Category Archives: Cardiovascular Disease - Page 2

HDL and Immunity

Posted by on April 12, 2011 42 comments

HDL – high-density lipoprotein – particles are good for you: High HDL levels are associated with lower mortality overall and lower mortality from many diseases – not only cardiovascular disease but also cancer and infection.

People with high HDL are only one-sixth as likely to develop pneumonia [1], and in the Leiden 85-Plus study, those with high HDL experienced 35% lower mortality from infection [2].

Each rise of 16.6 mg/dl in HDL reduced the risk of bowel cancer by 22% in the EPIC study. [3]

In terms of overall mortality, in the VA Normative Aging Study, “Each 10-mg/dl increment in HDL cholesterol was associated with a 14% [decrease] in risk of mortality before 85 years of age.” [4]

This must be surprising to those who think HDL is only a carrier of cholesterol. The lipid hypothesis presumed that the function of HDL is to clear toxic cholesterol from arteries, cholesterol having evolved for the purpose of giving us heart attacks. HDL then brings cholesterol to the liver which disposes of it returns it to the blood via LDL (which evolved for the purpose of poisoning arteries with cholesterol, and giving HDL something to do). (Hat tip to Peter for this formulation of the lipid hypothesis.)

But there is an alternative hypothesis: that infections cause disease, and that HDL has an immune function. This hypothesis would explain why HDL protects against infections and against all diseases of aging.

Immune Functions of HDL

I got interested in immune functions of HDL upon reading an article in ScienceDaily last year (“How Disease-Causing Parasite Gets Around Human Innate Immunity,” Sept 13, 2010). The article states:

Several species of African trypanosomes infect non-primate mammals and cause important veterinary disease yet are unable to infect humans. The trypanosomes that cause human disease, Trypanosoma brucei gambiense and T. b. rhodensiense, have evolved mechanisms to avoid the native human defense molecules in the circulatory system that kill the parasites that cause animal disease….

Human innate immunity against most African trypanosomes is mediated by a subclass of HDL (high density lipoprotein, which people know from blood tests as “good cholesterol”) called trypanosome lytic factor-1, or TLF-1….

The parasite that causes fast-onset, acute sleeping sickness in humans, T. b. rhodensiense, is able to cause disease because it has evolved an inhibitor of TLF-1 called Serum Resistance Associated (SRA) protein…. T. b. gambiense resistance to TLF-1 is caused by a marked reduction of TLF-1 uptake by the parasite….

To survive in the bloodstream of humans, these parasites have apparently evolved mutations in the gene encoding a surface protein receptor. These mutations result in a receptor with decreased TLF-1 binding, leading to reduced uptake and thus allow the parasites to avoid the toxicity of TLF-1.

“Humans have evolved TLF-1 as a highly specific toxin against African trypanosomes by tricking the parasite into taking up this HDL because it resembles a nutrient the parasite needs for survival,” said Hajduk, “but T. b. gambiense has evolved a counter measure to these human ‘Trojan horses’ simply by barring the door and not allowing TLF-1 to enter the cell, effectively blocking human innate immunity and leading to infection and ultimately disease.”

So HDL is actually an immune particle carrying proteins that poison pathogens. The TLF-1 HDL subclass consists of those HDL particles carrying two anti-trypanosome proteins, apolipoprotein L-1 and haptoglobin-related protein. [5]

Any HDL particle can become an anti-trypanosome defender simply by acquiring and carrying these proteins.

It turns out that HDL can carry a great assortment of immune proteins. The orchestrator of HDL’s immune functions seems to be a circulating plasma protein called phospholipid transfer protein (PLTP), which forms complexes with immune molecules and then associates with apolipoprotein A-I (the primary HDL protein). PLTP brings 24 different immune molecules into HDL particles, including apolipoproteins such as clusterin (apoJ), coagulation factors, and complement factors. [6] These immune protein complexes add protein but not fat to HDL particles:

Unexpectedly, lipids accounted for only 3% of the mass of the PLTP complexes. Collectively, our observations indicate that PLTP in human plasma resides on lipid-poor complexes dominated by clusterin and proteins implicated in host defense and inflammation. [6]

It looks like HDL may not be primarily a carrier of cholesterol, but rather a carrier of antimicrobial proteins. Its cholesterol and lipids may serve, as the ScienceDaily article suggests, to make the HDL particle attractive to pathogens so that it may enter as a “Trojan Horse.”

HDL-associated immune proteins under strong selection

As pathogens evolve, immune proteins have to evolve. It turns out that apolipoprotein L-1, the immune protein that protects against trypanosomes, is under strong selection in both Africa and Europe.

The version selected in Europe does not protect against Trypanosoma brucei rhodesiense, cause of one of the African sleeping sickness diseases, but the version selected in Africa does. Unfortunately, the African version also increases risk of kidney disease – which may explain why African-Americans have higher rates of kidney disease than white Americans. [7]

So Africans have sacrificed kidney health for greater immunity against sleeping sickness. This suggests that African sleeping sickness may be a relatively recently evolved human disease.

HDL neutralizes toxins

HDL binds bacterial endotoxins, especially lipopolysaccharide (LPS), and neutralizes their toxicity. As a result, people with high HDL have substantially less release of tumor necrosis factor-alpha (TNF-α) during infection. [8]

TNF-α is an inflammatory molecule that stimulates the acute phase response to infections. Levels of C-reactive protein are a good index of TNF-α levels, so generally speaking high HDL will lead to low TNF-α and low CRP.

What’s the best HDL profile?

It should be desirable to have more HDL particles. Since each HDL particle is capable of poisoning a pathogen, the more you have, the stronger your immune defenses.

However, the weight of each HDL particle is likely to be an indicator of infection severity. An infection-free person will have few immune proteins to pick up; the HDL particles will be fat-rich and buoyant. But a person with extensive infections will have heavier HDL particles freighted with immune proteins.

Conventional tests in the doctor’s office measure the weight of HDL in mg per deciliter of blood. Since having more HDL particles (which raises the weight) is good, but having heavy HDL particles indicates infection which is bad, mass is not the best measure of HDL status. We would expect the number or concentration of HDL particles to provide a better indicator of health.

Indeed, this appears to be what is observed. The most important determinant of HDL status is the number of HDL particles:

The association between HDL size and CAD risk was abolished on adjustment for apolipoprotein B and triglyceride levels (adjusted odds ratio, 1.00 [95% CI, 0.71 to 1.39] for top vs. bottom quartile), whereas HDL particle concentration remained independently associated with CAD risk (adjusted odds ratio, 0.50 [CI, 0.37 to 0.66]). [9]

Conclusion

HDL particles are “Trojan Horses” that attack pathogens and neutralize their toxins.

If you want to remain free from infectious diseases – which is to say, all diseases – to a ripe old age, it’s important to make your HDL particles numerous.

On Thursday, I’ll discuss ways to do that.

References

[1] Gruber M et al. Prognostic impact of plasma lipids in patients with lower respiratory tract infections – an observational study. Swiss Med Wkly. 2009 Mar 21;139(11-12):166-72. http://pmid.us/19330560.

[2] Berbée JF et al. Plasma apolipoprotein CI protects against mortality from infection in old age. J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):122-6. http://pmid.us/18314445

[3] van Duijnhoven FJ et al. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut. 2011 Mar 7. [Epub ahead of print] http://pmid.us/21383385.

[4] Rahilly-Tierney CR et al. Relation Between High-Density Lipoprotein Cholesterol and Survival to Age 85 Years in Men (from the VA Normative Aging Study). Am J Cardiol. 2011 Apr 15;107(8):1173-7. http://pmid.us/21296318.

[5] Kieft R et al. Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16137-16141. http://pmid.us/20805508.

[6] Cheung MC et al. Phospholipid transfer protein in human plasma associates with proteins linked to immunity and inflammation. Biochemistry. 2010 Aug 31;49(34):7314-22. http://pmid.us/20666409.

[7] Genovese G et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010 Aug 13;329(5993):841-5. http://pmid.us/20647424.

[8] Henning MF et al. Contribution of the C-terminal end of apolipoprotein AI to neutralization of lipopolysaccharide endotoxic effect. Innate Immun. 2010 May 25. [Epub ahead of print] http://pmid.us/20501516.

[9] El Harchaoui K et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med. 2009 Jan 20;150(2):84-93. http://pmid.us/19153411.

What Telomeres Tell Us About Human Disease

Posted by on April 7, 2011 18 comments

We believe that almost all diseases are caused by food toxins, malnutrition, and infections. Toxic and malnourishing diets depress immunity and make infections worse.

Once you have this point of view in mind, supporting evidence is everywhere.

Take, for example, a story today in ScienceDaily about depression. Depression is not just a mental illness, but a whole body illness:

Previously considered a mental illness affecting only the brain, major depressive disorder, or MDD, now is believed to be tied to significant physical damage outside the brain, explained Wolkowitz. For example, depressed individuals are more likely to develop the diseases of advanced age, including diabetes, heart disease, osteoporosis, stroke and dementia. [1]

The ScienceDaily article summarizes new research showing a link between depression and telomere length in white blood cells. Telomeres are the end-caps on chromosomes. If telomeres become too short, DNA becomes unstable, genetic integrity is lost during cell division, and cells become senescent (crippled beyond hope of recovery) or commit apoptosis (suicide).

An enzyme called telomerase lengthen telomeres. Normally, most cell types maintain a balance between telomerase levels and replication so that telomeres are maintained at healthy lengths throughout normal cell life.

It turns out that in depressed people, white blood cell telomeres are shorter than in normal people, even though telomerase is more active. [2] Moreover, for a given telomere length, the more telomerase activity, the more depressed the patient. [3] Finally, telomerase activity predicts which patients will recover: patients who recovered from depression had the highest telomerase activity along with their short telomeres. [3]

This suggests that some exogenous factor, not part of normal human biology, is shortening telomeres in the depressed; and that the body’s capacity to resist this factor determines its ability to recover from depression. If the body can overcome the exogenous factor, eliminating its ability to shorten telomeres, then the depression goes away.

What could this exogenous factor be?

Telomeres and Viral Infections

Well, it happens that a number of viruses shorten telomeres in white blood cells.

Cytomegalovirus reduces telomere length in T cells:

After primary CMV infection, we observed … a steep drop in telomere length. Moreover, we found in a cohort of 159 healthy individuals that telomere shortening was more rapid in CMV-seropositive individuals and correlated with the amount of differentiated T cells in both CD4(+) T cells and CD8(+) T cells. [4]

The Epstein-Barr virus (EBV) is carried by more than 90% of the adult world population and has been implicated in several human cancers. [5]  EBV disrupts the caps of telomeres, creating dysfunctional telomeres: “The telomere capping protein TRF2 was partially displaced from telomeres in EBV-infected cells, suggesting an EBV-mediated uncapping problem.” [5]

HIV also shortens telomeres: “Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening” [6]. Interestingly, telomere shortening by HIV was reversed by providing N-acetylcysteine, suggesting that NAC should be beneficial for AIDS and possibly other chronic viral infections.

Connections between viruses and telomere loss run deep. In fact, it has been proposed that cellular senescence, the usual outcome of telomere loss, evolved as an anti-viral defense mechanism. [7]

If viruses cause major depression, then they probably also cause the diseases associated with depression. After all, they have to infect the rest of the body before they can infiltrate the brain. So we should look at viruses and other systemic diseases, and see if the connection with telomere shortening holds in those diseases.

Cancer and Blood Cell Telomeres

There is steadily increasing evidence implicating viruses as causes of cancers. Wikipedia (“Infectious causes of cancer”) has a summary:

Worldwide approximately 18% of cancers are related to infectious diseases…. Viruses are usual infectious agents that cause cancer but bacteria and parasites may also have an effect.

A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein-Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi’s sarcoma herpesvirus (Kaposi’s Sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.[2] Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[3]

According to some authors, viruses are one of the most important risks factor for cancer development in humans, second only to tobacco use.[4]

This summary overlooks some known associations (such as that between XMRV and prostate cancer, see our post Retroviruses and Chronic Fatigue Syndrome, Aug 24, 2010) and evidence that tobacco use raises cancer risk primarily in people with a high viral infectious burden (see ref. [10] below). Although only 18% of cancers may yet have been confidently linked to infectious pathogens, it is not impossible that 100% of cancers are caused by as-yet-mostly-unidentified infectious pathogens, probably mainly viruses.

If viruses cause cancers, and if viruses shorten white blood cell telomeres, then we would expect cancer patients to have shortened telomeres.

Well, gastric cancer patients have shorter white blood cell telomeres, and being in the bottom half of telomere length doubles gastric cancer risk:

GC patients had significantly shorter average telomere length than matched controls (mean +/- SD 0.89 +/- 0.19 vs 1.06 +/- 0.25, P < 0.001)…. We found that short telomere length was associated with a significantly increased GC risk (adjusted odds ratio = 2.14, 95% confidence interval = 1.52-2.93)…. Collectively, our findings provide the first evidence linking the short telomere length in peripheral blood lymphocytes to elevated GC risk. [8]

Lung cancer patients have shorter white blood cell telomeres, and being in the bottom half of telomere length triples lung cancer risk:

Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001)…. [I]ndividuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). [9]

Bladder cancer patients also had short white blood cell telomeres. Being in the bottom quarter of telomere length increases risk 4.5-fold, 6.3-fold for smokers:

Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. [10]

Same story with head and neck cancer [11], renal cancer [12], breast cancer [13], and probably also thyroid cancer [14].

Cardiovascular Disease

A weakness of those cancer studies is that they only looked at blood cell telomeres and the presence of cancer; they didn’t also measure viral burden, for instance by looking for antibody seropositivity.

So I was pleased to find a study that did that in coronary heart disease. Again, white blood cell telomeres were shorter in heart disease patients:

Telomere length (TL) was approximately 0.5 kilobases (kb) shorter in leukocytes from patients with CHD than in their age-matched control subjects….

TL shortening was particularly pronounced in CD8+CD28(-) T cells obtained from cytomegalovirus-seropositive CHD patients. [15]

So cytomegalovirus may be involved in coronary heart disease.

The reason all these studies have looked at white blood cells is because it is easy to get blood samples. But sometimes it is possible to get samples from diseased and normal tissues and do a direct comparison.

That was done in this study of atherosclerotic plaques:

Arterial segments which did not develop atherosclerosis such as the saphenous vein and internal mammary artery, had longer telomere length than aortic segments. On the other hand, telomere length was shorter in aortic tissues which presented atherosclerotic lesions compared to corresponding tissues without atherosclerotic lesions. These results also suggest tissue regulation of telomere size by local factors likely related to oxidative stress responses.

So the normal vessels have long telomeres, indicating an absence of viral infections, but the atherosclerotic plaques have short telomeres, suggesting of high infectious burden.

Conclusion

Telomere shortening is probably a marker of infectious burden, especially of viral infections. Telomere shortening in blood cells is associated with major depression, cancer, heart disease, and probably nearly every other disease.

Diseases probably result from a combination of factors, but a heavy burden of chronic infectious pathogens is probably almost always one of them. These pathogens are usually little more than parasites, sapping nutrients from human cells and disabling their immune defenses. But combined with toxic and malnourishing diets, they cripple the body and shorten lifespan.

The association of shortened telomeres with shortened lifespan may be due to the life-shortening effects of infections.

This is why the immunity-enhancing dietary steps discussed in Step Four of our book are so central to a long and healthy life. We cannot avoid exposure to these pathogens. But we can keep their numbers down, so that they do minimal harm to us throughout life.

References

[1] University of California – San Francisco (2011, April 6). Link between chronic depression and accelerated immune cell aging. ScienceDaily. Retrieved April 7, 2011, from http://www.sciencedaily.com/releases/2011/04/110405151223.htm.

[2] Wolkowitz OM et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress – preliminary findings. PLoS One. 2011 Mar 23;6(3):e17837. http://pmid.us/21448457.

[3] Wolkowitz OM et al. Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry. 2011 Jan 18. [Epub ahead of print] http://pmid.us/21242992.

[4] van de Berg PJ et al. Cytomegalovirus infection reduces telomere length of the circulating T cell pool. J Immunol. 2010 Apr 1;184(7):3417-23. http://pmid.us/20176738.

[5] Lacoste S et al. Chromosomal rearrangements after ex vivo Epstein-Barr virus (EBV) infection of human B cells. Oncogene. 2010 Jan 28;29(4):503-15. http://pmid.us/19881539.

[6] Pollicita M et al. Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line. BMC Neurosci. 2009 May 22;10:51. http://pmid.us/19463156.

[7] Reddel RR. Senescence: an antiviral defense that is tumor suppressive? Carcinogenesis. 2010 Jan;31(1):19-26. http://pmid.us/19887513.

[8] Liu X et al. Constitutive telomere length and gastric cancer risk: case-control analysis in Chinese Han population. Cancer Sci. 2009 Jul;100(7):1300-5. http://pmid.us/19432888.

[9] Jang JS et al. Telomere length and the risk of lung cancer. Cancer Sci. 2008 Jul;99(7):1385-9. http://pmid.us/18452563.

[10] Broberg K et al. Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. Carcinogenesis. 2005 Jul;26(7):1263-71.  http://pmid.us/15746160.

[11] Wu X et al. Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer Inst. 2003 Aug 20;95(16):1211-8. http://pmid.us/12928346.

[12] Shao L et al. Telomere dysfunction in peripheral lymphocytes as a potential predisposition factor for renal cancer. J Urol. 2007 Oct;178(4 Pt 1):1492-6. http://pmid.us/17707063.

[13] Shen J et al. Short telomere length and breast cancer risk: a study in sister sets. Cancer Res. 2007 Jun 1;67(11):5538-44. http://pmid.us/17545637.

[14] Capezzone M et al. Telomeres and thyroid cancer. Curr Genomics. 2009 Dec;10(8):526-33. http://pmid.us/20514214.

[15] Spyridopoulos I et al. Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation. 2009 Oct 6;120(14):1364-72. http://pmid.us/19770396.

[16] Nzietchueng R et al. Telomere length in vascular tissues from patients with atherosclerotic disease. J Nutr Health Aging. 2011;15(2):153-6. http://pmid.us/21365170.

Jaminet’s Corollary to the Ewald Hypothesis

Posted by on February 11, 2011 46 comments

In Tuesday’s comments, Kriss brought up Paul Ewald, father of the “Ewald hypothesis.” (Also brought up by Dennis Mangan here.) Ewald did some of his work in collaboration with Gregory Cochran, who may be familiar to many for his appearances on blogs (notably at Gene Expression) and for his recent book The 10,000-Year Explosion.

In a 1999 Atlantic article, “A New Germ Theory,” Judith Hooper summarizes Ewald’s hypothesis:

Darwinian laws have led Ewald to a new theory: that diseases we have long ascribed to genetic or environmental factors — including some forms of heart disease, cancer, and mental illness — are in many cases actually caused by infections.

Regular readers won’t be surprised to hear that we wholeheartedly endorse the Ewald hypothesis. We believe that nearly all diseases are caused by infections and bad diet. Malnourishing, toxin-rich diets impair immune function and create vulnerability to infectious disease.

The Ewald Hypothesis

Ewald’s reasoning goes as follows. Quotations are from the Atlantic essay.

First, genetic causes of disease are unlikely. Any gene that led to impaired functioning of the human body would be selected against and removed from the genome. Therefore, genetic diseases should have the abundance of random mutations – about 1 in 100,000 people:

As noted, the background mutation rate — the ratate which a gene spontaneously mutates — is typically about one in 50,000 to one in 100,000. Not surprisingly, genetic diseases that are severely fitness-impairing (for example, achondroplastic dwarfism) tend to have roughly the same odds, depending on the gene.

Diseases that are fitness-impairing and reach higher prevalence – and this includes nearly all major diseases – must have a cause other than genetic mutations.

Germs, on the other hand, are plausible candidates as causes for disease. Germs can benefit from doing us harm. At a minimum, they would like to modify human functioning in order to make us better hosts for themselves — by suppressing immune function, for instance. Also, they wish to induce behaviors that help them spread to new hosts – like sneezing, coughing, diarrhea, or sexual promiscuity.

Germs evolve quickly. Gene exchange, and lack of error checking during gene replication, modifies genomes quickly. Short reproductive time scales – on the order of 20 minutes – mean that helpful mutations proliferate rapidly. Big evolutionary changes can occur in a few weeks:

“The time scale is so much shorter and the selective pressures so much more intense [in microbes]. You can get evolutionary change in disease organisms in months or weeks.”

This means that germs quickly optimize their disease characteristics through natural selection. For example, virulence, or the severity of the disease that a pathogen causes, is rapidly optimized.

One factor determining virulence is how easily the organism can spread to a new host. If the organism can spread easily, there’s little cost to harming the current host, and microbes produce severe disease. If it’s hard to spread, on the other hand, organisms will be mild and peaceable toward their hosts. It pays to keep their hosts alive and healthy.

Ewald and his students collected empirical data supporting their explanation for virulence:

The dots on Saunders’s graphs made it plain that cholera strains are virulent in Guatemala, where the water is bad, and mild in Chile, where water quality is good. “The Chilean data show how quickly it can become mild in response to different selective pressures,” Ewald explained…. Strains of the cholera agent isolated from Texas and Louisiana produce such small amounts of toxin that almost no one who is infected with them will come down with cholera.

In the last few decades, evidence has only grown for the infectious origins of most diseases. In 1999, over 80% of serious diseases were known to be caused by pathogens:

Of the top forty fitness-antagonistic diseases on the list, thirty-three are known to be directly infectious and three are indirectly caused by infection; Cochran believes that the others will turn out to be infectious too. The most fitness-antagonistic diseases must be infectious, not genetic, Ewald and Cochran reason, because otherwise their frequency would have sunk to the level of random mutations.

If this analysis were repeated today, the percentage would be still closer to 100%. More cancers are now known to be caused by viruses, and the links between microbes and cardiovascular disease, dementia, and multiple sclerosis are stronger than ever.

I think Ewald and Cochran are correct in asserting that mental and neurological illnesses are especially likely to be infectious in origin. These illnesses tend to have a big impact on number of descendants, supporting the evolutionary argument for an infectious origin. And, due to their dependence on glucose, neurons are unusually susceptible to infections.

Schizophrenia is a good example of a disease that must be infectious in origin:

From the fitness perspective, schizophrenia is a catastrophe. It is estimated that male schizophrenics have roughly half as many offspring as the general population has. Female schizophrenics have roughly 75 percent as many. Schizophrenia should therefore approach the level of a random mutation after many generations.

Ewald and Cochran suggest we need a “Human Germ Project”:

In Ewald and Cochran’s view, evolutionary laws dictate that infection must be a factor in schizophrenia. “They announced they had the gene for schizophrenia, and then it turned out not to be true,” Cochran said one day when I mentioned genetic markers. “I think they found and unfound the gene for depression about six times. Nobody’s found a gene yet for any common mental illness. Maybe instead of the Human Genome Project we should have the Human Germ Project.”

I concur. Medical research should make much bigger investments in detecting, understanding the effects of, and developing treatments for human infections. Many existing lines of research, including many of the “autoimmune” and genetic hypotheses for disease origins, are not panning out, but continue to monopolize funding.

Jaminet’s Corollary

In the last century, sewage and water treatment has cleaned up our water supply and removed sewage and water as a vector for disease transmission. Hygienic methods, such as daily bathing and the use of soap, also tend to inhibit disease transmission.

Just as cholera is an extremely mild constituent of gut flora in hygienic Texas, but creates acute disease in unclean Guatemala, so we can expect that germs that created acute disease in (unclean) 1900 will have evolved to create mild chronic infections in (hygienic) 2011.

This is Jaminet’s corollary to the Ewald hypothesis:  Microbes are evolving away from severe acute disease toward milder chronic disease.

The focus of modern medicine on acute conditions, and its neglect of chronic conditions, adds to the selective pressures on microbes. Any pathogen that creates acute disease is subject to the full arsenal of modern antimicrobial drugs. But pathogens that create mild chronic disease are generally left untreated.

Modern medicine has created a powerful selective pressure on pathogens to generate chronic illnesses that are just mild enough, and that resemble aging closely enough, to elude the attention and antimicrobial arsenal of medical doctors.

Why No Dementia in Kitava?

Staffan Lindeberg in the Kitava Study found no evidence of stroke, diabetes, dementia, heart disease, obesity, hypertension, or acne on Kitava.

Why were these diseases absent? Partly due to the Kitavans’ excellent toxin-free diet, no doubt, but partly also due to an absence of the pathogens that cause these diseases.

Why was there no multiple sclerosis in the Faeroe Islands until British troops were stationed there in World War II? Because the pathogen that causes MS was absent from the islands, until the Brits introduced it.

Why has the incidence of chronic diseases increased tremendously in the last century? Partly due to longer-lived populations, but also, I believe, due to evolution of pathogens toward these diseases.

I predict the incidence of chronic disease will increase further in decades to come; and we will gradually come to appreciate that nearly all forty year olds today are not fully healthy, but are mildly impaired by a collection of chronic infections.

Conclusion

Fifty thousand years ago there were a few hundred thousand humans in the world. Today there are over 6 billion.

If a pathogen today wants to adapt to a specific host, its best bet is to adapt to humans. And within humans, its best way to flourish is to develop a chronic infection that persists for many decades.

The evolutionary arms race is not over. It has simply moved to a new field of battle. And medicine will have to evolve as the microbes do. The microbes are developing a new style of fighting. Medicine needs to shift its focus toward this rising threat of mild chronic diseases.

The Red Sox (USDA) Diet, Lymphoma, and Vascular Malformations

Posted by on October 18, 2010 7 comments

I want to say a bit more about the “Red Sox diet” – which basically consists of a rigorous adherence to the Dietary Guidelines put out by the US Department of Agriculture – and the diseases it causes.

My first post discussed two of the main problems with this diet:

  • Grain toxins are abundant in the diet.
  • Vitamin K2 is almost absent.

My second post discussed why vitamin D deficiency is also a concern. Insufficient vitamin D is especially dangerous for people who eat a lot of grains, since wheat, oats, and other grains interfere with vitamin D action and can induce rickets.

These three factors alone have tremendous influence on disease and mortality rates:

  • In the China Study, wheat consumption is more strongly associated with mortality and cardiovascular disease than any other dietary factor.
  • Vitamin D status has a huge impact on health. Those in the highest quartile of serum vitamin D have 35% lower mortality than those in the third quartile, and 52% lower mortality than those in the bottom quartile. [1]
  • Vitamin K2 status is nearly as important for health. In the Rotterdam Study, those ingesting a mere 41 mcg of vitamin K2 a day had 29% lower mortality (57% lower heart disease mortality) than those in the bottom third of K2 consumption. [2]

So it pays to remove grains (except rice) from the diet, get plenty of sunshine, and plenty of vitamin K2 from animal and dairy fats.

Today’s Diseases: Lymphoma and Cavernous Malformation

Last week we were mainly concerned with the Red Sox broken bone epidemic. Today I want to look at two other diseases that have struck Red Sox players in recent years – lymphoma, and cerebral cavernous malformation – to see if they might be caused by grain toxins and by vitamin D and K2 deficiencies.

In recent years among Red Sox players and prospects:

  • Pitcher Jon Lester developed anaplastic large cell lymphoma in 2006. He was diagnosed shortly after making his major league debut.
  • First baseman Anthony Rizzo, a top minor league prospect, developed Hodgkin’s lymphoma in 2008.
  • Top outfielder Ryan Westmoreland developed a cavernous malformation in his brain in March 2010. It began to cause headaches and numbness, and required surgery which has left him with a difficult recovery, comparable to that from a severe stroke.

These diseases are rare:

  • Lymphoma strikes about 1 person in 4,500 in the US each year.
  • Cerebral cavernous malformations develop in about 1 person in 200, but most are asymptomatic; only 5% of those (i.e., 1 person in 4,000) develop headaches, and fewer still need brain surgery to remedy neurological defects. A cavernous malformation of the severity of Mr. Westmoreland’s is an extremely rare occurrence.

Let’s compare Red Sox lymphoma incidence with its expected value. (Since we have two cases of lymphoma, statistics are better than for cavernous malformations.)

The Red Sox have a major league team and 6 minor league teams, with about 175 players total. So the Red Sox should expect 0.039 cases of lymphoma per year, or less than 0.2 cases in five years. They’ve experienced two, ten-fold higher than expected.

One might expect elite athletes to be healthier than the public, and thus to have lower lymphoma rates than the general population. Indeed, if professional baseball players developed lymphoma as frequently as the public, major league baseball players would experience 1.2 cases per year. A Google search turns up a couple of baseball players who developed lymphoma while playing – former first baseman Andres Galarraga, diagnosed 1999, and Scott Hodges, who played briefly for the Expos in 2004 – and several others who developed it after retirement – former Yankee star Roger Maris, diagnosed in 1983, and former Red Sox speedster Dave Roberts, diagnosed in 2010. Overall, however, the MLB rate seems to be much lower than 1.2 cases per year. The Red Sox lymphoma rate may be as much as 50-fold higher than their MLB peers.

Is this epidemic of lymphoma just bad luck? Or is it bad diet?

Grain Consumption and Lymphoma

Wheat and other grains contain toxic proteins. One kind is called gluten. About 99.6% of people are genetically capable of developing antibodies to wheat gluten; about 11% of the population develops systemic IgG antibodies against gluten. In some of these, auto-antibodies, or antibodies that target both gluten and self tissue, develop. These auto-antibodies primarily attack the thyroid and gut, but they can also destroy the heart and other organs. Severe auto-immune disease is called celiac disease.

Celiac disease patients tend to have leaky guts that let wheat toxins into the body, and (unless they quit eating wheat) the dysfunction and inflammation caused by these toxins generates other diseases. Up to 20% of celiac disease patients develop cancers, and 50% of those cancers are lymphomas. [3] The likelihood of intestinal lymphoma is 77 times higher in celiac disease patients than in the general population.

Going in the other direction, about 35% of Hodgkin lymphoma patients and 25% of non-Hodgkin lymphoma patients have anti-wheat IgG antibodies [4], compared to 11% in the general population.

It certainly looks like grain toxicity, or autoimmunity caused by grain consumption, may contribute to lymphoma development. The more wheat is consumed, the more likely that anti-wheat antibodies – and the various diseases caused by wheat toxins – will develop.

Vitamin D and Lymphoma

Vitamin D protects against many cancers; the protective effect is strongest for solid tumor cancers like breast cancer, ovarian cancer, and colon cancer. But it may also protect against lymphoma.

An Australian study found that “risk of non-Hodgkin lymphoma fell with increasing reported sun exposure hours” [5]. A recent review reported “an inverse association between sun exposure and NHL risk.” Too little data was available for Hodgkin lymphoma to form a conclusion. [6]

Vitamin K and Lymphoma

Vitamin K exhibits strong anti-cancer effects, especially against blood cancers. [7] Vitamin K can block proliferation of T-lymphoma cells [8] and induce cell death in B-lymphoma cells and myeloma cells [9]. Vitamin K has been tested in clinical trials against leukemias but not lymphomas, but has shown positive results. In AML specifically, a dose of 45 mg/day K2 led to regression of AML in 71% of patients in Japanese pilot studies. [10] In the ECKO trial, vitamin K supplementation reduced cancer incidence by 75%. [11]

Cavernous Malformations

If you’re not tired – and I apologize for stuffing so much into one post, but for the benefit of the Red Sox and their players I want to get it out – let’s look at Ryan Westmoreland’s cavernous malformation.

A cavernous malformation is a degeneration of blood vessels consisting of:

  • Missing matrix. Capillaries are dilated and thin-walled: they have the usual monolayer of endothelial cells but crucially, elastic fibers generated by smooth muscle cells are absent from the vessel walls. A fibrotic wall of variable thickness forms.
  • Hemorrhage. The capillaries usually show visible bleeding. Clotting may be present

Other pathological features commonly but not always seen in cavernous malformations are “haemosiderin deposits, gliosis, thrombosis, fibrotic changes, hyalinised vessel walls, calcification and cholesterol crystals.” [12]

Let’s work from this body of defects and see how they may be induced by grain toxins and vitamin D and K2 deficiencies.

Vitamin K and Vascular Malformations

In infants, vitamin K deficiency produces vascular malformations. [13]

Vitamin K deficiency is also known to produce hemorrhage. In fact, a leading cause of hemorrhagic stroke is vitamin K deficiency:

  • In one study of the causes of hemorrhagic stroke, 20 of 24 victims had vascular malformations, and 5 cases had clinical vitamin K deficiency [14]. (All 24 were probably subclinically vitamin K deficient.)
  • A Chinese study of hemorrhagic strokes in children concluded, “Vitamin K deficiency was a major etiology in 72 of 94 hemorrhagic strokes (76.6%).” [15]

What about the calcification observed in many vascular malformations?  Vascular calcification is the universal signal of vitamin K2 deficiency. Interestingly, vitamin K2 deficiency specifically leads to damage to the elastin matrix:

[M]ineralization induced by warfarin was observed limited to elastic fibers … In a recent paper, dermal elastic fiber calcification has been extensively described in patients affected by coagulation disorders due to a genetic defect in vitamin K recycling … [16]

Warfarin is a drug that interferes with vitamin K2. It seems clear that a loss of K2 function, due to deficiency, genetic defects, or warfarin, leads to specific damage to the elastin matrix.

Gluten and Cavernous Malformations

Another reason the elastin matrix might be missing from the vessels in a vascular malformation is autoimmune attack.

Both human elastin and wheat gluten are elastic proteins with similar structures. Intriguingly, it has been reported that anti-wheat antibodies may trigger autoimmune attacks on elastin. [17]

Could Vitamin D Play a Role?

While vitamin D deficiency has not been directly tied to cavernous malformations, it has been linked to hemorrhagic stroke. [18]

If Vitamin D deficiency contributed to his vascular malformation and cerebral bleeding, then grain consumption would have exacerbated the problem.

In Edward Mellanby’s pioneering experiments, he induced the disease by feeding dogs a diet of oats or wheat bread, and then cured it by adding cod liver oil (which contains vitamin D). Either dietary fats or sunlight cured rickets; a cereal-based diet combined with confinement indoors caused rickets. [19]

Grain consumption remains the leading risk factor for rickets in the world today. Today, rickets is mainly found in sunny countries such as Nigeria, South Africa, and Bangladesh, where it is the result of “cereal-based diets with limited variety.” [20]

In recent decades, more progress has been made in understanding how wheat and other grains induce rickets. First, wheat consumption leads to rapid loss of vitamin D. Eating just 20 g (0.7 ounces) per day of wheat bran causes vitamin D to be depleted 43% faster. [21] Second, wheat germ agglutinin, a wheat toxin, can block activation of the Vitamin D Receptor. [22]

Ryan Westmoreland was at risk for vitamin D deficiency. He lives in Rhode Island; the low sun during the northern winter, combined with the tendency to cover the skin when outdoors in winter, tends to induce a vitamin D deficiency.

Vitamin D levels are lowest in March, at the end of winter. Mr. Westmoreland experienced his cavernous malformation in March.

Conclusion

As with most diseases, we don’t yet know precisely what dietary factors contribute to lymphomas and cavernous malformations. There is plenty of room to disagree about the degree to which diet contributed to the Red Sox players’ lymphomas and cerebral hemorrhaging.

Nevertheless, we believe that:

  • Diseases don’t happen by accident. On a nourishing and toxin-free diet, the body should be able to maintain great health for a century or more.
  • Diseases are caused by food toxins, malnourishment, and pathogens. Eating a toxin-rich, nutrient-poor diet undermines the immune system and creates vulnerability to pathogens. So food toxins and malnourishment may be considered the “root cause” of disease.

Unfortunately, a toxin-rich, nutrient-poor diet is what the Red Sox have embraced. It seems quite possible that their high-grain, high-soy, high-vegetable oil, low vitamin K2 diet, combined with possibly insufficient vitamin D in some players, has raised players’ risk for many diseases 10-fold or more.

Ten-fold or more seems to be roughly the disease incidence rate the Red Sox are actually experiencing.

I believe that the Red Sox are paying the price for their diet in injuries, disease, and – very likely – weaker athletic performance. It behooves them to adopt a healthier diet.

References

[1] Dobnig H et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008 Jun 23;168(12):1340-9. http://pmid.us/18574092.

[2] Geleijnse JM et al. Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5. http://pmid.us/15514282.

[3] Volta U et al. High prevalence of celiac disease in the Italian general population. Dig Dis Sci. 2001 Jul;46(7):1500-5. http://pmid.us/11478502. Freeman HJ. Adult celiac disease and its malignant complications. Gut Liver. 2009 Dec;3(4):237-46. http://pmid.us/20431755.

[4] Cil T et al. Screening for Celiac disease in Hodgkin and non-Hodgkin lymphoma patients. Turk J Gastroenterol. 2009 Jun;20(2):87-92. http://pmid.us/19530040.

[5] Hughes AM et al. Sun exposure may protect against non-Hodgkin lymphoma: a case-control study. Int J Cancer. 2004 Dec 10;112(5):865-71. http://pmid.us/15386383.

[6] Negri E. Sun exposure, vitamin D, and risk of Hodgkin and non-Hodgkin lymphoma. Nutr Cancer. 2010 Oct;62(7):878-82. http://pmid.us/20924963.

[7] Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev. 2003 Aug;8(3):303-18. http://pmid.us/12946240.

[8] Kovalenko DV, Zelenin AV. Molecular mechanisms of the antiproliferative effect of vitamin K3 on Jurkat cells. Biochemistry (Mosc). 1999 Apr;64(4):468-72. http://pmid.us/10231603.

[9] Tsujioka T et al. The mechanisms of vitamin K2-induced apoptosis of myeloma cells. Haematologica. 2006 May;91(5):613-9. http://pmid.us/16670066.

[10] Miyazawa K et al. Vitamin K2 therapy for myelodysplastic syndromes (MDS) and post-MDS acute myeloid leukemia: information through a questionnaire survey of multi-center pilot studies in Japan. Leukemia. 2000 Jun;14(6):1156-7. http://pmid.us/10865985.

[11] Cheung AM et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008 Oct 14;5(10):e196. http://pmid.us/18922041.

[12] Frischer JM et al. Cerebral cavernous malformations: congruency of histopathological features with the current clinical definition. J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):783-8. http://pmid.us/17986498.

[13] Berger TM et al. Imaging diagnosis and follow-up of infantile hepatic haemangioendothelioma: a case report. Eur J Pediatr. 1994 Feb;153(2):100-2. http://pmid.us/8157013.

[14] Takeshita M et al. Hemorrhagic stroke in infancy, childhood, and adolescence. Surg Neurol. 1986 Nov;26(5):496-500. http://pmid.us/3764653.

[15] Wang JJ et al. Risk factors for arterial ischemic and hemorrhagic stroke in childhood. Pediatr Neurol. 2009 Apr;40(4):277-81. http://pmid.us/19302940.

[16] Gheduzzi D et al. Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients. Lab Invest. 2007 Oct;87(10):998-1008.  http://pmid.us/17724449.

[17] Bödvarsson S et al. Dermatitis herpetiformis–an autoimmune disease due to cross-reaction between dietary glutenin and dermal elastin? Scand J Immunol. 1993 Dec;38(6):546-50. http://pmid.us/8256113.

[18] Pilz S et al. Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke. 2008 Sep;39(9):2611-3. http://pmid.us/18635847.

[19] Mellanby E. (March 15 1919) An experimental investigation on rickets. The Lancet 193(4985):407-412. Reprinted in Nutrition. 1989 Mar-Apr; 5(2): 81-6; discussion 87. http://pmid.us/2520279.

[20] Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin Nutr. 2004 Dec;80(6 Suppl):1725S-9S. http://pmid.us/15585795.

[21] Batchelor AJ, Compston JE. Reduced plasma half-life of radio-labelled 25-hydroxyvitamin D3 in subjects receiving a high-fibre diet. Br J Nutr. 1983 Mar;49(2):213-6. http://pmid.us/6299329.  

[22] Miyauchi Y et al. Importin 4 Is Responsible for Ligand-independent Nuclear Translocation of Vitamin D Receptor. J Biol Chem. 2005 Dec 9;280(49):40901-8. http://pmid.us/16207705.