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.