Big Picture: Blackburn has extended her Nobel Prize–winning work on telomeres to develop measures that aim to assess overall risks for heart disease, cancer and other chronic illnesses.
A molecular timepiece that resides inside each cell still makes headlines, decades after Elizabeth H. Blackburn conducted pioneering studies into how it works. The most recent experiments by Blackburn and other researchers have demonstrated that these cellular clocks, known as telomeres, may act as barometers of whether a person will remain healthy or not.
Telomeres, stretches of DNA at the ends of chromosomes, protect chromosomes from fraying and sticking to one another. But every time a cell divides—as immune and skin cells do—the telomeres get a little shorter. This shortening has made telomeres a marker of cellular aging. In some cells, an enzyme called telomerase replenishes lost segments. In other cells, though, shortening goes on unimpeded. When the telomere erodes past a certain point, the cell stops dividing and either enters an arrested state of senescence or dies. Blackburn and her one-time graduate student Carol W. Greider, now at Johns Hopkins University, along with Jack W. Szostak of Harvard Medical School, won the 2009 Nobel Prize in Physiology or Medicine for elucidating many of these processes.
Blackburn, who is based at the Universi-ty of California, San Francisco, has never stopped to catch her breath. In 2004 she and health psychologist Elissa S. Epel published a paper linking psychological stress with telomere shortening in white blood cells. It lit a fire under telomere research. Today numerous studies show connections between shorter telomeres and various diseases. Conversely, longer telomeres have been tied to behaviors such as exercise and stress reduction. These studies have pointed to the direct possibility of using telomere length, measured through a simple blood test, to provide a snapshot of overall health and a glimpse into the aging process.
Last year Blackburn co-founded a company, Telome Health in Menlo Park, Calif., to offer that blood test both to research centers as well as to individuals through medical providers. Another group has launched a telomere-testing company, Life Length, in Madrid. News of the imminent release of these tests ignited a controversy about their usefulness. Science writer Thea Singer recently spoke to Blackburn about her work. Excerpts follow.
Scientific American: We’ve heard a lot about how cells “age” as telomeres shorten. But how does this shortening relate to the aging of the whole body?
Blackburn: Many studies show that telomere shortness anticipates risk for conditions such as cardiovascular disease, diabetes, Alzheimer’s and certain cancers—and even for mortality. In part of my U.C.S.F colleague Mary Whooley’s Heart and Soul Study that followed 780 people in their 60s and older for four years, telomere shortness proved a risk for mortality. University of Utah geneticist Richard Cawthon followed 143 people for 15 to 20 years and found that the mortality rate for those with shorter telomeres was nearly double that of people with longer telomeres.
Perhaps, then, we should change the way we talk about telomere shortening and replace words like “aging” and “cellular aging” with phrases like “risk for diseases of aging.”
Yep, I think so. I don’t like the aging idea, because I think that it is not quite so helpful.
What evidence is there that life events such as chronic stress and childhood trauma relate to shorter telomeres?
Let’s look at childhood trauma. The studies find that the number of childhood traumas relates, quantitatively, to the degree of telomere shortness in the adult: the more traumas, the shorter the telomeres. Our study showed a striking correlation between the number of years of chronic stress experienced by the caregiver mothers of a chronically ill child and the degree of telomere shortness.
Long-term studies also indicate that we may be able to slow telomere shortening—or even lengthen our telomeres—through behaviors such as diet and exercise. Tell me about this.
Looking at people with stable coronary artery disease over five years, we found that those with higher levels of marine omega-3 fatty acid in the blood had less telomere shortening overall and that those whose telomeres actually lengthened over the five years were much more likely to have started with higher omega-3 levels. We have data on what has happened to those people, but they have not been published yet.
Should I up my dosage of omega-3?
These subjects are in their 60s by now and have mild coronary disease, which was steady at the onset of the study. So these results relate to those people. It may not be true for people who are 80 or 90 or who are 15 to 20.
You’ve said that the “old medical model” focuses on running tests to decide which treatments can best eradicate an infectious agent. But today doctors very frequently grapple with chronic diseases that arise over time from a complex of causes. How does telomere research contribute to this new model?
Telomere research doesn’t usually look at a specific diagnosis per se. For most people, what we see are statistical relations with a set of progressive diseases that often go together and are more prevalent with aging. We think they may have some similar underlying biology. People are very interested in the idea that chronic inflammation—which may be read out by telomere shortness in white blood cells or perhaps even caused in part by telomere shortness—might underlie some of these things that we separately call, say, diabetes and cardiovascular disease and treat separately. Telomere length is one number that captures a multitude of physiological influences.
Do you think clinicians are catching up with this perspective?
I think clinicians want to find out what is actionable. I think the idea of using telomere length as a monitoring device—that might be actionable.
Your paper on “cancer interception”—using drugs and other active means to stop cancer before it becomes established—dovetails with this concept.
That’s right. The point is to intercept early—before you get to the stage of full-blown disease, which has huge human and economic costs. Cancer research has led us to understand earlier and earlier stages of cancers and how cancers progress. So now we know that a particular drug might actually work at a very early stage in a given cancer. That idea, carried to its extreme, would be: perhaps we can think of what the risk factors are for people to even develop certain cancers and can then treat them before disease strikes. Researchers are looking at high-risk groups for some colon cancers, and there are certain ways of intercepting them, for example.
Where do telomeres fit into the interception picture?
In mice, it’s clear that telomere shortness is a dramatic cancer risk. We still have to learn how that plays out in humans. But it’s been seen in cohorts of people; if you look at, say, risks for groups of cancers or some individual cancers, telomere shortness predicts later risk. This could be because the immune system—which is what you’re querying when you look at telomeres in white blood cells—is getting compromised. Or it could be that there’s a chronic inflammatory state, which is promoting the cancer. Or the cancer cells themselves have genomic instability because their telomeres are too short, and that’s promoting cancer.
Is there a genetic component to telomere length and cancer risk?
Jian Gu of the University of Texas M. D. Anderson Cancer Center led an interesting study implying that the answer is sometimes yes. He and his colleagues took an unbiased look to see if telomere shortness and cancer risk went together genetically. The paper they published concentrated on bladder cancer. They asked: What variance in the genome is associated with risk of cancer? And they found a genetic variant that went with both telomere shortness and cancer risk. Then they looked for the gene itself and found it was one associated with immune cell function.
Recent headlines say that telomere tests for individuals will tell you how long you’ll live. Please explain, based on the science, what it is that telomere tests will tell us.
The business that somehow the test will predict how long you’ll live—that’s what I call silly. The test is not going to diagnose a disease. And it won’t tell you if you’re going to live to be 100. But over time, if you look at it statistically, it tells you probabilities—that, say, you have a likelihood that you might or might not be more prone to get some of the common diseases of aging. A company in addition to ours that formed to measure telomere length gave itself the name “Life Length,” which I think started meaning certain things to people. That was probably an unfortunate name.
What’s the most beneficial way to use the test’s measurements?
We don’t know yet whether there is an optimum way. We do know you can see telomere-length changes in six months or even four months but not in a week. Based on scientific principles, the more measurements you can plot on a curve, the better you can see trends. So the six-month approach seems reasonable.
The test sounds similar to cholesterol tests: it gives you a percentile—where you fall relative to a norm for people of similar age, gender, lifestyle behaviors, and so on.
That’s right, although cholesterol more specifically relates to cardiovascular disease. The telomere test is more general. You could think of it as weight: weight can be an indicator of many aspects of health. Clearly, if it’s way too high, that’s not good. Likewise, if telomeres are really, really short, that’s not good. But then there’s a whole range. And doctors use weight, right? It’s a useful thing. And they look at it over time. I think telomere length is similar; it’s a number that integrates many different things. And clinically, you wouldn’t use it alone.
Critics of telomere testing have said that cholesterol tests are useful because enough data exist to permit scientists to establish norms for things like “high” and “low” cholesterol but that there are not enough data yet to establish norms for telomere length.
I don’t think that’s true. Scientists are sophisticated these days—we don’t have to lump everyone together. We can put people into groups. There are now hundreds and thousands of telomere lengths in various cohorts, and I think we have a decent idea of what sort of things to expect. Of course, more is always better. But you have to start somewhere. There was a very strong demand for getting telomere measures done both in research settings and among individuals. The idea was that we could start getting these measures out there without overstating the precision of what you can deduce from them.
Why did you decide to start a company rather than doing the measurements in your lab at U.C.S.F.?
It was important to have a responsible, reliable technology for providing such measurements. We were overwhelmed in our ability to handle all the requests at U.C.S.F., so we transferred the technology to the company.
How do you respond to concerns that life and medical insurance companies might use telomere-test results to determine eligibility for coverage?
We can’t hide information. But we can certainly try to make sure that any clinical information we provide is accurate and is taken in the proper context and not misused scientifically for exclusionary reasons. Besides, given that telomere-test measurements provide only probabilities, they’d be a poor source for making such decisions. But it’s something that one has to keep thinking about. Our aim is to provide the tests as a way to help people take greater charge of their own health.
Critics compare telomere tests with the sometimes hyped direct-to-consumer genetic tests that offer to find your genetic variations and tell you your susceptibility to certain diseases. How are these telomere tests different?
The telomere tests are not direct-to-consumer. We should be very clear. We plan to start offering them in October through health professionals. Multiple cohorts and multiple studies have established clear statistical links with telomere shortness and risks for diseases. Telomere science has been emerging at a rapid pace recently, and it’s sometimes hard for scientists not involved in such studies to keep up.
Are you getting your own telomeres measured?
Yes, when the company starts offering individual tests. I look forward to it.
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