The Next Big Thing In Medical Lab Tests Will Focus On C-Reactive Proteins And Telomere Length Measurement
What Are Telomeres?
Repeated DNA that forms protective caps at the ends of our chromosomes, telomeres perform a similar role to the plastic tip at the end of a shoelace. Like these plastic tips that keep shoelaces from becoming damaged or frayed, telomeres protect our chromosomes from the critical shortening and damage that may ultimately lead to cellular death and loss of health. Telomeres shorten over time, and this shortening is considered both a marker of cell aging — a clock of the cell’s lifespan — as well as a causal factor in cell aging. Telomere shortening is like a “genetic time clock” — indicating a reduced cellular lifespan. When telomeres reach critically short lengths, the clock “runs out of time,” and cells cease to function normally and can die altogether.
How Are Telomeres Related to Health and Aging?
Telomere shortening is intimately involved in human disease and mortality. Short telomeres impair the ability of cells to divide properly. When the DNA in a cell is unable to properly replicate, the cell either undergoes cell death, or potentially worse, continues to stay alive but functions poorly. Poorly functioning cells can alter a healthy physiological balance in the body, by, for example, creating a high level of pro-inflammatory cytokines in the blood.
Studies have shown associations between shorter telomere length and various types of cardiovascular disease (e.g., stroke, heart attacks), cancer, and diabetes. Shorter telomeres have also been associated with osteoporosis, cognitive function, dementia, depression, and inflammatory diseases like arthritis. Conversely, longer telomeres are linked to healthy aging and overall longevity.
How Are Telomeres Different from the Rest of Our DNA?
Telomeres consist of a special DNA sequence (TTAGGG repeats in humans) and specialized telomeric proteins that together form a protective cap on our chromosomes. Unlike any other part of the genome, they are considered a biological marker of the accumulated wear and tear of living, integrating genetic influences, lifestyle behaviors and stress. Most importantly, telomeres are the only known part of our genetic sequence that are dynamic, and they appear to be influenced by non-genetic factors such as lifestyle changes (diet, behavior, and mental well being).
Why Test Telomeres?
Telomeres are a general risk factor underlying most diseases of aging, in contrast to risk factors that are specific to a disease (as cholesterol or CRP is to heart disease). By monitoring your telomere length, we believe you can gain unique knowledge about disease risk, and your rate of biological aging. This knowledge may also help to inform your lifestyle and, eventually, as research reveals more specific applications, it may help inform therapeutic or prophylactic drug choices and decisions.
What Does Telomere Testing Measure?
Testing will measure average telomere length in specific cell populations within the body (typically white blood cells). The data will indicate a person’s average telomere length relative to the distribution of average lengths in the general population of the same age range. Also, telomere length measurement is based on an established telomere length assay.
Can Telomere Length Predict Years of Healthy Life?
Yes, to some extent. Mounting evidence suggests that, on average, people with longer immune cell telomeres have reduced risk of disease and less disability in old age compared to people with shorter immune cell telomeres.
Can I Protect My Telomeres from Shortening?
There are a critical mass of studies that show associations between telomere length and lifestyle factors, such as smoking, exercise, high stress, and nutritional factors. Therefore, it is a reasonable assumption that one can protect their telomeres. In vitro studies show that telomere shortening can be slowed, or even reversed, through the natural enzyme telomerase, which synthesizes telomeric DNA. One study so far has observed an increase in telomerase activity (which protects and lengthens telomeres) by persons enrolled in a health program including eating a healthy diet, getting daily exercise, and using stress reduction techniques such as yoga and/or meditation. This study did not have a control group and further studies are needed. In addition, early evidence indicates that a natural product derived from a Traditional Chinese Medicine can activate telomerase and slow the rate of telomere loss in immune cells and in a recent study in humans, a similar product appears to reduce the percentage of short telomeres in immune cells and have positive effects on several biomarkers of aging.
Based on the cross-sectional studies so far, linking telomere length to psychological states or certain lifestyle factors, it is likely that the following may help maintain or even lengthen our telomeres:
Increasing vigorous exercise to 4 to 5 times a week, such as getting on a bike, going for a brisk walk or jog, joining a gym, or practicing yoga, activities that increase your heart rate or make you sweat.
Improving Nutrition: Eating a low-fat diet, eating less red and processed meat, like hot dogs and sausages, or taking dietary supplements that activate telomerase.
Improving Metabolism: If overweight, losing some extra weight or reducing waist circumference.
Enhancing Wellbeing: Reducing psychological stress and depression, and increasing feelings of personal control and purpose in life.
Can Telomere Length Diagnose a Disease?
No. However, extremely short telomeres are observed in people with genetic mutations in genes for telomerase or telomeric protein. So having an extremely short telomere length (lowest few % in the population) may indicate an underling genetic disease, including Dyskeratosis Congenita, pulmonary fibrosis, or aplastic anemia.
In the general population, short telomeres do not diagnose or predict specific diseases, but rather are a measure of disease risk in multiple tissue and organ systems in the body. Because of this, short blood telomere length is a better predictor of general vulnerability to diseases than are conventional disease biomarkers which are specific for certain diseases (e.g., cholesterol and heart disease). Moreover, some studies have shown that average telomere length can actually be better in predicting specific disease risk than conventional risk factors.
The good news is that, unlike most genetic markers of disease risk, telomere length is modifiable. From our own research, we believe it can change within as short a period as one year (or possibly even less), in part due to one’s environmental exposures and lifestyle.
How Does Stress Play a Role?
Studies have shown that various conditions linked to psychological suffering, including high perceived stress, depression, anxiety, and exposure to early trauma, are linked to shortened telomeres. It is still unclear exactly how psychological stress shortens telomeres. It may be through creating an environment of biochemical stress. For example, stress can increase levels of cortisol and oxidative stress. In vitro studies show that cortisol can dampen down telomerase, and oxidative stress can shorten telomeres. It may be that reducing stress might improve and stabilize telomeres, creating a slower rate of shortening. In one study, reductions in distress were related to increases in telomerase, and in another study, improvements in wellbeing were related to higher telomerase levels taken after a meditation intervention.
C-Reactive Protein (CRP) is produced by the liver. The level of CRP rises when there is inflammation throughout the body.
The CRP test is a general test to check for inflammation in the body. It is not a specific test. That means it can reveal that you have inflammation somewhere in your body, but it cannot pinpoint the exact location.
A CRP test, called a high-sensitivity C-reactive protein (hs-CRP) assay, is available to determine a person’s risk for heart disease. Many consider a high CRP level to be a risk factor for heart disease. However, it is not known whether CRP is merely a sign of cardiovascular disease or if it actually plays a role in causing heart problems.
According to the American Heart Association:
* You are at low risk of developing cardiovascular (heart) disease if your hs-CRP level is lower than 1.0mg/L
* You are at average risk of developing cardiovascular (heart) disease if your levels are between 1.0 and 3.0 mg/L
* You are at high risk for cardiovascular (heart) disease if your hs-CRP level is higher than 3.0 mg/L
What Abnormal Results Mean
A positive test means you have inflammation in the body. This may be due to a variety of different conditions, including:
* Connective tissue disease
* Heart attack
* Inflammatory bowel disease (IBD)
* Pneumococcal pneumonia
* Rheumatoid arthritis
* Rheumatic fever
Cholesterol vs C-Reactive Protein Lab Tests
The predictive powers of a cholesterol test only go so far. If your LDL is low, your C-reactive protein may be a better sign of impending heart trouble.
The gap between knowing what’s good for you and actually doing it can be huge, especially when it comes to something like getting exercise. (Never underestimate the appeal of the sedentary life.) Many of us need a warning-some might say a bit of a kick in the pants-before we’ll change our ways and get with a heart-healthy program.
For decades, cholesterol testing has served as that warning for many. An elevated level of “bad” LDL cholesterol has been just the warning people needed to change their ways. It has played that role for several reasons. People like tests because the results seem objective. Reliable measurement of cholesterol is easy and relatively inexpensive. It makes sense biologically. LDL cholesterol, a protein-wrapped package containing fat and cholesterol, tends to slip out of the bloodstream and lodge in blood vessel walls, forming the plaque that leads to clots and heart attacks.
And it makes sense statistically. The correlation between lowering your LDL and lowering your chances of having a heart attack or developing other forms of heart disease is well documented. Indeed, exercise and dietary changes are good for the heart partly because they lower LDL cholesterol levels.
The Blind Spot
But for all its virtues, cholesterol testing is seriously flawed. Research has shown that only about 50% of the people who have heart attacks have high LDL. If LDL levels are supposed to be an alarm, then it’s not going off for half of those who might benefit from a wake-up call.
This shortcoming presents two problems. First, and most obviously, many people at risk are being missed. So there’s a need for a different test that will “capture” those who slip through the fingers of cholesterol screening.
Second, because cholesterol screening does miss so many incipient heart attacks, it suggests that cholesterol doesn’t adequately explain heart disease.
Inflammation seems to be that explanation, and C-reactive protein (CRP), a by-product of inflammation, may provide the test.
Inflammation Causes Heart Attacks
Experts who study blood vessels, plaque, and heart attacks in minute detail have been developing an inflammatory explanation for heart attacks. They’ve described a process quite different from the clogged plumbing analogy. Blood vessels aren’t solid pipes, but slender tubes of layered, living tissue, some of it quite delicate. LDL cholesterol doesn’t simply lodge in arterial walls-it injures them. And like injuries elsewhere in the body, this stirs up an inflammatory response. Swarms of cytokines, macrophages, and other cells swoop in. They enlarge and transform deposits of LDL cholesterol into accumulations of fat-laden foam cells sealed by fibrous caps of collagen.
Other inflammatory molecules can so weaken a fibrous cap that eventually it bursts open. The contents of the plaque spill out and activate clotting factors in the blood. A massive blood clot forms. The result: a blocked artery and a heart attack.
Why C-Reactive Protein?
If inflammation explains heart attacks, then a test that helps doctors gauge inflammatory activity inside the blood vessels might be valuable. CRP is nothing new to medical science. The protein was discovered over 70 years ago.
Researchers quickly figured out that it was part of the immune or inflammatory response because levels soared in response to Streptococcus A infection. In fact, doctors have used CRP measurements for decades to monitor patients with lupus, rheumatoid arthritis, and other conditions related to the immune system.
But as a way to screen for heart disease risk? That was a different story. All the momentum and much of the science used to be behind cholesterol testing. Now, however, CRP testing seems ready to catch on for several reasons.
People have heard or read about the reasoning behind it.
The inflammatory explanation of atherosclerosis and heart attacks has trickled down from rarefied research circles to doctors and the public. Dozens of newspaper, magazine, and newsletter articles have been written about it. People are more likely to get a test-maybe even demand one-if they have some understanding of what’s being measured and why. The same goes for doctors.
It’s A Good Predictor of Heart Disease.
Even if heart attacks were caused by inflammation, CRP testing wouldn’t be useful unless it’s proved to be a good predictor. In other words, studies have to show that there’s a tight correlation between high C-reactive protein levels and the chances of having a heart attack.
To make a long story short, that’s just what a series of studies published in prestigious journals has shown. One, in the Nov. 14, 2002, New England Journal of Medicine, concluded that CRP outperforms LDL cholesterol as a predictor of cardiovascular risk. In addition, the authors found that the two tests identify different high-risk groups, so using both is better than relying on either alone. (If you’re interested in the details of this and other CRP studies, visit our Web site.)
It’s A Better Predictor Than Other Measures of Inflammation.
There are other ways to measure inflammation. But a study in the March 23, 2000, New England Journal of Medicine concluded that C-reactive protein was a better predictor of cardiovascular events (heart attacks, strokes, bypass surgery, or angioplasty) than other inflammatory markers.
Until fairly recently, the test available to doctors couldn’t reliably measure low (below 10 milligrams per liter) CRP levels. Tests are now sensitive enough to measure levels of 1 milligram per liter or less. That’s a crucial development because it’s fairly minor differences at those low levels that sort out cardiovascular risk.
The test costs $12-$16, and it takes only a small amount of blood. In fact, the same blood sample could be sent to a lab for both cholesterol and C-reactive protein testing.
Some Cutoffs Have Already Been Established.
Without preset cutoffs, doctors wouldn’t know how to interpret CRP test results. Dr. Paul Ridker, a Harvard researcher, was principal investigator on most of the crucial CRP studies and is co-inventor on related patents. He says it’s now possible to classify CRP levels in terms of low, moderate, or high risk.
Less than 1 milligram per liter of blood corresponds to a low risk for heart attack or other cardiovascular problems; 1-3 milligrams per liter corresponds to moderate risk; and over 3 milligrams, to high risk. These cutoffs might change with more research (as have those for cholesterol), but they’re a starting point.
You Can Do Something About High Levels.
Imagine your doctor telling you that a newfangled test of inflammation shows that you have a worrisome level of a telltale protein, but, um, there isn’t much you-or she-can do about it. That wouldn’t be a popular or helpful test, even if it were a perfect prognosticator of heart attacks.
A big reason behind the growing enthusiasm for C-reactive protein tests is that levels can be lowered. The statin drugs (Lipitor, Zocor, other brands) made their name by lowering LDL; research has shown that they also lower C-reactive protein levels. Exercise is a great way to bring down your CRP level; losing weight also seems to work.
C-reactive protein “hawks” think the time has come when everyone should get the test and that it may eventually supplant cholesterol testing. “Doves” say that there just isn’t enough evidence about how doctors should treat high levels, even if there is a link to cardiovascular risk.
As we went to press (2003), neither the American Heart Association (AHA) nor the American College of Cardiology had made a formal recommendation on C-reactive protein. Published comments from AHA leaders hint that it might stake out a middle ground and suggest testing people who fall into an intermediate-risk group because of their age (60 and older), weight, or blood pressure. AHA and other guidelines will influence how doctors will use the CRP test during the next year or so. Ultimately, though, the fate of the test rests with prospective, randomized studies of CRP-lowering interventions still in progress.
High CRP/Low LDL
Dr. Ridker’s November 2002 study comparing C-reactive protein and LDL found that cardiovascular risk was actually greater for people in the high CRP/low LDL group than for those in the low CRP/high LDL group. Clearly, cholesterol testing would have missed people in the high CRP/low LDL group.
If these results hold up, CRP testing might be most advisable for people with low LDL levels. Because the test is inexpensive, doctors might just order both tests right off the bat rather than wait for the cholesterol results.
Coming Full Circle
No test, no matter how good it is, changes anyone’s health. It’s what we do in response that matters. Statins have put a pharmaceutical face on heart disease prevention, but the old truths about getting exercise, eating right, and not smoking still hold. If the CRP test gets more people to follow that advice, then it may be worthwhile.
Ridker PM, Libby P. Risk Factors for Atherothrombotic Disease. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, Pa; Saunders Elsevier; 2007: chap 39.Go back