Is telomere length a better predictor of longevity than astrology?

How and why we'll die

Palm reading chart. Mal Corvus Witchcraft &
Folklore artefact private collection owned by
Malcom Lidbury (aka Pink Pasty),
Witchcraft Tools; Wikimedia Commons

Many more or less plausible ways to predict when and what we'll die of have been proposed over the centuries.  Palm reading and astrology have been around forever, as have omens of many sorts, while more sociological causation has been the focus of more recent thinking, so the stresses we might have undergone during childhood or the effects of the lifelong stress of racism or poverty are considered possible predictors of illness and early death.

More proximal biological predictors such as what our mothers ate when we were in utero, or what we ourselves ate in early childhood have been the subject of other kinds of studies, and at the cellular level, the effect of the length of the telomeres on the ends of our chromosomes on longevity has caused much excitement.  As of course has genetics.

Telomere erosion
Prediction is one facet of this, but the other is explaining the mechanism.  Why will what's going to kill us kill us?  Two papers in the October issue of BioEssays address these questions.  One, called "Early life stress and telomere length: Investigating the connection and possible mechanisms,"  does just what the title says it will, investigates the connection between early life experiences and telomere length, a proxy for longevity.  Telomeres are repetitive sequences that cap the ends of chromosomes, presumably protecting them from damage.  The suggestion is that stresses such as 'maltreatment' in childhood may have 'powerful negative effects on health decades later' via telomere erosion.  

Stress in early life is known to have a powerful direct negative effect on health in later life. This direct effect requires one or more underlying mechanisms that can maintain it throughout the course of life. Interest in the etiological pathways that mediate the effect of early-life stress on physical and mental health has focused on key biological systems, including the sympathetic nervous system, hypothalamus-pituitary-adrenal axis, immune system, and the epigenome, leading to important insights into the systemic effects of stress. Some of the adversities associated with early life trauma include neurological and respiratory problems, cardiovascular disease, and metabolic disorders, to name but a few. However, the questions of how and when childhood stress impacts at the cellular level, specifically in humans, remain to be answered.

The paper reviews the literature on the effects of stress on telomere erosion, but says it lacks 'clarity as to cause and effect in later life.'  That is, the evidence is as clear as mud. Telomere length is clearly associated in some ways with aging, and has been promoted by some as 'the' major cause, since it is a trait shared by many different species and might be related to each species' typical aging rate.  But it seems that telomere shortening can be reversed; this study measures average telomere length of 5 and 10 year olds, but if indeed telomere length is associated with lifespan but 'healthy living' can reverse this, this suggests that the stress and longevity connection is not really useful for prediction of lifespan. Plus, there are tons of other causes that also have to do with death and longevity.

Dilution is the solution!
The other paper in this issue of BioEssays, "On the cause of aging and control of lifespan: Heterogeneity leads to inevitable damage accumulation, causing aging; Control of damage composition and rate of accumulation define lifespan," proposes that cells inevitably suffer damage because cell processes are imperfect and cells are affected in unpredictable ways, and that the damage is 'diluted' when cells divide, but not reversed.  This, says the author, "is due to the high cost of accuracy, the greater number of damage forms compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world."

Further, the cause of aging is not the same as control of lifespan. We won't reproduce the whole argument here but briefly, "Damage dilution is a basic strategy of cellular life: Its prevention leads to aging."  The explanation is a bit too teleological for our taste; Nature, says the author, has found a way to deal with all the damage that accumulates in the cell, and "that solution is dilution!"  Thus, cells don't have to develop energetically expensive ways to prevent or repair damage, they just divide.

But, he writes, asymmetric cell division leads to unequal distribution of the damage, and this leads to the aging of the mother cell or whichever of the daughter cells inherits more damage.  And 'damage overload' leads to senescence.  And, "lifespan is modulated by the landscape of molecular damage and the rate of its accumulation."  To conclude, "...heterogeneity leading to inevitable damage accumulation is the cause of aging, and the control of damage forms and the rate of their accumulation is the regulation of lifespan."  But, lifespan can be expanded "with dietary and genetic interventions."  So, like telomere length, it can be altered by environmental variables.  Which makes the cause and effect aspect of these explanations a bit less convincing.

And, with similar genomes, cell turnover rates, and so on, why is it that large organisms don't die off at faster rates than small organisms, since we're accumulating damage at a much faster rate?  Instead, we are orders of magnitude larger than mice, with gazillions more cells and cell divisions, but we live more than an order of magnitude longer.  And what about animals with very anomalous lifespans compared to their close species compatriots?  Again, one-cause arguments are so tempting, especially in this lobbying era in science.  Each cause may contribute, but needn't be 'the' or even the major cause....if there even is such a thing.

How do we know what's right?
But our point is not to evaluate the arguments in these papers so much as to show that the damaged cell story is a very different one from the telomere, stress and aging story which appears in the same journal.  Both are proposing to explain why experience, either of the whole person, or of a person's cells, is associated with longevity but the arguments aren't even really compatible.

But let's say that on their own, both of these stories are more or less plausible.  And remember, they are just two of a plethora of proposed explanations for how and why we age and ways to predict when and of what we'll die.  Why are there so many of them, similarly plausible?  And how do we evaluate them?

In part the problem is that there are many many more correlations between causes and effects than there are demonstrated associations.  So, a palm reading or an astrological prediction may in fact contain enough truth to seem plausible.  And might even 'come true.' Does this prove that astrology is a useful predictor?  Not convincingly enough for someone of a scientific bent, looking for material explanations of cause and effect.

In part it's because the satisfaction content of an explanation depends on the level at which you're trying to explain a phenomenon.  What causes HIV/AIDS?  The virus?  Is it risky behavior?  Not having the protective CCR5 genetic allele?  Is it being poor in Africa?  All of the above? 

Thus, there may be multiple explanations for the same observations.  The correlation between childhood stress and shortened lifespan might be explained by telomere erosion, but it might also be explained by the confounding variable of childhood poverty, which means perhaps lower likelihood of childhood vaccinations being completed, or of adequate maternal nutrition during pregnancy, or of just plain lower well-being.  And any of this may or may not have anything to do with telomeres. All this, of course, assumes that we have a clue how to define and measure stress.

Death is an event, but disease and the actual thing that precipitated death are varied and often very hard to define.  They are the result of interacting, gradually increasing risk of various kinds of failure.  They involve totally different types of cells and not all causes clearly related to genetic events within those cells.  Events do have causes, unless you're a mystic.  Even astrologers believe in cause and effect.  But this doesn't mean that there is a particular hierarchy, generality, or unity of their underlying mechanism.  Your lifespan is the time before any particular one even takes you down, and it can be viewed as an aggregate phenomenon.

This does leave as an open question, the correlation of lifespans with things like body size, among closely related species.  This is a very curious fact and terrific subject for investigation -- it's something Ken has been interested in for decades, especially in the context of cancers, that appear to be generally a cellular-genetic set of diseases.  This regularity is yet to be explained.

What you bring to the table
And finally, we're back to something we blogged about a few weeks ago -- your prior beliefs may well determine how you weigh the evidence.  If you're a telomere erosion shortens lifespan adherent, this BioEssays paper is yet more evidence in favor, and you're more likely to believe this story.  And maybe you even see a link between these two papers, and could argue that telomere erosion is a form of cellular damage, so combined, these papers go far toward explaining aging and shortened lifespan.  Maybe you believe that social factors affect longevity, and are satisfied that that mechanism has now be explained.  Or maybe you're a skeptic in general, and don't see that either paper has accomplished what it set out to do; the cellular damage and division argument seems teleological and circular, and so you're not going to buy it at all. Or, there are too many methodological problems with the stress/telomere paper, and you're not going to buy that one either.

Maybe we need some other sorts of approaches, or even definitions, of the 'trait' (if it is a trait) we call 'aging'.

Caveat emptor! The latest snake oil being hawked by geneticists.

Telomeres (public domain photo)

The British newspaper The Independent reported on May 16 that a £435 ($700) test to determine telomere length will go on sale in Britain within the year.  Telomeres are structures on the tips of chromosomes that have been found to shorten with age, and the company, Life Length, claims that the test results will predict a person's lifespan.

Scientists behind the €500 (£435) test said it will be possible to tell whether a person's "biological age", as measured by the length of their telomeres, is older or younger than their actual chronological age.

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.

And they are certain that public demand will increase.  

Asked why the general public would be interested in taking a telomere test, Dr Shay [a consultant to Life Length] said: "I think people are just basically curious about their own mortality. If you ask people what they worry about, most people would say they are worried about dying."

He added: "People might say 'If I know I'm going to die in 10 years I'll spend all my money now', or 'If I'm going to live for 40 more years I'll be more conservative in my lifestyle'.

Curiously, the reporter adds, "The worrying thing is that if this information ever got to a point where it is believable, insurance companies would start requiring it in terms of insuring people."  Throughout the story the reporter strives to be agnostic as to whether the science is up to the claim, quoting scientists on both sides of the issue (though, it must be said that those in favor are tied to Life Length) and yet he apparently doesn't believe it himself.  Why isn't that the story here?  Why give free advertising to a product that isn't obviously  ready for prime time?

Indeed, a follow-up story in the same newspaper by the same reporter on May 17 under the headline "Concerns grow over DNA test that determines your lifespan", tells a more cautionary tale. 

Experts are worried that people may misunderstand the limitations of the test, which purports to measure a person's true "biological" age rather than the usual chronological age. They are also concerned that the information may be used by insurance companies and organisations trying to sell fake anti-ageing remedies.

"I'm sceptical and concerned about this test mainly because of the lack of evidence that this information is useful and yet this test touches on really significant issues, such as predictions of life expectancy," said Colin Blakemore, an Oxford neuroscientist and former head of the Medical Research Council.

"My pressing concern is just how reliable these tests are in terms of anything significant. We need to know an awful lot more before we make predictive statements. People worry about how predictive it is."

This sounds an awful lot like what's being said by some about direct-to-consumer genetic testing companies.  We, for example, have said it here, and here.  How predictive genes 'for' disease or telomere length actually are is simply not known, and sales of these results as though it is is just snake oil.

Yes, telomere length has been found to be correlated with lifespan, but as everyone knows, correlation does not mean causation.  Which comes first, illness which shortens telomeres, or short telomeres, which cause illness?

And even more significant for this story is the fact that apparently telomeres can be lengthened.  A paper published in The Lancet in 2008 looked at telomerase activity (the enzyme that maintains telomeres) in men with low-risk cancer of the prostate. 

30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 24 patients had sufficient PBMCs [peripheral blood mononuclear cells] needed for longitudinal analysis. This study is registered on the ClinicalTrials.gov website, number NCT00739791.

PBMC telomerase activity expressed as natural logarithms increased from 2·00 (SD 0·44) to 2·22 (SD 0·49; p=0·031). Raw values of telomerase increased from 8·05 (SD 3·50) standard arbitrary units to 10·38 (SD 6·01) standard arbitrary units. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=−0·36, p=0·041) and decreases in psychological distress (r=−0·35, p=0·047).

And, telomere length has been linked with chronic stress exposure and depression.  Indeed, some studies have shown, according to the May 16 story, "that meditation or other forms of stress reduction may lengthen telomeres" (one such study is here). Even some of the pro-testing scientists interviewed for the story suggest that people who find out they have short telomeres can beat the odds by improving their diet and exercising. So, why should anyone buy this $700 test if telomere length is essentially a reflection of lifestyle, and a short term one at that? 

And that's just the beginning.  Other issues include the variance around the predicted (statistically 'expected') age of death.  And how stable that is--since it must be based on actual deaths in some way, relative to the dynamics of telomere degradation per year.  And whether death-age estimates are based on prior lifestyle exposures which cannot be extrapolated to the future.  And whether the prediction is any better than that based on your close relatives' experience, your weight, diet, smoking and other habits, your job hazards, and so much else.

Telomeres are important aspects of genomic health, but organismal health is more complicated than just telomere length (measured in blood samples, whereas death rarely occurs because of blood failure!).  There are correlations with body size and lifespan, but the relationship to telomeres and their maintenance across species and over evolutionary time are not so simple.

So, snake oil is still snake oil.  Caveat emptor!  And scientists: be restrained in what you accept and what you teach your students.

The strange case of the cart pulling the horse: the runner's telomeres

Our culture, and certainly our science culture, firmly believes in the concept of causation that is directed in time order. Only some rather esoteric physicists toy with the idea that time is reversible, or doesn't exist, or is some sort of illusion. In everyday life, at least, cause comes first, then effect. Always. The horse always pulls the cart, never the reverse.

But that may not allow us to identify which comes first, at least if we think sloppily as seems to happen daily in the science press and hence also in the journals the reporters are reporting on. Just-So stories of how something came to be are just too appealing.

So, in the New York Times on Jan 27, there was a story about aging and running....or is it running and aging? It turns out--at least it's reported--that older men who run have bodies like young studs. They may look old on the surface, but if you gaze pruriently at the ends of their....chromosomes, you find that those chromosome ends are capped by structures, called telomeres, that are as long as younger guys' telomeres. Size matters!

Telomeres protect chromosomes from chemical degradation in the cell, so they're good for genetic function. But generally they are reported to shorten with age, and this is argued to be one cause of biological aging and senescence.

In general, telomere loss was reduced by approximately 75 percent in the aging runners. Or, to put it more succinctly, exercise, [the principle investigator] says, ‘‘at the molecular level has an anti-aging effect.’’

If runners' telomeres are longer for their age than non-runners, running must be good for you, right? And then, indeed, we must be able to find an evolutionary explanation for that.

Well, not necessarily. This may be a case of causal order, of carts and horses. Does running inhibit telomere degradation, or do longer telomeres let older men run better? That would be easy to explain: if the whole idea of telomeres and aging has merit, maybe guys with damaged telomeres feel lethargic or in other ways are not inclined to run, or can't run comfortably. One would see the same association: older runners have longer telomeres. In this case, telomeres are the horse, the running man the cart.

Of course it is also possible, though not easy to understand, that running boosts your telomere length, so if older guys run, they maintain their telomeric health. How a cell knows that you're running and how that leads it to keep up telomere maintenance is a critical subject if the man is the horse and the telomere the cart.

But all that assumes there really is a causal connection between running and telomere length, whichever way it may go. Because another widely practiced fault, an obvious one everyone knows about but a temptation few can resist, is to equate correlation with causation. Telomere length may be correlated with running in one's dotage, but there need be no causal connection between them. Older running men probably are (on average) more educated and more into health cultures; they probably also watch more Public Television than slothful older guys, who probably watch more online poker or wrestling. But we doubt that PBS shows lengthen telomeres.....or might they? What if thinking harder has that effect?