What Telomeres Tell Us About Human Disease

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.

Leave a comment ?

18 Comments.

  1. Great post, Paul. And I’d have to agree in that once you study disease pathology through this lens the supporting evidence does seem to be strong.

    On a related note: I’ve just ordered some of Ewalds books that I hope will shed some more light on the topic. Facinating stuff!

  2. A wonderful post as always. I have also become fascinated by Ewald’s hypothesis and hope that researchers starting looking more at underlying viruses as the potential cause of disease, especially those currently labeled as auto-immune.

    On a side note, I noticed in your book that you mentioned MIT as part of your physics career. Did you work there or go there?

    -Course 6 🙂

  3. I guess you are not in favor of taking TA-65 / Astragalus / Cycloastragenol to activate telomerase?

  4. Hi Anne,

    Undergrad at MIT (courses 8 and 24), PhD at Berkeley, back to Harvard for 4 years.

    Hi Jeremy,

    No, I wouldn’t be in favor of that as a rule. Interfering with our evolved biology is more likely to do harm than good…. Maybe there are some circumstances in which it would be beneficial, but I doubt viral diseases are one of them.

  5. Hmm, my recent bout with EBV 2 years ago now has me concerned about my future health. Would you mind expanding a bit on the conclusion, “…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.”

    I see two ways to read this, please tell me that both #1 and #2 are correct?

    1. By taking the immunity-enhancing dietary steps, we should limit our body’s reaction when FIRST exposed to pathogens.

    2. By taking the immunity-enhancing dietary steps, we should limit our body’s reaction to latent pathongens that have already taken their course when the body was in a less healthy state.

  6. Hmm. Interesting.

    Nit-picking here: You posted links that suggest a connection between telemeres and disease, but your part of the chain — that disease is caused by (bad) diet — isn’t quite so well supported. I realise you have other data elsewhere showing that.

    Going back to Chris Masterjon’s perfect storm: bad industrial diet + pollution + natural aging + widespread viruses may be the key — rather than just focusing on diet.

    Not to bring up the Kitavians, but what I actually noticed from one of the studies is they all smoked. OK, J curve, so maybe a limited supply of cigarettes isn’t bad for you but certainly an interesting factoid.

  7. Hi Matt,

    These infections are chronic – they persist lifelong, and tend to grow more severe in old age, as immunity weakens.

    The pathogens are parasitic — they mostly persist with minimal symptoms after the initial infection, but seek to replicate and become more numerous.

    The immune system is constantly trying to destroy them.

    By “immunity-enhancing dietary steps” I mean steps that enable the immune system to more effectively destroy the viruses during their decades-long parasitic period. As a result, their numbers will be much lower in old age and the odds of developing a “disease of aging” will be much reduced.

    Hi Robert,

    Well, can’t do everything in one post.

    I thought this post did focus on viruses, not diet.

    I think another thing that’s clear about Kitava is that until recently it had very few pathogens, apart from malaria. I think few Kitavans got infected with our disease-producing pathogens (most of which are recently evolved, since the Neolithic) until recently, so they haven’t had time to develop “diseases of aging” which require multi-decade incubation periods.

    As I hinted in the post, smoking is probably not that dangerous in the absence of infections. So Kitavans could probably smoke safely in the 20th century … but they probably won’t be able to in the 21st.

    Best, Paul

  8. A really heavy schedule of the anti-viral medication valacyclovir (Valtrex) might be a good idea if you can be successfully diagnosed with Epstein-Barr or human cytomegalovirus. It’s not as effective as against herpes simplex but there have been some studies that show it can work.

  9. Well, as I said it was nit-picking.

    Not sure how I missed this:

    http://www.economist.com/node/18440801

    (Micro nutrion)

    perhaps there is something about vitamins and economists.

  10. Friday 4/15/11 • Derby City CrossFit – Louisville, KY - pingback on April 14, 2011 at 9:04 pm
  11. Hi Paul,

    Do you have any suggestions for what I can do if I likely have HPV? I am being treated for cervical dysplasia (getting the affected tissue removed via LEEP procedure in a couple weeks). I need to get my copy of your book back from the friend who borrowed it. I’ll read Step 4 again but if there is anything you can add or anything specific to HPV I would really appreciate hearing about it. Thanks for the great blog!

  12. Hi Jackie,

    I would say that our general approaches for anti-viral/bacterial immunity are best — an emphasis on promoting autophagy through intermittent fasting and periodic ketogenic or low-protein dieting.

    HPV has evolved a mechanism for preventing autophagy (http://pmid.us/21743956), and the more of this anti-autophagy is present, the more severe the cancer becomes. So I would say that autophagy promotion is extremely likely to help.

  13. What are your thoughts on HPV vaccination?

  14. I’m not a fluent interpreter of research studies, something I’ve become more aware as I’ve endeavored to regain my health.

    I’ll take a stab here though. The Wolkowitz study found increased risk of diabetes, heart disease, osteoporosis, stroke and dementia in depressed individuals not on medication.

    SSRI treatment has been linked to:

    1. osteoporosis
    http://www.ncbi.nlm.nih.gov/pubmed/17242321
    2. diabetes
    http://www.medscape.com/viewarticle/590844
    3. cardiovascular disease
    a.) http://archinte.jamanetwork.com/article.aspx?articleid=773902#qundefined
    b.)http://shared.web.emory.edu/whsc/news/releases/2011/04/antidepressants-linked-to-thicker-arteries.html

    Part of the qualifying parameters required participants to have not taken antidepressant treatment for the 6 weeks before the study. Yet given the frequency with which depression is treated with SSRIs, I’d consider the possibility that some or many of the participants had histories of psychiatric medication use.

    I come to this idea from personal experience.

    I used to work for a non-profit and our clients suffered from mentall illness. We helped them to file for disability, find work, find housing, find medical care, etc. Participating in studies was a common source of side income for our clients. Unfortunately, they frequently would pause some or all of their medication for a time in order to qualify.

    I would be curious to learn if there are more data about past depression treatments. One possibility strikes me. That’s the apparent overlap between increased health risks of depression and the increased health risks of the typical Rx depression treatment is due to the pool of participants likely past treatment experience with SSRIs.

    The sciencedaily article indicated the Wolkowitz team intended to trial SSRIs themselves to see if the drugs reverse the effect. Maybe they’re still recruiting?
    http://www.clinicaltrials.gov/ct2/show/NCT00285935

    Im any case, looked but couldn’t find the results. Maybe there are other data that make my observation moot.

    I still wanted to chip in with it, my observation.

  15. Hi Paul,

    For four years, I have been trying to pinpoint the underlying cause of my children’s round-the-mouth rash, which sometimes blisters and cracks, or even bleeds. Sometimes the ring is so wide that it affects all the skin up to the nose, down to the chin, and on both sides of the mouth (my younger son’s lips crack, but my eldest’s don’t).

    Both children tend to get it at once, and the rash can develop seemingly out of nowhere, in a matter of hours. Sometimes it goes away for weeks or even months, but then it comes back – this latest bout has been more or less severe since Sept. 2013.

    I have often suspected that herpes is involved, but I am at a loss for what to do about it! I’ve tried topical applications of coconut oil, kefir, probiotics, aloe, tea tree oil, other essential oils (diluted in a carrier), and beeswax-based lip balms. I’m hoping that increasing starches (we were doing a very low-starch/sugar gut-healing protocol previously), which we did four months ago, will help their immunity – but so far there’s no change in the rash. They’re good sports, considering that the pain is sometimes severe, and their pediatricians just say it’s “lip-lickers’ rash.” (My son says, “They just don’t understand! You can’t NOT lick it, once it starts!”)

    I’ve been scouring your website and book, trying to find further ideas for enhancing kids’ immune systems – it seems like intermittent fasting might not be a good idea for 7- and 10-year-olds, but I notice that you mention its efficacy in inducing autophagy to deal with HSV-1, etc. Have you any further thoughts on this topic? Have you addressed it elsewhere?

    Thank you so much,
    Sarabeth

  16. Hi Paul,
    I have been living by PHD principles for 4 years. After a recent period of feeling very tired and having swollen glands my bloodtest show I have glandular fever (Pfeiffer). Very odd at 52, but there you go.
    Besides chapter 4, are there any other suggestions, also given the connection between EBV and telomore shortening, as well as certain cancers?
    It was an absolute joy to see Luke being such a healthy happy and resilient infant, thank you for posting.
    Thank you if you have the time to answer.
    Sofie

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