Telomeres: something to fear, or merely a seer?

Attention Conservation Notice: 1200+ words, with an estimated read time of seven minutes, of exuberant extrapolation from a new study which I was not associated with in any way. I am not an expert in telemore biology, nor am I a doctor.


In case you’ve been busy obsessing over whether or not to post things to social media over the past decade (oh wait, that’s me), you may not know that much about telomeres.

Telomeres are repetitive sequences of DNA at the end of chromosomes that get shorter with each cell division. If they get too short, they can promote cellular senescence.

They also are responsible for some of the prettiest pictures of DNA, in which people stain for the telomere “cap” at the end of the chromosomes, such as this classic image:

from the US DoE HGP via Wikipedia User:Gustavocarra

from the US DoE HGP via Wikipedia User:Gustavocarra

Much of the extrapolation of telomeres to aging is built around “Hayflick limit” models of aging.

However, these models do not explain all aspects of aging, and in fact, in most organ systems, cells do not die in large numbers during normal aging (a key exceptions being the thymus) [1]. Instead, cell numbers usually remain constant, because most cells in the body are post-mitotic.

Nevertheless, average telomere length has emerged as a very promising biomarker for aging, and a study on 60,000+ Danish people came out a few weeks ago that gives us a lot of new data on the subject. As far as I can tell, it is the largest such study to date.

Associating telomere length with mortality 

This study measured average telomere lengths in white blood cells (leukocytes) from peripheral blood samples.

They then measured death rates in a 0-22-year follow-up period (with a median follow-up length of 7 years).

Adjusting for age only, the individuals in the shortest decile of telomere length had an increased risk of death of 1.54 (95% CI 1.38 to 1.73).

And even after adjusting for age, sex, BMI, systolic BP, smoking status, tobacco consumption, alcohol consumption, physical activity, and cholesterol level, individuals in the shortest decile of telomere length still had an increased risk of death of 1.40 (95% CI = 1.25 to 1.57).

This shows that telomeres are, at the very least, a biomarker for aspects of aging other than those seen by these traditional clinical parameters.

It’s also possible to go further say “we corrected for nearly everything and still found an effect of telomeres on mortality, so there must be something causal” but that’s fraught with problems — the biomedical literature is truly littered with effects seen in correlational studies that didn’t replicate in causal ones — ibuprofen for Alzheimer’s disease, estrogen replacement therapy, etc.

This doesn’t mean it’s wrong, of course, but that the reference class probability is not as high as you might think.

Luckily, the genetic data in their study offers a way to address this question directly.

Genetic variants of telomere length as a window into causality

The authors genotyped participants for three SNPs that affect telomere length, one associated with each of the following genes:

  • Telomerase reverse transcriptase (TERT)
  • Telomerase RNA Component (TERC)
  • A gene that helps replicate and cap telomeres (OBFC1)

Each of these SNPs has two major alleles, which means that there are three possible states for each individual at each of the SNPs: a) no telomere-shortening alleles, b) one telomere-shortening allele, or c) two telomere-shortening alleles.

Since there are three total SNPs and two alleles at each, there are six total telomere-shortening alleles that each individual could have.

When the authors built a linear “score” from those SNPs, they found that it had a very strong effect on telomere length. I made a visualization of their raw data to show this:

Telomere length versus the sum of telomere-shortening alleles in each individual (allele score), +/-  the standard error; data from doi: 10.1093/jnci/djv074

Telomere length versus the sum of telomere-shortening alleles in each individual (allele score), +/- the standard error; data from doi: 10.1093/jnci/djv074; code

Under the assumption that these alleles don’t influence the aging process in any other way, this allele score offers a tremendous “natural experiment” into the causal role of average telomere length in blood leukocytes in humans.

What the authors found using this natural experiment is that telomere-shortening alleles led to a decrease in the risk of cancer (OR of 0.95 +/- 0.04 per telomere-shortening allele), but had no effect on all-cause mortality (OR = 0.99 +/- 0.02 per telomere-shortening allele).

One suggested mechanism for the cancer effect is that shorter telomeres give potentially cancerous cells a shorter “fuse” before they become senescent. So, people with shorter telomeres may be less likely to develop an actual malignancy.

So, my conclusion is that, despite the correlation seen in the section above, average telomere length likely does not play a causal role in age-related mortality in humans [2]. A few possible critiques of this conclusion:

1) The study not be well-powered enough to detect a difference in all-cause mortality. Some possible solutions here would be to a) increase sample size or b) do studies to find more variants affecting telomere length and then re-do the analysis with increased association power. But, needing a sample size > 60,000 to find an effect would mean that any effect that you did find would be very small.

2) Maybe it is not the average telomere length but rather some other property of telomere length distribution (such as the proportion of cells below or above some “critical threshold”) that is the relevant parameter. This is possible, but biology in generally doesn’t operate on such threshold mechanisms.

3) Josh Mitteldorf, if I understand him correctly, suggests that these three SNPs may affect telomere length only later in life, but not earlier in life. Although I don’t know the actual argument, I suppose it’s possible that telomere lengths early in life play the major causal role in later aging rates, and that these SNPs don’t affect telomere length until later in life. One possible solution here could be a longitudinal study of telomere length, or a cross-sectional study in infancy/childhood. Still, I don’t find either aspect of the argument here very likely.

Conclusions

Genetic evidence suggests that average telomere length (in blood leukocytes, in a Danish population) likely does not play a causal role, or at least does not play a strong causal role, in promoting aging.

That said, average telomere length in blood leukocytes does appear to be an excellent biomarker for aging, capturing large effects not accounted for by measuring traditional clinical factors that affect aging, such as smoking status or cholesterol levels.

This bolsters the evidence for Bojeson’s argument that telomere length should be used as a biomarker for aging and for assessing risk of age-related diseases in routine clinical practice.

References

Rode L, Nordestgaard BG, Bojesen SE. Peripheral blood leukocyte telomere length and mortality among 64 637 individuals from the general population. J Natl Cancer Inst. 2015;107(6):djv074.

Mitteldorf J, “Large New Survey Tracks Telomere Length and Mortality”. 2015. http://www.webcitation.org/6YYKb3OWm

Bojesen SE. Telomeres and human health. J Intern Med. 2013;274(5):399-413.


[1]: What about the brain, do I hear you say? A key tenet of the Alzheimer’s disease model is that neuronal loss in aging is not normal and only occurs in Alzheimer’s disease.

[2]: Let me be quite clear and point out the obvious that I agree this is a bad thing. That is, it would be great if telomere length were causal for aging, because it would suggest an obvious intervention to decrease the risk of age-related diseases: therapies to extend telomere length. Unfortunately, this study suggests that such an intervention will probably not have a beneficial effect on age-related mortality.

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