Telomere Length Studies So Far Say Little On Cause and Effect

Telomeres are caps of repeating DNA sequences at the end of chromosomes. A little of their length is lost with each cell division, dropped in the process of copying the cell's genome. This acts as a clock in some types of cell population, those in which there is a lot of cell turnover and in which cells divide frequently to replace losses: shortening telomeres count down to the point at which the cell should self-destruct or at least stop dividing. The system is more complex than just a clock, however, as telomeres can be lengthened by the activity of the enzyme telomerase. When measuring average telomere length, or the proportion of very short telomeres in a cell population, you must also think about how much work is being done by stem cells: how often are the stem cells supporting a given tissue creating fresh new cells with comparatively lengthy telomeres?

In this system of dynamically lengthening and shortening telomeres, researchers have found that average telomere length - or the proportion of very short telomeres - in at least some tissues correlates moderately well with health and aging. Blood cells are those most often used for these measurements. If you are stressed or ill or damaged by aging then the proportion of short telomeres tends to be higher, and this can change on a short-term basis.

There is some debate over whether progressive shortening of telomeres over the years is one of the primary causes of aging or whether it is a secondary reaction to levels of cellular damage and other environmental factors. Even if it is a secondary reaction, it might still go on to cause further harm. Researchers have shown that mouse life span can be extended by boosting levels of telomerase, but there is still the question of whether this is happening because of lengthened telomeres, or because of some other effect of telomerase - such as the possibility that it might help protect mitochondria from damage, where mitochondrial damage is a much more convincing primary cause of aging. It is also worth noting that mouse telomere biology is quite different from that of humans.

What is needed in the process of obtaining more definitive answers is a way to globally lengthen telomeres without telomerase, and ideally without altering anything else in cells in the course of doing so - a challenging goal for any specific piece of cellular machinery, given the interconnected nature of cellular systems and the extensive reuse of proteins in multiple types of machinery. A way to repair forms of cellular damage thought to contribute to aging would also be useful: if rejuvenation therapies, once created, have the side-effect of lengthening telomeres then that will strongly suggests that telomere erosion is not a meaningful cause of aging. In the meanwhile, research results tend to reinforce interest in telomeres, but not add a great deal to the debate on whether age-related shortening is a cause or an effect.

Telomeres May Hold Clues To Effects Of Aging

KNOX: Ornish and his colleagues, including a scientist who won the Nobel Prize for her work with telomeres, studied two groups of older men. One didn't do anything special. The other adopted healthier habits that will sound familiar. Five years later, the telomeres of the men who did these things were different.

ORNISH: The more people changed their lifestyle, the more their telomeres got longer.

NIR BARZILAI: Certainly everybody in our field will agree that the telomere length is telling us something.

KNOX: But it's not clear what. And he says the new study doesn't answer that either.

BARZILAI: At the end of the day, this hasn't stopped any argument. You know? Either you're healthy, so you have longer telomeres. Or you have longer telomeres, and that's why you're healthy. You can pick and choose what you believe in and make an argument.

KNOX: Apart from this fundamental disagreement, there's something that troubles scientists. It's not only healthy cells that have longer telomeres - so do cancer cells. That may be what keeps them dividing out of control.

AUBREY DE GREY: My sense is that the cancer problem is a really, really big problem. The implicit hope is that cancer either will not be stimulated in the manner that many people think it will. Or else that even if it is, we'll find ways to get around cancer somehow.

Here is the paper that prompted the article quoted above:

Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study

This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes.

Relative telomere length increased from baseline [in] the lifestyle intervention group, but decreased in the control group. When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up.

Comments

IMHO telomeres are only markers of health, and not perfect ones either. I'm far more interested in research into telomerase and its mechanisms of action and I hope all telomere scientists will also follow this path eventually.

Posted by: Musli at September 17th, 2013 6:51 PM

I find it difficult to believe that telomere shortening itself is a primary cause of aging. Telomere maintenance is clearly a regulated process and the cellular turnover varies between cell types (neurons are replaced less frequently than, say, blood cells). I think telomere length is a bio-marker rather than a cause of aging.

All of the evidence is pointing towards mitochondrial DNA damage being a primary cause of aging. Biotime is developing therapies for rejuvenating stem cells using telomere elogation. One would think this therapy could be modified to include repair or replacement of mitochondrial DNA as well. Both processes could be combined into one therapy.

Posted by: Abelard Lindsey at September 18th, 2013 9:42 AM

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