1033 replies to this topic

[QuestforLife]

My ideas on aging are moving apace.

The selfish cell lives longer

Arguments for the evolution of aging depend on a non aging (selfish) individual being bad for the group.

I think I see a parallel in the cells that survive in the aged body. Whenever I look into an aspect of aging, I always see the same thing. The cells that survive are the ones that are the worst for the body. Everyone seems to assume that a mysterious process called aging is causing these cells to fail with age. But what if it is a selection process that leaves the most selfish cells alive?

I can give concrete examples(discussed in this thread before, references not repeated). Briefly, epidermal stem cells respond to stress signals through asymmetric division producing a replacement stem cell plus epidermal skin cell. But naturally some stem cells are more resistant to stress and instead with the appropriate growth signal they divide symmetrically, with two(more stress resistant) stem cells spreading out and eventually coming to dominant the epidermis. In this way skin replenishment requires ever greater stress signals and fails. Another example. Fibroblasts produce collagen from glycine at a limited rate that necessities recycling of most of the collagen produced. But eventually more collagen has to be made and this requires diversion of glycine from glutathione production and a rise in ROS (the glutathione level decline with age is secondary to declines in the blood levels of glycine and cysteine).This means the cells that produce most collagen are the most likely to die. Again, you’re always left with the most selfish cells.

 

I have a plan to try and fix skin aging. As I wrote a couple of posts up, skin doesn't seem to run out of stem cells, they just get lazy. As per my quote above the selfish (least responsive) epidermal stem cells come to dominate the basal layer, once the more responsive stem cells have differentiated. So to get these coach potato stem cells working again we need a stronger stimulus. The problem is most skin treatments are generally very hard on the surface layers without really giving the basal layer a good 'kick'. Deep derma needling works better than shallow, but makes a mess of the surface. Retin-A increases surface turnover, often with severe peeling, to get the basal layer moving. What if we could hit the basal layer but keep the surface relatively intact?  

[aribadabar]

What if we could hit the basal layer but keep the surface relatively intact?  

 

Would something like High Intensity focused ultrasound (HIFU) at mid to high depths help?

 

[QuestforLife]

Would something like High Intensity focused ultrasound (HIFU) at mid to high depths help?

Sounds interesting (no pun intended). Any positive reports?

[QuestforLife]

Some thoughts on telomerase inhibition and the action of splicing regulators like resveratrol

Resveratrol and potentially other compounds that increase telomerase through splicing factors have far more effect on senescent cell cultures than those still passaging. Compare [1] to [2]. There is also a wealth of other literature on the more modest effects of resveratrol and normal cell cultures.

These substances have not been shown to increase telomerase at Sierra sciences (Bill Andrews) where they use a standard cell culture assay (various interviews).

They also only rejuvenate a subset of the cell culture [1] and [2].

This suggests to me that they are only rejuvenating cells rendered senescent by telomere erosion, not those with damaged DNA, etc. See the question at the end of this interview [3] for Faragher's position on this.

The fact that telomerase is boosted far more in cells already senescent (see also the effect of tocotrienols on cells at various stages [4] Fig 7d) also suggests such substances are operating via the short telomere effect - whereby short telomeres are preferentially elongated by telomerase because of the fact short telomeres tuck into a different location than long telomeres (See Shay and Wright work [5]), and therefore do not have the same degree of inhibition by the presence of the telomere. Note it is likely that telomerase is primarily inhibited by the telomere tail itself, which when long tucks into a location close (once the DNA is wound up) to HTERT, but even once this is removed other repressors are still in place. It is my opinion that splicing factors are this back up repression,making sure even if telomerase is produced it is in an inactive form with introns still present. It is this alternative splicing that is reversed by resveratrol until the telomere is long enough to re-extablish primary telomerase inhibition. This is most likely why telomerase upregulation by resveratrol is so short lived.

Another way of increasing telomerase is via unwinding DNA, with HDAC inhibitors (i.e. sulforaphane). This might be a way of elongating even long telomeres, by again removing the influence of the telomere on HTERT - it would still be tucked in a the same location but removed from HTERT but the unwinding of histones. Various papers have looked at combining different compounds and achieved synergistic effects [6].

Then there are substances like epitalon that are purported to increase telomerase by interpolating itself in-between the DNA strands at the HTERT location and force expression that way. The work was done in Russia [7], and hasn't been replicated elsewhere (so treat it with caution), but it is supposed to be able to match Henrietta Lacks cells for telomerase expression [8], and my results suggest it is effective.

There are concerns that increasing the lifespan of a cell line will increase their epigenetic age via methylation changes, possibly because the time such somatic cells exist before being replaced by the epigenetically younger stem cell pool will increase. There is evidence for this as when my telomere age decreased by 3 years using epitalon, my epigenetic age as measured by methylation patterns increased by a similar amount. It is an open question how much this matters. I've pointed out before that the increase in epigenetic methylation aging caused by telomere elongation is not the same as that experienced during normal aging. For example those on sartans [9] have been shown to have an older epigenetic methylation age. But the increase in epigenetic methylation age that comes with old age (and which is correlated with lower survival) is not occuring because telomeres are longer but because they are shorter. As stem cells lose telomeres and/or numbers, they slow down their replacement of the soma and hence those cells must survive for longer. So just as longer telomeres in somatic cells mean the soma CAN endure (i.e. self-renew) for longer without replacement, shorter telomeres (in stem cells) mean the soma HAS to survive for longer without replacement (as the replacement cells are in short supply). In the case of shorter telomeres the diagnosis is terminal. With longer telomeres a longer life beckons, unless the somatic cell line is kept going for so long it gets damaged in other ways. It is worth bearing that possibility in mind. I intend to continue testing both telomeres and epigenetic methylation age to keep a close eye on this. I am hoping it is possible to balance both. There is also the possibility in the future of boosting telomeres only in stem cells via TERC (the RNA template) rather than TERT (the protein) [10]. I've posted on this previously. That's enough for now.

[1] https://www.ncbi.nlm...les/PMC5645932/
[2] https://link.springe...522-020-09896-6
[3] https://m.youtube.co...o&v=cBmrKaBlQ6M
[4]
https://www.hindawi....ri/2011/506171/
[5] https://www.ncbi.nlm...les/PMC5826875/
[6]
https://pubmed.ncbi....h.gov/27433836/
[7] https://www.ncbi.nlm...les/PMC7037223/
[8] https://link.springe...A:1025493705728
[9] https://www.ncbi.nlm...les/PMC6286862/
[10] https://www.cell.com...87?showall=true

[Iporuru]

This suggests to me that they are only rejuvenating cells rendered senescent by telomere erosion, not those with damaged DNA, etc. See the question at the end of this interview [3] for Faragher's position on this.

 

I agree with your points and additionally I have found some confirmation to the fragment quoted above:

 

 

The observation that human diploid fibroblasts have a finite replicative life span in vitro paved the way toward the term replicative senescence (RS) [4]. Telomere attrition was firstly identified as possibly responsible for this phenomenon, as overexpression of the catalytic subunit of the enzyme telomerase (human telomerase reverse transcriptase [hTERT]), a reverse transcriptase that corrects normal telomere erosion, was shown to overcome RS in human cells [5]. However, the observation that single or repeated short exposure to various subcytotoxic stressors (UV, hyperoxia, hydrogen peroxide, etc) can accelerate CS [6,7] led to the introduction of the term stress-induced premature senescence (SIPS), which can also occur independent of telomere length and hTERT expression [8]. Overexpression of hTERT cannot bypass also another type of stress-induced CS [9], named oncogene-induced senescence (OIS) [10] and prompted by aberrant activation of oncoproteins (ie, RAS, BRAF). sci-hub.se/10.1016/j.nutres.2014.02.006

[Andey]

Interesting new paper on telomeres, specifically how T cells could extend their lifespan

The common view is that T-lymphocytes activate telomerase, a DNA polymerase that extends telomeres at chromosome ends, to delay senescence. We show that independently of telomerase, T cells elongate telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs). Upon contact with T cells, APCs degraded shelterin to donate telomeres, which were cleaved by TZAP, and then transferred in extracellular vesicles (EVs) at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled them to fuse with T cell chromosomal ends causing an average lengthening of ~3000 base pairs. Thus, we identify a previously unknown telomere transfer program that supports T cell lifespan.

 

https://www.biorxiv.....10.09.331918v1

I dont think its relevant to this thread, its more of example what bizarre ways could biology use.

Edited by Andey, 11 October 2020 - 07:25 AM.

[QuestforLife]

Interesting new paper on telomeres, specifically how T cells could extend their lifespan
https://www.biorxiv.....10.09.331918v1
I dont think its relevant to this thread, its more of example what bizarre ways could biology use.

Thanks. I wonder if this telomere transfer method is related to the alternative lengthening of telomeres (ALT) method so often used by cancer cells when telomerase is blocked. Quite clever really - just sacrifice some cells so others can continue to proliferate. But not a very selfish, cancer thing to do so maybe the mechanism is not the same.

[Iporuru]

Interesting new paper on telomeres, specifically how T cells could extend their lifespan

https://www.biorxiv.....10.09.331918v1

I dont think its relevant to this thread, its more of example what bizarre ways could biology use.

 

From the study:

 

Why do T cells use telomere transfer in addition to telomerase activation
to maintain long telomeres? Our data suggest that telomere transfer is required to

limit the burden of ultra-short telomeres in T cells (Extended Data Fig. 11b). These
ultra-short telomeres are critical for activating the senescence program but may not
be eliminated by telomerase23,32. A more substantial telomere elongation than that
evoked by telomerase (~100-200bp) is required to eliminate these ultra-short
telomeres: this is ensured by the intercellular telomere transfer program described in
this report. It is possible that a loss of telomere transfer capacity rather than a loss of
telomerase is responsible for telomere shortening at the basis of ageing. We propose
that transfer of telomere vesicles may be implemented in a number of ageing-related
pathologies characterized by telomere shortening as well cancer immunotherapy,
where it is clear that replicative senescence of T cells present an outstanding medical
challenge that cannot be solved simply by activating telomerase33-35. Whether
telomere transfer may occur universally across the animal kingdom whenever cells
interact with each other to modulate their reciprocal lifespan remains to be
determined.

 

[QuestforLife]

Interesting new paper on telomeres, specifically how T cells could extend their lifespan

https://www.biorxiv.....10.09.331918v1

I dont think its relevant to this thread, its more of example what bizarre ways could biology use.

 

What a paper this is!

 

Just shows how much molecular biology has advanced in the last few years.

 

Some key takeaways:

 

1. Chunks of telomeres are transferred from APCs to T Cells (APC= Antigen Presenting Cell not Armoured Personnel Carrier although this analogy functions well if you image telomeres to be the personnel being carried);
2. This enables greater telomere elongation than via telomerase (which T cells also intermittently enable) during expansion;
3. This allows 3 folder greater expansion of the T cell pool than without such transfer from APCs;
4. The burden of the shortest telomeres (<3K bp) in T cells is reduced 4 fold with such transfer enabled;
5. Senescence markers such as beta-galactose are also prevented;
6. The chunks of telomeres are cut off the APC telomeres after Shelterin proteins are downregulated;
7. Telomeres are released in exosomes from the APCs, with an average of 5K bp of telomere in each exosome;
8. They are then fused by endonucleases to the receiving T cells' telomeres;
9. The T cells benefit by an average of 3K bp extension each over 24 hours ;
10. Various antigen and T cell signalling is normally required;
11. But the authors find you can substitute these with a calcium ionophore (moves calcium into cells) antibiotic called ionomycin;
12. The APCs will then release telomere filled exosomes into the cell culture even in the absence of T cells;
13. Incidentally this mechanism is conserved between humans and mice and murine APCs were able to extend the telomeres of human T cells in culture ;
14. They validated this process occurs in vivo, using fluorescent telomeres in APCs injected into mice and verified these were taken up into the nuclei of antigen activated T cells also injected into the mice ;
15. The authors suggest that the telomere transfer process is required to limit the senescent signalling of T cells with very short telomeres, which telomerase mediated elongation (~100-200bp) is unable to to prevent;
16. The authors suggest using telomere vesicles to solve various problems with T cells and age; finally
17. It is not clear what other cells use this process, or whether there is some sort of trade off with the loss of telomeres in APC cells to assist the rapid expansion of T cells.

PS

1. this process is different to ALT (alternative lengthening of telomeres), which uses DNA synthesis and which was eliminated as a cause by the authors.

Edited by QuestforLife, 12 October 2020 - 10:57 AM.

[sub7]

This thread has become a great repository of a lot of information and has also turned into sort of a crossroad where the topics of telomeres and stem cells meet. I hope you don't mind if I sum of some of my questions so that guys like QFL, Turnbuckle and others can correct me where I am wrong in my grasp of the ideas so far.

 

Now especially Turnbuckle believes that extending telomeres will impair the process of old cells getting eliminated and being replaced by stem cells. My questions are the following
How does this view fit with this experiment where mice with longer telomeres are just healthier?

https://www.nature.c...467-019-12664-x

 

Also, has there been any experiment where the telomeres of a cell or those of cells in a particular tissue or cells throughout an organism have been elongated and worse cellular or organ health observed? Have there been any instances of this theory holding up in experimental settings?

 

This is perhaps too detailed to answer with a few sentences but what exactly would you expect to happen if we keep making telomeres longer and keep the cell alive longer and longer? In what way would the cell get old? Is it the accumulation of DNA damage, is it the buildup of misfolded proteins....?

 

Finally, the idea behind not wanting to extend telomeres is that we can somehow keep a sufficient population of stem cells around to step in and fill the gap left behind by removed old cells. Turnbuckle is trying to do that with his protocol. Now, are we somewhat close to a point where we have enough stem cells to keep doıng this indefinitely? i.e. have we reached "escape velocity" in terms of stem cell renewal, so that however many stem cells we need, we will not run out of them?

 

 

[Turnbuckle]

 

Now especially Turnbuckle believes that extending telomeres will impair the process of old cells getting eliminated and being replaced by stem cells. My questions are the following
How does this view fit with this experiment where mice with longer telomeres are just healthier?

https://www.nature.c...467-019-12664-x

 

 

 

 

See posts 272-274 on the thread, Old human cells rejuvenated in breakthrough discovery on ageing. As I pointed out there, the first try resulted in control mice living much longer than the treated, while the second try had the treated mice living modestly longer (8-13%) than the controls. In the second case, the treated mice were essentially identical clones of treated embryonic cells. If the embryonic cells were from a superior mouse, then all mice created from it will be equally superior. The correct way to have done this experiment would be to create all the mice from one set of embryonic cells, with half treated to produce longer telomeres.

 

 

we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells.

 

Edited by Turnbuckle, 17 October 2020 - 06:38 PM.

[sub7]

Thanks so much Turnbuckle.

How about this earlier question

 

Also, has there been any experiment where the telomeres of a cell or those of cells in a particular tissue or cells throughout an organism have been elongated and worse cellular or organ health observed? Have there been any instances of this theory holding up in experimental settings?

[zorba990]

Would something like High Intensity focused ultrasound (HIFU) at mid to high depths help?

Interesting. I can't quite read the three frequencies on any of their pictures. They seem to be exclusively in London.
Some ultrasound frequencies increase risk of stroke (20Khz which is also ideal for killing cancer calls unfortunately), so I hope that they have been careful with that.

Therapeutic Application of 20-kHz Transcranial Ultrasound in an Embolic Middle Cerebral Artery Occlusion Model in Rats
https://www.ahajourn...257966.32242.0b

Perhaps humans are not so susceptible or the energy used is much less in strength or duration?

[Turnbuckle]

Thanks so much Turnbuckle.

How about this earlier question

 

Also, has there been any experiment where the telomeres of a cell or those of cells in a particular tissue or cells throughout an organism have been elongated and worse cellular or organ health observed? Have there been any instances of this theory holding up in experimental settings?

 

 

When I tried adding telomerase enhancers to my SC protocol, I saw a rapid increase in epigenetic age, and looked older as well. It took the better part of a year to get back where I was. As for an experiment showing longer telomeres reducing lifespan, the first experiment with hyper-long telomeric mice showed a reduction. See here. 

 

I've also tried reducing telomere length in the hope that faster cellular turnover would decrease epigenetic age faster. This didn't pan out as my epigenetic age actually increased, but not nearly as fast as it did with telomerase enhancers. So it may be best to let telomeres do their thing without interference.

[QuestforLife]

This is perhaps too detailed to answer with a few sentences but what exactly wo....?

As Turnbuckle rightly points out we've just had this discussion on another thread so I'm loathe to repeat the arguments here.

I'm more than happy to answer any specific questions though.

I disagree with Turnbuckle about the lifespan extension in Blasco's mice being a function of the embryonic clone used, other than the fact it was cultured for an extended period to give it longer telomeres.

The body is a mosaic of short and long telomeres and elongating telomeres in all cells will have complex effects. I do believe the net effect will be lifespan extension however.

Turnbuckle's protocol relies on there being some embryonic stem cells left even in an adult body and as these are embryonic they can express telomerase. His protocol aims to increase their number.

Edited by QuestforLife, 17 October 2020 - 07:48 PM.

[aribadabar]

Interesting. I can't quite read the three frequencies on any of their pictures. They seem to be exclusively in London.
Some ultrasound frequencies increase risk of stroke (20Khz which is also ideal for killing cancer calls unfortunately), so I hope that they have been careful with that.

Therapeutic Application of 20-kHz Transcranial Ultrasound in an Embolic Middle Cerebral Artery Occlusion Model in Rats
https://www.ahajourn...257966.32242.0b

Perhaps humans are not so susceptible or the energy used is much less in strength or duration?

 

The labels on the picture are: 4MHz for 4.5mm depth and 7MHz for 3 and 1.5mm

 

I see several handheld devices showing 3MHz operating frequency so it's above 1MHz for sure.

[sub7]

When I tried adding telomerase enhancers to my SC protocol, I saw a rapid increase in epigenetic age, and looked older as well.  

 

I've also tried reducing telomere length in the hope that faster cellular turnover would decrease epigenetic age faster. This didn't pan out as my epigenetic age actually increased

 

Turnbuckle,

 

I respect you tremendously -totally honest comment. Even if every single comment of yours ever recorded on this site turns out to be inaccurate, my respect to you would remain intact, due to the sheer amount of work you have put into this endeavor. And, needless to say, I do not expect all of your views to be proven false at all; with time and the accumulation of knowledge, some will be proven right and some wrong.

 

With all this in mind let us take a moment to list all the conditions that must hold true, in order for your above-quoted comments to be valid / useful - in other words, the assumptions underlying the above:

 

- You are able to meaningfully extend telomeres without resorting to such risky means as AA-Viruses, which the research community has to use for the same purpose. You didn't even have to order something really exotic, unusual or hard-to-obtain from someone like a Sigma.

 

- The extension of your telomeres also correlates with the age recorded by the epigenetic age test. The said test does not measure telomere length directly.

 

- "and looked older as well"  This is near-impossible to swallow really. The elongation of your telomeres is not only increasing your epigenetically-measured-age, but is having such a substantial impact that you are able to tell a difference in the mirror??!!

 

- Not only are you able to extend telomere length, but if you so desire you can also shorten them at will; again, merely by taking substances that are available (albeit, only after resorting to creative measures maybe) to the general public.

 

- Again, the epigenetic age is able to pick up this shortening effect.

 

I just do not find the above realistic.

[QuestforLife]

- You are able to meaningfully extend telomeres without resorting to such risky means as AA-Viruses, which the research community has to use for the same purpose. You didn't even have to order something really exotic, unusual or hard-to-obtain from someone like a Sigma.

I'll leave Turnbuckle to respond to this in detail but the above quoted section captures the nub of the issue.

You do not need to meaningfully extend telomeres only delay their shortening to have an effect on epigenetic methylation marks, IF the theory that extending the life of a cell line via telomeres delays their replacement by epigenetically younger stem cells.

It then follows that clearing old cells early via telomere shortening would further speed replacement, but Turnbuckle's experiments have not borne this out as yet.

The key thing for me in the telomerase good or bad argument is the extension of telomeres of stem cells. This is a good thing if the limited supply of stem cells is the underlying cause of aging. It may be that extending telomeres of all cells delays replacement of somatic by stem cells to some degree, but that this delay is capped by other senescent inducing effects like oxidative stress. And if that is the case extending telomeres of all cells will end up being good. If extending telomeres in somatic cells allows them to NEVER be replaced by stem cells then clearly this is a bad thing, possibly leading to cancer. That would mean we'd need to look at ways of just benefiting telomeres in stem cells (such as TERC).

On the point you make about needing to resort to viral vectors or exotic substances to elongate telomeres I'm convinced we're close a solution. In vitro asiaticoside has been shown to induce 17% of the telomerase level of HELA cells, and if you believe the in vitro Russian epitalon work, it can already match HELA.

[Turnbuckle]

 

- "and looked older as well"  This is near-impossible to swallow really. The elongation of your telomeres is not only increasing your epigenetically-measured-age, but is having such a substantial impact that you are able to tell a difference in the mirror??!!

 

 

 

 

Yes. It was quite noticeable even before I saw any epigenetic results. This is likely due to the rapid turnover of skin cells, which have a lifespan of some three weeks or thereabouts. And as epidermal cells are generated from highly active transit amplifying cells (TACs) rather than directly from relatively slow acting stem cells, using a telomerase enhancer can block the senescence and replacement of TACs and thus rapidly raise epigenetic age when measured in rapidly replaced tissue. (White blood cells turn over even faster, and buccal cells faster yet.) If aging is occurring primarily in TACs, then the response can be rapid. In just a few months, one's appearance will reflect changes in the underlying epigenetic age.

 

The generational sequence is as follows, where VSELs are recently discovered embryonic like cells that travel about in the bloodstream and likely act as a backup for SCs. —

 

VSELs ► SCs ► TACs ► somatic cells

Edited by Turnbuckle, 18 October 2020 - 01:10 PM.

[sub7]

On the point you make about needing to resort to viral vectors or exotic substances to elongate telomeres I'm convinced we're close a solution. In vitro asiaticoside has been shown to induce 17% of the telomerase level of HELA cells, and if you believe the in vitro Russian epitalon work, it can already match HELA.

 

Such confidence based solely on in vitro results? and 1 out of these 2 examples is very suspect as it comes out of Russia

[QuestforLife]

Such confidence based solely on in vitro results? and 1 out of these 2 examples is very suspect as it comes out of Russia

That is why we are dependent on members here getting tested before and after interventions. I do a Lifelength telomere test per year, and I posted my results previously. By this measure epitalon appears effective.

[sub7]

As Turnbuckle rightly points out we've just had this discussion on another thread so I'm loathe to repeat the arguments here.
 

 Mind reminding us where that discussion is? 
Thanks a lot in advance

[Castiel]

Thanks so much Turnbuckle.

How about this earlier question

 

Also, has there been any experiment where the telomeres of a cell or those of cells in a particular tissue or cells throughout an organism have been elongated and worse cellular or organ health observed? Have there been any instances of this theory holding up in experimental settings?

 

There was an experiment were mice were engineered to lack telomerase, after a few generations they suffered from short telomeres like humans do.   Activating telomerase, strongly rejuvenated all their tissues and vastly improved their health, essentially it reversed the signs of aging.

 

https://www.nature.c...s.2010.635.html

 

In the lab, telomerase causes old human skin cells that produce old looking wrinkled skin to change and start producing skin indistinguishable from young skin.

 

Actually, if you asked me when we would first able to reverse human aging, technically I’d have to say it already happened back in 1999. That was when we showed in the lab that when you reset the telomere length in individual human cells like fibroblasts, you reset the pattern of gene expression, and then they act like young cells.

 

Alright, but that’s cells. Let’s get a little more realistic: what about human tissue? There, the answer is the year 2000, when someone showed that you could grow young human skin cells. 

http://geroscience.c...imers-and-more/

 

That's one of my problems with claims that telomeres increase epigenetic age.  Epigenetic age means changes in gene expression.   But it has been seen that telomerase essentially restores gene expression to youthful gene expression.    How can it restore gene expression to youthful gene expression if it is increasing epigentic age which should show gene expression of even more advanced age?

Edited by Castiel, 20 October 2020 - 07:35 PM.

[Castiel]

 

Geron and in academic labs as well— showed that researchers could reverse aging both in cells and in the tissues made from those cells. For example, if you take the most common types of human skin cells (fibroblasts and keratinocytes) from an old person and allow them to grow together, these cells form skin tissue that is thin, friable, and typical of the skin we see in an old person. If you do the same with cells from a young person, the skin tissue that forms is thick, complex, and typical of the skin seen in a young person. But if you take skin cells from an old person and reset their telomere lengths, then the skin tissue that forms is typical of young human skin.2 In short, we could reverse aging in old skin cells and thereby grow young skin.

 

Similar results occur with human vascular cells, using old cells to grow young vascular tissue and using old human bone cells to grow young bone tissue. In all cases, when we restore telomere lengths to the lengths seen in young cells, we can grow young cells from old cells: tissue that looks and functions like young tissue. 

https://www.singular...michael-fossel/

[QuestforLife]

Mind reminding us where that discussion is?
Thanks a lot in advance

https://www.longecit...n-ageing/page-9

[Turnbuckle]

 

That's one of my problems with claims that telomeres increase epigenetic age.  Epigenetic age means changes in gene expression.   But it has been seen that telomerase essentially restores gene expression to youthful gene expression.    How can it restore gene expression to youthful gene expression if it is increasing epigentic age which should show gene expression of even more advanced age?

 

 

Gene expression goes to pot with senescence, so restoring telomeres and thereby banishing senescence will restore health.

 

despite their inability to replicate, senescent cells are metabolically active and develop an aberrant gene expression profile with proinflammatory behaviour, the so-called Senescence Associated Secretory Phenotype (SASP), that can induce or accelerate changes in normal surrounding tissues, explaining the possible implication in tumor promotion, aging and age-related pathologies

https://journals.plo...al.pone.0098669

 

 

The drawback is that cells will continue to get epigenetically older. Better if those senescent cells could be replaced with shiny new cells (as happened when you were young), but there is a second problem, and that is the crash of stem cells pools that would supply those new cells. The loss of VSELs (very small embryonic-like cells) can be precipitous.  See this paper, for instance. It's unfortunately behind a paywall, but here is a very interesting finding --

Attached Thumbnails

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[QuestforLife]

That's one of my problems with claims that telomeres increase epigenetic age. Epigenetic age means changes in gene expression. But it has been seen that telomerase essentially restores gene expression to youthful gene expression. How can it restore gene expression to youthful gene expression if it is increasing epigentic age which should show gene expression of even more advanced age?

I've got a lot more to say on this subject. But for now I'll just add this.

Horvath has a lot to answer for with his various claims that his method of mapping methylation changes is 'epigenetic aging' or even 'aging'. His clock doesn't even map to any known adult age related changes in gene expression.

The epigenetic age state of a cell type is set by telomere length, as you rightly point out Castiel.

Horvath's changes are unrelated to this and continue to any cell line that continues to replicate. But it's not clear that this impairs a cell's function in any way. His clock is probably a passive continuation of something that happens to differentiate cells during development.

Ps it's worth mentioning that cells that have become senescent through telomere shortening cease to age via Horvath's clock. Hence restoring telomeres will increase epigenetic age. (https://www.ncbi.nlm...les/PMC6224244/)

Edited by QuestforLife, 20 October 2020 - 09:20 PM.

[Castiel]

I've got a lot more to say on this subject. But for now I'll just add this.

Horvath has a lot to answer for with his various claims that his method of mapping methylation changes is 'epigenetic aging' or even 'aging'. His clock doesn't even map to any known adult age related changes in gene expression.

The epigenetic age state of a cell type is set by telomere length, as you rightly point out Castiel.

Horvath's changes are unrelated to this and continue to any cell line that continues to replicate. But it's not clear that this impairs a cell's function in any way. His clock is probably a passive continuation of something that happens to differentiate cells during development.

Ps it's worth mentioning that cells that have become senescent through telomere shortening cease to age via Horvath's clock. Hence restoring telomeres will increase epigenetic age. (https://www.ncbi.nlm...les/PMC6224244/)

 

I heard that naked mole rats show increasing epigenetic age, or at least seem to have an age related methylation clock, but they are said to be a negligible senescence species.    I've heard they experience some decline in function, despite the claims of negligible senescence, but that could be due to the other type of senescent cells accumulating( non telomerase responsive dna damaged senescent cells).    Since there's a type of senescent cells that might not only occur but accumulate due to dna damage even in the presence of telomerase, these could potentially impair function on negligible senescent species if there's no clearance mechanism.

 

epigenetic clock on naked mole rats

https://pubmed.ncbi....h.gov/32126024/

 

telomerase positive no replicative senescence naked mole rats

https://www.ncbi.nlm...les/PMC5828632/

 

negligible senescence naked mole rats

https://pubmed.ncbi....h.gov/31927681/

 

 

Edited by Castiel, 21 October 2020 - 12:50 AM.

[Turnbuckle]

The epigenetic age state of a cell type is set by telomere length, as you rightly point out Castiel.

 

 

 

This is simply wrong. Epigenetic aging is due to the buildup of epimutations, while telomeric age is due to telomeric erosion. One doesn't set the other.

 

This study shows, for the first time, the relationship between two biological markers of ageing: telomere length and the DNA methylation-based epigenetic clock. In our data, both associate independently with chronological age. The measures do not correlate with each other nor do differences in baseline epigenetic clock measures predict change in telomere length. 

https://www.ncbi.nlm...les/PMC4864882/

 

 

Edited by Turnbuckle, 21 October 2020 - 11:04 AM.

[QuestforLife]

Thanks so much Turnbuckle.

How about this earlier question

 

Also, has there been any experiment where the telomeres of a cell or those of cells in a particular tissue or cells throughout an organism have been elongated and worse cellular or organ health observed? Have there been any instances of this theory holding up in experimental settings?

 

Extending telomeres restores youthful gene expression. Extending telomeres allows continual proliferation (see Castiel’s comments for some references using cell lines and using tissue). Here is an in vivo example readers of this thread will be familiar with:
https://pubmed.ncbi....h.gov/26214555/

Conclusion: We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

As I pointed out in my last post, replicative senescence stops the Horvath Clock (even though we know senescent cells continue to be metabolically active)
https://www.ncbi.nlm...les/PMC6224244/

Although hTERT did not induce any perceptible change to the rate of epigenetic ageing, hTERT-expressing cells, which bypassed senescence, continued to age epigenetically.

We also see this in vivo when users of sartans, despite their improved health, have ‘age acceleration’ (AA) according to the Horvath clock.
https://www.ncbi.nlm...les/PMC6286862/

After fully adjusting for potential covariates including hypertension, any AHM (anti-hypertensive medication) use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

Can we find any evidence of harm from ‘accelerating’ the Horvath clock by extending telomeres?
The short answer is no.
There is a theoretical concern that we might increase cancer from keeping cell lines proliferating endlessly, for example if random genomic instability caused them to lose epigenetic control of their cellular identity. But cells with long telomeres have better genomic stability than cells with short telomeres (https://www.ncbi.nlm...les/PMC2842081/). Nevertheless, it might not be pertinent to allow cells to proliferative forever (with active telomerase) unless we have a cast iron anti-cancer mechanism, such as employed by mole rats (they have stronger contact inhibition using hyaluronic acid, see: https://www.nature.c...467-020-16050-w).
The likes of Bill Andrews advocate turning on telomerase in all human cells. Perhaps he is right. I am more cautious, Given the choice I would lengthen my bone marrow stem cells to the length they had when I was 20 and then let them differentiate out to renew my body, shortening naturally. I would repeat this process every 10 years. I don’t think it would be a problem if you ended up lengthening all the telomeres in your body in this way, so long as they could then shorten naturally. This is the aim of occasional gene therapy treatments advocated by Michael Fossel (https://telocyte.com/media) and Liz Parrish.