Telomere Length and Good Health Practices
One of the original researchers involved in telomere length studies is currently publishing a book on general health. It is in no way novel in the lineage of such things save for the relentless emphasis on telomeres, the repeating DNA sequences that cap the ends of chromosomes. Telomeres shorten with each cell division, and stem cells generate daughter cells with fresh, long telomeres, so the average length in a cell type is some function of cell division rates and stem cell activity. The thing is, telomere length as presently measured in immune cells from a blood sample is actually a terrible biomarker (of aging or health status) for individual purposes: the well-publicized erosion of average telomere length with age is a statistical phenomenon that only shows up in the data for large populations, and even there it isn't a robust measure. Pick one individual and their health concerns and it isn't yet at all clear that telomere length measures have any practical utility. Two people with the same condition can have quite different telomere lengths, and changes over time are not yet correlated well with health status for any one individual. This is far worse for use in diagnostic medicine than the sort of long-standing metrics obtained from standardized blood tests at the present time.
Molecular biologist Elizabeth Blackburn shared a Nobel Prize for her research on telomeres - structures at the tips of chromosomes that play a key role in cellular aging. But she was frustrated that important health implications of her work weren't reaching beyond academia. So along with psychologist Elissa Epel, she has published her findings in a new book aimed at a general audience - laying out a scientific case that may give readers motivation to keep their new year's resolutions to not smoke, eat well, sleep enough, exercise regularly, and cut down on stress. The main message of "The Telomere Effect," is that you have more control over your own aging than you may imagine. You can actually lengthen your telomeres - and perhaps your life - by following sound health advice, the authors argue, based on a review of thousands of studies.
Telomeres sit at the end of strands of DNA, like the protective caps on shoelaces. Stress from a rough lifestyle will shorten those caps, making it more likely that cells will stop dividing and essentially die. Too many of these senescent cells accelerates human aging. This doesn't cause any particular disease, but research suggests that it hastens the time when whatever your genes have in store will occur - so if you're vulnerable to heart disease, you're more likely to get it younger if your telomeres are shorter. Other researchers in the field praised Blackburn and Epel's efforts to make telomere research relevant to the general public, though several warned that it risked oversimplifying the science. "I think it's a very difficult thing to prove conclusively" that lifestyle can affect telomere length and therefore lifespan, said Harvard geneticist and anti-aging researcher David Sinclair. "To get cause-effect in humans is impossible, so it's based on associations." Judith Campisi, an expert on cellular aging at the Buck Institute for Research on Aging in Novato, Calif., said the underlying research is solid. "If you have a terrible diet and you smoke, you're definitely shortening your life, and shortening your telomeres. Short telomeres increase the likelihood of cells becoming senescent and producing molecules that lead to inflammation, which is a huge risk factor for every age-related disease. So there is a link there, it's just not this exclusive magic bullet, that's all."
One of the challenges with telomere research is that most studies measure the length of telomeres in blood cells. But it may be that the liver is aging faster or slower than the blood - we're not all one age throughout. By measuring telomere length in the blood, "what you're really reporting on is the capacity of immune stem cells to function well," said Matt Kaeberlein, who studies the molecular basis of aging at the University of Washington. "What this may be really telling us is the immune system may be particularly sensitive to lifestyle and environmental factors." Kaeberlein said he's only at the periphery of telomere research, but is skeptical about the predictive value of shorter versus longer telomeres. "It's not at all clear whether the methods are quantitative enough or of high enough resolution to really make those kinds of arguments. I think it has the potential to be a biomarker predicting health outcomes, but I don't know that I would feel comfortable saying people should make lifestyle changes based on a measure of their telomere length."
Link: https://www.statnews.com/2017/01/03/aging-control-telomere-effect/
Another book added to my to-read list.
Sounds like it will be well worth the read too. I also share her frustrations with Academia, It's one of the main reasons I'm glad Michael Greve put up the $5million for start-ups, we need to take it upon ourselves to do something.
Telomere attrition is a Hallmark but it isnt the magic bullet that is for sure.
Hi, very interesting.
It's true that telomeres are not the most robust marker of aging, but nonetheless I think they have validity (even if certain studies invalidate them completely), mostly over the long run. One study had shown that a 115-year old woman had very small telomeres in her blood immune white cells (about 3k (3000 basepairs) size. The study said she was at the 'limit' of human lifespan, we have to remember telomeres are far more than telomeres - they are also cell cycle counters. If short telomeres are stabilized and still capped, there can be more cycle rounds but others studies have shown that stabilizing short telomeres is not exactly easy, they continue to shorten and the inflammatory gene signaling gets just too overbearing. Plus, shorter telomeres are closer to their M1 M2 crisis point (M1 replicative senescence entry barrier and M2 transformation/immortalization after a couple more rounds, if M1 is overcomed). Her telomeres were still capped but the problem is they were so low that inflammatory gene activation (p53/p21/p16/TNF-a/IL-6/increased ROS production and reduced quenching) was very strong (basically she was becoming immunosenescent), studies have shown completely linear loss of naïve T-cells with age (meaning the immune system loses its capability to fight off new invaders because it is stuck with old T-cells who have just a certain 'memory' of previous invaders/pathogens/virus...for new capacity and T-cell memories you need naïve T-cells formation coming from the thymus organ.
The thymus is the fastest aging organ in the body (thymic involution). Since that woman was showing small telomeres because of her old age and her thymus had shrunk, immunosenescence was a clear sign she was dying/would die soon by a lack of immunity made by telomeric replicative senescence from the many cycles in her long life - now exhausted. Telomere length in leukocytes, lymphocytes and peripheral blood monocytes are predictive of maximum lifespan, so is thymus involution speed. Mice that have thymus grafts have aging reversal and mice that have thymic boosting/T-cell naïve boosting can have a double lifespan extension (as strong as Calorie Restriction if more). Mice's T-cell longevity is 6 to 10 weeks, while humans' T-cell longevity is 6 to 10 years. There is something going on here...why so long for humans ? When you do the math, 3650 days vs 70 days = 50-fold difference, about the difference between a human and mice life (2 years (mice lifespan) x 50 = 100 years old (human lifespan)). I don't know if it's just a pure random correlation or something more, but clearly, something is going on.
I fell on a study that proves beyond the shadow of a doubt that aging is really an oxidative homeostasis loss that then alters epigenetics DNA methylation patterns towards more inflammation/more aging and more damage accrual. Damage is the main source of the problem (though not the only one, but a major one), it shifts the epigenetics program and alters the oxidative susceptibility.
''Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency''
This study showed that stromal cells - are the cause - of thymus involution, these cells have a lack of antioxidative protection; hence thymus shrinks with time - and so does the immune system because immunosenescent (since it is 100% dependent on thymus capacity). They stipulate they accumulate much Hydrogen Peroxide H2O2 which is not quenched since CAT (catalase, the main H2O2 quenching enzyme) is not present in them. This in turn damages mitochondrias (whom produce H2O2 after super oxide production in the mitochondrial electron transport chain ETC at Complex I and III). The stromal cells had higher mitochondrial lesions :
''we used a simple enrichment procedure
involving repeated cycles of gentle physical liberation
of lymphoid cells from thymic tissue, followed by unit gravity
sedimentation of enriched stromal rudiments. Even though
histological examination of such tissue indicated that it still
consisted of >50% lymphoid cells (not shown), a sizeable 3- to
4-fold increase in 8OHdG levels was seen''
''Figure 5. Epithelial Stromal Cells Accumulate More H2O2 and Are
More Sensitive to H2O2 Damage Than Their Lymphoid Counterparts
in the Thymus''
''Thymic Stromal Cells Exhibit Elevated Levels of the
Hallmarks of Oxidative Damage
The hypothesis that genetic complementation of catalase in
stromal cells would confer resistance to [thymus] atrophy (Figure 3) also predicts that unprotected thymic stromal cells would exhibit elevated
levels of lesions associated with ROS.''
''First, we used the
fluorescent chemical probe MitoPy1 (Tocris Biosciences) to
directly measure H2O2 levels in mitochondria from TEC or
lymphoid cells in the same biological sample (distinguished by
gating as described in the preceding section). The results of
this highly specific assay show that TEC exhibit higher levels of
mitochondrial H2O2 than paired lymphoid cells (approximately
one log10 level of fluorescence, Figure 5A), consistent with
decreased catalase activity. We then directly challenged freshly
isolated cell suspensions directly with 500 mM H2O2 and
measured mitochondrial membrane potential (DiIC1 staining)
as an indicator of mitochondrial integrity. Even prior to H2O2
treatment (directly ex vivo), freshly isolated TEC exhibited lower
membrane potential than paired lymphoid cells from the same
thymus (Figure 5B), consistent with higher levels of pre-existing
damage. Treatment with H2O2 resulted in a further decrease in
mitochondrial membrane potential in TEC, while lymphoid cells
from the same sample were barely affected by this treatment.
These results further confirm that TEC exhibit high concentrations
of the catalase substrate H2O2, as well as elevated sensitivity
to H2O2, both of which are further characteristic of
decreased activity of the reducing enzyme catalase.''
They end by saying :
''Finally, we note that while reconstitution of catalase in stromal
cells reduces atrophy, it does not abolish it. It is possible that
the mitochondrially targeted catalase transgene is not optimal
since H2O2 is also produced in substantial quantity by peroxisomes.
However, neither endogenous nor transgenic catalase
completely prevents metabolic damage, in the thymus or any
other tissue, and aging (and atrophy) thus continues, albeit at a
slower rate, regardless of antioxidant levels or other modulation
of metabolic activity.''
And this specially :
''These studies provided strong evidence that thymic atrophy is
impacted by redox state...
Figure 3. Thymic Atrophy Is Responsive to Redox State in a Stromal-Dependent Manner...
''
I believe one of the reasons why catalase enrichment was not enough to Completely Reverse and Abolish thymus aging and thus reverse immune aging and, Aging itself (since intrinsic aging is greatly dependent on immune aging), is because it is the main redox that decides so, not a single redox enzyme alone.
This also proves with certainty that the redox is the very core and heart of why we age. The fact that human T-cells live 10 years while mice T-cells live 10 weeks is a clear indication that the mice's immune redox capabilities are weak and lost (redox loss). In the study they use ascorbate and, especially, NAC (n-acetyl-cysteine, cysteine amino acid being the 'mother' of all redox reactions) :
'' First, mice
were given literature-consensus doses of two common antioxidants
(n-acetylcysteine or L-ascorbate) in drinking water from
the time of weaning, and thymic size was measured at 10 weeks
(Figure 3A), at which point thymuses from WT mice had lost
approximately 40% of their size. Despite no efforts to optimize
antioxidant dose, thymuses from antioxidant-supplemented
mice were significantly larger than controls (p < 0.002),
****with n-acetylcysteine almost eliminating atrophy in supplemented
mice****''
Why then would NAC or vitamin C not be capable of making mice live all that much longer ? They do say that thymus still involutes despite catalase, and so despite NAC or vitamin C antioxidants...
and the reason is that the redox couple is unaltered and becomes oxidized even so. (GSH:GSSG),
one study showed that is what not so much the redox GSH:GSSG couple that decided the cell's redox state but it was it's level whole gsh. That is the levels were higher, the cell was capable of being a maintained in a 'reduced' state (unsusceptible to oxidization by ROS such H2O2, ROS is still being made - it just is inconsequential anymore by unsusceptibility to them/they don't damage DNA anymore and create SSBs DSBs DDR (DNA Damage Response)). Whole gsh was able to make the cell have as much as -30 mV lower negative potential (meaning the cell is 'ultra-reduced' and as such, damage is nill, from no susceptibilit to oxidative stress caused by normal aerobic metabolism creating aerobic mitochondrial ROS). This demonstrates that immune aging can be reverted (and aging iteslf too), as long as redox is controlled, damage will then be nullified and so will transcriptional aging/epigenetic drifting.
Telomeres are still quite important and we should keep them in mind. But it's true they are not the best marker though (in short-term, in long-term they are better and more accurate, since all humans dispaly telomere loss and immune system function loss with aging). The Hayflick limit is a big determinant in humans (replicative senescence) and it is tied with immunosenescence (which leads to Oncogene-induced senescence (cancer) when the immune system's macrophages/killer cells can't wipe out rogue tumor cells anymore and aslo Stress-induced Spontaneous-induce senescence by excess oxidative stress (also leading to cancer since anti-oxidative loss accelerate oxidation which lowers telomere and most cancers are in the low 2kb region of telomeres (small telomeres in cancers at the start from excess oxidative stress by inflammation)). One study proved that oncogene-senescence/cancers are 'accelerated epigenetic aging', and so, immunosenscence = accelerated epigenetic aging. Your thymus shrinks (seen in patients with accelerated aging), your naïve T-cells reduce too (in fact one study showed increased telomeres after the disease was cured, this means telomerase can reverse the effects of aging and diseases/the immune system if the diseases are reversed; once study showed that redox loss of gsh:gssg couple makes a 80% loss of telomerase activity, meaning they are in tandem and communicate to each other. ROS makes the telomerase increase (telomerase is called-upon (leaves nucleus and translocated in mitochondria to reduced mitochondrial ROS and then back on nuclear chromosome telomeres) but at a certain point telomerase leaves and becomes defective, too much telomerase has been shown to compromise chromosomes - same as too little telomerase). Certain Immune cells depend on telomerase. The Thymus is activated/rejuvenated by telomerase. Thus, Telomeres are important for the immune system and for, aging (although as a aging biomarker they are less reliable). What is certain is that aging is a loss of resolvability of daily aerobic oxidation phenomenon (leading to damage accrual and genetic/epigenetic switches, and so, redox loss; the main driver and protector of/an against these changes).
Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency
1. http://www.cell.com/cell-reports/pdf/S2211-1247(15)00734-2.pdf
@CANanonymity
Is the hierarchy (oxidative) damage -> epigenetic gene expression shift established? I read that gene expression can be controlled by the redox state of the cell?!
Why would we even care about telomeres when the real underlying cause of the telomere attrition is the decresing ability of stem cells to replace cells with long telomeres? Doesn't it make more sense to enhance stem cell activity (i know cancer is always a problem) than tinkering with the telomeres of the somatic cells. Am i missing something in this picture?
Hi K., Just a 2 cent :
Truthfully it is still in contentious dubious terrain, thus, no. There are different camps I believe :
programmation side
epigenetic gene expression changes -> DNA damage
damage side
DNA damage -> epigenetic gene expression changes
and the both sides (that's where I think it lies and inclues myself in that one)
epigenetic gene expression changes DNA damage
I add a precision that goes both ways :
epigenetic gene expression changes DNA damage
But if DNA damage is the ultimate decider (and that could be true since nucleotide lesions have great consequences on chromosomes/stability) :
epigenetic gene expression changes Redox loss
For the programmation side, it would be just the epigenetic the causal source :
DNA damage Redox loss
I finally put it as (all three can be interchanged and intercommunicate/interactivate/deactivate each other):
DNA damage epigenetic gene expression changes Redox loss
''I read that gene expression can be controlled by the redox state of the cell?!''
Absolutely. Redox loss epigenetic gene expression changes. Once study demonstrated very clearly that as epigenetic drifting continues its course in the later years of life, there is a direct correlation between loss of redox homeostasis and gene transcriptional fidelity loss (meaning the epigenetic drifting causing DNA methylation/demethylation pattern changes (mostly demethylation in CpG-poor islands since they positively regulate redox function) is in turn changing the cell's redox state - which becomes much more positive mV (in an oxidized redox milieu, thus loss of negative millivoltage potential), it truly is both ways - epigenetic aging can control redox - and the redox controls epigenetic aging, also in reverse/inter-connected fashion:
Redox loss epigenetic gene expression changes.
''Why would we even care about telomeres when the real underlying cause of the telomere attrition is the decresing ability of stem cells to replace cells with long telomeres?''
just my 2 cents, I think it has to do with the fact that stem cells are bound by telomeres - like other non-dividing post-mitotic long-lived somatic cells; stem cells can't evade telomere erosion themselves, their very own telomeres shorten, too. Telomeres touch the whole thing. Only sexual/gonadal germ stem cells also called 'primordial germ cells' in the early testicules have the power of telomerase to maintain their telomere length, these stem cells are immortal - not the other ones in human body beside sexual organs and certain immune ones that also employ telomerase (most somatic cells have not detectable telomerase although there is much contention and in fact, they do have some small telomerase but it's small and not enough to retard much of anything), these non-sexual stem cells' telomeres keep on eroding despite them keep quiescent or dividing, makes no difference and one day they can't replace anything anymore when their telomeres are too low/entering replicative senescence (when they divide faster telomere erosion happens quicker this why the stem cell niche must remain quiescent and divide rarely/occasionnaly to replace an injury in the tissues or and old organ needing some tissue rejuvenation by stem cell differention into said tissue. Stem cell use is a sparingly thing and a costly thing to them. Animal studies showed taht accelerated aging made accelerated stem cell niche depletion and fast dividing/self-replicating non-quiescence and then differentiating into other cells: 'trying to compensate' until it niche was exhausted) ,
''Doesn't it make more sense to enhance stem cell activity (i know cancer is always a problem) than tinkering with the telomeres of the somatic cells. Am i missing something in this picture?''
You're not missing much : For the reasons stated earlier above, quiescence is important to maintain stem cell niche function and numbers in it.
Enhanced stem cell activivy both good (repair/rejuvenate) and bad (costly on niche if faster demand vs self-renewal; it's a fine balance between differentiation vs self-renewal/dividing), on top of the fact these stem cells have their telomeres slowly shortening too; one day or another, it's game over, even for stem cells (except for exclusive specific non sexual primordial ones or certain immune ones who use telomerase for their advantage; the rest telomerase is not used if, not enough, at least to counter telomere erosion in them just like in other somatic cells. Hayflick limit). I believe increasing stem cell activity would yield positive results - only in the short term or sporadically - not in the long term and constantly; it would definitely tip the balance towards exhaustion at a certain point. Stem cells increased activity will not be able to stop aging on its own though, it will have a great 'health' effect and allow someone to possibly reach MLSP (122 years) but to say that stem cell injection would reverse aging so much (like LEV) that is fallacy, because mice were injected with young mesenchymal stem cells and they never lived all that much longer, yes there was a life extension, akin to calorie restriction basically and greatly improved healthy - but nothing in terms Longetivy extension (where that mouse would have live 10 years...rather 3 years 'healthy' with periodic stem cell injectios or stem cell bost of activity inside mouse - in fact, Ames Dwarf mouse that lives long life : one study showed taht v-cells (very small stem cells) in dwarf mouse were much higher in them then regular shorter lived wild type ones showing that some of the benefits of those stem cells were increased protection and improved lifespan in Ames dwarf mouse ...but did that mouse live a 100 years by its stem cells ?...no it lives 4 or 5 years tops...it's not a naked mole rat that lives 35 years..same thing with another study showing that centenarians (humans) who live a 100 years kept their adult stem cells niches better and more orderly for longer (more quiescence longer, they 'strechted' their niches activity for longer, giving a healthy boost and orgain reparation - thus living healthy and up to a 100 years old).
Why would a naked mole rat live 35 years...a dwarf mouse live 3-5 years and a human live a 100 years - if all of them have stem cell activity en masse ? Because stem cells are not the main decider, redox is : One study showed that naked mole rats NMR vs mice, the mice were far more quickly oxidized redox potential - over time. The NMRs had higher redox thiols pool content right from the bat and also kept its cysteine residues unoxidized for over 20 years, while the mice it oxidized in less than 24 months. This means : the redox protects the NMRs crucial proteins and DNA nucleotides that are important for lifespan/longevity. Same thing in humans, if even better : centenarians studies showed that maintain higher redox couple, higher blood thiols and higher plasma membrane redox activity. All of this points to maintaining your capacity - against oxidative stress - over aging - that is the reason why we can live longer, much longer lives (years...centuries even : Quahog clams who live 500 years...they maintain redox couple and their total cytoplasmic and mitochondrial gsh levels create a permanent 'haven' of antoxidation (one study showed they are up constantly in the -300mV cell redox state, overreduced pretty much the negative potential is so strong that cell oxidative stress susceptibility is absolute nil), hence their barely accumulate nucleotide lesions and proteins oxidation carbonyls/protein unfolding; and go on living 5 centuries, what's more is they display some telomerase in their tissues; but trust me, it's not the reason why they live that long : other quahogs of the same specie barely live 5 years and have telomerase in permanence.... I rather put my bets on long lived animals as a sure way to live Longer than a 100 yaers old than in a tiny mouse who will live maybe a year or two more - that will never translate in humans...because of divergent evolutionnary specie program goals (mice are made for 'sex' and lots procreation and lots of 'replacement' of 'mortal dying population' (dies in 3 years tops, needs replacement), humans, long lives...little children (no need for replacement)).
Just a 2 cent..
PS: for some reason. the website did not show what I wrote correctly (keyboard text language error) so I wrote in words (I apologize):
and the both sides (that's where I think it lies and inclues myself in that one)
epigenetic gene expression changes making DNA damage
and
DNA damage making epigenetic gene expression changes
I add a precision that goes both ways :
redox changes first, making epigenetic gene expression changes and DNA damage changes
But if DNA damage is the ultimate decider (and that could be true since nucleotide lesions have great consequences on chromosomes/stability) :
DNA damage first, making epigenetic gene expression changes making Redox loss
For the programmation side, it would be just the epigenetic the causal source :
epigenetic gene expression changes first, making DNA damage and Redox loss
I finally put it as (all three can be interchanged and intercommunicate/interactivate/deactivate each other):
DNA damage, making epigenetic gene expression changes, making Redox loss
DNA damage, making Redox loss, making epigenetic gene expression changes
making epigenetic gene expression changes, making DNA damage, making Redox loss
making epigenetic gene expression changes, making Redox loss, making DNA damage
Redox loss, making epigenetic gene expression changes, making DNA damage
Redox loss, making DNA damage, making epigenetic gene expression changes
Thank you CANanonymity for taking your time once again.
I have no doubt redox homeostasis is very important.
The hierarchhy of redox loss, damage and gene expression shift must be established without a doubt. It is probably a highly interconnected loop of feedback, but I guess one of them starts this whole thing off which then slips into high dynamic. I just wonder...if it wasn't damage that changes redox states, what exactly would it be? Why would the epigenetic gene expression change wihout a first cause of redox loss, which in turn must be explained by an earlier cause? Nothing changes "just like that", there must be a feedback loop and for me it doesn't make sense that epigentic gene expression starts off this loop. It could be damage or redox loss and I think their intertwined in some way.
Coming back to the stem cells, I think if gonadal stem cells can keep their telomeres long, other stem cells should in principal be able to do that as well? Why they don't? Maybe they were not evolved to do so, but there has to be a fine balance of telomerase activity that keeps the telomeres of the stem cells unshortened. Niche depletion follows from the shortened telomeres of the stem cells right? Then there must be ways of stopping that shortening with a finebalanced dose of telomerase?
Thank you too K.
That is very good explanation (interconnected loop of feedback) and it would make a lot of sense, they really, seem, to communicate to each other - continuous negative/positive feedback/lopp signaling. I'm not sure really of what else could it be, not much else, damage is a major driver that is assured but if not that one...epigenetic gene expression changes I guess...and is damage the sole one or the one that starts it it all; it's very hard to say so much overlapping going on that it is all muddled and I sort of believe there is no 'starter' or one thing, i think it like it is a whole ensemble/group that just starts if you will; no one of them can claim to be (more) responsible it seems than the others. They are about equal share. We always think it is a single driver (more important or the One), but in aging, many drivers can drive the whole thing (and each contribute a tiny % of the 100% of aging). Normally speaking, it should be damage the ultimate driver, but seeing some studies that showed no or little damage - and still cell cycle arrest even so...demontrastes it's more complex than we think than just 'damage accrual/rust/oxidation/junk'...
there are still very subtle layers that we don'T even know yet (when we think we discovered it all by now and know it all).
I think that if we can detect cell cycle arrest without oxidative insult or other damage, it means that this arrest was a 'signal' that came from somewhere - most likely a (epi)genetic signal that commanded it. In that case, epigenetic gene expression would supercede damage explanation and, truly, be the Main causal element of aging (not the Only One, but a Main one - More So, than damage...which sounds absurd since we all think we are like a car that 'rusts' to take the old rusting car analogy/wear and tear...apparently wear and tear can happen - without damage (cell cycle arrest is deadly/creating senescence yet it happened - without damage or DDR (DNA Damage Response)). I think damage is just 'one form' of many different 'signals' that are interpreted by (epi)genome and (epi)genes who then decide what they should do next. What'S more is sometimes damages are inconsequential or there is no susceptibility to them - as if they just never happened, makes no difference whatsoever and all is merry and things go along like they like never happened. Again with the 'signals' some signals can be ignored, some can be detected, apprehended/decoded...all of this is the domain of (epi)genetics and pure DNA/RNA's genes - all in nucleotide DNA/RNA 'code' (Cytosine, Guanine, Adenine, Thymine, Uracil, Pyrimidines, Purines...). These signals or codes seem, truly, to be at the heart of it...these nucleotides can have damages : Oxidative DNA lesions and errors like flipping of nucleotides/combinational errors during DNA synthesis. This would in effect damage the 'genes' segments/blocks that are composed of them...but, clearly, things can still work despite that - and the DNA can repair itself and make it all new as if it never happened - so the question still lingers...damages ?...apparently not. Apparently, it's more a sort of DNA 'program' of 'signals' epigenetic or otherwise that decides so - how long you live - how much of that damage is 'consequential' or 'inconsequential'...it decides it all. Still, I'm just wondering too and I continuously change opinion with new studies saying otherwise; I now stick with the - it's all of them/they all contribute and interact with each other in no particular order/fashion and not 1 of them above all.
''Coming back to the stem cells, I think if gonadal stem cells can keep their telomeres long, other stem cells should in principal be able to do that as well? Why they don't? Maybe they were not evolved to do so, but there has to be a fine balance of telomerase activity that keeps the telomeres of the stem cells unshortened''
Exactly, they should and technically, they do already, they found low telomerase activity
in most - all - cells (the earlier discovery that telomerase was utterly absent is not true, there is - some - telomerase in alls cells, but as said it is low, sometimes undetectable even, that they postulated they didn't make use of telomerase (when using other methods of detection they found that, indeed, there was some very small levels of telomerase - even in somatic cells. They are just not enough to make all that much of a difference, these cells' telomeres are still eroding and telomerase levels are just not sufficient in them to stop that). As to why these other stem cells don't make use of higher levels of telomerase - like the gonadal stem cells or immune stem cells whom actually benefit from it by extending their own telomeres ... you have solid point there, that they were not evolved to do so...
Since we are mortal and these gonadal stem cells are immortal, there is an evolutionary scheme at play;
why were the gonadal stem cell selected for immortality while the rest of the stem cell were not :
specie survival - assurance of progeny. By making sure, these specific - sexual - stem cells are immortal - it assures the progeny possibility and increase likelihood of specie survival by offspring/conception capability assurance. Thus, Immortal gonadal stem cell will improve the likelihood of having kids and as such making survival of population. We have to understand that immortality - Requires - that the cell Works Well...sure there are cells that can be immortal and totally wack (cancer for example), but these cells needs to function 100% to make sure a baby happens (and not lose a child).
Immortality is a clear sign of Superior capacity/function or let's put it as 'evolutionary selective advantage' - by access of telomerase (they actually use it in much higher levels). It truly is a Sexual Selection at play, Darwinism 101 in action right here. There was also a theory in which, these sexual gonadal germ cells are ancient bacterias (germ bacteria) that 'want to transfer themselves in the next 'host'' (basically, in the next child boy testicule)...the purpose on these ancient bacterias was to become immortal to be able to continue to proliferate forever. How they could do that, was only through sexual conception/procreation and transfer into 'new host' (the child). That way they remained immortal and always 'supported' in a 'host environment' : called bacterial symbiosis (this goes back billions years ago when cells were called 'proto-cells' and Uni-cellular cells before the eukaryote cell..and some of them were bacterias (like our mitochondrias, which are ancient bacterias themselves that evolved in a 'symbiotic manner' were they live 'inside a host' and exchange they do a 'favor' mitochondrias produce ATP energy for the cell (the host), so in a sense a bacteria penetrating/merging/housing inside a cell in the case of mitochondrias; pure symbiosis or also called parasitic hosting (the parasite being the mitochondria, but it's not a parasite per say). Yeah, just like Alien (the film, the Alien is inside the Human, and bursts out its ribcage, this 'hosting' the human serves the Alien as the host... for it to be born; there is symbiosis (the human body providing housing/'pregnancy'), the parasite is the Alien inside). So if we apply to that gonadal primordial germ cells, they 'primordially' wanted 'to live' and that meant being immortal and to make sure they did not die in a single individual, procreation was needed (transfer themselves continuously/their descendants in the next child male testicule host).
I believe some of it because it truly is fascinating, but it makes sense, these bacterias, unicellular organisms had to survive (bilions of years ago) when there was 'Oxygenation Event' on Earth (When sulfur or other gases were replaced by Oxugen on earth) they decided to 'Move In' and do 'Symbiosis' 'Work as a Team'...but did not want to die either..the whole point Was Survival. Immortality and Sexual Procreation was the best answer to 'Continue'.
Also...
The fact is, as men age, though they gonads encounter damage from aging, their testicule sperm's telomeres - increase (they do not shorten, that's why they sometimes say longevity of child depends of age of father at conception (by his taller sperm telomeres at conception, if older ('mature sperm')). They call it the 'old father conception, long-lived children'. The older man gives longer telomeres at conception in its sperm, this creates a child that has an extra boost 'chunk' of telomeric DNA TTAGGG repeats vs other children born from 'young fathers (whose sperm has smaller telomeres)' (thus the child is 'younger' biologically at conception, right from the very very very very start the moment the spermatozoid stucks its head in the female ovule egg)..there is some contention though, older father are older and some carry sever defects in their testicules and their sperm (- despite having longer telomeres! in their sperm, although my bet is that this compromised 'old father sperm' is damaged and as such, Would have lower telomeres in the bunch of taller ones - thus is bad); and that is transmitted to the child..my guess, it's a compromise : if the old father is healthy 'enough' there should be no major DNA damage transfered/gene defects to the child even the father is old and in that case, the Spermatozoids' Telomeres Will Be Much Taller...that is 100% sure. And, that is because, an old man had a long time of telomerase in the testicules, thus many years of 'time' to 'extend' its 'sperm telomeres'; while a young 20-year old man has 'immature sperm' (meaning it did not have 'enough time' (he's young..), to 'get there' and to let telomerase extend the sperm telomeres; as such, no longevity-effect in the child from conception in young men). In exchange, younger men give 'cleaner sperm' with less DNA defects (they are young, their sperm is virginal/'healthier'/less DNA damage accumulated over the young (lesser) years, thus less chance of giving child 'old damaged sperm'; like from an old man). The best is truly 'old healthy men', they give the healthiest and most 'mature' sperm with the tallest telomeres and this translates into his children possibly living to a 100 years old (becoming centenarians). It's kind of like a repetition : Old father = Old Living Child who Will Become an Old person (as old as his own father or older even, reaching a 100 years old). It's an assurance if you will, an old man is a testament if he lived a long life thus he 'transfers' the power of his 'longevity' to his child (by the taller telomeres in his sperm than in a young man's sperm).
''but there has to be a fine balance of telomerase activity that keeps the telomeres of the stem cells unshortened''
Yes, that's right, but it's just not enough telomerase activity to maintain the telomeres size..like it does in gonadal ones.
'' Niche depletion follows from the shortened telomeres of the stem cells right? Then there must be ways of stopping that shortening with a finebalanced dose of telomerase?''
Yes, niche depletion happens when there is a strong Demand for tissue replacement; and as such, stem cells are mobilized and translocate to the area of injury for example and differentiate into other cells. But this can be very taxing and if the stem cells 'Back Home at the Niche' are not exactly self-diving themselves to create new ones, it's a problem; the numbers dwindle, it's a very fine balance. And, in the case, of accelerated niche depletion there is often an oxidative challenge - requiring compensation by stem cell mobilization. But stem cells niche depletion is 'compensated' by accelerated self-division to try to mitigate dwindling numbers - that can accelerate the process of telomere loss (replicatiion can be costly, we always think that the newly self-divived daughter stem cell will have longer telomeres, that's not always the case; there can be loss of telomeres duting these intense bout of self replication; and as such, it would be a reason why stem cells keep quiescent, don't self-replicate -only in the rare occasion where they are called on to differentiate/it's a pure game of 'streching the resources as most as possible by remaning 'silent/unspending resources''), also when stem cells themselves face oxidative challenge like the rest they lose telomeres. When the redox is loss, stem cells have accelerated telomere loss too.
'' Then there must be ways of stopping that shortening with a finebalanced dose of telomerase?''
Yes, studies have shown hTERT gene can be expressed in them thus activating telomerase enzyme activity, and they do live much longer (can become immortal exactly like gonadal ones), but there is a cancer risk because of excess telomerase on chromosomes creates abnormalities (fusions/recombinational error possibility by way too tall telomeres, tall telomeres are important but if continuously getting taller, that is problematic and chromosomes become dysfunctional. This increases chances of cancer by genomic instability - while also, telomerase can increase cancer and metastasis invasion odds in malignant tumor cells (malginant cancerous cells high-jack telomerase for themselves and they become,thus, immortal too; or use ALT telomere lenghtening/recombinational/telomere fusions lengthening).
Telomerase is really good and bad sadly, it's actually ironic that gonadal stem cells function quite well, without cancer, and have high telomerase...while the others don't, are mortal and can get cancer (how nice...that's not to say that sexual gonadal cancer formation is non-existant, it does happen, these gonadal stem cell 'are playing with fire' and as such testicular cancer is very possible) again with the evolutionary 'compromises' between mortality and immortality.
Hi CANanonymity,
Thanks for your personal insights. Some things still elude me...I'm still left with many "..but why?"
I will try to read some more papers on the topic and then gain somehwat of an understanding. But you already helped me, thanks.