There's been a lot of discussion about telomeres recently, with some new tests hitting the market that claim to be able to discern a patient's biological age—and, in essence, tell people how long they will live. Are tests that measure telomere length valuable to age management practitioners as a patient assessment tool?
The newest development in this field was the news that Life Length, a company based in Madrid, Spain, will begin marketing a new over-the-counter test. This announcement gained wide attention because of headlines that proclaimed it was a “£400 test that tells you how long you’ll live.” The founder of Life Length and inventor of the test is Dr. Maria Blasco of the Spanish National Cancer Research Centre (CNIO) in Madrid. Dr. Blasco obtained her Ph.D. in 1993 for her research at the Centro de Biología Molecular and that same year, she joined the Cold Spring Harbor Laboratory in New York as a Postdoctoral Fellow. In 1997 she returned to Spain to start her own research Group at the Centro Nacional de Biotecnología in Madrid. She joined the CNIO in 2003 as Director of the Molecular Oncology Programme and Leader of the Telomeres and Telomerase Group, and was appointed CNIO Vice Director in 2005.
Dr. Blasco clearly has the credentials one would expect in someone developing a test designed to measure telomere length. The question remains, just how useful is this test? To attempt to answer that question, let’s review some of what is known about telomeres and telomerase.
Telomeres are stretches of repetitive DNA that protect the ends of chromosomes during cell division; they have been compared to the tips on the ends of shoelaces that keep them from unraveling. As cells divide the telomere sequences get shorter and shorter, which limits cells to a fixed number of divisions. Eventually a point is reached where the telomeres are too small to maintain the structural integrity at the chromosome ends, the cells can no longer divide—and they end up dying. Telomere shortening is thought to be responsible for aging on a cellular level.
Telomerase is the enzyme that protects the tips of chromosomes—the telomeres—and has been found to either prevent telomere shortening or lengthen telomeres when replenished or reactivated, and thus reverse the cell aging process.
Various studies have shown that people with shorter telomeres in their white blood cells are more likely to develop illnesses like cancer, heart disease and Alzheimer’s disease, or even to die earlier. In February of this year, Dr. Blasco told interviewer Caitlin Sedwick of the Journal of Cellular Biology, “My laboratory has always focused on trying to understand the role of telomeres and telomerase in cancer and aging. Our main tools in our work have been various mouse models. First we studied a telomerase-deficient mouse, which showed us both that telomere loss can cause aging and also that telomeres act primarily as a tumor-suppressing mechanism. In other studies we showed that short telomeres could interfere with the normal repair of lesions in the genome. We also generated telomerase-overexpressing mice, through which we demonstrated one of the most significant contributions my laboratory has made: that increasing telomerase expression extends the lifespan of mice. That was really the first time it was shown that telomerase has anti-aging activity in a mammal. And, of course, we have also been using mice to try to understand the role of telomerase in cancer.”
Other research conducted in Boston has recently shown that when mice are engineered to lack telomerase completely, their telomeres progressively shorten over several generations. These animals age much faster than normal mice; they are barely fertile and suffer from age-related conditions such as osteoporosis, diabetes and neurodegeneration. They also die young. "This has implications for thinking about telomerase as a serious anti-aging intervention," Ronald DePinho, a cancer geneticist at the Dana-Farber Cancer Institute and Harvard Medical School who led the Boston study, told Nature last November after its results were released.
One of the foremost researchers of cell aging is Dr. Elizabeth Blackburn, who shared the 2009 Nobel Prize in Physiology or Medicine for her work on telomeres. After receiving her B.Sc. and M.Sc. degrees from the University of Melbourne, she moved to the UK, where she earned her doctorate from the University of Cambridge, then moved to the U.S. in 1975 for postdoctoral work at Yale. It was there that Dr. Blackburn discovered that the DNA sequence ends of chromosomes consisted of simple repeated DNA sequences, though the revolutionary nature of the discovery wasn’t fully appreciated at that time.
After completing her post-doctoral work, Dr. Blackburn joined the faculty of the University of California at Berkeley in 1978, where she continued her study of telomere biochemistry. There she and one of her graduate students, Carol Greider, discovered telomerase, the enzyme that adds telomere DNA sequences to the ends of chromosomes, finally confirming that they had isolated the correct enzyme in 1985. In 1990 Dr. Blackburn moved her lab to the University of California at San Francisco, where she continues to study telomere function and biochemistry. Her Blackburn Lab focuses on the mechanisms of telomere and telomerase functions, and how perturbations in these functions signal to cells. The lab’s research is based on accumulating evidence suggesting insufficient telomere maintenance may limit the extent of healthy life, including increasing the risks and incidences of common chronic diseases that become prevalent as humans age.
Meanwhile, Dr. Greider received her Ph.D. and continued research on the biochemistry of telomerase and the biological function of telomeres at Cold Spring Harbor (the same lab where Dr. Blasco later worked, and trained under her), first as an independent fellow and then as an Investigator. She moved her lab to the Department of Molecular Biology and Genetics at Johns Hopkins University School of Medicine in 1997 where she is continues her research today.
Now, both Dr. Blackburn and Dr. Blasco are moving forward with tests of telomere length—and Dr. Greider is one of their critics. As reported in The New York Times on May 18, “Life Length has begun selling a test for 500 euros (US$712), that says that it can tell people their biological age, which may not correspond to their chronologic age. Another company, Telome Health of Menlo Park, CA, plans to begin offering a test later this year for about $200. It was co-founded by Elizabeth H. Blackburn of the University of California, San Francisco, who shared a Nobel Prize in 2009 for discoveries related to telomeres. Calvin B. Harley, the chief scientific officer at Telome Health, said the test would be akin to a car’s dashboard signal, a 'check engine light.' He compared it with a cholesterol test, but more versatile since it can predict a risk of various illnesses, not just heart attacks."
The Times continued:
But among the critics of such tests is Carol Greider, a molecular biologist at Johns Hopkins University, who was a co-winner of the Nobel Prize with Dr. Blackburn. Dr. Greider acknowledged that solid evidence showed that the one percent of people with the shortest telomeres were at an increased risk of certain diseases, particularly bone marrow failure and pulmonary fibrosis, a fatal scarring of the lungs. But outside of that one percent, she said, “The science really isn't there to tell us what the consequences are of your telomere length.” Dr. Greider said that there was great variability in telomere length. “A given telomere length can be from a 20-year-old or a 70-year-old,” she said. “You could send me a DNA sample and I couldn't tell you how old that person is.”
The Times added that Dr. Peter Lansdorp, a telomere expert at the British Columbia Cancer Agency, also had doubts. “If telomeres are short for you or me, what does it mean?” he said. Dr. Lansdorp has also started a company, Repeat Diagnostics, which conducts telomere testing for medical researchers only.
"We know that people who are born with shorter telomeres than normal also have a shorter lifespan. We know that shorter telomeres can cause a shorter lifespan," Dr. Blasco told The (UK) Independent. "But we don't know whether longer telomeres are going to give you a longer lifespan. That's not really known in humans," she added. “Short telomeres are clearly bad, but it is not obvious that relengthening telomeres
will have a significant impact on lifespan,” concurs Dr. L. Stephen Coles, co-founder
of the Los Angeles Gerontology Research Group. Dr. Coles has been watching developments at Life Length for the past year.
Life Length, Telome Health and Repeat Diagnostics are also competing with SpectraCell Laboratories of Houston, which has offered telomere testing since 2009. Both Telome Health and SpectraCell use a quantitative polymerase chain reaction (Q-PCR) to obtain a measure of the average length of telomeres in cells from saliva samples. SpectraCell currently charges $290 for their test, while Telome Health says theirs will only cost about $200.
Dr. Blasco says that what is new about her test is that "it is very precise. We can detect very small differences in telomere length and it is a very simple and fast technique where many samples can be analysed at the same time. Most importantly, we are able to determine the presence of dangerous telomeres – those that are very short." According to The Independent, Dr. Blasco's company is in talks with medical diagnostic companies across Europe, including the UK, to market the test and collect blood samples for analysis in Spain, and a deal with a company operating in Britain is likely within a year. “Life Length is anticipating hundreds of requests from people wanting to have their telomeres tested and is expecting demand from thousands more once the company is able to bring down the cost of the test as public demand increases,” says the UK publication.
Dr. Earl H. Eye, CEO and Institute Physician of Cenegenics® Medical Institute in Jacksonville, FL, is investigating the various tests and is planning to discuss them at next Age Management Medicine Conference coming up in November. "I'm interested in how they will fit into our goals of managing telomere length,” says Dr. Eye. “Is there a potential correlation between telomere length and longevity? No. There are too many contributing factors; you’re on a kind of bell-shaped curve. These tests can put you in the ballpark, but there’s no way they can tell you how long you’re going to live.” On the other hand, says Dr. Eye, such tests are potentially of value to age management practitioners. “It can identify people with whom we need to intervene—that’s helpful.”
From what he has gleaned about the various tests on the market so far, Dr. Eye is inclined to believe that the Life Length test will be the most clinically useful. “Being able to measure individual telomeres would be very valuable for us, and currently only the Spain lab is doing that type of testing. All the others do average telomere length, which is helpful in general, but does not answer the question if a person has the single or few short telomeres that may need intervention at much a younger age.”
The most accurate method, says Dr. Eye, is Q-FISH, in which the individual telomeres that are short, glow. The method was first described in 2001 by Predrag Slijepcevic of the Department of Biological Sciences at Brunel University, Middlesex, UK. His article in Methods in Cell Science [23: 17-22] stated:
Telomeres are essential functional elements of eukaryotic chromosomes involved in genome stability maintenance. The most important indicator of correct telomere function is telomere length maintenance within the range typical for each species. Telomere length can be estimated by the classical methodology based on Southern blot. However, this methodology is relatively crude and can provide estimate of average telomere length only. To overcome disadvantages of classical telomere length estimate, a new technique termed Q-FISH has been invented. Q-FISH provides estimate of length in each individual chromosome with the resolution of 200 base pairs.
“Let’s say there are 92 telomeres and one or two are short,” explains Dr. Eye. “The other tests look at the average; in the Q-FISH the short ones glow. It's a lot more helpful and costs more. This is the only test that currently identifies the individual telomeres that are short.”
In the New York Times, the disputes about how to measure telomeres were acknowledged. “Life Length says its technique, while more expensive, can detect not only average telomere length but the shortest telomeres in cells,” reported the Times. “The shortest telomeres cause the health problems, said [Professor Jerry Shay of the University of Texas Southwestern Medical Centre in Dallas, who is a scientific consultant for Life Length]. Telome Health and SpectraCell use a DNA amplification technique called polymerase chain reaction, or P.C.R., which is cheaper but provides only an average length. And there are some questions about the accuracy. Dr. Harley of Telome said the P.C.R. test was more relevant because virtually all the studies correlating telomere length with disease had used that test.”
For her part, Dr. Blackburn, asked by Nature if a telomere test could predict how long you will live, replied, “That's just silly, isn't it? It is statistical. Yes, there are mortality connections, but it's silly to say this will tell you your life length. You need to take it in context with other information.” Challenged to explain how such tests could be useful in medicine, Dr. Blackburn gave this response:
You get a statistical association with risks for common diseases. In the past, most of the big medical problems have been specific, drastic things — infectious diseases, broken legs — that you had to fix. Medicine has been successful by treating diseases in a very specific way once the damage is done. But telomere length integrates a lot of factors together and gives you an overall picture of risk for what is now emerging as a lot of diseases that tend to occur together, such as diabetes and heart disease. That is not a familiar model to the medical world.
Interventions might include doing things that allow people to cope with their stress, for example, and encouraging exercise, which emerging studies show is associated with telomere maintenance.
Dr. Blackburn further stated that in making lifestyle changes, it may be particularly useful to have a physiological biomarker to show patients they are making progress.
Dr. Eye says that while the saliva test Dr. Blackburn’s Telome Health is coming out with would be good for a cheap screening, for someone with a specific condition you’d be better off going with Life Length. And, he says, depending on the outcome he would then recommend a specific protocol, and would “probably need to put the patient on TA-65”—that, of course, being the telomerase activator that was discovered by Geron Corporation, the California biotech company, and licensed to New York-based T.A. Sciences. TA-65® is a widely used treatment among Cenegenics physicians. T.A. Sciences already includes telomere length testing as part of its “Patton Protocol.” Whether widespread availability of telomere tests, and inevitable lowering of the prices for such tests, will result in more people flocking to age management practitioners remains to be seen. However, it seems logical to assume that increased public awareness will lead to a greater demand for treatments designed to maximize and preserve telomeres. As Dr. Blackburn told Nature, “Challenges in medicine are moving from 'treat the symptoms after the house is on fire' to 'can we preserve the house intact?' Can we use what we learn about disease processes to think about prevention and earlier interception?”
Further information on Dr. Eye's upcoming session at the November Age Management Medicine Conference will be available at www.agemed.org.