Thursday, November 1, 2012

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'.


  1. I think much of the telomere story is a mess. For instance, how can telomerase negative cells maintain such long telomeres over hundreds of years and many cell divisions? Does it make a difference to shrink from 10kb to 6kb? Is this 4kb responsible for aging? (Chiang Y J et al. PNAS 2010;107:10148-10153) How about mice that grow normally for five generations with normal telomeres despite being telomerase negative. In cancer cells it is just as confusing...Telomerase is active but the telomeres are very short.

    1. It's another example of one-size-fits-all claims to discovery and explanation. Such things--and they're to be found all over the place these days--typically elide the exceptions (and they're usually all over the place, too)!

  2. Dan Eisenberg has published some on this - first a review of overall biology here ( and had some data on early nutritional stress and infectious disease exposure at the last HBA meetings. I think some of the questions outlined above about different types of early life stress and telomere length (nutrition, growth, infection) should start to have information soon.