Death and telomeres

There are more and more questions about telomeres on the net these days.  One appeared recently asking what happens when an 82 year old women dies of respiratory failure from the standpoint of her telomeres.   The answer is long and complex but it does take you through the very basics of aging. So if you are up for a little science, here it is.  If not, go back to sipping your Piña Colada (or better yet, your “Edge” cocktail!) and enjoy your day.

An 82 year old woman dies of reparatory failure – what has happened to her telomeres and what role does this play in her death?

Telomeres are non-coding, repetitive sequences at the end of the chromosome, occurring in a repetitive TTAGGG (in humans!).

When we are conceived, they are approximately 15,000 base pairs long.  Cellular replication alone is enough to shorten the telomeres because of the “end replication problem” which essentially means the DNA replicative mechanism “falls off” the end of the chromosome before they can replicate telomere segments.  The enzyme that does replicate telomere ends – telomerase – is repressed or expressed at very low levels in somatic cells. Because of the massive cellular replication it takes to go from zygote stage to newborn and the inability of most differentiated cells to express enough telomere lengthening “telomerase” to replace those passively lost pairs. Thus you are born with an average of 10,000 base pairs in your telomeres.  A telomere length of 5,000 base pairs is usually enough to induce cellular senescence ( see below).

In addition, telomeres are not linear but rather looped structures, so a “zero” length telomere is not needed to induce cellular demise.  Changing the 3D structure and interfering with the loops is likely enough to activate senescence or apoptosis. 

By newborn stage 5,000 base pairs have already been lost, leaving another 5,000 to determine the length of replicative cell life. When those 5,000 are gone and the telomere length is now reduced to 5,000 base pairs, cellular gatekeepers (like p53 and others) trigger replicative senescence.   Many “slings and arrows” of daily living can accelerate telomere loss such as stress, lack of exercise, oxidative exposures of any kind, poor diet, lack of sleep and others and increase the speed of telomere loss. Almost every disease process of aging is associated with some kind of increased telomere shortening.  The standard cell population used to measure mean telomere length is White Blood Cells for ease of acquisition and because of their relation to immunosenescence.

Studies now suggest that the fate of the individual cell is more tightly correlated to the “shortest telomere”. That means that one short telomere can induce cellular damage, senescence, or apoptosis.  The number of short telomeres many not be directly related to the mean telomere length in all individuals but the forces that shorten them are.

If cellular mechanisms fail to stop replication at 5,000 base pairs and telomere loss continues, then somewhere around 1,000 to 3,000 base pairs intracellular gate keepers should trigger apoptosis.  If this does not occur and cell division continues, the genome is unstable and this is where we feel most adult cancer occurs.

Other tissue telomere length is not absolutely the same as WBC but usually correlates well with WBC length in terms of “short or long”.  The argument has long been made that not all tissues age by telomere length.  The cardiomyocyte in particular is often cited as a way of “disproving” the telomere theory of aging.  Cardiomyocytes have longer than average telomeres.  This makes interpretation of their absolute length difficult. The theory goes since they do lose telomere length during their lifespan and do not replicate at the rate of WBC, etc.,  they “should not” be affected by telomere loss in the same fashion.  They are not. It is likely that a smaller amount of telomere shortening is required to cause mitochondrial dysfunction as Passos et. al. showed in 2010.  Telomere length, function and integrity appear to be responsible for mitochondrial mutagenesis, biogenesis and influence redox functions as well suggesting an intimate relationship between telomere length and mitochondrial health.  It is thought that cardiomyocytes accumulate myocardial dysfunction via the same mechanisms with less direct telomere loss.

A fact often overlooked by even cardiologists is that independent of whether telomere loss explains how and why cardiomyocytes age, telomere loss clearly explains vascular aging.  Cardiomyocytes (as with all other post mitotic tissue) are dependent on blood supply.  Cardiologists and cardiovascular surgeons do not restore cardiomyocytes to health, they restore the blood supply, and the blood supply clearly ages by telomere loss!

In addition it is important to know that adult stem cells – a significant part of the regeneration mechanism -also suffer telomere loss and damage, leading to the aging of this population of cells. The creation of IPS (induced pluripotent stem cells) creates embryonic like stem cells and lengthens the telomeres again, by telomerase activity.

Aging occurs when the damage to an organism exceeds the rate at which that organism can repair said damage.  Your 82 year old woman begins to lose lung tissue long before she is 82.    Repair requires the existing mass of lung cells to be able to replace damaged tissue by replication (thus inducing more rapid telomere loss)  and in concert requires a stem cell population that can supply new cells for differentiation where needed.  If the existing cell mass is in replicative senescence or apoptosis and her adult stem cell population has been damaged to the point of dysfunction, she has no way of repairing her damaged tissue.

Basically she has long since lost the ability to repair her lung or other tissues and when the reserve is gone, she dies of “respiratory failure”.

Dave Woynarowski, MD, co-author The Immortality Edge

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