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Telomerase Gene Therapy Used to Cure Fibrosis in a Mouse Model

Maria Blasco's research group has been working on telomerase gene therapy to lengthen telomeres for some years now; they are quite enthusiastic about this approach as a means to treat aging. One can't argue with the data showing extension of mouse life span, nor the results announced today in which induced telomerase activity is shown to reverse fibrosis. We can argue about what is going on under the hood, and whether or not addressing telomere length is in fact tackling the root causes of aging. Perhaps the most important difference between the views of aging outlined in the SENS rejuvenation research proposals and the later Hallmarks of Aging is that the latter places telomere length front and center as being of importance. In the SENS view, telomere length is a secondary marker, a consequence of other forms of damage.

So how can a therapy that induces telomerase activity to lengthen telomeres, something that to my eyes doesn't address root causes of aging, produce significant impact on mouse longevity? Well, there are many proven ways to produce significant gains in mouse longevity that have nothing to do with repairing damage after the SENS model. Calorie restriction, for example, is exactly a slowing of aging, a slowdown of the accumulation of damage, and it produces a larger gain in life span than telomerase gene therapy in mice. It doesn't do that much for human life span, sadly, though it is certainly good for health.

As a general rule we should expect approaches based on manipulating the operation of metabolism to produce comparatively poor effects in humans. We should expect approaches based on repairing the root cause cell and tissue damage of aging to produce better results in humans. Judging from the data in mice obtained to date - let us say comparing senolytics to remove senescent cells, one of the root causes of aging, with telomerase gene therapy, and with calorie restriction - all of the methodologies produce results that are in the same broad ballpark in terms of life span gained, in the 20-60% range.

The next decade will settle the critical question of what a rejuvenation therapy can achieve for human life expectancy in older individuals. The data will primarily involve senolytic treatments, as those the only one ready to go into trials right now. We can then compare that data with what is known of calorie restriction in humans, which is to say little gain in life span, even while delivering measurable health benefits. But for now, the research community only has data for direct comparison in examples of what is thought to be the less effective way forward, slowing aging by the adjustment of metabolism. That data exists for calorie restriction and growth hormone receptor dysfunction only.

It is far from clear that one can lump telomase gene therapy into either the bucket holding calorie restriction (slowing aging) or the bucket holding senolytics (damage repair to reverse aging). It may need a bucket of its own, for approaches that force a reversal in a secondary or later issue in aging, while leaving the underlying damage to continue to fester. Naively, one might guess that this will be better than slowing aging, and worse than repairing root causes. But the data isn't there in humans, and the entire issue is enormously complicated by the fact that all of the methods examined to date are far less capable of extending life span for long-lived species such as our own - which may or may not be the case, or the case to the same degree, for repair-based approaches.

But let us consider what is going on in this study. The mice were given lung fibrosis via bleomycin treatment, a chemotherapeutic that causes lung inflammation. It is known that inflammation of lung tissue produces the disruption of regenerative processes that result in fibrosis, the inappropriate construction of scar-like connective tissue that degrades normal tissue function. Research of the past few years points squarely towards senescent cells and their inflammatory signaling as the primary cause of this issue. There is good evidence for the removal of senescent cells to turn back fibrosis. Toxic chemotherapeutics like bleomycin cause cells to become senescent, putting them under enough stress to trigger that irreversible state change.

In humans with lung fibrosis who exhibit shorter average telomere length, replicative senescence may be the more important source of lingering senescent cells. Senescence occurs in somatic cells when they reach the Hayflick limit, the end of a countdown in which each cell division results in shorter telomeres. Shorter average telomere length implies that stem cells are not keeping up with delivering fresh new cells with long telomeres, and this may produce all sorts of systematic changes in the function, inflammatory state, and signaling environment of a tissue.

So the question here is how telomerase induction helps this situation. The researchers believe their gene therapy vector preferentially targets lung cells, so we can probably put aside consideration of possible immune system effects, such as more energetic clearance of senescent cells. One possibility is that telomerase induction in senescent cells mutes the inflammatory, harmful signaling they produce, the senescence-associated secretory phenotype (SASP). Another possibility is that it pushes senescent cells into self-destruction, either directly, or perhaps indirectly through other changes to the overall signaling environment in the tissue, particularly the contributions made by stem cells. Past work has suggested that some of the benefits in mice given telomerase gene therapy are due to renewed, more youthful stem cell activity in tissue maintenance. Regardless, I think that, given other work on fibrosis and cellular senescence, one has to look at this with a focus on senescent cells.

Researchers cure lung fibrosis in mice with a gene therapy that lengthens telomeres

Idiopathic pulmonary fibrosis is a potentially lethal disease associated with the presence of critically short telomeres, currently lacking effective treatment. Researchers have succeeded in curing this disease in mice using a gene therapy that lengthens the telomeres. Telomeres are protein structures located at the ends of each chromosome; like caps, they protect the integrity of the chromosome when the cell divides. But telomeres only fulfill their protective function if they are long enough; when they shorten too much, the damaged cells cease to divide preventing tissue regeneration. Short telomeres are associated with ageing - as age increases, cells accumulate more divisions and more telomeric shortening - and also with several diseases. Pulmonary fibrosis is one of them.

In lung fibrosis, the lung tissue develops scars that cause a progressive loss of respiratory capacity. Environmental toxins play an important role in its origin, but it is known that there must also be telomeric damage for the disease to appear. Patients with pulmonary fibrosis have short telomeres whether the disease is hereditary - it runs into the family - or not. The most likely explanation is that when the telomeres become too short, the damaged cell activates a 'repair program' that induces scar formation that leads to fibrosis.

Researchers decided to address the problem about five years ago, starting with the development of an animal model that faithfully reproduces the human disease. The most widely used model until then was to apply bleomycin into the mouse lungs to induce damage, in an attempt to reproduce the environmental insult. However, in these animals the disease goes into remission in a few weeks and there is not telomere shortening. The researchers sought after a mouse model in which the environmental damage synergized to that produced by short telomeres, that is what happens in human pulmonary fibrosis. They succeeded in 2015.

The treatment consisted of introducing the telomerase gene into the lung cells using gene therapy. The researchers first modified a virus innocuous to humans (known as vectors) so that their genetic material incorporated the telomerase gene, and then injected those vectors into the animals. The basis of this work is the hypothesis that age-associated diseases can be treated by targeting the molecular and cellular processes of ageing, specifically telomere shortening. In 2012, the researchers generated mice that not only lived longer but also showed improved health by treating them with telomerase. Their work since then has aimed to develop this therapy to specifically treat age-associated diseases and telomere syndromes.

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII).

AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.

Comments

Pulmonary fibrosis is a disease by which environmental toxins cause widespread fibrosis in the lungs of people who are genetically predisposed to it - its been known for some time that this is a short telomere disease; turnover in the lungs is high anyway, and this is why there is so much cellular senescence in those with the disease. Therefore this is a step in the path towards the first human clinical application of this technology.

Just thought I should explain it, as you seem busy trying to come up with reasons why extending telomeres can't possibly be a good thing.

Posted by: Mark at January 30th, 2018 3:25 PM

I want to start something similar to Erowid but on geroprotectors, neuroprotectors etc. Here an example about neuroprotectives ,ginko biloba and vinpocetine at Erowid:

https://erowid.org/smarts/ginkgo/

https://www.erowid.org/smarts/vinpocetine/

Both I have tried and vinpocetine really enhanced creativity.

Maybe I can get in touch with someone who wants to build upon this idea.

Posted by: Norse at January 30th, 2018 3:48 PM

Self experimenting with senolytics and candidates could be listed at such site.

Posted by: Norse at January 30th, 2018 3:54 PM

" ... as you seem busy trying to come up with reasons why extending telomeres can't possibly be a good thing" ... you offer to explain to him, but he is stuck on an idea, he won't get it. this individual is posting the same thing over and over again in his blog here: telomerase is bad, it causes cancer, it is just messing with metabolism (how?), etc. ... he is just repeating the same dogma established by sens/degrey/michaelrae/etc. ... see how "right" was rae/sens in their posts:

"Tale of Telomerase: Lessons and Limits in a Late-Life Launch"
http://www.sens.org/research/research-blog/tale-telomerase-lessons-and-limits-late-life-launch

just compare what they "cooked" there vs. this study ... ever wonder why they don't get it right with oncosens?

... why you think degrey joined AgeX, which is using this very same technology of induced telomerase?

... and more studies using telomerase are on their way out ...

Posted by: abc at January 30th, 2018 8:24 PM

If you look at the known factors for lung fibrosis, covering several conditions, they are all things that (plausibly) mess up stem cell activity or create senescent cells. Increasing stem cell activity can definitely happen with telomerase, but I think the evidence is thin on the ground for how it interacts with senescent cells in a tissue. Clearly it reduces their numbers, but how? Since clearing senescent cells addresses lung fibrosis, isn't that likely a cleaner approach to the senescence issue? Also inflammation and cellular senescence hurts stem cell activity. It is all one big connected circle. One can't argue with success in a therapy, but that's not what I'm doing here - I'd like to know what is actually going on under the hood.

Posted by: Reason at January 30th, 2018 8:43 PM

@Norse
A half-dozen people from BioAge made MortalityPredictors.org for biomarkers. See paper in Aging 2017 doi: 10.18632/aging.101280
And that was on the side while doing a startup. Shouldn't be too hard for a small group of knowledgeable people to put together something similar for geroprotectors with just a lit review.

Indeed, Laura Deming by herself put together a list of "95 things that make mice live longer" and "70 drugs in the clinic that might make people live longer" as part of her Longevity FAQ at ldeming.com/longevityfaq/

That could easily be a starting point for wrapping just a tiny bit more info around each thing if it isn't good enough by itself.

Posted by: Karl Pfleger at January 30th, 2018 9:55 PM

Abc said:

"just compare what they "cooked" there vs. this study ... ever wonder why they don't get it right with oncosens?"

What's exactly wrong there?

How exactly the fibrosis result disproves that article?

What proof do you have that oncosens has failed?

Posted by: Antonio at January 31st, 2018 2:31 AM

There is some merit in asking what telomerase therapy is doing in mice that don't suffer from replicative senescence, or what for that matter it is doing to remedy fibrosis. The problem Reason, is that you'll never figure it out with the mindset that telomeres aren't one of the fundamental causes of aging.

It's true that with a good enough stem cell treatment (which would probably involve senescence cell clearance, correct signaling and the correct type of stem cells in the correct place), you might not need to do anything for telomeres - but even at Age-X (where Aubrey now works) they are saying they will probably need to do a telomerase treatment along with their stem cell treatments.

Maria Blasco (and the potential of telomerase therapy) deserves better treatment than you give her on this blog. I am willing to bet Aubrey would agree.

Posted by: Mark at January 31st, 2018 2:59 AM

Called it over a year ago :)

Posted by: Steve Hill at January 31st, 2018 3:23 AM

Here's a simple layman's theory:

Fraying telomeres are just a cancer prevention system that kills off a lot good cells to prevent a few from becoming cancerous due to too many divisions. If we repair telomeres, we are recovering a lot of good cells in exchange for some extra cancer risk.

All in all, evolution errs on the side of caution and tries to prevent an early cancer. So mice with repaired telomeres on the whole live longer and healthier, even though some extra cancers may crop up.

This doesn't really repair underlying damage, but it may be a good tactic for squeezing out some extra years while we wait for something that does repair the damage. The telomere system kept you alive while young through middle age, but fails you when you're older. So wait until you're old, extend the telomeres for some extra healthy life, and take your chances with cancer.

Posted by: paul at January 31st, 2018 4:18 AM

Telomeres are a hallmark of aging and are almost certainly a root cause of aging along with the other hallmarks, the data support this. They won't fix everything on their own and the data thus far suggests resetting epigenetics resets them anyway but they are very important in aging. Like I said almost two years ago, we will start seeing more data for telomerase and it will turn some assumptions upside down.

Posted by: Steve Hill at January 31st, 2018 4:22 AM

Good effort Paul, but there's a lot more to telomeres than this - yes they are used as a cancer prevention defense; a growing cancer will come up against replicative senescence (and potentially immune clearance) - but then again cancer needs short telomeres and the genomic instability this brings in order to gain the mutations it needs in order to escape this trap, and that is why cancers maintain short telomeres even after they have activated telomerase. So it's a two-edged sword, you don't want unlimited proliferation but you also don't want short telomeres. There is also the fact that telomeres regulate genes and as they shorten this brings on altered gene expression in the cell; primary slowed proliferation (which is a large part of aging) but no doubt this also sets off other knock-on changes too (in genes far from the telomere) which are deleterious to health. When all this is understood it is clear keeping telomeres at youthful lengths is a good thing (for both mice and men) and does not lead to increased cancer risk, especially when you take in to account a rejuvenated immune system too. This last point has long been a get out of jail card for Reason et al, claiming all benefits are down to this effect alone, but I hope I've given you some food for thought that this is not the case.

I agree with Steve, developments will soon show the full benefits of maintaining youthful length telomeres and we can put this argument to bed once and for all.

Posted by: Mark at January 31st, 2018 4:44 AM

@Steve - what do you think the actual mechanism of action in reversing fibrosis is?

Posted by: Jim at January 31st, 2018 7:09 AM

Well, we know from some studies that when there are not suitable cell types available to repair the damage then fibroblasts stand in and make a shoddy repair instead, so if reserves of lung cells are short fibrosis will happen. In short, the contribution of stem cell depletion to the mix as replacement cells are not available.

Also, Blasco and her team suggest that cells with critically short telomeres also likely initiate a poor repair program, this is consistent with the gene regulating element of telomeres and epigenetic changes and is most plausible given the data.

Some of these cells will be senescent too and be producing SASP and be interrupting tissue repair via inhibiting stem cells which touches upon Reason's point. When stem cells are being inhibited by age-related inflammation this also retards tissue repair. In fact, Blasco demonstrated that telomerase rescues stem cell mobility in an earlier paper and from discussions I have had with the Conboys this makes sense.

Likely its a combination of these three things but I am confident we are not far off discerning exactly what mechanisms are at play here. We are reaching the point where assumptions are likely to be turned upside down as mentioned.

Posted by: Steve Hill at January 31st, 2018 8:25 AM

So question to Steve again...

We figured out last year that both AgeX and George Church's team were working on the OKSM route to rejuvenation.

There has got to be more to it, but I'm not a biologist and I'm hoping you can help me out with more of the nuts-and-bolts of this.

So, its been said in the past that telomere elongation was not the be all and end all of rejuvenation. OK, I get that. Some cells just don't divide etc etc etc.

Now with the OKSM factors, what else do they do to the cells? I know that part of the deal is they reset telomere length. But there has to be more...

Also.. Have you seen the latest from Agex?

http://www.agexinc.com/wp-content/uploads/2018/01/AgeX-World-Stem-Cell-Summit-Jan-25-2018.pdf

https://www.youtube.com/watch?v=X0K2ntvCXmI&t=315s

Check out slide 30-31. Looks like West and Aubrey are on to something.....

Posted by: Mark Borbely at January 31st, 2018 9:25 AM

@Mark: Thanks for the response. I wonder why telomeres would shorten, evolutionarily speaking, if long telomeres are always good. Where's the survival value? Perhaps it is an unavoidable consequence of cell division?

@all: No need to give my views any weight--No medical background, I'm just a guy who likes reading this stuff :)

@reason: Your site has done more to promote and popularize the life extension cause than any other place I can think of. Where would we be without you?

I must say that a single shot gene therapy that clears fibrosis and extends life is very, very impressive. Hope to see it available in reputable Thai clinics soon!

Posted by: paul at January 31st, 2018 9:26 AM

Paul: It hasn't cured idiopathic pulmonary fibrosis in humans. Nor in mice, either. What it has cured is an artificial fibrosis in mice. It hasn't proven life extension in any of the two, either. So don't jump so eagerly to use this.

Posted by: Antonio at January 31st, 2018 9:33 AM

@Mark

OKSM reprogramming is part of a route to rejuvenation, but one that reduces things significantly to the "de-differentiation" component of the reprogramming equation, and in many ways should be refered to as OKSM de-differentiation

Too often the terms "reprogramming" and "de-differentiation" (to pluripotency) are used inter-changeably and this is slightly incorrect

De-differentiation to a state of pluripotency is a uni-directional dynamic from a differentiated terminal state 'G' or 'K' or 'S', back to a starting state 'A'

Reprogramming denotes a bi-directional process, either going back to pluripotent state 'A' and then induced forward into a new set of lineages (in the case of embryonic or epimorphorphic or symplasmic generative dynamics) or, in the case of morphylaxis, a sideways trans-differentiation dynamic between terminal lineages

But more to your point to understand the degree of rejuvenation by OKSM, you must spend some time studying the past 40+ years of work that led to the 2012 Nobel Prizes for both Gurdon and Yamanaka to understand the subtle (and not so subtle) differences

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html

Whether the move from Gurdon's thousands of ooplasm factors to "Yamanaka 4" leaves a lot out is still being worked on in the literature - but clearly ooplasm is responsible for doing a lot more than an epigenetic clean-up / reset, including organelle remodeling, protection of the new embryo from infectious/oxidative/inflammatory damage, providing a bio-chemical regulatory "architecture" for support until embryonic genome activation, etc.

Posted by: Ira S. Pastor at January 31st, 2018 9:48 AM

@ Mark (B) The short answer is that we don't know what partial OSKM de-differentiation gives you that telomere elongation does not, just as we don't know if epigenetic aging as measured by the Horvath clock is harmful or is just a measure of aging. I would speculate based on in vitro results on immortalized somatic cells that epigenetic aging is not harmful to those cells, but it may well be that it can disable stem cells by drifting them down into a differentiated cell state. This may be what the systemic rise in inflammation is all about - an attempt by the body to de-differentiate cells back into a stem state.

@Paul, as I said we don't want unrestricted proliferation as that is too easy for cancer to take advantage of - so we don't want unlimited telomerase, but at the same time we don't want short telomeres either, so the obvious solution is to periodically restore telomeres to youthful lengths. And finally this brings me to...

@Antonio, Blasco's work cured pulmonary fibrosis in a mouse model of the disease, and this is as I'm sure you are aware the step that must be done before the first clinical trials in humans. Similarly her earlier work did extend median AND max lifespan in wild type mice given a single AAV TERT therapy in middle or old age. This is not a guarantee of effectiveness against either pulmonary fibrosis or general aging in humans, just as senolytics have yet to be proven in humans. But we can hope....

Posted by: Mark at January 31st, 2018 10:21 AM

This mouse model is a very good model for the actual disease compared to the traditional method of using a cancer drug to induce environmental insult, which FYI heals in a few weeks and does not damage telomeres. They have produced a mouse model now that models very closely the disease in humans and develops the same way.

They also have data for treating heart infarctions and aplastic anemia but by all means we can continue to ignore the data, and try to claim mouse models are not useful (this goes against medical scientific thinking since the year dot) but the excuse above has more holes than a slice of Emmental cheese. We won't be able to hide behind that get out of jail card much longer either.

We will see what the human data shows and you had better believe that is coming and soon, and I am not talking about questionable self-testing "data" I mean credible data from CNIO, Agex or another reputable lab.

Posted by: Steve Hill at January 31st, 2018 11:42 AM

@Mark

"Blasco's work cured pulmonary fibrosis in a mouse model of the disease"

Yes, it's a model, not the real disease.

"Similarly her earlier work did extend median AND max lifespan in wild type mice given a single AAV TERT therapy in middle or old age."

No, they didn't. CR was not accounted for to an extent enough to assure that LE was due to the therapy and not to CR. See abc's link above.

"This is not a guarantee of effectiveness against either pulmonary fibrosis or general aging in humans, just as senolytics have yet to be proven in humans."

The difference is that in the 2016 senolytics paper they used wild-type mice and they removed their natural (not induced) senescent cells. Yes, it needs to be proven in humans, but at least in mice it has been proven to work in a realistic situation.

Posted by: Antonio at January 31st, 2018 12:16 PM

Just wait for the data and stop this pointless slap fight it's silly.

Posted by: Steve Hill at January 31st, 2018 12:31 PM

For those of you interested in this or any other Blasco study LEAF is interviewing Dr. Blasco in the next week or so and we will include questions about this study and ask her to elaborate on the mouse model and why it is significant. If anyone has any suggestions of what to ask her let me know via the usual channels or on here.

Posted by: Steve Hill at January 31st, 2018 12:34 PM

Talk about desperation Antonio. Your one hope of these results being bogus is the AAV TERT treatment somehow made this group consume less calories than the control or AAV inactive TERT control group?

I am fully on-board with Aubrey's vision of curing aging. But we cannot be wedded to any one approach. Remember he has said himself that if others find better ways he will be happy! One way this looks likely is that WILT plus comprehensive stem cell replacement will not be ready for SENS 1.0. More likely well have telomerase therapy plus some limited stem cell replacement, along with cancer immunotherapy instead, (for this first iteration).

Posted by: Mark at January 31st, 2018 3:16 PM

I am going to ask Blasco about what Antonio said and then we will have it from the horse's mouth and we will see what her response to this comment is. I will also be asking her more about the mouse model and raising his concerns regarding this too. I cannot wait to see what she says :)

Posted by: Steve Hill at January 31st, 2018 4:01 PM

oh, and what the heck, I am might even ask her to comment about this other comment about CR influencing the lifespan changes seen in their 2012 study. Sure to be entertaining Mark.

Posted by: Steve Hill at January 31st, 2018 4:06 PM

Mark: What?? I'm only pointing out the errors in the logic that make some people here overvalue this result and present it as what it is not. It's certainly an interesting result, but it has not been proven to be a cure for IPF nor a LE treatment. Maybe it will become that someday or maybe not, but certainly it hasn't been proven so. This result is also not a proof of the failure of the senolytic approach to IPF. If you are happy with the hype, OK, go ahead with it, but still it's only hype.

Posted by: Antonio at January 31st, 2018 5:41 PM

These concerns/comments will be raised with Blasco in the next week or so then we can have a proper response from an actual scientist who understands the topic properly. It should be informative for the community too when she responds to the concerns raised here. This is how we progress by asking the hard questions and getting proper informative answers so hopefully, we will all learn something of value from this.

Posted by: Steve Hill at January 31st, 2018 6:09 PM

@paul

Hi Paul ! Just a 2 cent.

''I wonder why telomeres would shorten, evolutionarily speaking, if long telomeres are always good. Where's the survival value? Perhaps it is an unavoidable consequence of cell division? ''

I think there are many reasons and not one more valuable, all valuable and all happening at the same time:

- As said, a cancer curbing mechanism when the system is getting damaged and mainly cells are geronconverted to senescence; 'hastening the telomere shortening' demonstrates that the body is trying to fight the possible cancer formation, and in doing so, kills you (SASP/IL-6/ROS overproduction). Kills you because cancer/mutations are incompatible with life, they compromise the specie survival (you have compromised genetic which is to be removed and not allowed to be transfered to offspring if reproducing/evolution chose that for elimination from the pool, just like a 'bad weed' in a garden, it cannot (must not) reproduce and be destroyed; or else, compromise the garden 'healthy population'. It ressembles the same thing with recessive genes which are to disappear from gene pool; now it's not genes, it's you in entirety that must disappear (senescence will kill you by compromised health - while cancer, if it wins, will overtake you and kill you, too).

- A counting mechanism, replicative rounds. Taller telomeres, more replicative bouts left; shorter ones, less replicative bouts left. Thus a 'measure' just like a clock that measures time in hours/min, it counts/in unities of bp (base pairs TTAGGG in telomeric DNA)).
A measure, and a 'limit' mechanism - an imposed limit on our cells. When the telomere is new empty (2-3 kb (2000-3000 bp)) there are many things that happen; which is mainly 'telomere signal' becomes stronger and less 'silenced'; thus, gene silencing stops and gene activation starts; which is the main 'program' of inflammation activation (of late aging): p53, p16ink4a, p21 (oncogenes that curb cancer but promote inflammation/extreme ROS production), IL-6, TNF-a...TNF-a because it is there to curb cancer tumors (Tumor Necrosis Factor-alpha/TNF-a)).
This genetic program is located at 2000-5000 bp level on the telomere, We go down from 10,000 bp to 2000 bp from 13 to 115 years old in the leukocytes. As you can see, by 115 years old, the immune system is (near) gone and is in immunosenescence, because it is in that 'critical' zone of 2000-5000bp, where inflammation activation signalling is at the strongest.
This also manifests on the epigenetic clock, which works in tandem with telomeres, because both require methylation and work through methylation systems.

To answer your question, I think the most straight answer to it, is that this telomere shrinking is a consequence of mortality vs non-mortality (the I(mm.) word); and complexification vs simplication. I.e. Complex animals are mortal. Uncomplex animals obtain Imm/Eternal life. Making a complex animal 'work' and obtain this Eternal life has been asking too much so far; that is why you see 'simple' animals get it, like a Hydra Jellyfish being eternal thanks to telomerase in its germ cell line. The many things we get to do, are not free and 'costed' Samething, our life/we traded 'simplicity' for complexity, in return we obtained mortality. While the simples one, obtained eternal life. When you have a complex animal made of complex organs ...and complex systems..full of complex cells...it can fail somewhere, errors happen and mutations happen (random/entropy). Mortality is then assured.

Telomere became an answer: how to 'limit' these problems such specie survival (compromising/contamination) by 'compromised genetic' in one individual - télomères would curb cancer/mutations and 'end' the animal once they would be emptied; thus a 'balance' was found. A trade-off yet again, evolution is All About trade-offs/balances and (re)(re)(re)balancings things like a juggler. And that's because life is a balance (yin/yan, there is 'balance' that 'works' in the body and it was honed over thousand of years through evolution (espeically will selection pressure on longevity genes (grand-mothering theory/ancient grand-mas transfering longetivy genes to offspring/increasing life of 'everyone')) and lipidome in humans).

If certain animals can obtain eternal life through using telomerase in their cells and others can't - and it defies comprehension - why would evolution 'select those' and make mortality in the others, it means that the purpose of telomeres is to safeguard genome, be (imposed) limits and other reasons I mentioned.

Life is a balance, and evolution found that this balance works enough that these mortal species still live on/survive as specie despite this mortality problem. That's a handicap they have to live with, in exchange they obtain 'Complexity'; it had a cost - their life ending.

My guess is that if evolution Could Allow telomerase to be used, just like in Hydras, for Eternal life, it would have been a fait accomplit long ago even in complex mortal animals. Thus, it means, it is incompatible, and pretty much unfeasable in 'complex' animals, but it is feasible in uncomplex ones.

Just a 2 cent.

Posted by: CANanonymity at January 31st, 2018 7:34 PM

PS: I should mention that because you obtain inflammation with telomere shrinking and senescence accelerating - you are dying - and this is the evolution's 'Answer' to the cancer problem. Killing you Is its answer because it will not allow you to compromise the specie; it prefers to remove you from the population and avoid any of your gene transfer. This means that evolution thought 'in numbers', what was more important in a group : one person with cancer or a 1000 persons that are healthy. If that one person became health compromised and got cancer, evolution would select it from 'removal/being killed' through the evolution-evolved mechanism of inflammation (ROS/TNF-a/p53...) that is there to 'fight cancer'. Evolution does not care for you, once you are compromise/mutations because you then compromise the whole specie (if you do reproduce yourself and transfer your compromise genetic to your offspring (which they will be suffering and compromised too/and weaken the survival of the Later/future specie). It's very harsh like that (emotionless, evol does not care at all, only bioimperative survival), if you become cancerous, for evolution it equals to a bad weed that must be dealt with - and the way it does, is by killing you (through inflammation/ROS/SASP/TNF/p53)). Its job is to stop that cancer in you and it uses Fire/inflammation (Fight Fire with Fire). And if you die 'in the process' then it was meant to be/ a 'side effect' of cancer killing (from evol point), because it would not allow you to reproduce while being cancerous and transfering compromised genes to your offspring (and as said, compromising the 'future' of the specie survival (in your kids) once you are gone).

Simply put, evolution will always select the most 'non-compromised' in genetic and the most healthy DNA; the one that will assure survival and thriving; and not compromise it - genome instability = cancer = full specie death.

Trade-offs/balances; then you think...evol might not care if you are that 1 person with cancer vs 1000 other healthy people; but you are in YOU and thus you ahve to Twarth it; and decide that you will Change evolution and fight your own cancer (cancer survivors are a clear demonstration that evolution can be outwitteD and changed to your liking; it will just (re)adapt to whatever (new) happened).

Posted by: CANanonymity at January 31st, 2018 8:05 PM

I would also add that in the 2012 paper where telomerase was used to increase lifespan, C57BL6 mice were used and these are very very standard lab mice and are not special in any way really. The excuse that they are not normal mice is very weak, though I am addressing this in the upcoming interview all the same. It is a poor excuse though.

Posted by: Steve Hill at February 1st, 2018 5:33 AM

@ Steve -

("For those of you interested in this or any other Blasco study LEAF is interviewing Dr. Blasco in the next week or so ...")

Here are couple questions for Dr. Maria Blasco:

1. Sens group cast doubts on your research during past years, suggesting
that there are other causes (like Calorie Restriction) that generates the results in the
mice that you used in your studies.

Please see here:

http://www.sens.org/research/research-blog/tale-telomerase-lessons-and-limits-late-life-launch

Please can you comment on this? How plausible is that the results from your studies are a result of Calorie Restriction.

2. How relevant to human aging, is your recent study/research using telomerase to cure lung fibrosis?

Again, Sens and their supporters are casting doubts and they claim that this study is curing just the fibrosis that was artificially induced into mice.
So as a result this study is not relevant to "natural aging" in humans.

3. Sens group (see the above link) is claiming that resetting gene expression using telomerase, as in your approach,
is mere "messing with metabolism". Please can you explain, what exactly could/would do to an organism resetting gene expression using
telomerase therapy in comparison with modulation of metabolism.

4. Mice studies are nice, but we all know that mice are not humans, nor large mammals.
Do you plan to translate your research into aging humans? so we can all see results and close these
never-ending arguments that are kept brought in discussions by Sens and their supporters, that telomerase
therapy is neither good (as causes cancer) neither does anything for reverse aging.

(on a side note, it is funny though that Sens group is attacking every study that is done in mice, but they are
trumpeting a "robust mouse rejuvenation" as final convincing argument ... talking about can't see the forest for the trees
…)

Thanks.

Posted by: abc at February 2nd, 2018 4:44 PM

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