The New Year starts with telomeres as the trendiest of trendy biomarkers. As seen in Time, telomeres are the means to monitor our well-being so we can protect ourselves from all sorts from threats, including early death.

A skeptic needs to do considerable homework in order to muster the evidence needed to counter the latest exaggerated, premature, and outright pseudoscientific claims about telomere length being a measure of “cellular aging” and therefore how long we’re going to live.

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What is a telomere and why does its length matter?

Harriet Hall recently described telomeres:

Every chromosome has a telomere, a repeated sequence of nucleotides at the end of the DNA strand. It is a disposable section that carries no genetic information. For vertebrates, the nucleotide sequence is TTAGGG; this repeats from 300 to several thousand times according to the species of animal. Telomeres are sort of like the aglet, that little hard piece on the end of a shoelace that keeps it from unraveling. They protect the end of the chromosome and keep it from losing important genes or sticking to other chromosomes.

By Ian W. Fieggen (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Telomeres are sort of like aglets. Photo by Fieggen CC BY-SA 3.0 via Wikimedia Commons

Talk of telomeres isn’t just being used to sell dubious diagnostic tests and dietary supplements. There is a strong push to make telomere length the currency of how we think, measure, and do science about our health and well-being, and how we target our health interventions. Strong efforts are made to attach the science of telomeres to urgings that we take up yoga, meditation, and “being there” to save our lives.

We’re told by a physician who won the Nobel Prize for her work on telomeres that it is “a bit ‘loosey goosey’ to talk about lifestyle and things like that” but telomere length “gives a very concrete — albeit statistical — readout of how you are doing.”

In order to evaluate all this, we cannot rely on the usually dependable “sourcing heuristic”. A lot of hyped and nonsense claims in other areas of science and medicine can readily be dismissed by looking at who is represented as the authority and where their evidence comes from. We don’t have to give much thought to claims depending on homeopaths or from research reported in the Chinese Journal of Homeopathic Medicine.

But what if the person making a claim about telomeres is a Nobel Prize winner or an author on a paper that contributed to someone else winning a Nobel Prize? Or a blogging Director of an NIH institute? And what if the claim cites an article in a prestigious, peer-reviewed, high-impact journal?

There is a lot of money in play. Patents and products tied to telomeres have obvious commercial potential, but there is also another temptation in that making wild claims could send wannabe bench-to-boardroom researchers flying business class to give five-figure/hour talks to corporations.

NIMH Director tells psychotherapy researchers to pay attention to telomeres

Incentives for hype and distortion arise in places where we might not expect them. NIMH Director Thomas Insel has singled out telomere length as a key target in his personal blog. He sets funding priorities which could be even more important to scientists than truth. Otherwise-responsible scientists will feel pressured to make extravagant claims connecting their work to telomeres. And when scientists exaggerate the strength and significance of their findings as a deliberate strategy to make their next NIH grant application more fundable, it is not a declarable conflict of interest. You cannot rely on “no conflicts of interest to declare” statements in the scientific journals for reassurance that articles are not tainted by their authors’ agenda.

Psychotherapy researchers who were previously secure in regularly getting NIMH funding now find they must demonstrate their therapy changes biomarkers, not just reduces depressive symptoms, if they are going to get refunded. And what can be more significant and innovative than to slow the shortening of telomeres?

“Nobel Prize winning based research”?

What do we make of a video of William H. Andrews, PhD, presenting his “Nobel Prize winning based research” on reducing aging and even lengthening telomeres?

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What does it mean that his research is “Nobel Prize winning based”? Do a Google Scholar or Web of Science search on him. Is he credible? Then go to Harriet Hall’s post that thoroughly-debunks claims about Product B, an herbal product marketed by Andrews, that he claims will slow the rate of telomere shortening.

Once we know that Andrews is hawking herbal remedies, we don’t have to give him much time.

But an actual Nobel laureate says…

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Dismissing Elizabeth Blackburn, M.D., is not so easy. She won international praise in 2002 when George W. Bush kicked her off the President’s Council on Bioethics Research because of her stubborn support for stem cell research. She shared the 2009 Nobel Prize in Physiology or Medicine with Carol Grieder and Jack Szostak for discovering “how chromosomes are protected by telomeres and the enzyme telomerase”.

She continues to do basic research published in high-impact journals, but she also does studies of mindfulness with psychologist Elissa Epel, who discusses their work together in presentations at Deepak Chopra’s Sages and Scientists Symposium. Epel is quoted as saying in a TEDMed talk, “Our cells are listening to our suffering.”

Epel cites a study co-authored with Blackburn and published in a decent peer-reviewed journal, Clinical Psychological Science where she claims to have found measures of the mind wandering (“How often in the past week have you had any moments when you felt you didn’t want to be where you are, or doing what you are doing at the moment?”) were related to telomere length. So, the article concluded “A highly wandering mind may indicate a more rapidly aging body.” Egads! Get that wandering mind under control, your health is at risk!

According to Daniel Engber, Blackburn and Epel now have at least a million-dollar book contract for:

The Telomere Solution: How the Nobel-Prize-Winning Discovery Can Help You Fight Cellular Aging and Improve Lifelong Health [which] will reveal “how we can keep our cells healthy and dramatically reduce aging by simple diet, exercise, stress-reduction, and psychological techniques, including a way to discover our true biological age.

Blackburn and Epel founded the diagnostic company Telomere Health (since renamed Telomere Diagnostics), although they have sold their stock in it. Clicking on Telomere FAQs at the website homepage takes you to “Telomeres and Your Health: Get the Facts”:

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.

Does drinking soda kill you quicker than smoking?

Blackburn and Epel co-authored a paper with a group that included Jue Lin, who still has a financial interest in Telomere Diagnostics:

Leung, C. W., Laraia, B. A., Needham, B. L., Rehkopf, D. H., Adler, N. E., Lin, J., Blackburn, E. H., & Epel, E. S. (2014). Soda and cell aging: associations between sugar-sweetened beverage consumption and leukocyte telomere length in healthy adults from the National Health and Nutrition Examination Surveys. American Journal of Public Health, 104(12), 2425-2431. PMID 25322305; PMC 4229419; DOI: 10.2105/AJPH.2014.302151

The paper got covered in Time with the headline “Soda May Age You as Much as Smoking, Study Says“. The headline is faithful to what is actually claimed in the journal article:

coke kills

We found that each daily 8-ounce serving of sugar-sweetened sodas was linearly associated with shorter telomeres, roughly equivalent to 1.9 additional years of aging, independent of sociodemographic and health-related variables. For a daily 20-ounce serving, the current standard serving size, this translates into approximately 4.6 additional years of aging. More than 20% of adults in the study population reported at least 20 ounces of sugar-sweetened soda consumption per day. Although these are modest associations, the magnitude of the association for consuming 20 ounces of sugar-sweetened soda is comparable to observed associations between telomere length and moderate/vigorous levels of physical activity (4.4 years) and smoking (4.6 years, in the opposite direction).

The American Journal of Public Health article also prompted a withering critique from Daniel Engber in Slate. The Slate article draws on high-quality recent research in debunking the hype and sheer nonsense in the telomere craze. The article is worthy of bookmarking because it is so accessible, but accurate and informative. And you will need it in the future.

 

Engber exposes the inconsistencies and statistical tricks in the American Journal of Public Health article as the authors relentlessly pursued their absurd conclusion:

Their raw numbers appear to show the opposite, in fact, with subjects who drink more sugar-sweetened beverages having longer telomeres instead of shorter ones. The reverse effect disappeared when they controlled for possible confounders including age, gender, race, and overall diet. But even that analysis did not support their original hypothesis: Sugary drinks had no association with the length of people’s telomeres.

If at first you don’t succeed, keep analyzing data! Undeterred by negative results, Epel’s team split sugar-sweetened beverages into two subcategories—those with bubbles and those without—and, voila, they found a correlation. According to their models, those who drank more carbonated soda (but not uncarbonated soft drinks) showed the signs of premature cellular aging. What’s more, the effect appeared to be dramatic: Among the subjects in their pieced-together, guesstimated sample, heavy soda-drinkers (but, again, not those who preferred energy or fruit drinks) suffered from an additional 4.6 years of aging than their peers, as measured by their blood cells. As the authors pointed out, that’s the same degree of damage you’d get from smoking a pack of cigarettes per day.

I think it’s plain to see this is a deeply implausible result. It suggests, first of all, that bubbly sugar water might be more dangerous than flat—a totally unfounded and unsupported claim. Second, it hints (though never says outright) that a 20-ounce soft drink is as harmful to your health as a pack of cigarettes. That’s just plain wrong: Many more people in the U.S. consume sugary beverages than smoke cigarettes, yet 440,000 people die every year from tobacco use compared with just 112,000 from obesity. In any case the new results don’t really jibe with previous findings: A similar study, published in 2008, found no connection whatsoever between carbonated-soda intake and cellular aging. That one blamed shortened telomeres on processed meat instead.

What emerges is a simple, all too common tale of investigators flexibly re-analyzing their data after a peek revealed results that didn’t support a dramatic conclusion.

The editor and reviewers at American Journal of Public Health should be deeply embarrassed. They ignored the authors’ transparently-described obvious tricks. More importantly, they were distracted by the hype around telomeres from readily-available data that drinking soda does not kill more people than smoking.

Debunking extravagant claims about telomeres is labor intensive. I stumbled upon the Slate article when I was gathering material for a blog entry about NIMH Director Thomas Insel’s blog post praising a seriously flawed study that examined telomere length in the daughters of depressed mothers. Insel had undoubtedly relied upon an earlier Stanford University press release declaring that as a result of living with the stress of their mothers’ depression, young teen girls had already lost six years of life by time they were 10 to 14 years old. And they hadn’t even experienced their own first episode of depression, although Insel claims that 60% of them would by age 18. Rubbish piled upon rubbish!

Even with the rich set of scientific papers referenced in Engber’s Slate article as a start, critiquing the Insel blog entry and the Molecular Psychiatry article that it praised took lots of work. And I’m sure that we will continue to have to contend with a lot of similar telomere porno: airbrushed, carefully-orchestrated edited depictions of findings that will leave us disappointed with what we find in our own science and medicine.

Some background to prepare you to debunk claims about telomeres

So, I’ve summarized some of the science of telomeres that will save us the trouble of having to spend much time debunking what we will inevitably encounter in the future.

Start by keeping in mind that talk about telomeres as equivalent to cellular aging or accelerated aging involves a lot of assumptions that have not yet been confirmed and probably won’t ever be. Basically, the claim is being made that telomere length is a biomarker for aging or –depending on the context– a surrogate outcome. We thus can apply what we know about the need to validate candidates for biomarkers and further, acceptance of them as surrogate outcomes. Biomarkers are indicators that can be used to assess health or disease, and have to be shown to be invariant across studies, mode of measurement, populations, and statistical models. For telomere length, this goal has only been approached for chronological age, race, and sex. Think about the impact of doctors prematurely accepting an elevated PSA score as a biomarker for prostate cancer. So much needless worry, treatment, and so many men left with impaired functioning, with negligible effects on prostate cancer mortality.

biomarkers-unlimited-small

Even stricter criteria need to be met for accepting apparent changes in telomere length observed in intervention studies as a surrogate for other health outcomes. In a funny blog post, Hilde Bastion documented the sometimes not-so-funny and costly pitfalls of prematurely accepting changes in surrogate outcomes as equivalent to changes in actual health outcomes. I have previously talked about scat in the woods as a surrogate outcome for assessing the threat posed by bears; shooting or cleaning up scat has no discernible impact on the presence of or risk posed by bears

Once we appreciate these problems, we can appreciate how dismissible estimates are of how many years of human life are saved or lost based on associations of telomere length with particular variables.

elmer fudd

We are nowhere near clinic- and community-ready measures of telomeres because our methods disagree with each other and with assessments analyzed in other labs, and because efforts to develop summary numbers depend on the assumptions and statistics that are used. Importantly, there are no commonly-accepted calibrators or standards, so comparison across laboratories and the studies that rely on them is difficult.

The Molecular Psychiatry article praised by Insel gives a sense of how messy measurement of telomere length can be:

To control for interassay variability, eight control DNA samples were included in each run. In each batch, the T/S ratio of each control DNA was divided by the average T/S for the same DNA from 10 runs to get a normalizing factor. This was carried out for all eight samples and the average normalizing factor for all eight samples was used to correct the participant DNA samples to get the final T/S ratio. The T/S ratio for each sample was measured two times. When the duplicate T/S value and the initial value varied by more than 7%, the sample was run a third time and the two closest values were reported. Using this method, the average CV for this study is 2.1%.

Even after these efforts, the data were highly skewed. Data for an unknown number of participants had to be winsorized. That means scores for extreme outliers had to be artificially brought closer to the scores of other participants by assigning a less extreme value in order for the assumptions of statistical analyses to be met.

Many of the strongest claims about telomere length and health outcomes come from studies that are so small that finding large effects is statistically improbable, even if they are present. This suggests a strong confirmation bias that exploits flexible rules for aggregating and analyzing data, and selective reporting. Bigger epidemiological studies obtain modest, if any, associations with telomere length, while small clinical samples get what appear to be stronger effects with many fewer participants. As Ioannidis has demonstrated, this is typical in hot areas of research: there will be a lot of false discoveries and inflated claims that will not be reproducible when replication is attempted by independent investigator groups in larger, better-designed studies.

Reviewing telomere papers, I found even the citing of literature was unreliable. When I checked reference sections against Google Scholar and Web of Science, I found lots of contradictory studies were left out or misrepresented, exaggerating the consistency of past research with the findings of a particular study. Again, this is not a phenomenon limited to telomere research, but has been documented elsewhere when a group of investigators tries to establish dominance in a still-controversial area of research with conflicting findings.

Building on my follow up of papers cited in the Slate article, my own literature searches confirmed:

  • Widely-accepted claims about telomeres predicting mortality are contradicted by some quality meta-analyses and large-scale population-based studies.
  • Predictions of future onset of chronic illnesses from telomere length have not been reproducible in meta-analyses and large-scale population-based studies.
  • Even when found, the associations in large scale, quality studies between telomere length and outcomes like disease onset and mortality are quite modest.
  • Associations claimed between exposure to stress and telomere length have not been reproducible in large scale studies.
  • Cross-sectional associations of telomere length are often not borne out in prospective longitudinal studies.
  • Telomere length is reliably associated with age, sex, and race. The association between telomere length and clinical variables is reduced or disappears when age is statistically controlled for in large scale studies. Older people have shorter telomeres than younger people, and males have shorter telomeres than females. This corresponds to life expectancy. But wait, whites have shorter telomeres than nonwhites. So, they die earlier? No, of course not, and this robust association needs to be ignored if anyone wants to claim consistency of findings about telomere length and aging.

Many of the strongest claims about telomere length come from authors who already have a record of extravagant claims that are likely not to be reproducible in larger studies by independent investigator groups. Many of the extravagant claims come directly –or have only a few degrees of separation– from the original University of California, San Francisco group. I found that when researchers who have been associated with this group co-author articles with investigators just entering telomere research, they provide a lot of the selective citations of their own work in the new authors’ papers.

So maybe the “source heuristic” still somewhat applies in evaluating claims about telomere length as an indicator of accelerated aging. Sources who:

  • Have previously made unsubstantiated and even outrageous claims,
  • Have direct and indirect ties to dubious tests and herbal supplements, or
  • Have made extravagant claims in talks at Deepak Chopra’s Sages and Scientists Symposium and TEDMed

should not uncritically be accepted without corroboration from other, independent sources without this baggage.

Stay tuned for my analysis at PLOS Mind the Brain of Tom Insel’s biomarker porn concerning a study in Molecular Psychiatry of the telomere length of daughters of depressed mothers. Go to the study now and see if you can detect the hype, selective attention to the existing literature,  and dodgy statistical tricks.

 

 

Posted by James Coyne

James C. Coyne, Ph.D. is Professor Emeritus of Psychology in the Department of Psychiatry, and previously Director, Behavioral Oncology Research of the Abramson Cancer Center, and a Senior Fellow at the Leonard Davis Institute for Health Economics, all at the Perelman Medical School of University of Pennsylvania. Currently, he is Professor of Health Psychology, University Medical Center of Groningen, the Netherlands. Previously, he served on the faculties of University of California, Berkeley and University of Michigan School of Medicine. Dr. Coyne has been elected a Fellow of the American Psychological Association, Society of Behavioral Medicine, and Academy of Behavioral Medicine. His critical commentaries have challenged whether psychosocial intervention extends the survival of cancer patients, whether recommended and mandated depression programs improve patient outcomes, and whether meta analyses of behavioral medicine commissioned by professional organizations are valid and credible. A 2008 systematic review and meta-analysis in JAMA of screening for depression among cardiovascular patients was designated by BMJ as one of the eight top papers of the year. He is known for presenting and defending controversial positions and for promoting reform of the clinical and health psychology journals. He is the co-author or editor of a number of books including the 2009 Screening for Depression in Clinical Settings: An Evidence-Based Review (Oxford University Press) with Alex Mitchell.

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