IARC 50th Anniversary Conference
Telomeres, biology and cancer
Prof Elizabeth Blackburn - The Salk Institute of Biological Studies, La Jolla, USA
Telomeres are simply the ends of chromosomes and the molecular structure is a very specific DNA sequence which is sheathed by a group of protective proteins, all of which have been well defined at the molecular level. The repeated DNA sequences, normally we’re born with about ten kilobases at the ends on each of our chromosomes but that can dwindle down to about half on average as we go through aging. That dwindling down means that a fraction of telomeres no longer function.
What factors are influencing these processes?
Telomere length is inherited to a fairly large degree but we don’t know how much of that is genetic and how much is simply the telomeric DNA itself carried through on the chromosomes through the parental gametes. So we do know that there are many non-genetic influences on telomere length which show both dose dependency and severity dependency in how much they wear telomeres down during life.
What do you already know about telomeres and their influence?
What we know is at the cellular level if the telomeres wear down too much then they no longer protect the ends of chromosomes and that can lead to chromosome instabilities and hence has a role in cancer aetiology because of chromosome instabilities. Very importantly though, when the telomeres get too short a normal cell will set up a response: sometimes it will go into a senescent state, sometimes it will die and sometimes it will have a transcriptional programme change that makes it more pro-inflammatory. So it can have effects where cells no longer regenerate themselves but also have adverse effects systemically because of the pro-inflammatory factors.
What are the known molecular mediators of the wearing down of telomeres?
There are probably more hundreds of molecular mechanisms than you can ever imagine because every mechanism one has looked at affects both the wearing down and in addition the ability of the telomeres to be regenerated by the enzyme telomerase which we discovered can add back telomeric DNA to chromosome ends. But in humans that typically doesn’t keep up with the wearing down in our somatic tissues, although it seems to be able to regenerate from one generation to another in the normal range of telomere lengths. However, what we do know is that the non-genetic effects include many malleable effects and, in particular, chronic psychological stress which, of course, we know the brain has clear physiological read-outs when it’s under chronic stress such as dysregulation of cortisol that has major effects. We find chronic stress has major quantifiable effects on accelerating the wearing down of telomeres throughout the body but usually measured in blood cells. That in turn clearly increases risks of common diseases of aging, they include cardiovascular and some cancers. Cancer is more complicated because some cancers are actually spurred on by having better telomere maintenance determined genetically. These are weak but discernible effects.
Aside from stress, what other factors can influence telomere durability?
So the converse of stress, if you will, is if one has exercise and social support and sees that that ameliorates the sort of average wearing down. One also sees some effects that can now be pinned down to certain dietary effects. So in large studies omega-3 measured amounts of DHA and EPA in people predicts less telomere wearing down and longitudinal studies that in turn has been related to cardiovascular disease effects as well as mortality from cardiovascular and other causes. So we see telomere length is statistically a predictor of all cause mortality and a predictor of overall cancer risks but within the groups of cancers, of course cancer is hundreds of diseases, there are differences where there are some cancers which are adversely affected by having… that is risks go up when the telomere shortening is greatest, particularly clear in Mendelian diseases of telomere genes that are mutated and haploinsufficiency leads to very accelerated telomere shortening and very greatly increased risks of cancers for certain subsets of cancers.
Are there any “dos and don’ts” coming out of your research so far?
Yes, but they’re everything your mother told you. So get a good night’s sleep, have a good attitude, get good exercise, even moderate exercise, cope with stress if you can possibly do it and some dietary… we’ve certainly seen, we meaning large cohort studies, effects that are related to, for example, the Mediterranean diet versus processed food, clear effects of smoking in dose dependent fashion based on history, clear effects of alcohol consumption and clear effects of sugared sodas in dose dependent fashion. Exercise turns out the more categories of exercise one does the longer ones telomeres are, this is in very large population studies. So one sees essentially it’s essentially everything your mother told you but probably don’t take quack medicine that purports to increase telomerase because there’s good biological reasons and good cancer genetic reasons that argue that that could push one into higher risks for certain cancers.
Regarding cancer prevention, how strong is the message regarding influencing telomeres versus smoking and lung cancer?
I can’t give you really good numbers as to the relative contribution of the risks but they all go in the same directions. The very interesting challenge is to understand what fraction of the risk which is clearly caused by things, by tobacco, smoking, lack of exercise and other factors. We don’t know much about stress factors in cancer aetiology but those effects of stress on telomeres are somewhat comparable in magnitude to the effects of these other well-known cancer risk factors. I’d very much like to know if that is a role that may be played in cancer aetiology or not. It’s simply not known at the moment but now there’s a strong pointer that one should at least look based on this particular biomarker.
Could one take a pill to keep telomeres in good shape?
Yes, if you’re prepared to risk cancers and we do not know in which cell types and so forth the increased action of telomerase which has been shown genetically to increase risks for melanomas, gliomas and non-smoker lung cancers, small changes genetically that increase telomere maintenance increase those risks. So we don’t know which tissue types that’s critical in. So the bottom line is I would strongly advise against taking any pill that purports on the internet to push your telomere maintenance up because the biological long-term effects of this on cancer risks are simply unknown but there’s very good biological reason to think that that might push one into statistical risks. However, there’s very good guidance from all of the other factors that telomere measures can give you a kind of quantifiable read-out into some of these interventions that one would look at, such as exercise, dietary interventions and even perhaps looking at how coping with stress could be useful in terms of certainly other disease relationships and potentially in cancers, we just don’t know.
What is the interrelationship between telomerase and telomeres?
Telomerase is one factor that can elongate telomeres. Its action on telomeres, if you’re in the clinically important zone where you have haploinsufficiency for telomerase, that 50% level of telomerase compared with the normal 100% is extremely drastic and you get a clear set of diseases including very high incidence of some cancers. However, in the middle zone of telomere length, telomere maintenance and telomerase, it’s one of hundreds of factors that molecularly control telomere length. So it’s not a simple relationship in the normal range although there’s generally a positive effect of higher telomerase base level and telomere length but that is not necessarily simple, it’s a very highly controlled maintenance system.
What is your take-home message?
For telomere maintenance what we’ve found is that all of the health practices that are very simple kinds of practices that traditionally one’s mother tells one to do – exercise, get a good night’s sleep, stress reduction, eat sensibly and so forth, don’t do too many diet sodas and do not smoke or have excessive alcohol – all of those quantifiably in dose dependent ways relate to adverse effects on telomere maintenance. So some of those will play into cancer prevention modes but they probably interact with a lot of other factors as well and that’s where there’s a lot to be learned in the interactions.
