The Optimal LDL is not 50 to 70 mg/dL (P ...

The Optimal LDL is not 50 to 70 mg/dL (Part 1)

Aug 21, 2022

In 2004, O'Keefe and colleagues published a paper called "Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal" (1).

Despite its numerous flaws, this paper has been cited over 630 times in the literature.

Upon reading, one of the first flaws I noticed was the following figure, which shows the blood cholesterol levels of hunter-gatherer humans, wild primates, wild mammals, and modern humans (adult Americans):

According to this figure (Fig. 1), the average cholesterol level in adult Americans is 208 mg/dL (corresponding to an LDL of approximately 130 mg/dL).

In contrast, average cholesterol levels for hunter-gatherers and other adult mammals are much lower, ranging from about 70 to 140 mg/dL (corresponding to an LDL range of about 35 to 70 mg/dL).

O'Keefe and colleagues then argue that atherosclerosis is common in modern Westernized humans, like adult Americans, because their cholesterol levels are higher than the "optimal" or "normal physiologic" levels of hunter-gatherers and other mammals.

To quote:

Atherosclerosis is endemic in our population in part because the average person’s LDL level is approximately twice the normal physiologic level (Fig. 1).

But there are major problems with this claim.

Selective Citation

To support their position, O'Keefe and colleagues only cited a selective portion of the data that concurred with their biases. They ignored relevant data on other populations with cholesterol levels greater than 150 mg/dL.

As Dr. Lindeberg pointed out, there are many "non-Westernized" populations with cholesterol levels comparable to Westerners. These include populations with high intakes of coconut (e.g., Tokelauans, Kitavans), the Inuit with high total fat intakes, and certain East African nomads with high consumption of milk (2).

To quote (3):

In several cases, other aboriginal populations have shown an average serum cholesterol of 5 mmol/L [193 mg/dL] or higher, i.e. fully comparable with Westerners. This applies to populations in the South Pacific with a high intake of coconut and Eskimos with a high total fat intake.

And:

Hypercholesterolaemia was not an unusual condition [on Kitava]. The primary cause is possibly the high intake of saturated fat from coconut. . . . Traditional cattle-herding nomads are a special case: East African nomads (with the exception of the Masai, see below) have had serum cholesterol levels that match those of Westerners.

Note well, the average cholesterol levels in these populations could range from 180 mg/dL to approximately 250 mg/dL, but cardiovascular events appeared uncommon in all.

Additional reports of indigenous groups with higher than "optimal" cholesterol levels include the Johannesburg Bantu (over 160 mg/dL), the Gambian Africans (over 160 mg/dL), the Pukapukans (at least 170 mg/dL), and the Australian Aborigines (over 200 mg/dL) (4-8).

For studies reporting LDL cholesterol, values were usually above 70 mg/dL. Kitavan females and males had LDL levels of 151 mg/dL and 120 mg/dL, respectively (9). For other groups, Lea et al. reported a range of mean values from 72.7 to 92.81 mg/dL (10). Kaplan et al., for example, reported a mean LDL of 91 mg/dL for the South American Tsimane (11).

In summary, there is no doubt that a large percentage of individuals in these "low risk" populations have cholesterol levels above the alleged "optimal," sometimes well above.

A Word on the Inuit

O'Keefe and colleagues claimed an average cholesterol value of 141 mg/dL for the Inuit, but this was based on a small study published in 1937 (by Corcoran and Rabinowitch). Subsequent studies generally showed much higher levels, similar to adults in the United States.

To quote Robinhold and Rice (12):

Serum cholesterol values have been studied in Eskimos by Corcoran and Rabinowitch (1937); Scott (1956, 1958); Wilber and Levine (1949); Sinclair et al. (1949); Rodahl (1954); Pett and Lupien (1958); and others. With one exception, these studies on various sized groups have shown that serum cholesterol levels of adult Eskimos are roughly in agreement with values for adults in the south 48 United States. Our results further confirm this.

Thus, cholesterol levels over 200 mg/dL would not be unusual for the Inuit.

Even the 1937 study reported a wide range of individual cholesterol levels, from a low of 93 mg/dL to a high of 222 mg/dL. This large inter-individual variability is lost when values are simply reported as averages.

Cholesterol: A Poor Explanation

Truth is, researchers long knew that blood cholesterol was a poor explanation for the massive differences in cardiovascular event rates across populations.

This eventually led to better hypotheses, including the potential role of inflammatory processes, thrombosis, tissue omega-6 to omega-3 imbalances, and oxidized LDL (13-19).

Interestingly enough, O'Keefe and colleagues mention oxidized LDL at the beginning of their paper, stating:

In an atherogenic millieu, oxidized LDL infiltrates the intima where it stimulates inflammation, endothelial dysfunction, and eventually atherosclerosis.

But then they go on to blame "LDL" throughout the paper without qualification.

Later papers, however, would acknowledge the real issues. In 2018, Dr. O'Keefe himself coauthored a paper with the following conclusion (20):

The consumption of the omega-6 polyunsaturated fat linoleic acid has dramatically increased in the western world primarily in the form of vegetable oils. OxLDL is thought to play an important role in atherosclerosis formation; however, it is the oxidised linoleic acid contained in LDL that leads to harmful OXLAMs, which induces atherosclerosis and CHD.

Also, a 2005 paper with Dr. O'Keefe acknowledged (21):

In the current US diet, the ratio of n−6 to n−3 PUFAs has risen to 10:1, whereas the ratio in hunter-gatherer diets predominant in wild animal foods has been estimated to be between 2:1 and 3:1.

And again in 2016 (22):

Vegetable oils were never a part of the diet of early humans. Only in the past century have human beings consumed vegetable oils in any substantial quantity. The increase in the intake of vegetable oils has paralleled the rise in chronic disease in the U.S. Moreover, we are unaware of any population that is relatively free of heart disease that consumes such high amounts of industrial seed/vegetable oils as recommended by the Dietary Guidelines.

Besides vegetable/seed oils rich in omega-6, populations that transition from their traditional diets to "industrialized diets" often consume more refined carbohydrates.

In this context, a 2022 paper concluded that sugar and refined carbohydrates were the key dietary factors associated with negative health outcomes (23):

Across 11 populations, NCDs [non-communicable chronic diseases] were associated with increased refined carbohydrates more than increased calories, reduced activity or other factors, but cannot be attributed to SFA [saturated fats] or total fat consumption.

Thus, we should not be blaming cholesterol levels for the poor ill-health of "Westernized" populations, but rather their poor lifestyle choices.

The Alleged "Normal Range"

O'Keefe and colleagues state:

Although an LDL level of 50 to 70 mg/dl seems excessively low by modern American standards, it is precisely the normal range for individuals living the lifestyle and eating the diet for which we are genetically adapted.

But an LDL of 50 to 70 mg/dL is excessively low by almost any standard, not just American standards.

Without supplements or drugs, the vast majority of modern humans will fail to reach such levels, and even many vegans and vegetarians would struggle.

In the Oxford Vegetarian Study, for example, vegans had an LDL cholesterol of 88 mg/dL (24). And the Tarahumara Indians, whose saturated fat and cholesterol intakes are among the "lowest on the planet," were reported to have an average LDL of 87 mg/dL (with large inter-individual variability) (25,26).

(Image: Do O'Keefe and colleagues really expect us to achieve the cholesterol levels of the Hadza or Pygmies on a hunter-gatherer diet?)

We cannot expect modern populations to replicate the cholesterol levels of some hunter-gatherers. Nor should we want to.

Take the Pygmies, for example, the group with the lowest cholesterol levels (about 106 mg/dL). According to available data, the Pygmies are in poor general health, heavily exposed to infections (e.g., malaria), and have one of the lowest life expectancies (27-29).

Needless to say, the Pygmies are one of the last groups I would look at to determine what is "optimal." Furthermore, like most hunter-gatherer groups, their high infectious burden may not only contribute to their high mortality but also their very low cholesterol levels (30).

(Image taken from reference 31. Malaria is just one of numerous diseases associated with low cholesterol levels. Other conditions in hunter-gatherer populations associated with lower cholesterol are measles, tuberculosis, rheumatic heart disease, viral diarrhea, parasitic worms, undernutrition, etc.)

This supports the idea that low cholesterol levels are often a sign of ill-health, and that higher cholesterol levels are often seen in well-fed populations with better immunity and longevity (32,33).

In fact, the low cholesterol/LDL levels that O'Keefe and colleagues recommend are consistently associated with increased mortality in modern populations:

(Image: Taken from reference 34. The endpoint here is all-cause death. Low cholesterol levels are linked to the highest death rate. Based on over 12 million adults)

For LDL, a paper just released in late July of 2022, showed that LDL levels less than 70 mg/dL were associated with increased mortality risks. As the authors stated (35):

In a nationally representative cohort with a median follow-up of 23.2 years, we found very low LDL-C levels <70 mg/dL was associated with increased risks of all-cause, CVD and stroke mortality.

Thus, perhaps very low cholesterol/LDL levels are actually harmful, not optimal or normal as claimed.

I should also point out that we do not know the true incidence of cardiovascular disease in many of these hunter-gatherer populations. As Gurven and Kaplan admit (36):

Many causes of death are difficult to assess in traditional populations without physicians or autopsies, and especially when causes of death are elicited during retrospective interviews. Even in modern hospitals, determining cause of death is sometimes elusive or ambiguous because of multiple levels of causation. Malnutrition, infections, and disease are common in our [hunter-gatherer] study populations, making designation of the primary cause of death problematic, if not inevitably incomplete.

And as Brian Wood notes of the Hadza (37):

Yale University anthropologist Brian Wood, who has studied Hadza health and demography, is also skeptical that the Hadza enjoy rude health. “It seems like they have less cancer and cardiovascular disease than we do, but we do not have good data to evaluate the actual incidence,” he says. In any case, he notes, accidents, malaria, tuberculosis, and other diseases limit the Hadza’s life expectancy at birth to only 34 years, too short for cancer and heart disease to be significant killers.

In general, we should not use populations with diseases and high mortality rates to determine an "optimal" or "normal physiological level." This should be done on healthy populations with no detectable diseases (as far as possible).

Neonates and Cholesterol

O'Keefe and colleagues state:

The LDL levels of healthy neonates are even today in the 30 to 70 mg/dl range.

So what? Since when are neonates, defined as a child under 28 days of age, the standard for what is healthy in adult humans?

I highly doubt O'Keefe and colleagues would argue that the heart rate, body weight, blood pressure, diet, and activity level of a neonate is physiologically normal for a healthy adult, so why cholesterol?

Also, why specifically neonates? Why not, say, three to six-month-old breastfed infants with higher LDL levels (> 70 mg/dL)? Surely, breastfed infants must be in a physiologically normal state too (38):

As breastfeeding is the natural method of feeding an infant and breastmilk is superior to formula/bovine milk with respect to the specific nutritional needs for the optimal growth and development of infants, the plasma lipid pattern of the breastfed infants must be considered physiological during infancy.

Truth is: Neonates and infants need "massive amounts of cholesterol" for growth and development (39), which partly explains their lower cholesterol levels (from increased uptake).

Thus, the cholesterol level of a neonate simply reflects physiological development and should not be taken as a template for what adult values should be.

A blood pressure of 70/50 may be normal for a healthy neonate, for example, but such low levels could cause undesirable symptoms and possible death in adults.

Furthermore, it is common knowledge that variables change as we develop from a neonate. Blood pressure rises, heart and respiratory rates fall, white blood cell count decreases, plasminogen and antithrombin levels rise, and so on.

Perhaps O'Keefe and colleagues would do better by remembering that little adage in pediatrics: Children are not little adults.

Conclusions

Contrary to what O'Keefe and colleagues claim, the population data (including hunter-gatherers) do not support an optimal LDL of 50 to 70 mg/dL. Instead, good cardiovascular health appears compatible with a wide range of LDL levels, and very low LDL levels might even be disadvantageous.

Unfortunately, the flawed idea that low LDL levels are good has led to useless and potentially harmful dietary recommendations. These include vegetarianism/veganism, increased intakes of omega-6 linoleic acid, and decreased intakes of saturated fat.

Funnily enough, O'Keefe and Cordain (the latter being the second author) have argued against these strategies. We already noted papers with O'Keefe arguing against vegetable/seed oils, but he was also involved in a 2016 paper arguing against the recommendations for lower saturated fat intakes (20):

Several recommendations in the 2015 DGA lack sound scientific evidence. The recommendations discussed in this review, such as the consumption of grains, low-fat dairy, saturated fat intake < 10% total calories, sodium < 2,300 mg/day, and industrial seed/vegetable oils up to 27 grams per day, may lead to unintended consequences such as an increased incidence of cardiometabolic disease, diabetes, obesity, dyslipidemia, CV disease, and cancer.

Rightly so!

The second author, Dr. Cordain, also made some interesting statements about vegetarianism, saturated fat, and LDL. His 2012 book, in fact, contains a chapter titled "Vegetarianism Can Be Hazardous to Your Health" (40).

And then there's this passage from Cordain about saturated fat and LDL (40):

If you are faithful to the basic principles of the Paleo Diet, consumption of saturated fats within the range of 10 to 15 percent of your daily calories will not increase your risk for heart disease. In fact, the opposite may be true, as new information suggests that elevations in LDL cholesterol may actually reduce systemic inflammation, a potent risk factor for heart disease. Consumption of fatty meats and organs had survival value in an earlier time, because fat provided a lot of energy and organs were rich in nutrients including iron, vitamin A, and the B-vitamins.

A step in the right direction.

Go to Part 2.


References

1) O'Keefe, J. H., Cordain, L., Harris, W. H., Moe, R. M., & Vogel, R. (2004). Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. Journal of the American College of Cardiology, 43(11), 2142-2146.

2) Lindeberg, S., Nilsson‐Ehle, P., Terent, A., Vessby, B., & Schersten, B. (1994). Cardiovascular risk factors in a Melanesian population apparently free from stroke and ischaemic heart disease: the Kitava study. Journal of internal medicine, 236(3), 331-340.

3) Lindeberg, S. (2009). Food and western disease: health and nutrition from an evolutionary perspective. John Wiley & Sons.

4) Walker, A. R., & Arvidsson, U. B. (1954). Fat intake, serum cholesterol concentration, and atherosclerosis in the South African Bantu. Part I. Low fat intake and the age trend of serum cholesterol concentration in the South African Bantu. The Journal of Clinical Investigation, 33(10), 1358-1365.

5) Prior, I. A., Davidson, F., Salmond, C. E., & Czochanska, Z. (1981). Cholesterol, coconuts, and diet on Polynesian atolls: a natural experiment: the Pukapuka and Tokelau island studies. The American journal of clinical nutrition, 34(8), 1552-1561.

6) Schwartz, C. J., Day, A. J., Peters, J. A., & Casley-Smith, J. R. (1957). SERUM CHOLESTEROL AND PHOSPHOLIPID LEVELS OF AUSTRALIAN ARORIGINES. Australian Journal of Experimental Biology & Medical Science, 35(5).

7) Schwartz, C. J., & Caseley-Smith, J. R. (1958). Serum cholesterol levels in atherosclerotic subjects and in the Australian aborigines. Medical Journal of Australia, 2, 84-86.

8) Gilles, H. M., & Carrington, S. C. (1958). Serum cholesterol in Gambian Africans. Transactions of the Royal Society of Tropical Medicine and Hygiene, 52, 476-477.

9) Lindeberg, S., Berntorp, E., Nilsson-Ehle, P., Terént, A., & Vessby, B. (1997). Age relations of cardiovascular risk factors in a traditional Melanesian society: the Kitava Study. The American journal of clinical nutrition, 66(4), 845-852.

10) Lea, A. J., Martins, D., Kamau, J., Gurven, M., & Ayroles, J. F. (2019). Urbanization and market-integration have strong, non-linear effects on metabolic health in the Turkana tribe. bioRxiv, 756866.

11) Kaplan, H., Thompson, R. C., Trumble, B. C., Wann, L. S., Allam, A. H., Beheim, B., ... & Thomas, G. S. (2017). Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet, 389(10080), 1730-1739.

12) Robinhold, D., & Rice, D. (1970). Cardiovascular health of Wainwright Eskimos. Arctic Anthropology, 7(1), 83-85.

13) Simopoulos, A. P., & Cleland, L. G. (Eds.). (2003). Omega-6/omega-3 essential fatty acid ratio: the scientific evidence (Vol. 92). Karger Medical and Scientific Publishers.

14) Okuyama, H. (Ed.). (2007). Prevention of coronary heart disease: from the cholesterol hypothesis to [omega] 6/[omega] 3 balance (Vol. 96). Karger Medical and Scientific Publishers.

15) Dégano, I. R., Elosua, R., Kaski, J. C., Fernández-Bergés, D. J., Grau, M., & Marrugat, J. (2013). Plaque stability and the southern European paradox. Revista Española de Cardiología (English Edition), 66(1), 56-62.

16) Lands, B. (2008). A critique of paradoxes in current advice on dietary lipids. Progress in Lipid Research, 47(2), 77-106.

17) Lands, B. (2014). Historical perspectives on the impact of n-3 and n-6 nutrients on health. Progress in lipid research, 55, 17-29. - "The authors of the 1995 report [35] suggested dietary factors that affect inflammatory processes and thrombosis were “of great importance”.

18) Okuyama, H., Sultan, S., Ohara, N., Hamazaki, T., Langsjoen, P. H., Hama, R., ... & Nakamura and Kentaro Oh-hashi, M. (2021). Lipid Nutrition Guidelines: A Comprehensive Analysis (p. 100). MDPI Books.

19) Kafatos, A. G. (2019). Diet, Antioxidants, and Health–Case Study: The Cretan Experience. In Antioxidant Status, Diet, Nutrition, and Health (pp. 119-130). CRC Press.

20) DiNicolantonio, J. J., & O’Keefe, J. H. (2018). Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis. Open Heart, 5(2), e000898.

21) Cordain, L., Eaton, S. B., Sebastian, A., Mann, N., Lindeberg, S., Watkins, B. A., ... & Brand-Miller, J. (2005). Origins and evolution of the Western diet: health implications for the 21st century. The American journal of clinical nutrition, 81(2), 341-354.

22) DiNicolantonio, J. J., Harcombe, Z., & O’Keefe, J. H. (2016). Problems with the 2015 Dietary Guidelines for Americans: an alternative. Missouri medicine, 113(2), 93.

23) Pressler, M., Devinsky, J., Duster, M., Lee, J. H., Glick, C. S., Wiener, S., ... & Devinsky, O. (2022). Dietary Transitions and Health Outcomes in Four Populations–Systematic Review. Frontiers in nutrition, 9.

24) Appleby, P. N., Thorogood, M., Mann, J. I., & Key, T. J. (1999). The Oxford vegetarian study: an overview. The American journal of clinical nutrition, 70(3), 525s-531s.

25) Conner, S. L., & Conner, W. E. (1992). The new American diet system. Simon and Schuster.

26) Connor, W. E., Cerqueira, M. T., Connor, R. W., Wallace, R. B., Malinow, M. R., & Casdorph, H. R. (1978). The plasma lipids, lipoproteins, and diet of the Tarahumara Indians of Mexico. The American journal of clinical nutrition, 31(7), 1131-1142.

27) Mann, G. V., Roels, O. A., Price, D. L., & Merrill, J. M. (1962). Cardiovascular disease in African Pygmies: a survey of the health status, serum lipids and diet of Pygmies in Congo. Journal of chronic diseases, 15(4), 341-371.

28) Mann, G. V. (1980). Food intake and resistance to disease. Lancet.

29) Migliano, A. B., Vinicius, L., & Lahr, M. M. (2007). Life history trade-offs explain the evolution of human pygmies. Proceedings of the National Academy of Sciences, 104(51), 20216-20219.

30) Gurven, M. D., Trumble, B. C., Stieglitz, J., Blackwell, A. D., Michalik, D. E., Finch, C. E., & Kaplan, H. S. (2016). Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?. Evolution, medicine, and public health, 2016(1), 338-357.

31) Visser, B. J., Wieten, R. W., Nagel, I. M., & Grobusch, M. P. (2013). Serum lipids and lipoproteins in malaria-a systematic review and meta-analysis. Malaria journal, 12(1), 1-16.

32) Bloomberg, B. M., Lazarus, F., Mrost, I., & Schneider, R. (1958). Serum lipids in South African Bantu and white subjects. Circulation, 17(6), 1021-1028.

33) Stehbens, W. E. (1993). The lipid hypothesis of atherogenesis. RG Landes.

34) Yi, S. W., Yi, J. J., & Ohrr, H. (2019). Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Scientific reports, 9(1), 1-10.

35) https://doi.org/10.1161/JAHA.121.023690

36) Gurven, M., & Kaplan, H. (2007). Longevity among hunter‐gatherers: a cross‐cultural examination. Population and Development review, 33(2), 321-365.

37) De Vrieze, J. (2014). Gut instinct.

38) Harit, D., Faridi, M. M. A., Aggarwal, A., & Sharma, S. B. (2008). Lipid profile of term infants on exclusive breastfeeding and mixed feeding: a comparative study. European journal of clinical nutrition, 62(2), 203-209.

39) Woollett, L. A., & Heubi, J. E. (2016). Fetal and neonatal cholesterol metabolism.

40) Cordain, L. (2012). AARP The Paleo Answer: 7 Days to Lose Weight, Feel Great, Stay Young. John Wiley & Sons.

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