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Telomere Length Suggested as the Mechanism Limiting Heart Regeneration

Evolution has left mammals with only a limited ability to regenerate heart tissue. Unlike very regenerative species such as salamanders or zebrafish, we lose most of our ability to heal the heart very early in life. Here, researchers suggest that this is keyed to reduced telomere length in heart cells, but in a way that is very different to the more familiar erosion of average telomere length that occurs over the course of aging. In this case that reduced length is a developmental process occurring in early childhood. If this work bears out, it actually sounds like a much more compelling argument for the use of telomerase therapies in medicine than those based on trying to address age-related telomere erosion, as that erosion is most likely only a marker of age-related damage, not a cause:

Researchers have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells' ability to proliferate and replace damaged heart tissue. Newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, but this regenerative capacity is lost as the mice grow older and the majority of their cardiomyocytes withdraw from the cell cycle.

Researchers wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short - due, for example, to a loss of the telomere-extending telomerase enzyme - cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle. The researchers therefore examined the length of telomeres in newborn mouse cardiomyocytes and found that the telomeres rapidly eroded in the first week after birth. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21.

Telomerase-deficient mice have shorter telomeres than wild-type animals, and, the researchers discovered, their cardiomyocytes already begin to stop proliferating one day after birth. When the researchers injured the hearts of one-day-old mice, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, wild-type cardiomyocytes were able to proliferate and replace the damaged tissue. They also found that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals. Maintaining the length of cardiomyocyte telomeres might therefore boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. "We are now developing telomerase overexpression mouse models to see if we can extend the regenerative window."

Link: http://www.eurekalert.org/pub_releases/2016-05/rup-msl052516.php

Comments

Yes this paper further confirms the findings of DePhino and Blasco and builds upon that. We are starting to get to the bottom of the telomerase mystery. I believe it has value as a therapy and with the data piling up we will know one way or the other soon enough.

Posted by: Steve Hill at May 31st, 2016 7:50 AM

Surely an obvious next step is to genetically engineer mice so that the telomerase gene can be toggled on and off in the heart cells, and see what happens after an induced heart attack in both cases?

Posted by: Jim at May 31st, 2016 5:46 PM

@Jim

Hi Jim ! TgTERT mice have had genetically overexpressing telomerase and increased their mean lifespan 15-25% by maintenance of health/healthspan. Before I answer that question, slightly derailing, It's becoming clear that health maintenance is crucial to reach the maximum (anomalous) age of a specie individual (and we talked about morbidity compression is what is in store for us ie reaching a 100, and dying the next day at 100, and 'one day'). For longevity and maximum specie indivdiual lifespan, telomerase is a part of the deal (in certain cells, most somatic cells don't even use telomerase since they are non-mitotic/non-cycling, althought this is becoming more and more wrong (telomerase is more common in our cells than we think, somatic or not, these studies demonstrate precise cells who need telomerase for organ tissue regenerative power), by maintaining that optimal health. Although, as can be seen, babies may have that telomerase activity but after that during early childhood, it's gone (instead of total skin wound healing, we get scarrification).
But, it's not what's important, telomerase can't stop glucosepane AGEs crosslinks, lipofuscin drusen, ceroid and other wastes from cumulating. Damages are what is important to regular intrisinc aging.

Back to question, just my 1 centt, I think that toggling off or on gene would cause :
ON: the regular program, their cardiomyocytes and heart stem cells would heal the damage, a heart Attack is a loss of oxygen to the cardiac tissue; which means ichemia /hypoxia injury causing severe tissue lesions (the tissue dies either by apoptosis or necrosis (apoptosis is activated by ATP, while necrosis is activated when apoptosis can't be activated (by loss of ATP to a very low level) to even activate apoptosis mechanism (since it requires ATP energy itself; funny (but not) that even the 'death machine program' needs energy to be executed). Otherwise, necrotic tissue forms in the heart and arteries)
OFF: this would be catastrophic, not being capable to mitigate this dramatic ROS production by O2 loss at the heart local tissue level; it would be much deadlier and the lethality would be assured. Mice won't survive their heart attacks (fatal) without telomerase (since cardiomyocyte and heart stem cells use telomerase themselves). Ischemia, in mammals, by a heart Attack caused mitochondrial dysfunction by loss of respiration mechanism, OXPHOS is unbalanced, and the mitochondrias make a Burst of ROS during the heart Attack process by local tissue ischemia. This can 'make or break' the heart depending on the locality of the tissue and the time of Telomerase removal. Why also...because telomerase is shunted from the nucleus to the mitochondrias to mitigate ROS damage (during ischemia by heart Attack tissue oxygen deprivation); no telomerase going to the mitochondrias is Huge effect; the mitchondrias will produce folds more ROS bursts; this will dramatically alter the local Redox Milieu (shifting towards oxidizes state from the reduced state, aka oxidative stress -by the folds; a heart Attack is oxidative stress in order of magnitude). IT's also why humans Can survive them, but it's very hard to survive them, with permanent damage (most barely survive a 2ND one). Men survive some, women survive some, men being slightly hardier survive some more; women succomb more to heart attacks (yet their DNA is stronger having XX chromosomes (and estrogen activating telomerase/Tert receptors; no Wonder menopause is linked with heart attacks in women; they lose telomerase by loss of endocrine youth (hormonal loss/estrogen drop), while men it's Xy weaker chromosomes, andropause also bad; since testosterone is converted by aromatase to estrogen in man's body; to reach hTERT receptors like females; just less than women; it's an important gender boost they have (a evolutive natural selection for specie survival; women are crucial since they, only, give birth to humans, men only contribute their semen); women are at 90% all the centenarians there are; for 9 women centenarians, there is one man centenarian; now you wish you were born a woman (no luck for us dudes, guess we'll have to stick around the girls to 'get that forever-young girl vibe in us : P ...sh*t odds are stacked against us by our birth sex).

Posted by: CANanonymity at May 31st, 2016 11:16 PM

ps:
I should add, one study demonstrated that when the redox is altered, telomerase is altered in parallel; meaning redox communicates to/with telomerase; they work in tandem during cell cycling. The study showed that blocking gsh production from GCL (glutamate-cysteine ligase) by BSO (l-buthionine(S,R)-sulfoximine) altered telomerase activity : upon a 30% drop there was a 80% drop of telomerase activity; this means telomerase is highly sensitive to redox changes (and for causes too, because like many other enzymes; it has cysteines residues that are 'phosphorylated' in its enzyme for expression and activtiy; which are redox elements from the place). As the milieu change by BSO, it became more oxidative-stress prone (shifting the ratios of reduced to oxidizes states). BSO, add up to being like a stressor, just like ischemia because it deprives the system of intracellular/intramitochondrial antioxidative ROS quenching power. 80% loss of telomerase would be akin to a heart Attack with telomerase toggled off/deficiency during it. Since, a heart Attack is ischemia, it behaves like BSO, it damages important enzymes such as CGL, TRX, GPRx, PRx and hTERT; which can't protect the heart anymore; yielding lesions that create a fatal organ heart arrest.

Posted by: CANanonymity at May 31st, 2016 11:53 PM

pps:
Also, it was found that GCL (glutamate-cysteine ligase, or formely called gamma-glutamyl cysteine) has a dual function, not only increasing glutathione, it acts as gluthathione peroxidase (GPx) co-factor despite whatever GSH levels. This is very impressive and demonstrates a double, even triple whammy : BSO blocks GCL, which blocks GSH production, which increases Oxidate-Stress, which blocks GCL quenching ROS, which increased Oxidative-Stress Even More; which, finally, ends ups blocking Telomerase activity; which is the nail in the coffin in the cell. A massive destruction, BSO, does that, and a heart Attack is about the same when in mice they will toggle off telomerase at the same time, since heart Attack is oxidative stress event that alters, like BSO, the oxidized state of the O2-deprived cardiac tissue.

Targeting glutamate-cysteine ligase to mitochondria decreases ROS
1. http://www.nature.com/ncomms/journal/v3/n3/full/ncomms1722.html

Posted by: CANanonymity at June 1st, 2016 12:46 AM

ppps: it's late, late; (sorry, right link, wrong title, though targeting GCL to mitochondrias does indeed help) :

γ-Glutamylcysteine detoxifies reactive oxygen species
by acting as glutathione peroxidase-1 cofactor

1. http://www.nature.com/ncomms/journal/v3/n3/full/ncomms1722.html

Posted by: CANanonymity at June 1st, 2016 12:55 AM

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