Category Archives: Disease - Page 14

Omega-3 Fats, Angiogenesis, and Cancer: Part I

Posted by on April 26, 2011 69 comments

In the book we discuss the issue of omega-3 toxicity (pp 56-58, 71-72), why it is most dangerous when omega-3 fats are combined with alcohol or fructose, and why fish oil capsules are particularly dangerous (see Fish, Not Fish Oil Capsules, June 16, 2010).

We recommend eating about 1 pound per week of omega-3 rich marine fish, like salmon, sardines, or herring, but taking no omega-3 supplements. This amount is sufficient to optimize the tissue omega-6 to omega-3 ratio for cardiovascular health, and is not so great as to raise great risks of toxicity. We also recommend avoiding mixing omega-3 fats with sugar or alcohol – a point I reiterated in last week’s post (How to Raise HDL, April 20, 2011):

Drink alcoholic beverages – but only when consuming meals low in polyunsaturated fats. Drink up when you eat beef, but be cautious when the entrée is salmon.

Some new papers have recently come out on the subject of omega-3 toxicity, and may lead some in the Paleo community, possibly including us, to reconsider our advice about omega-3 fats.

High Omega-3 Intakes in the Paleo Community

Our 1 pound fish per week recommendation works out to about 1.5 g omega-3 fats per day. But some Paleo authorities recommend much higher intakes.

Various emailers and commenters have mentioned Robb Wolf’s recommendations. Beth summarized Robb’s advice:

Robb Wolf promotes a short period of hefty omega 3 supplementation for unhealthy folks — on the order of 1g/10lbs of body weight per day.

Which would work out to 18 g/day for me, about 12-fold more than we recommend. Of course, if this is only for a short period, it may not be a big deal. However, I know from emails that some people take large doses continuously. Here’s one of my emailers:

Supplements are 10g of fishoil – 3.5g of epa/dha …

Bit surprised about [recommendation to reduce] the Fish oil, since i’m on the very low end of what other people are recommending, for fat loss as well, ie. robb wolf, poliquin etc.

The Whole9 folks host a Robb Wolf fish oil calculator which recommends that a 180-pound man take 4.5 g EPA+DHA per day. Depending on whether it is accompanied by other omega-3 fats in fish oil, this could be anywhere from 3 to 10 times our recommended intake, and is in line with what my emailer was taking.

Some Known Consequences of Omega-3 Excess

What are the likely consequences of omega-3 toxicity?

The obvious dangers are those related to oxidative stress from lipid peroxidation. The concern with omega-3 fats is not direct toxicity, but toxicity from their oxidation products. Omega-3 fats have a lot of fragile carbon double bonds which are easily oxidized: EPA has 5 double bonds and DHA 6. These are therefore among the most fragile lipids in the human body.

We would expect such problems to show up primarily in the liver and in the nervous system, where EPA and DHA levels are highest.

Indeed, they do. In mice, high dietary omega-3, in conjunction with alcohol or sugar, induces fatty liver disease. [1] In pregnant rats, excessive doses of omega-3 fats cause offspring to have shortened life span and neural degeneration. The authors concluded, “both over- and under-supplementation with omega-3 FA can harm offspring development.” [2]

However, there are associations of high omega-3 intake with disease in other tissues. In particular, emerging work is linking high omega-3 intake to diseases of pathological angiogenesis.

Angiogenesis is the creation of new blood vessels in mature tissue. (Vasculogenesis is the creation of vessels in a developing embryo.) It is a normal part of wound healing, but over a dozen diseases feature inappropriate angiogenesis.

Omega-3 Intake Is Usually Anti-Angiogenic

Before I go further, let me emphasize that nothing I am saying here repudiates the idea that it is desirable to bring tissue omega-6 and omega-3 fats into proper balance.

There are many studies showing that when tissue omega-6 to omega-3 ratios are too high, as on the standard American diet (SAD), additional omega-3 DHA and EPA can improve the omega-6 to omega-3 balance, reduce inflammatory signaling, and through reduced inflammation exercise an anti-angiogenic effect.

The mechanisms linking the anti-angiogenic effects of omega-3 to a condition of omega-6 excess are fairly well understood. Here is one description of the mechanism:

Here, we demonstrate that omega-6 PUFAs stimulate and omega-3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major omega-6 PUFA arachidonic acid. The cyclooxygenase (COX)-mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the omega-6 PUFA-derived prostaglandin E2 augmented, whereas the omega-3 PUFA-derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of omega-3 PUFAs. [3]

So the question at issue is not whether omega-6 and omega-3 balance needs to be achieved. Rather, two points are at issue:

(a)  At what level of polyunsaturated (and omega-3) fat intake should balance be achieved – high or low?

(b)  Does overshooting toward an omega-3 excess generate significant or insignificant dangers?

If omega-3 toxicity is significant, then it will be important to achieve balance at low intakes of both omega-6 and omega-3, and to be careful to avoid overshooting to an omega-3 excess.

New Paper: DHA Linked to Cancer Progression

A new paper, just published yesterday, from “the largest study ever to examine the association of dietary fats and prostate cancer risk” has linked blood DHA levels to cancer risk. Specifically:

Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65) … [4]

This is a large effect: the highest quartile had 2.5-fold higher risk than the lowest-quartile.

That it was the omega-3 DHA specifically, and not polyunsaturated fats generally, that caused the problem, is supported by the fact that (note: edited to correct error in original post – PJ) omega-6 linoleic acid had no effect, and 18:1 and 18:2 trans-fats which are mostly obtained from partially hydrogenated vegetable oils were associated with protection against cancer:

TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). [4]

People in the top trans-fat quartile had only half the risk of people in the lowest omega-6 quartile. This makes it looks like omega-6-derived trans-fats were protective.

This result conflicts with the idea that the only influence of omega-3 fats is through regulation of inflammation; if so the anti-inflammatory omega-3 would have suppressed cancer. As lead study author Theodore Brasky said in the press release:

“We were stunned to see these results and we spent a lot of time making sure the analyses were correct,” said Brasky, a postdoctoral research fellow in the Hutchinson Center’s Cancer Prevention Program. “Our findings turn what we know — or rather what we think we know — about diet, inflammation and the development of prostate cancer on its head and shine a light on the complexity of studying the association between nutrition and the risk of various chronic diseases.”

Angiogenesis A Possible Pathway

Angiogenesis is very important for cancer progression. Cancers need to form angiogenic vessels if the tumor is to be able to grow beyond about 0.5 mm (0.02 inch) in diameter.

Indeed, angiogenesis seems to be a controlling factor for cancer mortality risk. It is believed that 50% of adults over age 40, and 100% of adults over age 70, have microscopic cancers. However, most tumors never develop an ability to induce angiogenesis and thus the tumors never grow beyond 0.5 mm and cause no observable disease.

Dietary factors that promote angiogenesis favor cancer progression, and anti-angiogenic factors tend to prevent cancer progression. Diet seems to be crucial for cancer prevention. Here is a TED video by Dr. William Li discussing the link between angiogenesis, dietary influences upon angiogenesis, and cancer.

Conclusion

So far, we’ve set the stage. On Thursday I’ll discuss a mechanism by which excessive DHA intake may promote angiogenesis. If this mechanism is important, then excessive fish oil or DHA supplementation may act as a major cancer-promoting food.

UPDATE: The next post in this series: Omega-3s, Angiogenesis and Cancer: Part II

References

[1] Nanji AA et al. Dietary saturated fatty acids: a novel treatment for alcoholic liver disease. Gastroenterology. 1995 Aug;109(2):547-54. http://pmid.us/7615205.

[2] Church MW et al. Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring. Neurotoxicol Teratol. 2010 March – April;32(2):171-181. http://pmid.us/19818397.

[3] Szymczak M et al. Modulation of angiogenesis by omega-3 polyunsaturated fatty acids is mediated by cyclooxygenases. Blood. 2008 Apr 1;111(7):3514-21. http://pmid.us/18216296.

[4] Brasky TM et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. Am. J. Epidemiol. April 24, 2011 DOI: 10.1093/aje/kwr027 (Will be at http://pmid.us/21518693.)

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.

Causes and Cures for Constipation

Posted by on April 4, 2011 288 comments

Constipation seems to be very common; we’re frequently asked about it. Constipation can afflict low-carb dieters: It was widely reported among Atkins dieters, and is the most common side effect reported on clinical ketogenic diets for epilepsy. [1]

Fortunately constipation is usually easily cured. There are a few common causes, and most of them have simple fixes.

Antioxidant Deficiency

Among the most common causes of constipation among low-carbers is deficient antioxidant capacity.

The gut is a challenging environment, full of oxidizing compounds. If glutathione and other antioxidants become deficient in intestinal cells, then the gut becomes leaky [2], leading to inflammation and the potential for constipation. Oxidative stress can also lead to loss of neurons or neuronal axons from the colon and consequently a loss of motility. Constipation is a common symptom of irritable bowel syndrome.

The cure is simple: supplement. Specifically:

  • Selenium, 200 mcg/day (perhaps 400 mcg during a starting period). Selenium is needed for glutathione peroxidase, a glutathione recycling enzyme.
  • Vitamin C, 1 g/day (perhaps 4 g/day during a starting period). Vitamin C and glutathione recycle one another.
  • Zinc and copper. Total zinc intake should be 30-50 mg/day including food and multivitamin; copper intake should be 2-5 mg/day. Food typically provides 15 mg zinc and 1 mg copper.
  • Cysteine and glycine. These are the component amino acids for glutathione. For constipation I would suggest eating some beef gelatin for glycine, and taking one 500 mg capsule of N-acetylcysteine per day.

Egg yolks also increase glutathione production [3], and eating a dozen per week is highly recommended. Lipoic acid may also help. [4]

Glutamine, a supplement frequently recommended for gut ailments, can also enhance glutathione production [5]. However, I would generally avoid this, because it can promote proliferation of pathogenic bacteria.

Hypothyroidism

Hypothyroidism may be the most common cause of constipation.

A vicious circle often develops: Gut problems lead to autoimmune hypothyroidism, and constipation is only one symptom of the damage hypothyroidism does to the gut. The vicious circle can be broken by treating the hypothyroidism.

The cure:

  1. Eliminate wheat, soy, and other autoimmune-promoting or goitrogenic toxins from the diet.
  2. Supplement with thyroid supporting nutrients like:
    • Selenium (as above).
    • Magnesium (citrate or chelate) 200 mg/day.
    • Zinc and copper (as above).
    • Iodine.
  3. Improve circadian rhythm. Circadian rhythm therapies for hypothyroidism were discussed in two posts, Intermittent Fasting as a Therapy for Hypothyroidism (Dec 1, 2010) and Seth Roberts and Circadian Therapy (Mar 22, 2011).
  4. See your doctor to consider replacing thyroid hormone and investigating related problems. Your doctor can prescribe thyroid hormone and can explore related problems that may contribute to hypothyroidism, such as adrenal fatigue or iron deficiency.

As always, a few cautions about iodine supplementation. Before starting iodine, eliminate wheat from the diet and supplement with selenium, copper, and magnesium. If you have thyroid-related effects from copper supplementation, before proceeding further supplement copper until your thyroid no longer reacts. Start iodine at a low dose, say 500 mcg (0.5 mg) per day. Increase the iodine dose no faster than one doubling per month. When you increase the dose, if you have a reaction to the higher dose, phase it in: say, alternate between 0.5 mg and 1 mg for a week before trying 1 mg/day every day. Go slowly, plan on spending 4 months to reach 3 mg/day, which is a quarter Iodoral tablet. Tablets can be cut into pieces with razor blades and liquid solutions can be diluted; don’t hesitate to reduce doses.

Insufficient Dietary Fat and/or Bile

Not long ago Jamie Scott (That Paleo Guy), a very smart nutritional advisor, discussed his solution for constipation. There were several gems in there, for instance, that foods that stimulate opioid receptors can cause constipation [5b]:

For example, both gluten grains (and I suspect grains in general) plus dairy contain opiate-like compounds that serve to reduce the motility (movement) of your gut.  This effect is commonly seen in those who have to take the likes of codeine (also an opiate) for any length of time.

Chocolate also has opioid peptides. But don’t worry, chocolate isn’t usually the cause of constipation!

But Jamie’s main advice was:

[M]any of the people I work with just are not eating enough fat….

People are a bit skeptical when I suggest increasing fat intake to overcome constipation.  Thankfully I can now point to a clinical study in which a high fat diet, in very short time, increased gastrointestinal transit time, reducing the likelihood of constipation occurring;

Gastrointestinal transit, post-prandial lipaemia and satiety following 3 days high-fat diet in men

High-fat diets promote stool passage for several reasons.

  1. Just a tiny bit of undigested fat can help grease the passage of stool through the colon. Even modest amounts of fat in the stool make it difficult to retain feces and cause fecal incontinence. This is why indigestible oils, like jojoba oil or Olestra, cause diarrhea.
  2. A second factor is that bile is released into the intestine when fats are eaten, and bile acids have a laxative effect. Both the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid deoxycholic acid (DCA) act as laxatives by inducing water secretion in the colon. An excess of bile therefore causes diarrhea and an insufficiency can cause constipation. [6] This is why people who have had their gallbladders removed typically develop diarrhea: bile is constantly leaking into the digestive tract.

Just be sure that the high fat you eat comes from healthy natural sources, not high-omega-6 industrially processed seed oils.

Also, bile acid metabolism has a diurnal rhythm. [7] Improved bile acid metabolism may be another pathway by which circadian rhythm therapies could help constipation.

Insufficient Gut Flora

Fiber is often recommended for constipation, and though I believe insufficient fiber is rarely the primary factor in constipation, it can help by several mechanisms.

First, bacteria, dead and alive, form a large fraction of the stool, and the more fiber you eat, the more bacteria you will have. Bacteria are surrounded by fatty cell membranes which are a little bit slippery.

Second, and probably more important, gut bacteria tend to increase the laxative effect of bile.

This is because the body controls water secretion in the colon in part by sulfation of bile acids; sulfation eliminates the induction of water secretion.

Gut bacteria usually want more water in the colon than the body does, so they’ve evolved sulfatase enzymes that desulfate human bile acids. [8, 9] The desulfated bile causes water release and the stool becomes soft and loose.

Some bacterial species do this more than others – especially virulent strains that spread by inducing diarrhea – and I’m sure everyone’s experienced at some time in their lives what happens when one of these species overpopulates the gut. We often call this “food poisoning” and it can be treated by large doses of probiotics, to displace the bad species with bacteria that release fewer sulfatase enzymes.

At the opposite extreme, if gut bacteria are lacking then bile acids will be excessively sulfated and won’t induce water secretion. Constipation may develop.

Thus, antibiotics can induce constipation. Presumably a zero-carb, zero-fiber diet would also make constipation more likely.

Adding some fiber to your high-fat diet, therefore, can relieve constipation.

Choline

Even though choline deficiency is not a proven cause of constipation, I’ll put this in because choline is so important for health. Choline is needed to produce the neurotransmitter acetylcholine. A deficiency of acetylcholine is associated with loss of colonic motility and constipation. [10]

Egg yolks and liver are good sources of choline. There’s nothing wrong with choline supplementation either.

Hypercalcemia

Some people over-do vitamin D supplementation and/or calcium supplementation. Elevated blood calcium levels, which can be brought about by too much vitamin D, will cause constipation. If you supplement either vitamin D or calcium and have constipation, ask your doctor to check serum 25OHD, 1,25D, and calcium levels.

Gut Infections

Some pathogenic bacteria are able to paralyze the gut and induce constipation. Some bacterial species that induce diarrhea can also induce constipation when they choose – for instance, C. difficile. This is one reason why patients with bowel disorders such as Irritable Bowel Syndrome or ulcerative colitis often experience both constipation and diarrhea.

Antibiotics like vancomycin that work well against Clostridium have successfully reversed cases of constipation. [11]

Infection-induced constipation may also cause bloating, gas, acid reflux, and gastroparesis, so if your constipation is accompanied by these symptoms you should see a doctor.

Don’t over-use laxatives

It can be risky to over-use laxatives. The riskiest is probably senna, which promotes bowel movements by (a) inhibiting water absorption by the colon and (b) promoting muscle spasms in the colon wall. Unfortunately, senna is a toxin that can cause lasting damage, notably to nerves.

If you must use laxatives, magnesium citrate liquids are the best. This will restore your body’s magnesium status as well as promote clearing of the bowels.

Conclusion

With good diet and nutrition, and normalization of thyroid function, constipation is usually easily cured. The exceptional cases are those of chronic gut infections; these may require some detective work on the part of a doctor.

I’m sure this reads like a laundry list, but it should give those with constipation some ideas!

References

[1] Neal EG et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008 Jun;7(6):500-6. http://pmid.us/18456557.

[2] Rao R. Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front Biosci. 2008 May 1;13:7210-26. http://pmid.us/18508729.

[3] Young D et al. Egg yolk peptides up-regulate glutathione synthesis and antioxidant enzyme activities in a porcine model of intestinal oxidative stress. J Agric Food Chem. 2010 Jul 14;58(13):7624-33. http://pmid.us/20540508.

[4] Chandrasekharan B et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil. 2011 Feb;23(2):131-8, e26. http://pmid.us/20939847.

[5] Cao Y et al. Glutamine enhances gut glutathione production. JPEN J Parenter Enteral Nutr. 1998 Jul-Aug;22(4):224-7. http://pmid.us/9661123.

[5b] Tuteja AK et al. Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil. 2010 Apr;22(4):424-30, e96. http://pmid.us/20100280.

[6] Hofmann AF et al. Altered bile acid metabolism in childhood functional constipation: inactivation of secretory bile acids by sulfation in a subset of patients. J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):598-606. http://pmid.us/18955863.

[7] Abrahamsson H et al. Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation. Scand J Gastroenterol. 2008;43(12):1483-8. http://pmid.us/18788050.

[8] Huijghebaert SM, Eyssen HJ. Specificity of bile salt sulfatase activity from Clostridium sp. strains S1. Appl Environ Microbiol. 1982 Nov;44(5):1030-4. http://pmid.us/7181500.

[9] Ridlon JM et al. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006 Feb;47(2):241-59. http://pmid.us/16299351.

[10] Burleigh DE. Evidence for a functional cholinergic deficit in human colonic tissue resected for constipation. J Pharm Pharmacol. 1988 Jan;40(1):55-7. http://pmid.us/2896776.

[11] Celik AF et al. The effect of oral vancomycin on chronic idiopathic constipation. Aliment Pharmacol Ther. 1995 Feb;9(1):63-8. http://pmid.us/7766746.