Telomere Length, Disease Risk, and Current Molecular Diagnostic Testing

Over the past twenty years several hundred DNA and RNA-based molecular diagnostic tests have been introduced that help physicians provide better care for their patients. Many tests predict individual risk for specific diseases, such as BRCA1 and -2 gene mutations for breast and ovarian cancer risk and CFTR gene mutation analysis for cystic fibrosis. Others tests identify infectious microorganisms which cannot be identified with culturing methods and several tests identifying gene mutations that both define a specific disease type and indicate the best treatment. For example, specific gene fusions between chromosomes 9 and 22 partially defines chronic myelogenous leukemia and determines its treatment – a drug that specifically blocks the novel protein resulting from the 9-22 chromosomal fusion. Other molecular tests identify individuals likely to have adverse reactions to specific drugs, sparing them sometimes life-threatening drug reactions. Many of these tests analyze individual-specific genetic variations to determine optimal treatment; hence the designation “personalized molecular medicine”.

Nearly all molecular diagnostic tests are applied to individuals with obvious disease, such as cancer, microbial or viral infections, or severe metabolic diseases such as diabetes or hemophilia. Recently however, molecular testing has been introduced to examine telomere length as a means to predict individual risk for a variety of diseases and indicate the need for specific interventions. Telomere length testing may also serve as a biomarker for the success of these interventions.

Telomeres are found at the end of chromosomes (see H+, March 28, 2011, Telomeres, Telomerase and Aging) which shorten with aging, either with each cell division, or with the oxidative stress that accompanies normal cellular functioning or that might be elevated in many disease states. Short telomeres occur with advanced age and many age-associated diseases, such as cardiovascular disease (heart attacks, atherosclerosis, and stokes), diabetes, and cancer. For example, one study demonstrated that aging adults who showed telomere shortening over a 2.5 year period where three time more likely to die from heart disease than matched older individuals without telomere shortening. Although the molecular mechanisms linking short telomeres to specific diseases are presently poorly understood, short telomeres appear to induce chromosomal instability and aging-associated gene expression patterns, such as genes whose products alter DNA structure and increase inflammatory responses. Additionally, short telomeres activate p53, which in turn suppresses genes required for mitochondrial function, likely contributing to the mitochondrial activity loss seen in aging.

A large number of different stressors associated with aging-related diseases cause telomere shortening. Major depression, obesity, post-traumatic stress disorder, childhood stress and abuse (including being an orphan), low socioeconomic status, stress from being a cancer victim, working as a caregiver in a stressful situation, and being a single middle-aged adult, all cause premature telomere shortening and are also associated with increased disease and death risk. Interestingly, exercise, meditation, and anti-depressants given to individuals with major depression, all stabilize telomere length. Meditation and anti-depressants actually increases telomerase activity, the enzyme that lengthens telomeres.

Since short telomeres are associated with many aging-associated diseases and interventions currently exist which can alter telomere shortening, molecular diagnostic testing to measure an individual’s average telomere length may provide useful clinical information. Presumably, once short telomeres are identified, an individual could take steps to preserve or even lengthen their telomeres and attenuate or stop disease processes secondary to short telomeres. Molecular testing of telomere length typical involves isolating an individual’s DNA from peripheral white blood cells following a blood draw, or by extracting DNA from cells lining the mouth (remove with a cotton swab). Telomere length is then analyzed by several different methods. Some companies hybridize fluorescent dye-labeled telomere binding DNA sequences to the extracted DNA to identify short telomeres on the assumption that the number of short telomeres is relevant to human disease. This technique is called “fluorescent in situ hybridization” or the “FISH assay”. Other companies examine telomere length with telomere-specific polymerase chain reaction; a technique that vastly increases (amplifies) the amount of telomere DNA present making analysis easier. This technique gives the average telomere length within a DNA sample. Currently, telomere length testing is offered by many companies, including Repeat Diagnostics, Life Length, and SpectraCell Laboratories. One company, Telome Health, was co-founded by Elizabeth Blackburn who received the 2009 Noble Prize in Physiology or Medicine for her work on the discovery of telomerase in 1984.

Although many researchers think telomere length testing has clinical value and commercial testing is now available, other telomere researchers believe that telomere testing is presently has little clinical value. Telomere length correlates well with many diseases, but is poor at predicting the risk for any specific disease. Also the risk for diseases secondary to short telomeres is high only for the 1% of the population with the shortest telomeres; making testing for most people appear unnecessary. Also telomere testing does not accurately predict how long any individual may have to live, although many researchers believe that testing may indicate an individual’s biological age, in contrast to their chronological age. Additionally, most healthcare providers do not know how to interpret telomere test results. Last most or all of the interventions suggested for short telomeres amount to lifestyle changes which promote healthy living (good diet, exercise, weight loss, smoking cessation, lowering stress levels, etc.); health choices that can be implemented without telomere length testing.

Some data does support a role for telomere testing as a biomarker for other medical treatments. For example, a recent study demonstrated that most men with one or more risk factors for cardiovascular disease benefit from receiving statins (drugs used to lower blood cholesterol). However men with telomere lengths in the top one third did not benefit from statin treatment. Since statins have significant side effects, telomere length testing could identify men who would not benefit from these drugs, thus sparing them medically unnecessary drug-induced side effects.

In the future however telomere testing may be useful to monitor telomerase-activating therapies. Some compounds, such as TA-65 (a small molecule from the herb Astragalus propinquus), have been shown to activate telomerase and elongate critically short telomeres. TA-65 supplementation resulted in improved glucose tolerance, skin fitness, and lowers osteoporosis without increasing the global cancer incidence in female mice, although it did not increase their life spans. Additionally, TA-65 supplementation in humans caused a steady decline over a 12-month period in the percent of senescent cytotoxic CD8+ lymphocytes, demonstrating this compound might have value in treating immune diseases associated with short telomeres. Thus, future healthcare interventions might include the use of telomerase activator supplementation combined with molecular testing of telomerase length to monitor treatment efficacy. Presently telomere length testing is in its early stages and its clinical efficacy will be determined over the next few years. In the more distant future telomere-length preserving therapies could be combined with other therapies, such as increasing mitochondrial function and DNA stability, and increasing nuclear DNA stability to slow aging and increase the healthy human life span.

Rodney E. Shackelford, D.O., Ph.D. is Assistant Professor, Tulane University Health Sciences Department of Pathology and Laboratory Medicine.

9 Comments

  1. I have several heart related problems, ascending thoracic aortic aneurism, endothelial dysfunction, (controlled) high blood pressure, (controlled) high cholesterol, require a left hip replacement. I’ve lost weight, am taking vitamin d3 and hyaluonic acid along with enalapril, hctz, lovastatin and warfarin. My cardiologist is amazed with my blood results since I’ve started this regime, yet I wonder if taking ta65 would assist in improving my health. My Mother died at a young age of a major stroke and my father also has had several TIA’s and has heart problems. Obviously, a lot of my problems were perhaps inherited, but I lead a very stressful life and now that I am leading a vegetarian calm life, I feel much better. Do you have an opinion regarding me taking ta65? I would like to hear what you have to say. I am asking you because my cardiologist would not even approach the subject.
    Thanks

  2. My wife of 63 years has CREST syndrome, an autoimmune disease. I am trying to convince her to speak with a physician about the regimen of the Patton Protocol using TA-65. She is afraid that the use of this substance would increase the progression of the disease rather than helping it. Is there any research to suggest that this is the case?

  3. I’m 80 year young and do every thing to achieve 100. 16 years ago the respectable doctors sentenced me to death penalty if I would ignore By-pass surgery and chemotherapy in cancer case I have not surrended, and on the base of the life experience of great predecessors have created my own active and healthy life extention system. I dont sell anything. My system has no cost, simple and very effective. For last 16 years I never used any medication, all diseases left my body. I would like to participate in any research of telomerase’ role in connection with shortening of span of human life.
    What is yours recomedtion of vit. D3 daily dose. If I understood correectly:no study for people has been made. Only on mouse, which life span has depended from other factors and not from telomeras(!?). Sincerly. Yours Gregory Ostrovsky. Am I wrong?

  4. Unless his telomere length is directly tested by molecular testing, it’s not possible to tell if his telomeres are unusually short. TA-65 might help him, but so far the data on humans is slight. There is also some chance that this TA-65 could increase the risk for cancer, although the present and incomplete data appears to indicate the risk is not great. TA-65 would be worth a try. Also your husband is overweight and likely has the Metabolic Syndrome (high blood pressure, high cholesterol, and adult onset diabetes) or is vulnerable to getting it. Obesity is likely to cause premature telomere shortening, so weight loss would be a very good idea. A largely plant based diet would help with weight loss.

  5. My husband has had severe myalgia pain for 2 years after taking a statin drug. The disability ages you over night and you walk around in pain like a 90 year old.- (he is 50) I think his telemeres were shortened by a previous spinal surgery, being overweight, and being on other medications and were even more damaged by statins which in turn affected the Mevolaic pathway destroying/blocking the COQ10 intake.I have just purchased the TA65 supplement because I believe that his telemeres must be rejuvenated. Supplementing with just COQ10 and fish oil have not helped. He is in desperate need for the TA65 supplement and I can’t wait until it comes in the mail. He only burns sugar in his body and not fat. He is only using 30 percent of the energy instead of 100 like a normal person per testing.His Vitamin D level is only at 32 which is ok but low. Anyways do you think my theory might be correct about the telemeres?

  6. Yes, mice can live five to six generations with telomerase activity completely ablated. They are not the optimal model for studying telomere function and dysfuction in humans. However we use the animal models we have. The data from murine studies is encouraging, but as you point out, the model does not relate directly to humans. One needs to keep in mind these things. For example, when cell and tissue culture are done, how well does an isolated cell population, growing in fetal boivine serum, on sulftated plastic, in supplemented isotonic saline, actually replicate the inside of the human body? It appears that to some degree, each species, species class, etc age by different mechanims which partially overlap. Insects seem to age mainly by the accumlation of age-related pigments. This also uhappens in humans, but appears to contribute less to human aging than to insect aging.

  7. Hello Dr as you probably are aware, but your readership may not be: mice do not primarily age by telomere loss. They age by accumulated oxidative damage based on their accelerated metabolic rates compared with larger mammals. Thus improving telomere dynamics would be expected to improve their health but not their life span. LifeLenth’s short telomere testing will allow us to see heretofore impossible small changes in human telomere length in as little as 3 months between initial testing and retesting. Best, Dr Dave Author The Immortality Edge

  8. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women1,2,3
    J Brent Richards, Ana M Valdes, Jeffrey P Gardner, Dimitri Paximadas, Masayuki Kimura, Ayrun Nessa, Xiaobin Lu, Gabriela L Surdulescu, Rami Swaminathan, Tim D Spector and Abraham Aviv

    1 From Twin Research and Genetic Epidemiology, St Thomas’ Hospital, King’s College, London School of Medicine, London, United Kingdom (JBR, AMV, DP, AN, GLS, and TDS); the Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, Newark, NJ (JPG, MK, XL, and AA); and the Department of Chemical Pathology, St Thomas’ Hospital, London, United Kingdom (RS)

    2 Supported by the Wellcome Trust (TDS and AV), the Arthritis Research Campaign (TDS and AV), the Chronic Disease Research Foundation (TDS and AV), the Canadian Institutes of Health Research (JBR), the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (JBR), NIH grants AG021593 and AG020132, and The Healthcare Foundation of New Jersey (AA).

    3 Address reprint requests to JB Richards, Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London SE1 7EH, United Kingdom. E-mail: brent.richards@kcl.ac.uk.

    ABSTRACT

    Background: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation.

    Objective: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL.

    Design: Serum vitamin D concentrations were measured in 2160 women aged 18–79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method.

    Results: Age was negatively correlated with LTL (r = –0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation.

    Conclusion: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases.

    Key Words: Vitamin D • telomere length • inflammation • aging

    INTRODUCTION

    Mounting evidence suggests that, in addition to its well-described roles in skin, bone, and muscle physiology (2), the hormone vitamin D acts as an inhibitor of the inflammatory response through several pathways (1). Decreased vitamin D concentrations have been associated with an increased risk of developing autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes (3-6). Vitamin D administration has been shown to prevent the initiation and to attenuate the severity of immune-mediated diseases, including type 1 diabetes (7, 8) and an animal model for multiple sclerosis (9). In addition, a recent open-label trial showed that vitamin D decreased rheumatoid arthritis disease activity (10).

    Subsets of leukocytes have receptors for the active form of vitamin D (1,25-dihydroxyvitamin D3; 11-13) that support the direct effect of vitamin D on these cells (14-16), which explains, in part, the connections between vitamin D and autoimmune disease. Furthermore, an inverse relation has been shown between vitamin D concentrations and C-reactive protein (CRP), a marker of inflammation, in both healthy subjects and patients with rheumatoid arthritis and frailty (17, 18). The inhibitory effect of vitamin D on the inflammatory response also points to a potential link between this vitamin and telomere dynamics (length and attrition rate) in leukocytes.

    Telomeres are the ends of chromosomes and undergo attrition with each replication (19, 20), a process that is accelerated by oxidative stress (21, 22). What is more, leukocyte telomere length (LTL) is relatively short in persons with chronic inflammation, because the inflammatory response entails an increase in leukocyte turnover. Consistent with this proposition, both vascular diseases (23-28) and autoimmune diseases such as lupus (29) and arthritis (30, 31) have been associated with shorter LTL. Furthermore, cigarette smoking and obesity, which provoke a proinflammatory milieu, are both a source of oxidative stress (32, 33) and are associated with shortened LTL (34, 35). In fact, several studies have documented associations of indexes of oxidative stress and inflammation with LTL (24, 27, 36). Recently, a randomized case-control analysis showed that shortened LTL was an independent risk factor for coronary heart disease, and the magnitude of risk attributed to shortened LTL was similar to that for conventional risk factors (37). Thus, shortened LTL seems to be a marker of aging-related diseases and conditions associated with an increased burden of oxidative stress and inflammation. Yet, little is known about the environmental factors, other than obesity and smoking, that may affect LTL.

    As humans age, both LTL and vitamin D concentrations decrease (17, 38), whereas inflammatory mediators increase (39, 40). In addition, CRP, a marker of systemic inflammation, displays an inverse relation with vitamin D concentrations (17, 18) and LTL (24). Given that vitamin D displays anti-inflammatory properties, we hypothesized that it may attenuate the rate of LTL attrition. To this end, we examined the associations between LTL and serum 25-hydroxyvitamin D concentrations and CRP in a population-based cohort of women across a wide age spectrum.

  9. I was under the impression that Telomere length would just diminish until death (though at variable rates). Never thought it was possible to actually grow them. How is that possible?

    Also, this means that Telomeres are not the only cause of aging, otherwise growing them back would make us younger, right?

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