$36,000
$25,176

Human Telomere Dynamics and the Balance Between Cancer and Atherosclerosis

Today I'll point out a great open access paper on the evolution of human telomere dynamics: telomere length, how that length changes over time, and especially how it changes with aging. This makes a good companion piece to another paper from last week that covered the differences in telomere dynamics between mice and humans. This is quite important, since most of the work on this topic involves mouse studies, not human studies. As telomerase gene therapies continue to extend average telomere length and - in mice at least - also extend healthy life span, this is becoming a hot topic in the aging research community. It is increasingly a good idea to have a grounding of the basics and current scientific thinking on this portion of our biochemistry. Sooner or later someone will be selling telomerase gene therapies to the public as an alleged method to slow the progression of aging, and most likely selling these treatments well in advance of any comprehensive human studies or definitive answers as to their effectiveness. You will find yourself in the position of deciding whether or not to pay the price and undertake the therapies. Better to figure out your position and what would change your mind today rather than later.

Telomeres are repeating sequences of DNA that cap the ends of chromosomes. Their purpose is primarily to act as a part of the limiting mechanisms on cell replication: a little of the length is lost with each cell division, and when they become too short the cell self-destructs or becomes senescent, ceasing replication. For any given tissue the distribution of telomere length among cells is a function of how often new cells with long telomeres are created by stem cells, and how often cells divide. Stem cells maintain long telomeres through the use of telomerase, which adds more repeating sections to replace those lost to cell division. In humans only stem cells use telomerase, but in mice it has a much more widespread activity. Mice also have much longer telomeres than humans. All of this has everything to do with cancer, of course. The whole complicated arrangement of cells that are limited coupled to a much smaller number of cells that are privileged has evolved because it limits uncontrolled growth sufficiently well for evolutionary success. Without it highly structured and comparatively long-lived species such as our own couldn't exist.

Since stem cell activity declines with aging, it isn't surprising to see that measures of average telomere length also tend to do so - but this is a very poor measure of aging, and really only shows up in statistical studies across populations. There are too many other influences over the most commonly measured types of cell, such as immune cells. So average telomere length, much discussed this past decade, looks a lot like a measure of age-related damage, far removed from root causes. Given that, why does increased telomerase activity extend life in mice? Most likely for the same reasons that any method of spurring greater stem cell activity improves matters in an old individual: greater tissue repair and maintenance, a net benefit even if it is old and damaged cells that do the work. There are also other, less well explored activities undertaken by telomerase that might be beneficial, such as improvements in mitochondrial function. In mice at least it seems that these benefits come with no greater risk of cancer. It may be that improved immune function destroys more potential cancers than are created through greater activity in age-damaged cell populations, but that is pure speculation at this point. For humans the effects on cancer risk are much more of a question mark, though it is worth noting that stem cell therapies to date have exhibited far less risk of cancer than was expected at the outset.

Telomere Length and the Cancer-Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. Telomere length genetics should be considered in the context of evolutionary forces that have left their signature on the human genome. Inspection of the human genome reveals that of the approximately 22,000 currently annotated genes, 13,000 genes (about 60%) are linked to biological pathways of "cancer". These include genes engaged in growth, development, tissue regeneration, and tissue renewal, which heighten cancer risk due to increased cell replication, and genes that suppress cancer, including those that ultimately promote senescence and apoptosis. Central among cancer-protective pathways might be telomere-driven replicative senescence.

Stem cells are likely to undergo more replications in large, long-living mammals than in small, short-lived ones; this is because more replications are necessary for developing and maintaining a larger body size. More cell replication confers increased risk of cancer through accumulating de novo somatic mutations, which happen during successive DNA replications. This concept is supported by work showing that the risk of developing major human cancers is related to the number of stem cell divisions occurring in the tissues from which the cancers originated. Yet, large, long-living mammals generally display no increase in cancer risk compared to small, short-lived ones, a phenomenon known as Peto's paradox, suggesting that mechanisms have evolved to mitigate cancer risk in tandem with increasing body size and longevity. One such mechanism has been described in elephants. The elephant genome contains many more copies of TP53, a potent DNA damage response and tumor suppressor gene; p53-dependent apoptosis is thus triggered at a lower threshold of accumulating mutations, conferring cellular resistance to oncogenic transformation.

Similarly, a telomere-linked mechanism has been proposed in mammals based upon observations that telomerase activity in somatic tissues tends to be inversely correlated with body size while telomere length is inversely related to lifespan. Repressed telomerase and short telomeres would, therefore, limit replicative capacity in humans. In this way, short telomere length might curb the accumulation of de novo mutations and reduce the probability of oncogenic transformation in large, long-living mammals. Given the wide variation in telomere length across humans, might longer telomeres increase cancer risk? While initial studies were inconsistent (perhaps partially due to flaws in study design and small sample sizes), more recent studies show that in individuals of European ancestry, long telomeres, as expressed in leukocyte telomere length (LTL), are associated with increased risk for melanoma, adenocarcinoma of the lung, and cancers of the breast, pancreas, and prostate. Moreover, Mendelian randomization studies using leukocyte telomere length associated SNPs support the inference that having a longer LTL has a causal relation to cancer risk.

The cancer protection conferred by short telomeres could come with an evolutionary trade-off, namely, diminished proliferative activity of stem cells and consequently less regenerative capacity. This would manifest in age-dependent degenerative diseases. Some of the leading degenerative diseases in humans are related to atherosclerosis, and atherosclerosis is associated with short LTL. As cancer and atherosclerosis strongly impact longevity, the diametrically opposing roles of TL in these two disorders might be relevant to understanding the lifespan of contemporary humans and future trajectories in life expectancy. Notably, in evolutionary terms, this would probably have become more relevant when agrarian societies emerged over the past ten thousand years or so and lifespans increased considerably. In fact, evidence of atherosclerosis has been detected in ancient human Egyptian mummies.

Recent studies have used LTL genome-wide association study findings to generate "genetic risk scores" for cancers and for atherosclerosis insofar as it is expressed in coronary heart disease. These studies have shown that the same cluster of LTL-associated alleles is a risk indicator for melanoma, lung cancer, and coronary heart disease, such that when the joint effect of the alleles results in a comparatively long LTL, the risk for melanoma and lung cancer is increased, whereas the risk for coronary heart disease is diminished. The opposite holds when the joint effect of the alleles results in a comparatively short LTL, which engenders a higher risk for coronary heart disease and a lower risk for cancer. This cancer-atherosclerosis trade-off might principally apply to contemporary humans because they live so long, but not to ancestral humans. This trade-off has been principally established through the force of evolution. In contrast to cancer, which is associated with over ten thousand genes, only several hundred genes in the human genome have been shown to relate to atherosclerosis. Yet, atherosclerosis is a major determinant in the longevity of humans because of their relatively long lifespan, especially in high- and middle-income societies.

Comments

'' More cell replication confers increased risk of cancer through accumulating de novo somatic mutations, which happen during successive DNA replications. This concept is supported by work showing that the risk of developing major human cancers is related to the number of stem cell divisions occurring in the tissues from which the cancers originated. Yet, large, long-living mammals generally display no increase in cancer risk compared to small, short-lived ones, a phenomenon known as Peto's paradox, suggesting that mechanisms have evolved to mitigate cancer risk in tandem with increasing body size and longevity. One such mechanism has been described in elephants. The elephant genome contains many more copies of TP53, a potent DNA damage response and tumor suppressor gene; p53-dependent apoptosis is thus triggered at a lower threshold of accumulating mutations, conferring cellular resistance to oncogenic transformation.''

Hey there !

A very interesting research Reason.

This elephant's p53 version is very akin to what is going on NMRs (naked mole rats) who do not develop cancer by having plump skin full
of long-chain hyaluronic acid (which acts to improve tissue stromal barriers/blocking cancer metastasizing to other organs) and, like the elephant,
more 'low-threshold' p53 and special variant. What is really funny and ironic is that an NMR is about 10,000 times smaller than an elephant.
Demonstrating size/growth vs speed of metabolism (an NMR RMR (resting metabolic rate) is faster than an elephant/human) vs cancer formation
can be all uncoupled; and render many evolutionnary theories to just that, theories who falter. Because there are outliers. In the very large
and vague animal kindgom, they hold, but when you go down and inspect each animal to see if that's true; some outliers pop up from the at-large trend.
Such as the NMR. For its micro-size, it should be filled with cancers. NMRs are even beaten by Queen Ants, who do no get cancer and live up to 35 years (!).
Queen ants are even smaller, insects, who have vitellogenin and special survivin like genes/molecules that are basically 'stem-cell like' activity (plus
they are fed a form of jelly produced by worker bee serfs under her called royal jelly (a supplement) that activates telomerase and funnily, these ants
have very high levels of cellular division; thus, have other cancer-proof mechanisms), much like cancers themselves; who are very stem-cell like. Yet, NMRs and Queen Ants
don't get huge like an elephant or a human. Showing that Peto's Paradox is correct but flawed in some points too and remains theory (theory can be retheorized/updated to precise it).
It's not because of cellularity increase/densification that necessarily the animal 'Grows Up' huge like an elephant. Giant Lobsters never grow big like us but they have extreme cellular proliferation
and telomerase activity - and no cancer. Cellular growth can uncoupled from Developmental Growth as seen in these examples. I won't go into the IGF talk cause it's deep, but IGF-1 is all behind
this developmental growth of a tiny queen ant or a mega elephant. IGF-1 (insulin Growth Factor-1), IGFR, Insulin, Sexual/Growth Hormones and Endocrinology are also behind cancer,
cancer growth, body develepmental growth, cellular growth/division/mitosis and immune system control.

''More cell replication confers increased risk of cancer through accumulating de novo somatic mutations, which happen during successive DNA replications.''

Very true. But as they say later, a elephant version of TP53 counterweights that, same in NMR, same in Queen ants.
As said, certain animals keep high telomeres - and no cancer. It is possible (such as in lobsters and bristle cone pines).
In humans, it's different, but there trade-off is partly true.

''The cancer protection conferred by short telomeres could come with an evolutionary trade-off, namely, diminished proliferative activity of
stem cells and consequently less regenerative capacity. This would manifest in age-dependent degenerative diseases.
Some of the leading degenerative diseases in humans are related to atherosclerosis, and atherosclerosis is associated with short LTL.
As cancer and atherosclerosis strongly impact longevity, the diametrically opposing roles of TL in these two disorders might be relevant
to understanding the lifespan of contemporary humans and future trajectories in life expectancy''

Yes and No. The tug of war between cancer/no atherosclerosis or other disease vs no cancer/atherosclerosis or other disease - due to LTL, is
a bit of a trend not a - finite trend. Myself, I suffered atherosclerosis (yeah it sucks that's why SENS needs to happen QUICK or I'm dead in 20. yet I am still young (below 40s)...
So...I mean it's BS..I actually have a lot of moles, nevus and what not on my skin, showing that my LTLs are Very Long (as it is said that higher
skin cancer/higher nevus/nevi mole skin count is associated with higher LTL and higher cell division rate which means higher cancer mutation load in total by extended cell replicative potential length/lifespan).
Yet, I suffered atherosclerosis - too (pulmonary artery weakened when I had ultra-high LDL cholesterol - yet. I'm thin, my macrophages and immune system was Wacked Out, they were depositing fat LDL in my arteries and creating a plaque rupture clot that jammed one time I had a huge deadly seizrue).
Showing it's very vague and it is 'large/vague' trend, but if you go down in the details, you found outliers - like me. Who can have both - cancer and both atherosclerosis (yay! talk about real bad luck..)
and, in young age on tope of that. So no, you can even have both, be in good health (like I was, full of energy but havoc was going on inside over the years - a silent killer is what atherosclerosis is - please make sure to reduce your cholesterol levels vLDL/oxidized LDL. it saved my life), be thin ... and die anyways - of both.

Posted by: CANanonymity at July 13th, 2016 9:20 PM

Hi,
This is unrelated but there is a portion of text about "when agrarian societies emerged over the past ten thousand years or so and lifespans increased considerably."
Actually, several studies have shown that after neolithic revolution, the average height was lower and health was deteriorated.
I suspect that that is due to the fact that with the increasing density in population, deseases propagated more easily, and that the food surplus that the neolithic revolution introduced, were confiscated by rulers groups to starved the other groups, not only because they needed food for their soldiers and craftmen but also to keep ruling them.
Another thing was that the diet was considerably less complex in agrarian societies than in hunter/gatherer societies, as you can not simultaneously cultivate many crops and have many sort of animals because all those activities have requirements that are in conflict with each other. This did not help to maintain a good health.

Posted by: JP Le Rouzic at July 14th, 2016 4:09 AM

Naked mole rats have short telomeres. Just like humans do.
Could they have other adaptations that make them long lived? Sure, they can, every species has a couple of advantageous adaptions.

In mammalia species with short lifespans are the outliers, not the other way around. A lot of mammals have an average expected lifespan of around 10-30 years depending on the species - squirrels which aren't significantly bigger than mice live around a decade in the wild and marmots which are not much bigger live up to 25 years. So mice clocking in at 2 and change are quite bellow the average in their size range. Of course humans reaching their 80s easily are outliers in the opposite direction because few animals as big as we are live much longer than 30.

It does make you wonder if there's any logic in experimenting with mice when we're an extreme in the opposite direction.

Posted by: Anonymoose at July 14th, 2016 5:22 AM

@Anonymoose: Longevity seems to depend mostly on predatory pressure. Squirrels have less predators because they live in the threes. Bats also live longer than mice because they can fly. Marmots are quite big and anyway pass a great part of their lives sleeping.

Posted by: Antonio at July 14th, 2016 7:25 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.