For years now, it’s been said that telomeres – the tips of your chromosomes – are the key to cancer and aging. The shorter they are, the worse off you are – so the story goes. But what do we really know about them? Can the length of your telomeres help predict how long you’ll live? Could telomere research unlock a modern fountain of youth? Could humans one day live to be hundreds of years old?
Dr. Ron Rosedale of DrRosedale.com and The Rosedale Diet is here to answer some of these questions in this special guest post. In it he will introduce you to these little bits of genetic sequences, and provide his expert commentary on the state of telomere science. It will get somewhat technical in parts, but it’s well worth the read.
Now, Dr. Rosedale…
Summary – The Good, the Bad, and the Ugly
The Good: With considerably more research in the control of telomere length specific to different issues, it may be a new and powerful therapeutic tool to improve health.
The Bad: It is not likely a modality to extend maximal lifespan. It is far from the fountain of youth.
The Ugly: Without proper and exact knowledge of when and where to control telomere length, it will likely greatly increase one’s risk of cancer. In other words, it may very well increase healthspan as it reduces lifespan.
Can the length of very simple, short genetic sequences at the tips of chromosomes called telomeres determine how healthy you are and how fast you will age? This has become a popular idea in paleo blogs and in the lay world of “anti-aging medicine”, especially now that telomere length (TL) can be relatively easily measured.
First, let’s examine very briefly the history of that idea. In 1961 Leonard Hayflick discovered that cells in a petri dish could only divide a limited number of times before cell division would cease permanently. This famously became known as the “Hayflick limit”. 10 years later Olovnikov, a Russian researcher, linked the tails of chromosomes to this cell division arrest. It was found that the enzymes that duplicate the DNA of chromosomes cannot continue this duplication all the way to the ends of linear chromosomes. If cells were to divide without telomeres, with each cell division they would lose a chunk of critical and functional DNA. The telomeres act as sacrificial lambs for DNA duplication. They are repeating nucleotide segments (TTAGGG) of relatively meaningless segments of chromosomes such that the loss of a small chunk of these when cells divide is genetically harmless… up to a point. If a cell divides too much, and its telomeres become too short, at best it can no longer divide. Worse, genetic harm befalls that cell. A process is initiated within the cell causing it to self-destruct (called apoptosis). Later, it was found that a natural enzyme that some cells manufacture called telomerase is capable of lengthening telomeres and potentially immortalizing that cell. The finding that telomeres shorten with increasing age has led to the theory that telomeres are at least a biomarker of aging, if not at least partially causative of the damage associated with aging (called senescence). It was, and still is in some circles, thought that increasing telomere length slows, if not reverses, aging. The telomere theory of aging was born. Should it continue to live, or die a peaceful apoptotic death as shortened telomeres themselves are apt to cause?
A full discourse on telomeres and the biology of aging would consume an excessive amount of all of our already telomere challenged lives. I will instead focus on telomeres as a potential biomarker and/or “anti-aging” therapy and the deeper meaning of this.
First, let’s get our terms straight. What is mean by “anti-aging”. The word itself is controversial. In the more scientific, biology of aging community where researchers are genetically manipulating specific (i.e. insulin) metabolic pathways and extending lifespan a hundred or more percent in some animals, that word has a negative connotation. To them, it conjures up images of modern day snake oil salesmen promising longevity treatments such as growth hormone therapy, that if anything, might likely shorten lifespan. To them, a slowing down of the typical aging process results in a lengthening of maximal lifespan as opposed to average lifespan. The two are quite different. The maximum human life span (that has been well-documented) is considered to be 122 years that Jean Calment, a French woman lived before dying in 1997. The average lifespan in the United States is roughly 78 years. If one greatly increased the health of the general population, one might increase average lifespan to be hypothetically 85 years. However, if no one still lived over 122 years, the maximal known human lifespan would continue to remain unchanged.
A treatment such as lengthening telomeres might well improve some, and possibly many, symptoms of aging and even the average or median lifespan, while leaving maximum lifespan unchanged…or perhaps even shortening it. It would not and should not then be considered an “anti-aging” treatment though possibly a good therapeutic modality.
On the other hand, biology of aging experts such as a friend of mine, Andrzej Bartke, past president of the American Aging Association, are able to extend the maximum lifespan in laboratory animals such as mice…a lot. He is the last recipient of one of the most prestigious and lucrative awards in aging research, the Methuselah Prize. He did this by genetically suppressing the growth hormone receptor in a strain of mouse such that it lived about twice as long as usual; the equivalent of a human living to be approximately 180 years old. In the published study that won the prize he states, “We propose that mechanisms linking GH [growth hormone] deficiency and GH resistance with delayed aging include reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1), reduced secretion of insulin, increased hepatic sensitivity to insulin actions, reduced plasma glucose…An important role of IGF1 and insulin in the control of mammalian longevity is consistent with the well-documented actions of homologous signaling pathways in invertebrates.” (Life extension in the dwarf mouse; Curr Top Dev Biol. 2004;63). I mention this also, since a similarly hyped and very popular “anti-aging” treatment is growth hormone therapy, whereby growth hormone is regularly injected with supposed rejuvenating properties…exactly opposite to what was done to win the coveted Methuselah Prize… Caveat emptor.
Many so-called experts on health and longevity talk a lot about increasing telomere length as proof of efficacy of some sort of diet or other health modality. Let’s look at that statement. What do they mean by increasing their telomeres? They have about 15 trillion cells. Did they increase the telomere length of all chromosomes in all cells? Were they all measured? Was a representative sample measured? Is telomere length even indicative of health, or aging? Is it even a biomarker of aging, and if so, is that relevant?
One of several major problems with all this; less than 1% of a person’s cells have the enzyme telomerase and thus are even capable of increasing their chromosome’s telomere length. The other 99% are incapable of doing so. What about neurons, and heart cells that typically do not divide and where their telomeres do not shorten with age? The large majority of liver and kidney cells can’t lengthen telomeres, etc., etc. Perhaps the 1% that can are the most critical. They include white blood cells (WBCs) and many stem cells. We will examine that a bit more later.
Is it even good to increase telomere length? Maybe not. 90% of cancer cells do it. The fact that telomeres shorten may actually allow us to live longer, as it may reduce the risk of cancer. The good news is that the telomeres in almost all the cells other than WBCs and stem cells do not increase, for if they did, dying of cancer would be all but certain.
The chromosomes of nearly all multicellular life are linear; they have a beginning and an end. As such, for these cells, telomeres are essential to life. The exception are bacteria whose chromosomes are circular. They do not have a beginning or an end and thus telomeres are a moot point. Thus, there are no telomeric restrictions on bacterial reproduction. They continue to reproduce as often and as fast as they can; like cancer, that seems to be their singular goal. The purpose of linear chromosomes and telomeres is often thought to be secondary to our evolution from single celled bacteria to large, complex, multicellular individuals such that their now linear chromosomes with telomeres prevent cells from easily reverting back to their ancestral bacterial ways, i.e. the singular purpose of reproduction, that in multicellular life is cancer. It is a must to continually lengthen telomeres to lift the restriction on cell division if a cell hopes to stay a cancer cell.
Another major problem with the telomere theory of aging; if anything there is a negative correlation between telomere length and lifespan of different species. For instance, mice have much longer telomeres than humans but live a small fraction as long.
However, numerous studies have shown a correlation within a particular species between telomere length and length of life. This has therefore been used as strong evidence that length is a good biomarker of aging within a particular species and even that telomere attrition causes aging itself. Hopefully they mean the damage associated with aging. It is unlikely that you would not be a day older tomorrow.
A major mistake made so frequently in medicine, but rarely in other sciences, is the confusion and interchange between correlation and cause. An example is the consistent reference to cholesterol being a cause of heart disease, when in fact it is an association, and even a weak one at that. An entire industry and economy has been built over that “mistake”. I digress; that is a story for another day (or you can read on the web what I have already said about that long ago).
Getting wrinkles is far more correlated, and is therefore a far better biomarker for aging than telomere length, however undergoing a dermabrasion is not likely to extend lifespan. Once again, it is science 101 to not confuse correlation with cause. It could very well be, and in fact is likely, that reduced telomere length is a byproduct of the cell damage and turnover associated with aging, rather than a prime cause of it, though it likely does have some adverse repercussions especially to the immune system and possibly stem cells.
How about current laboratory testing for telomere length? It merely requires a tube of blood since one of the very few cell types that is easily accessible and where telomerase is present such that telomere length can increase are white blood cells. Is the test meaningful? Probably not very. The rate of telomere attrition, the rate of decrease in telomere length that may be more important than absolute length, will increase with increased cellular damage and turnover such as that caused by oxidation, free radical damage, glycation, and inflammation. In other words, all that a higher rate of telomere shortening of any kind might indicate is an increased rate of cellular damage, but it doesn’t tell you what is causing the damage. Glucose perhaps?
Many, including myself, believe that all shortening of WBC telomere length in particular reflects, is the state of inflammation. There are many other much simpler and less expensive, albeit less glamorous markers for this such as a C-reactive protein or even the sedimentation rate. Furthermore, both a healthy, though at the time less active immune system, and an overly stressed or suppressed immune system might, at least theoretically, lead to less telomere attrition due to less cellular proliferation.
Though the rate of white blood cell TL shortening has been shown to decrease and TL may even increase with certain changes in lifestyle such as exercise and diet (that might just reflect improved immune response), TL also has been shown to oscillate even if you don’t do anything; not change your diet, nor exercise, take antioxidants, or think positively about your TL.
However, the biggest problem in measuring TL in WBC’s is that there are many different telomeres of different lengths in many different kinds of cells with differing rates of attrition. An increase in white blood cell TL or reduced rate of shortening does not necessarily reflect a change in other telomeres, especially from other cell types. For instance, in cells that don’t divide, such as heart and nerve cells, TL is somewhat meaningless. Telomere length even varies depending on the kind of white blood cells.
Robust evidence also shows that it is not the length of telomeres, or even the rate of telomere reduction with age that matters, but rather that telomeres must get to a critically short length for adverse genetic repercussions to take place. Measuring WBC TL only measures average WBC telomere length and not the number of critically short telomeres.
For all of the above reasons, I feel that current measurement of WBC TL is not a very good biomarker of aging and is virtually meaningless as an important independent indicator of the rate of aging.
What about the other major cell type that produces telomerase and is capable of increasing telomere length? What about measuring stem cell TL? This is done, but currently only in research laboratories and generally only in animals. Not very many people would volunteer for heart biopsies, for instance. A jilted lover might volunteer their ex perhaps. However, stem cell TL is actually where the rubber meets the road. Stem cells are very important as is their preservation. They are certainly capable of regenerating many tissues, including those not producing telomerase. Unfortunately, WBC TL does not necessarily reflect stem cell TL, nor does it reflect telomere attrition, especially since there are so many different types of stem cells from so many different types of tissue with so many different rates of cellular turnover and damage. I discuss this more below when I show excerpts from some studies that are quite revealing.
Telomere length is correlated with rate of cellular replication, and cellular replication is increased with increasing mTOR, IGF-I and inflammation. Therefore, it very well could be that the correlation between telomere length and longevity is only just that, a correlation, and not a cause, and the underlying mechanism of aging has much more to do with levels of glucose, mTOR, IGF-I…and insulin and leptin. That is likely true. Indeed, telomere length, has been shown to be highly (negatively) correlated with leptin levels (see below).
As I was actually writing this article, one of the most significant studies to be published pertaining to telomeres in recent years came out of Maria Basco’s lab from Spain. I will discuss it more at length below. It shows just how important it is to orchestrate telomere length and telomerase. It must be turned on, or off, at a certain time and place for there to be any chance at significantly improved health without increasing cancer risk.
The telomere theory as a cause of aging was hotly debated over a decade ago in many biology of aging conferences where university researchers got together to discuss their latest findings. Now, this is barely discussed outside of pseudoscientific circles… Perhaps the latest Basco study will reinvigorate this debate.
I believe that lengthening telomeres, most specifically in stem cells, and then only temporarily to mitigate against increasing cancer risk, may offer potential to increase health span and delay the onset and even treat certain chronic diseases of aging. However, this is not the same or as powerful as increasing maximal lifespan and stretching out youth that research into genetic pathways of aging regulated by nutrient sensors (insulin, leptin, and mTOR) offer, as illustrated by the increase in maximal lifespan of many species by 200% and more when insulin, IGF-I, and mTOR are genetically suppressed.
One must accurately define health before directions to be healthy are given and just like health is not low cholesterol, health is not defined or synonymous with long telomeres.
Life is dependent on the coordination of its constituent parts. This is especially true pertaining to the length of telomeres of the various cells and organs to maintain health but prevent a high risk of cancer.
As I have said so frequently in the past, we are 15 trillion cells and 90 trillion bacteria that must work harmoniously as one for us to be healthy and remain alive. This requires an intricate orchestration of communication between the different parts. That includes the genes, telomeres, and telomerase. It is where, when, and how much they are played, like the keys of a piano playing an infinite variety of music from the same keys, that determine who we are, diabetic or not, and if we stay alive or die.
What we do want to do is slow down the reduction in the length of our telomeres in an organ and tissue-specific manner that can be orchestrated only through proper genetic expression. Leptin and insulin are among the most, if not the most powerful influences of this. And these in turn are controlled by what you eat.
Review of Telomere Literature
Need more convincing? Confused? Have insomnia? Quotes from various references with brief discussions will follow. (Paper titles are bolded and hyperlinked, quotes from the papers are in the quote boxes, and my comments follow each box).
In contrast to the similarity of the sequence, the telomere length is highly variable among species, within species, within an organism, and even between chromosomes.
Telomere length of a few different species;
Humans 5–15 kb [kilobase; 1000 base pairs]
Mice Up to 150 kb
Rats 20–100 kb
Birds 5–20 kb
Ants 9–13 kb
…mice strains with longer telomeres do not seem to have an increased lifespan compared to mice strains with shorter telomeres…in African Americans telomeres generally are longer than in White Americans.
Rosedale: …yet have shorter average lifespans. All of this well known data will tell you immediately that telomere length, per se, is not critical to biological aging.
Telomere length [is] highly variable between organs from one subject. This may be explained by variable telomere attrition rate.
Rosedale: One could postulate that rather than absolute telomere length, telomere attrition rate might be significant. However, this could and indeed likely is a reflection of the rate of cellular damage, death, and degree of cellular multiplication to replace that damage. In other words, telomere length would be secondary to aging rather than a cause of it. Measuring telomere attrition rate would, of course, necessitate the measurement of telomere length over time.
The major disadvantage of using leukocyte telomere length is that it is a measure of the activity state of the immune system and one might argue that leukocyte telomere length is rather a representation of increased inflammation than of aging.
Rosedale: The state of inflammation is quite variable over time. A strep throat, upset stomach, and a scraped knee could increase your general state of inflammation for weeks and this could reflect in variably lower WBC telomere length secondary to a healthy immune system.
Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.
Rosedale: What about the potential of increasing telomere length?…
The fact that the vast majority of human tumors seem to depend on telomerase reactivation to prevent critical telomere loss and to divide indefinitely suggests that telomerase inhibition could be an effective way to abolish tumor growth.
The fact that telomerase deficiency only results in loss of organismal viability when telomeres reach a critically short length is an important point when considering possible secondary effects of these therapies.
In particular, this predicts that putative anticancer therapies based on temporary telomerase inhibition will only trigger loss of viability in those cells with short telomeres that depend on telomerase activity. Presumably, these include tumor cells but not healthy tissues, which generally lack telomerase activity and have sufficiently long telomeres to maintain viability during the human lifetime, thus providing a window of opportunity for intervention.
Therapeutic agents that could be designed to [re-activate telomerase temporary] would preferentially target those cell types that normally divide to maintain organ homeostasis—such as stem cells, which, although telomerase-proficient, do not have sufficient telomerase activity to maintain telomere length over time.
Rosedale: As in all disease, especially having to do with genes, it is where, when, and how they are read that determines their contribution to health, disease, and even who you are.
For instance, it has been shown that vascular endothelial cells that endure more hemodynamic sheer stress have shorter telomeres than endothelial cells in low pressure arteries [secondary to a greater rate of turnover]
Rosedale: i.e. TL is a secondary byproduct of aging, not a primary cause of it.
To further dissect the association of ischemic heart disease with mean overall leukocyte TL we need to establish whether mean overall leukocyte TL is a reflection of TL in different cell types or whether it is more or less specific for leukocytes. Of particular interest in this regard are the CD34 positive (CD34+) cells as it is thought that these cells might be cardiovascular progenitor [stem] cells and play a role in cardiovascular repair…Furthermore, mean leukocyte telomere length has not been compared to non-circulating non-vascular cells and it is unknown whether leukocytes might merely be a reflection of overall TL of the whole body… One of the aims of this study was determining whether telomere length of CD34+ cells is different in IHF patients compared to healthy controls. We did not find a difference in TL between IHF patients and controls in CD34+ cells. These results clearly indicate that there is no significant difference in CD34+ cell TL between IHF patients and controls.
The major difference in telomere length between IHF patients and controls was observed in the overall leukocyte pool, not specifically in CD34+, MNCs or buccal cells as a source of non-blood derived cells.
The comparable TL of CD34+ cells in cases and controls strongly suggest that telomere shortening of CD34+ cells is not a major player in the pathophysiology of IHD…In the elderly, specific immune responses might be diminished, but many other functions are unchanged or even augmented compared to young persons.
Rosedale: This study is important for several reasons, the main one being to illustrate that even though WBC TL may correlate with a disease state such as ischemic heart failure (secondary to correlating with cellular damage and turnover), WBC TL did not correlate, at least in this study, with representative cells of the only major cell group that may have significant therapeutic potential, stem cells. One cannot extrapolate WBC telomere length to other tissues.
Paradoxically, the introduction of telomerase is proposed as a method to combat ageing via cell therapy and a possible method to regenerate tissue, while telomerase inhibition and telomere shortening is suggested as a possible therapy to defeat cancers..
Rosedale; In other words, telomerase must be turned on and turned off at the appropriate time and location, i.e. it must be orchestrated.
Rosedale: And again, one cannot extrapolate WBC telomere length to other tissues.
Although the number of subjects was small, strong correlations between blood, buccal cells, and fibroblasts were observed in the study population as a whole. When taken individually, however, only cells from subjects with DC demonstrated significant correlation. [dyskeratosis congenita (DC). DC is a rare genetic disorder stemming from a defect in telomere maintenance.]
Rosedale: Can TL predict centenarians? Not in the following study. Also, WBC TL was again not correlated with another representative tissue type.
In this paper we analyzed the mean length of the terminal restriction fragments (TRF) [frequently how TL is measured] in fibroblast strains from 4 healthy centenarians, that is, in cells aged in vivo, and from 11 individuals of different ages. No correlation between mean TRF length and donor age was found.
…chromosome analysis did not show the presence of telomeric associations in early passage centenarian fibroblasts. In blood cells from various individuals, the expected inverse correlation between mean TRF length and donor age was found. In particular, a substantial difference (about 2 kb) between telomere length in the two cell types was observed in the same centenarian.
In humans, telomere length is relatively short, highly variable between tissues and individuals and, with regard to replicating somatic cells, inversely related to donor age
We show clearly in this study that the mean TRF length method is unable to detect small changes in telomere size or to visualise the length of individual short telomeres in a distribution of TRFs. There is increasing evidence suggesting that it is not average telomere length, but rather individual critically short telomeres that trigger cellular responses to the loss of telomere function
The latest study and the most promising to show health benefits in telomerase expressed mammals was published last week…
Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors telomerase treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively.
Owing to its ability to confer with unlimited proliferative potential, over-expression of the telomerase reverse transcriptase (TERT) is a common feature of human cancers and can increase cancer incidence in the context of classical mouse TERT transgenesis.
A drawback of mTERT over-expression in transgenic mouse studies has been an increased cancer incidence, except for cancer-resistant backgrounds.
Telomerase expression late in life leads to overall telomere lengthening and decreased abundance of short telomeres in various tissues.
…telomerase activation can delay normal mouse aging in cancer resistant mice…
However, with the exception of mice genetically engineered to be cancer resistant, increased telomerase expression is associated with a higher susceptibility to develop cancer both in mice and humans…
Notably, in these studies increased TERT expression is forced since early embryo development through germ line modifications, which may favour the expansion of cancerous cells and the development of cancer later in life…Here, we show that increased TERT expression later in life (adult and old mice) by using a gene therapy strategy has rejuvenating effects without increasing cancer risk…the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms. Finally, re-introduction of mTERT in both 1- and 2-year old mice increased significantly its median lifespan (24 and 13%, respectively).
Rosedale: It generally takes at least several years for cancer to reveal itself. These mice only live 2 to 3 years. Therefore expressing telomerase when these mice only had one or less years to live likely did not give cancer cells enough time to manifest themselves. This would not be the case when using this sort of therapy in humans with more than 1 to 2 years to live. Note further that it is median lifespan that was modestly increased rather than maximal lifespan.] Also note that humans have much more body mass than mice, and therefore artificially activating telomerase in humans may have significantly greater negative consequences especially relative to cancer rate as compared to mice. See study above.
A commentary to the above article in the same journal:
…numerous studies using mouse models have demonstrated that critically short and dysfunctional telomeres indeed present a powerful barrier to cancer growth.
A question that has therefore intrigued researchers for many years is whether it is possible to slow aging and improve health span by re-activating telomerase in all of our cells. Constitutive expression of telomerase, unfortunately, is a characteristic of almost all cancer cells. It is therefore no surprise that transgenic animals over-expressing the catalytic subunit of mouse telomerase (mTERT), develop cancers earlier in life, thereby masking the potential beneficial lifespan extending properties of telomerase.
While these studies provide a proof-of-principle that telomerase gene therapy is a feasible and generally safe approach to improve healthspan and treat disorders associated with short telomeres [in mice], a clinical application in humans is likely still some time away. Low levels of integration of rAAV vectors into genomic DNA have been observed, raising the possibility that rare integration events of constitutively overexpressed TERT into genomes of long lived species might eventually promote cancer growth.
Furthermore, as with other gene therapeutic approaches, targeting the virus to specific cells in the body remains an obstacle. Also uncertain is specifically which cells should be targeted using a telomerase gene therapy.
In conclusion, we did not find any evidence of association between [WBC] TL [telomere length] and overall survival or between TL and specific causes of death. We also report for the first time that longer TL is associated with self-reported health status and greater YHL. Findings suggest that TL, although not a strong biomarker of survival in older individuals, may be an informative biomarker of healthy aging.
The observation that telomeres shorten with increasing age and are implicated in cellular aging has led to the proposal that telomere length is a biomarker of aging.
Currently, telomere length does not fully meet American Federation of Aging Research criteria that telomere length is (a) a better predictor of life span than chronological age (Criterion 1) and that (b) it monitors a basic process underlying normal aging at the pop-ulation level (Criterion 2).
Interestingly, an increase in intra-individual telomere length for a minority of participants at follow-up (ie, with increasing chronological age) has also been observed in three independent studies (27,39,78). However, this may not represent an increase in overall telomere length but rather could reflect the loss of cells with shorter telomeres.
Rosedale: It has been found that likely only cells with extremely short telomeres are so adversely affected that the process of apoptosis is initiated.
Could the significance of TL be secondary to leptin levels? TL is inversely correlated with leptin levels.
But animal studies have failed to reveal any simple relationship between telomere length and lifespan… the youngest women had telomeres that were around 7500 base pairs long. Their length declined with age at an average rate of 27 base pairs per year.
When lifestyle factors were taken into account, however, dramatic differences emerged. The difference between being obese and being lean corresponds to 8.8 years of extra aging…
Smoking was the other big factor… Obesity accelerates the ageing process even more than smoking. Intriguingly, the link between high leptin concentrations and telomere shortening was even stronger than the link with obesity…The damage to telomeres is probably done by free radicals. Smoking causes oxidative stress a source of free radicals as does obesity [and high leptin]
Free radicals can cause mutations in DNA, and there is some evidence that mutations in telomeres cause larger chunks than normal to be lost during cell division. In other words, it is a byproduct of aging that results in cellular turnover and molecular damage and therefore shortening of telomeres and not the other way around.