelling a therapy seems theoretically or in the laboratory, it still must be proven clinically. And it is even truer that the overwhelming majority of putative therapeutic interventions either fail to work, or injure or kill the patient. There is absolutely no reason to think that this will not be the case with putative life extension drugs.

It is also usually the case that taking multiple drugs, or polypharmacy as it is formally known, negatively shifts the risk to benefit ratio (especially in the ill the debilitated or the elderly). This is so because the biochemistry of living systems is not only enormously complex; it is also interdependent and self regulating. The vast majority of drugs, or supraphysiological doses of nutrients, will perturb multiple biochemical pathways and the more molecules administered, the more likely it becomes resulting adverse interactions will occur. It is, as the Taoist maxim cautions, virtually impossible “to do just one thing” when dealing with a complex and dynamic system. Alter one part of the system in a desirable way and there will likely be consequences in other parts of it – and the odds are high that they will not be favorable.[2]

Thus, in making decisions about which putative life extension therapies to use, the most rational course is to start with those where there is Level-1 evidence of benefit. That may not even seem possible, since there are no known lifespan extending drugs or treatments in humans, let alone ones that have undergone extensive, well designed and repeated clinical trials. Or are there? The answer to that question will be the subject of the next article in this series.

Footnotes

 References

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2.            Ikonomidou C, Turski L: Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 2002, 1(6):383-386.

3.            Ozdemir FN, Akcay A, Elsurer R, Sezer S, Arat Z, Haberal M: Interdialytic weight gain is less with the Mediterranean type of diet in hemodialysis patients. J Ren Nutr 2005, 15(4):371-376.

4.            Whiteside GT, Adedoyin A, Leventhal L: Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology 2008, 54(5):767-775.

5.            Harber LC, Armstrong RB, Ichikawa H: Current status of predictive animal models for drug photoallergy and their correlation with drug photoallergy in humans. J Natl Cancer Inst 1982, 69(1):237-244.

6.            Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W et al: Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000, 32(1):56-67.

7.            Pound P, Ebrahim, S, Sandercock, P, Bracken, MB, et al.: Where is the evidence that animal research benefits humans?: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC351856/pdf/bmj32800514.pdf. BMJ 2004, 328:514-517.

8.            Dixit R, Boelsterli UA: Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discov Today 2007, 12(7-8):336-342.

9.            Caldwell J: Problems and opportunities in toxicity testing arising from species differences in xenobiotic metabolism. Toxicol Lett 1992, 64-65 Spec No:651-659.

10.          Wilbourn J, Haroun L, Heseltine E, Kaldor J, Partensky C, Vainio H: Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme. Carcinogenesis 1986, 7(11):1853-1863.

11.          Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, Diaz de Stahl T, Menzel U, Sandgren J, von Tell D, Poplawski A et al: Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 2008, 82(3):763-771.

12.          Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL et al: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001, 409(6822):928-933.

13.          Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N et al: Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999, 22(3):231-238.

14.          Beaulieu M, de Denus S, Lachaine J: Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics, 11(11):1573-1590.

15.          Beery TA, Smith CR: Genetics/genomics advances to influence care for patients with chronic disease. Rehabil Nurs, 36(2):54-59, 88.

16.          Cacabelos R, Hashimoto R, Takeda M: Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry Clin Neurosci, 65(1):3-19.

17.          Johnson JA, Liggett SB: Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther, 89(3):366-378.

18.          Schwab M, Schaeffeler E, Zanger UM, Brauch H, Kroemer HK: [Pharmacogenomics: hype or hope?]. Dtsch Med Wochenschr, 136(10):461-467.

19.          Kamal SM: Hepatitis C virus genotype 4 therapy: progress and challenges. Liver Int, 31 Suppl 1:45-52.

20.          Yoshida S, Sugawara T, Nishio T, Kaneko S: [Personalized medicine for epilepsy based on the pharmacogenomic testing]. Brain Nerve, 63(4):295-299.

21.          Wiendl H, Neuhaus O, Kappos L, Hohlfeld R: [Multiple sclerosis. Current review of failed and discontinued clinical trials of drug treatment]. Nervenarzt 2000, 71(8):597-610.

22.          Corman LC, Davidson RA: Why clinical trials fail: the hidden assumptions of clinical trials. South Med J 1992, 85(2):117-118.

23.          Krum H, Tonkin A: Why do phase III trials of promising heart failure drugs often fail? The contribution of “regression to the truth”. J Card Fail 2003, 9(5):364-367.

24.          Rimm E, Stampler, MJ, Ascherio, A, Giovannuci, E, Willett, GA, Colditz, WC.: Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993, 328::1450-1455.

25.          Stampfer M, Hennekens, CH, Manson, JE, Colditz, GA, Rosner, B, Willett, WC.: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993, 328:1444-1449.

26.          Stampfer M, Rimm, EB: Epidemiologic evidence for vitamin E in prevention of cardiovascular disease. Am J Clin Nutr 1995, 62:1365S-1369S.

27.          Reaven P, Witztum JL.: Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha- tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. Arteriosclerosis, Thrombosis, and Vascular Biology 1993, 13:601-608.

28.          Stampfer M, Hennekens, CH, Manson, JE, Colditz, GA, Rosner, B, Willett, WC.: A prospective study of vitamin E consumption and risk of coronary disease in women. N Engl J Med 1993, 328:1444-1449.

29.          Rimm E, Stampfer, MJ, Ascherio, A, Giovannucci, E, Colditz, GA, Willett, WC.: Vitamin E supplementation and the risk of coronary heart disease among men. N Engl J Med 1993, 328:1450-1456.

30.          Kushi L, Folsom, AR, Prineas, RJ, Mink, PJ,Wu,Y, Bostick, RM.: Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 1996, 334:1156-1162.

31.          Aizawa K, Shoemaker JK, Overend TJ, Petrella RJ: Metabolic syndrome, endothelial function and lifestyle modification. Diab Vasc Dis Res 2009, 6(3):181-189.

32.          Yusuf S, Dagenais, G, Pogue, J, Bosch, J, Sleight, P.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators:  http://content.nejm.org/cgi/content/full/342/3/154. N Engl J Med 2000;, 342(3):154-160.

33.          Lonn E, Bosch, J, Yusuf, S, Sheridan, P, Pogue, J, Arnold, JM, et al.: HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;, 293(11):1338 -1347.

34.          Vivekananthan D, Penn, MS, Sapp, SK, Hsu, A, Topol, EJ.: Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 2003, 1:2017 -2023.

35.          Dotan YP, I. Lichtenberg, D.  Leshno, M.: Decision analysis Supports the paradigm that Indiscriminate supplementation of vitamin E does more harm than good. Arterioscler Thromb Vasc Biol 2009, 29:1304-1309.