204 replies to this topic

[marcobjj]

 

The transfection was evidently successful in the sense that her telomeres have lengthened by about 9%. Obviously 20 years is much more than 9% of a human lifetime, so by implication senescence sets in well before the telomeres are fully depleted.

 

 

human lifespan begins at 8000 base pairs at birth and ends at 5000 pairs (roughly). 

 

so  you divide 620 bp that she lenghtened in this experiment by 3000 (8000-5000) and you'd get around 20% of the average female lifespan. 

[natasjlp]

It seems real enough imo, she said in an interview the process was very similar to previous gene therapy for boys with muscular dystrophy: http://www.nature.co...mt2014200a.html

 

I found this through the MIT Tech Review online here: https://www.technolo...f-gene-therapy/

 

Also, there is a Q&A direct with Liz Parrish on Reddit here: https://www.reddit.c..._the/?limit=500

 

However, correlation does not equal causation. Just because Telomere length appears to correlate with aging, does not mean that if you lengthen them, that you will live longer. For example, so does graying hair. Just because we may be able to revert to our natural hair color (still haven't seen solid results in this either, perhaps this gene therapy will help with this as well?), does not mean we have necessarily reversed our biological aging process as a whole. There are underlying processes we are still learning about. This does seem like a great breakthrough. If nothing else it will inspire more capital, inspiration, and dedication to longevity research.

 

I also enjoy the way it is being done, people taking the issue into their own hands, testing on yourself etc... much like this very website, and many other communities around the world. We will figure this out, and I am sure there will be more than 1 way to do it. We are the solution.

[natasjlp]

Here is an article about the gene therapy process from their website: http://bioviva-scien...m/gene-therapy/

 

3rd party verification, and more studies are needed, and will reveal how 'real' this is. Hopefully, it will shed more light that may help others seeking understanding about aging and longevity.

[Logjam]

There are basically 2 camps on this:

1. Telomeres are a protective recursion-limiting mechanism and no cell needs to replicate more than 60x (at least not if you want to live ~100 years).  Lengthening them will not increase lifespan, and probably causes cancer.  Lots of very intelligent people who have PhDs think this, and have violently argued with me that I'm foolish for believing #2.  They'll think taking cycloastragenol causes cancer, etc.


2. Telomeres are that, and also effect changes in lifespan via gene expression.  Lots of very intelligent people also think this.

See http://genesdev.cshl...4.full.pdf html

 

"Length-regulated long-range (megabases) telomere chromatin conformation changes may alter gene expression to optimize fitness in longlived species such as humans and may profoundly affect human physiology, aging, life span, and disease."

 

"Telomere shortening causes a change of chromatin organization."

 

"We show here that telomere length influences the formation of chromatin loops at a distance of up to 10 Mb from the chromosome ends. We identified 15 endogenous genes regulated by telomere length in fibroblasts and myoblasts. We named this phenomenon TPE-OLD in reference to the previously described classic TPEs."

 

The question is what happens when you "undo" the shortening.  At least in some cases, the expression will change back:

 

"To determine the nature of the relationship between telomere length and TPE-OLD gene expression, we reintroduced hTERT (Fig. 6). Telomerase activity reversed the expression of TPE-OLD genes [emphasis mine], a finding that corroborates observations made in a recent study of senescent-related gene expression (Lackner et al. 2014)."

 

Research from K Cao on progeria also supports this thesis based on her studies on progeria:

 

See http://www.ncbi.nlm....pubmed/21670498

 

Basically, progeria may be a disorder where the gene expression that is normally regulated by the telomere length to express more and more often as a death-encouraging alternative splice gets turned on chronically and way too early.  She focuses on the alternative splice that yields lots of progerin, which — yep, modifies the chromatin and gene expression.  In turn, it creates a vicious cycle that tears down the telomeres even faster.  She also observes this on the way:

 

"Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes.  Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening."

 

And somewhat paralleling this, the previous paper states:

 

Our results demonstrate that the expression of a subset of subtelomeric genes is dependent on the length of telomeres and that widespread changes in gene expression are induced by telomere shortening long before telomeres become rate-limiting for division or before short telomeres initiate DNA damage signaling. These changes include upregulation and down-regulation of gene expression levels.

 

As usual, disclaimer applies RE: armchair.  I'm a computer scientist, not a biologist.  But it's pretty clear if these studies aren't fabrications that telomeres do effect changes in gene expression and chromatin.

 

Progerin is not the aging mechanism.  It's probably just one.  Telomeres may also be just one, but they appear to be upstream of a bunch of them.  Telomeres flip on lots of alternative splicings that all effect changes in chromatin as function of length.  Progerin is one of the (terrible) results of altering chromatin expression.  And it seems to be very related to all the stuff that ages quickly in progeria sufferers:

 

http://www.ncbi.nlm....3819/figure/F7/

 

... but note that progeria sufferers are cognitively totally normal.  They're smart little kids that look old.  They just look old, though.  They will typically die of coronary artery disease or a stroke, but before that they're totally functional kids that look like little old people.  This can't possibly be the only regulator of age, which also yields terrible things like increasing amounts of mitochondrial and ER destruction.  Anyway, if you look at that list of genes, it's all cytoskeleton related, which is probably unbelievably interesting.

 

So it's all plausible.  They observe various "effect[s] of telomere shortening on histone modifications."

 

It's just less clear whether the chromatin and epigenetic changes in general regress when you make telomeres longer again after they were previously shorter.  The progerin is there now.  A feedback loop makes sure it also tears down your telomeres more quickly possibly even after you lengthen them again. Taking methylene blue will make progerin soluble and help remove it from the nucleus according to another Cao paper, but how many other things like progerin are in there?

Edited by Logjam, 24 April 2016 - 05:30 AM.

[marcobjj]

 

 

For example, no matter how long your beta cell's telomeres are, they only replicate about 15-20x before stopping unless something signals otherwise.  Nothing does, apparently.  Brain cells behave similarly.  Getting beta cells to express hTERT does absolutely nothing in some studies:

 

http://www.ncbi.nlm....pubmed/10856888

 

 

Cancer has figured out a way:

 

From: www.intechopen.com Pages 191 and 192 Hypoglycemia – Causes and Occurrences 

 

"The Akt 1 gene has also been described to induce beta-cell proliferation via CDK4 by increasing cyclin D1 and D2 levels. Transgenic mice which overexpress a constitutively active form of Akt 1 in islet beta cells exhibit striking increases in beta-cell mass, proliferation, cell mass and malignant tumor formation.

 

The Akt 1 gene is located on a region which has often found to be gained in insulinomas of malignant behavior. One of the growth factors which seems to trigger the PI3K/Akt pathway is the insulin-like growth factor receptor. Several components of the IGF system show differences in mRNA expression suggesting a prominent role of this system in growth promotion. This pathway has been extensively explored and is one of the molecular targets being used recently in malignant insulinomas"

 

http://cdn.intechope...fs-wm/21473.pdf

Edited by YOLF, 24 April 2016 - 08:22 PM.
Reorganization of copy>paste artifacts

[marcobjj]

 

And somewhat paralleling this, the previous paper states:

 

Our results demonstrate that the expression of a subset of subtelomeric genes is dependent on the length of telomeres and that widespread changes in gene expression are induced by telomere shortening long before telomeres become rate-limiting for division or before short telomeres initiate DNA damage signaling. These changes include upregulation and down-regulation of gene expression levels.

 

As usual, disclaimer applies RE: armchair.  I'm a computer scientist, not a biologist.  But it's pretty clear if these studies aren't fabrications that telomeres do effect changes in gene expression and chromatin.

 

 

 

We all know this to be true intuitively. For example a 35 year old carries a negligible amount of senescent cells, yet he looks more aged than his 25 year old self the vast majority of the time. But aging is pretty uniform among individuals, and you can usually guess a person's age in a fairly accurate manner just by looking at them. Within seconds you can tell if their early, mid or late 30s, early/late 40s, 50s, etc. The fact it's so predictable and programmatic is evidence that aging is rather genetically encoded, not environmental.

 

in my own guesstimate, evolution is phasing us out slowly to make sure that our obsolete DNA is not stinking up the gene pool 1000 years from now. Beginning in your late 30s you get slower, less atractive, ensuring you can compete for mates with the younger and more up to date specimens. However you can still have a secondary role in transmitting culture to the younger gens, and in the absence of these younger models you can still be useful in helping to repopulate the species. But the time you reach 70s, 80s you're done, that's when the the self destruct mechanism really picks up as you get poisoned with progerin.

Edited by marcobjj, 24 April 2016 - 06:22 AM.

[corb]

There are basically 2 camps on this:

1. Telomeres are a protective recursion-limiting mechanism and no cell needs to replicate more than 60x (at least not if you want to live ~100 years).  Lengthening them will not increase lifespan, and probably causes cancer.  Lots of very intelligent people who have PhDs think this, and have violently argued with me that I'm foolish for believing #2.  They'll think taking cycloastragenol causes cancer, etc.
2. Telomeres are that, and also effect changes in lifespan via gene expression.  Lots of very intelligent people also think this.

 

...

 

It's just less clear whether the chromatin and epigenetic changes in general regress when you make telomeres longer again after they were previously shorter.  The progerin is there now.  A feedback loop makes sure it also tears down your telomeres more quickly possibly even after you lengthen them again. Taking methylene blue will make progerin soluble and help remove it from the nucleus according to another Cao paper, but how many other things like progerin are in there?

 

 

Remember that tert therapies have been only tested extensively in vivo in mice so far.
Mice have a very high cancer incidence, it's hard to detect an increase in cancer incidence if most individuals of a species already die from cancer. I doubt anyone has run a big enough experiment for a 5% for instance increase to be detected. If such a percent increase is evident in mice it's anyone's guess what it would translate to in humans.

 

The other thing is telomerase governs senescence. Not aging.

 

 

To determine whether senescent cells alter their DNA methylation state in an age-dependent manner, we used primary endothelial cells (ECs) that were derived from the human coronary artery of a 19 year old male.

 

 

This point is reinforced in a separate, yet conceptually connected experiment. Analyses of cells immortalised by telomerase showed late (p50) passage cells to have aged, even without having been subjected to any known senescence inducers (Figure 3). These cells continue to proliferate in culture beyond passage 50 and do not exhibit any signs of senescence, demonstrating that the process of cellular ageing continues unabated in cells whose telomeres were maintained. This shows that removal of the inducers of senescence does not halt ageing, once again underlining the fact that cellular ageing is a process that is distinct from senescence.

 

Of course all of this makes sense if you bare in mind that:

 

 

Collectively, these two sets of observation make an effective case for the uncoupling of senescence from cellular ageing. This however, appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated elegantly by Baker et al., where removal of senescent cells slowed down ageing. In the light of our observations however, it is proposed that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors. These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues, which is interpreted as organism ageing

 

http://www.impactjou...83&path[]=21162

 

As for ideas of programmatic aging, they're interesting but also toxic because they propose an oversimplification of biology and give a false hope of a silver bullet. There is no single "death clock" or whatever you'd want to call it because if that was the case you'd have immortal mutants the same way you get kids with progeria.

At best we're talking about tens or maybe even hundreds of processes working in tandem but with little baseline interaction, we would have found it by now if it was there.

 

What's always bothering me is the fact most researchers ignore the much cheaper and much more realistic to treat mechanistic part of aging.

The same result of 20% median lifespan increase mice get from a tert therapy they can get from a couple of injections of endogenic stem cells.

I guess the silver bullet is too much of a temptation even for rational men, when they are faced with the much drier reality of realistic life extension farmed organs and tissues can provide.

[YOLF]

It seems real enough imo, she said in an interview the process was very similar to previous gene therapy for boys with muscular dystrophy: http://www.nature.co...mt2014200a.html

 

I found this through the MIT Tech Review online here: https://www.technolo...f-gene-therapy/

 

Also, there is a Q&A direct with Liz Parrish on Reddit here: https://www.reddit.c..._the/?limit=500

 

However, correlation does not equal causation. Just because Telomere length appears to correlate with aging, does not mean that if you lengthen them, that you will live longer. For example, so does graying hair. Just because we may be able to revert to our natural hair color (still haven't seen solid results in this either, perhaps this gene therapy will help with this as well?), does not mean we have necessarily reversed our biological aging process as a whole. There are underlying processes we are still learning about. This does seem like a great breakthrough. If nothing else it will inspire more capital, inspiration, and dedication to longevity research.

 

I also enjoy the way it is being done, people taking the issue into their own hands, testing on yourself etc... much like this very website, and many other communities around the world. We will figure this out, and I am sure there will be more than 1 way to do it. We are the solution.

 

Yes

[Logjam]

Can you cite the papers you quoted?  I want to read them.

 

Made to order tissue and organ will be more effective, but if larger endocrine and/or metabolic issues are not corrected, that fancy new kidney is sailing into the same storm that may have killed the first kidney.  You also can't replace a brain.

 

There are convincing correlations between dogs (closer to us than rats and mice), for example, that are born with longer telomeres and have a longer life (http://www.ncbi.nlm....pubmed/23260664). Nobody's looking for a single silver bullet who is rational, at least, but various data points make a compelling case that it's upstream of a few of the small silver bullets.

 

Allowing for more normal replication requires unlimited telomerase expression or ALT.  A 10-20% increase in telomere length isn't what cancer is looking for.  It needs more than that, which is why many cancers find a way to chronically express tons of it — and why Geron (yes, the cycloastragenol people) is creating a medication to halt said expression with Imetelstat.  Telomeres are the last checkpoint to stop cancer after all the relevant tumor suppressors fail to check it.  I think most sane individuals want to turn on telomerase then turn it back off.  Is anyone suggesting it be turned on chronically?

 

A very non-scientific argument based on FIFO (first in first out) would be that since telomeres are basically the last check to effect a self-destruct of a bad out of control replication program in cells based on the obvious heuristic that nothing needs to replicate that quickly, they might also be first and upstream for many things. Please note, I'm not using that argument, but it crosses my mind.

 

But I'd also expect that the heuristic can be enforced on endocrine cells more so than say, skin.  It may be almost entirely wrong to look at one type of cell to figure out what telomeres do.  Telomeres on one chromosome may do a lot less than they do on another.

 

With all due respect, I don't think we really know everything telomeres do.  Some studies say one thing, some another.  Telomeres are definitely are one of many things that govern senescence.  But there are so many intertwined feedback loops, and you'll see things like "Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a."  Plenty of those tumor suppressors are involved in senescence that also don't involve short telomeres.  They're there to stop cancers and their expression makes cells behave senescent in many cases.

 

But if you look at those 2 papers I posted, you'll see what you've said flies in the face of at least those 2 studies:

 

"Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes.  Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening."

 

And

 

Our results demonstrate that the expression of a subset of subtelomeric genes is dependent on the length of telomeres and that widespread changes in gene expression are induced by telomere shortening long before telomeres become rate-limiting for division or before short telomeres initiate DNA damage signaling. These changes include upregulation and down-regulation of gene expression levels.

 

I'm not saying they're right, but Cao's work that is involved with progeria adds some fuel to the fire.  I doubt telomeres are the clock.  But they may be a clock.

 

I also wouldn't expect mutant immortal children based on some statistics.  The reason is simple.  Telomeres are simple devices, but the genes they'd interact with (to effect alternative splices, etc.) are not.  Nobody is saying the progeria mutation is the only one that dictates age.  In order to had an immortal child, and assuming any of this is correct, you'd need hundreds or at least tens of these mutations to be favorably altered.  

 

That looks like:

 

RARE-EVENT^N, where N = 10 or greater.  That gets to be mathematically very unlikely with low exponents.  The laminA/progerin mutation is just 1 of many.  Progeria notably only affects cytoskeleton-related gene expression via a bad form of laminA.  Weirdly, everything else with these kids is normal, which is what makes it even more heart breaking to watch.  

 

So that mutation is just one of the smaller bullets, and it won't happen randomly in a reasonable amount of time.

 

Edited by Logjam, 24 April 2016 - 09:06 PM.

[marcobjj]

I guess the silver bullet is too much of a temptation even for rational men, when they are faced with the much drier reality of realistic life extension farmed organs and tissues can provide.

Its more than wishful thinking, theres support of concept for the silver bullet model. For example HeLa cells have outlived their donor for close to 70 years now. The patient died in 1951, her cells are alive in 2016. The only know pathway that these cells have found to to circumvent senescence and death is telomerase activity.

Edited by marcobjj, 24 April 2016 - 09:18 PM.

[marcobjj]

As for ideas of programmatic aging, they're interesting but also toxic because they propose an oversimplification of biology and give a false hope of a silver bullet. There is no single "death clock" or whatever you'd want to call it because if that was the case you'd have immortal mutants the same way you get kids with progeria..

It would interesting to know if there are any cases of an active Htert mutation in humans, There appears to be none in recorded history so far. Maybe evolution actually knows what it's doing? And its not as random as some rational minds like to believe. Personally I find the idead of inorganic matter evolving into single cell organisms and eventually mankind through a bunch of random ocurrences very far fetched, no matter how many billion,years youre willing to go back as the origin point. Far more than a silver bullet theory of anti aging.

Edited by marcobjj, 24 April 2016 - 09:16 PM.

[Logjam]

I'm a fan of the teleological argument as well, but we _have_ seen htert mutations:

 

Usually they're called "cancer."  Most cancers require the expression of telomerase.  It's not the reason for cancer, but it appears to be one of the necessary dysregulations on the way to many cancers.  It makes sense because cancer can only execute 40-60x without htert, right?

 

 

As for ideas of programmatic aging, they're interesting but also toxic because they propose an oversimplification of biology and give a false hope of a silver bullet. There is no single "death clock" or whatever you'd want to call it because if that was the case you'd have immortal mutants the same way you get kids with progeria..

It would interesting to know if there are any cases of an active Htert mutation in humans, There appears to be none in recorded history so far. Maybe evolution actually knows what it's doing? And its not as random as some rational minds like to believe. Personally I find the idead of inorganic matter evolving into single cell organisms and eventually mankind through a bunch of random ocurrences very far fetched, no matter how many billion,years youre willing to go back as the origin point. Far more than a silver bullet theory of anti aging.

 

 

Edited by Logjam, 24 April 2016 - 09:28 PM.

[marcobjj]

Cancer are a few rogue cell lines among trillions in the human body, im talking a about an individual whose every single cell ( or close to) is actively expressing Htert from birth. Call it reverse progeria if you will.

Edited by marcobjj, 24 April 2016 - 09:33 PM.

[corb]

 

As for ideas of programmatic aging, they're interesting but also toxic because they propose an oversimplification of biology and give a false hope of a silver bullet. There is no single "death clock" or whatever you'd want to call it because if that was the case you'd have immortal mutants the same way you get kids with progeria..

It would interesting to know if there are any cases of an active Htert mutation in humans,

 

All humans have an active form of telomerase in their stem cells. And yet we age. What a conundrum.

You know it's sad how people get so focused on the cells and not even on the whole cell but just on the nucleus when there's a whole universe of complexity outside the cell and inside of it as well. Far beyond DNA.

I'll ignore your dive into the theological, nothing positive has ever come out of such discussions on the internet.

Edited by corb, 24 April 2016 - 09:34 PM.

[marcobjj]

Lol Im,an Agnostic myself, im not saying the Christian God or Muslim God governs it all. I just dont have taboos either way, evolution doesnt have to be totally random just because atheism and rationalism.

[marcobjj]

All humans have an active form of telomerase in their stem cells. And yet we age. What a conundrum.
.

Stem cells age. They go through replicative senescence, why stem cell injection regenerative treatment are innefective in older folk. Only e,bryonic stem cells and cancer stem cells maintain their length.

Edited by marcobjj, 24 April 2016 - 09:45 PM.

[alc]

I hope BioViva will use Steve Horvath's DNA Methylation Age Calculator to prove a younger state of her tissues:

https://labs.genetics.ucla.edu/horvath/dnamage/

Or they can use other similar technologies:

 

http://www.cygenia.c.../biological-age

 

If younger biological age is shown by independent testing, then we have a game changer.

 

 

[marcobjj]

Lets be real here, an HD video showing her her face before and after will do a lot more to validate this experiment than any electronic age calculator. The average person wont submit to an experimental viral treatment, much less pay for, based on a few numbers representing methylation and telomere base pairs.

[corb]

 

All humans have an active form of telomerase in their stem cells. And yet we age. What a conundrum.
.

Stem cells age. They go through replicative senescence, why stem cell injection regenerative treatment are innefective in older folk. Only e,bryonic stem cells and cancer stem cells maintain their length.

 

Traditionally senescence has been used in relation to reaching the Hayflick limit - something stem cells should not be capable doing because they are constantly maintaining their telomere length. There are known genetic disorders which are caused by stem cells with inactive telomerase components.

 

As for aging, yeah of course they age. But it's important to make the distinction between senescence and aging, and that is what the article I posted was going on about, in short even "immortalized" cell lines age, even if they are not at all senescent.

[alc]

Lets be real here, an HD video showing her her face before and after will do a lot more to validate this experiment than any electronic age calculator. The average person wont submit to an experimental viral treatment, much less pay for, based on a few numbers representing methylation and telomere base pairs.

 

Nothing wrong with that.

 

"A picture is worth 1,000 words".

 

However in the scientific community won't count as a proof. (no offense, but the DNA methylation age technique is not a simple "electronic age calculator" - it is already used in forensics)

 

I hope they got documented her image/look  before therapy, so can it be compared with after.

 

... on the other hand if she keeps getting younger (I'm referring to her image), then things would become quite interesting! (honestly, I would like to see that happen!)

 

as for skin age, there are scientific non-invasive tests - so won't be that hard to measure that as well:

 

Physicists Measure The Real Age of Skin

 

https://www.insidesc...al-age-skin/911

 

Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy

 

https://www.osapubli...?uri=boe-4-1-77

 

There are plenty of tools to measure whatever we want.

 

 

[marcobjj]

Adult Stem cells aren't immortalized, I don't know where you got that from. Yes they do hit the hayflick limit. Pubmed it at will. It's the reason why Kobe was able to grow a new achilles heel using Regenokine injections (Stem cell grafting), while the same procedure fails in elderly patients. Because their stem cells aren't able to divide enough times to form new tissue.

 

http://www.ncbi.nlm....les/PMC2360127/

 

"Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing"

 

 

[corb]

The interesting thing about that paper - pretty much all of it covers adult stem cells with activated telomerase. In vivo. It's more or less a review and it's not experimental it's rather a review and scientist trying to make sense of conflicting information.

 

Some choice quotes:

 

 

On the other hand, mMSCs with their telomerase activity knocked-down completely failed to differentiate into adipocytes or chondrocytes, even in early passages

 

Interesting.

 

 

Low levels of telomerase activity are readily detectable in HSCs and in some of their differentiated progeny including peripheral blood lymphocytes

 

That one speaks on it's own.

 

 

However, several growth factors enhance the mitotic potential of hMSC, and we recently found that bone marrow-derived hMSCs maintained long telomeres without the upregulation of telomerase activity for more than 100 population doublings under culture with basic FGF

 

Might as well add FGF to the big rat stacks, huh?

 

 

Intriguingly, mesenchymal cell-like endothelial cells and hepatic satellite cells do not show this replicative senescence

 

Data from congenital disorders, like DKC and aplastic anaemia, suggest that disturbed telomere maintenance may play a role in replicative exhaustion of the HSC pool in vivo, which might be correlated with age-related diseases and senescence.

 

And so on. Next time read the paper before posting it.

 

In the end of the day it's down to interpretation. But even these scientists were saying that telomere shortening is probably a problem for only choice stem cells and more specifically under environmental pressures like infection and so on.
 

As for immortalized cell lines I will point you at the paper I posted for the third time and the conclusion. It's more or less the bottom line you don't want to hear.

[marcobjj]

 

And so on. Next time read the paper before posting it.

 

In the end of the day it's down to interpretation. But even these scientists were saying that telomere shortening is probably a problem for only choice stem cells and more specifically under environmental pressures like infection and so on.
 

 

 

CONCLUSIONS

Recent research has focused on telomeres and their role in cell cycle regulation, cellular senescence, and genetic instability; however, much remains to be learned, and what is clear is the complexity of telomere and telomerase interactions in cell cycle progression and cell signaling in both normal somatic cells and malignant cells. Both elements have a key role in determining proliferative capacity in all human cells. Telomere shortening occurs in most human somatic cells and triggers DNA damage responses that mediate cell cycle arrest or apoptosis, while HSCs can escape this trigger by employing a telomerase-dependent telomere lengthening mechanism in replication. This process in normal HSCs, however, appears to have only limited potential in extending the replicative capacity, because the telomere shortening occurs slowly but steadily in blood cells with ageing. In contrast, CSCs should have complete telomere-lengthening mechanisms that provide indefinite proliferation capacity.

 

----------------

^BOTTOM LINE: only CSC (aka Cancer Stem Cells) have full telomere lenghtening and full proliferative capacity. Other stem cells express a limited amount of telomerase that is insufficient to offset or reverse the trend of telomere loss through replication, (with possible exceptions?). As I've mentioned before. Their conclusion is clear. 

Edited by marcobjj, 25 April 2016 - 04:19 AM.

[marcobjj]

I missed your first post with the impactjournal article btw. Interesting.

Edited by marcobjj, 25 April 2016 - 05:12 AM.

[marcobjj]

 

 

... but note that progeria sufferers are cognitively totally normal.  They're smart little kids that look old.  They just look old, though.  They will typically die of coronary artery disease or a stroke, but before that they're totally functional kids that look like little old people.  

 

 

 

not totally functional. Cognitively, yes. But they are severely handicapped physically.

 

Edited by marcobjj, 25 April 2016 - 06:11 AM.

[Logjam]

I was imprecise.  Yes, they're not totally normal.  What's most interesting, objectively, is that they're cognitively normal.  You might not expect that with the other visible terrible effects.  HGPS is very focussed on a series of cytoskeleton-related genes.  I believe the reason is that HGPS/Progeria, and the progerin it produces is a deviant form of laminA, which is expressed in all the tissues that hit HGPS kids the worst.  LaminA is associated most in tissues like bones and connective tissue — the tissues with "stiff nuclei."  Brain tissue isn't one of those tissues.

 

We all produce progerin slowly.  HGPS kids produce it really quickly.  An alternate splice is turned on full time.

 

HGPS specifically affects tissues that express large amounts of laminA.  The normal laminA is off, and progerin is on instead of being an alternate splice intermittently.  Telomere length may normally dictate how often it's spiced intermittently in the normal case (see K Cao's http://www.ncbi.nlm....pubmed/21670498), but not in the case of HGPS.  Also see http://www.ncbi.nlm....6548/figure/F1/ to see which tissues have laminA.

 

It's pretty striking.  Progerin can't be the only actor in aging, but it's one of them.  We all produce it, and they really do look like they're aging 4-5x the normal rate in (only) those tissues.

 

The nuclear lamina (and laminA) does, in fact, regulate gene expression.  See:

http://www.ncbi.nlm....pubmed/20444586

http://www.horizonpr...mb/v/v14/27.pdf

http://www.ncbi.nlm....les/PMC3443488/

 

In particular:

 

"We demonstrate that progerin induces global changes in chromatin organization by enhancing interactions with a specific subset of genes in addition to the identified lamin A-associated genes."

 

Here's the problem: The progerin is there now.

 

I'm pretty sure the damage is done to gene expression unless you remove the progerin.  Otherwise I'd expect the gene expression changes effected by the progerin would still be affected by the ... progerin.

 

Making telomeres shorter may encourage progerin production, but lengthening them won't remove it, and it will still be influencing gene expression and possibly accelerating the shortening of the telomeres.  Yes, a feedback loop.

 

IOW, even if telomeres caused the progerin to be produced, lengthening the telomeres won't fix it unless you also remove the progerin.  Not removing the progerin will ensure that the telomeres get torn down faster than they did prior.  It's like a feedback-loop-network that enforces the program from multiple vectors if you believe in "the aging program."

 

Methylene blue might actually help with that: http://www.ncbi.nlm....pubmed/26663466.

 

But how many other things like progerin are there?

 

 

 

 

... but note that progeria sufferers are cognitively totally normal.  They're smart little kids that look old.  They just look old, though.  They will typically die of coronary artery disease or a stroke, but before that they're totally functional kids that look like little old people.  

 

 

 

not totally functional. Cognitively, yes. But they are severely handicapped physically.

 

 

 

Edited by Logjam, 25 April 2016 - 06:59 AM.

[corb]

 

 

And so on. Next time read the paper before posting it.

 

In the end of the day it's down to interpretation. But even these scientists were saying that telomere shortening is probably a problem for only choice stem cells and more specifically under environmental pressures like infection and so on.
 

 

 

CONCLUSIONS

Recent research has focused on telomeres and their role in cell cycle regulation, cellular senescence, and genetic instability; however, much remains to be learned, and what is clear is the complexity of telomere and telomerase interactions in cell cycle progression and cell signaling in both normal somatic cells and malignant cells. Both elements have a key role in determining proliferative capacity in all human cells. Telomere shortening occurs in most human somatic cells and triggers DNA damage responses that mediate cell cycle arrest or apoptosis, while HSCs can escape this trigger by employing a telomerase-dependent telomere lengthening mechanism in replication. This process in normal HSCs, however, appears to have only limited potential in extending the replicative capacity, because the telomere shortening occurs slowly but steadily in blood cells with ageing. In contrast, CSCs should have complete telomere-lengthening mechanisms that provide indefinite proliferation capacity.

 

----------------

^BOTTOM LINE: only CSC (aka Cancer Stem Cells) have full telomere lenghtening and full proliferative capacity. Other stem cells express a limited amount of telomerase that is insufficient to offset or reverse the trend of telomere loss through replication, (with possible exceptions?). As I've mentioned before. Their conclusion is clear. 

 

 

Cancers use other mechanisms to lengthen their telomeres on top of the telomerase in stem cells, some stem cells most probably make use of those as well, cancers do not have unique mechanisms of their own.

As for stem cells the worse conditions they are surrounded by the faster they lose their telomeres to a point at which they can't maintain telomere length. Regardless of that a lot of the most sizable or important tissues in our bodies are either telomere stable - muscles, or unaffected by telomere shortening - post mitotic tissues of the brain.

 

Anyway back to the main topic.

The results of the mice tert study are suspicious to me. I'm not sure how a single component of telomerase can be so beneficial especially not in an animal with pretty long telomeres to begin with and mice have been noted to maintain telomere length better than humans. The study never elucidated why that is - or rather they didn't even try to venture at an explanation. I have the urge to write it off as some deficiency of the tert gene that mouse strain has, every other telomerase experiment in mice has either had negative or no results.

 

Either way according to the results Bioviva has provided the therapy supposedly does something in humans.
On the other hand Parish had very short telomeres to begin with and we know from the few wide screenings of human telomere length that have happened recently that those can change in both directions on their own in a matter of months.

I'll give it a couple of years more of positive test results before I get excited.

[reason]

The Scientist has published a measured piece on the first results from BioViva's initial test of human gene therapy, telomerase and follistatin overexpression, and the broader context in which this single person test took place. The results indicate that the telomerase gene therapy most likely worked in the sense of delivering telomerase to a significant number of cells, including the immune cells used to measure average telomere length. That is an important thing to validate up front, before thinking about any sort of other outcomes, or expanding to a trial of some sort. Historically, gene therapies have proven to be highly varied in their effectiveness when it comes to uptake in target cells: in animal studies, the result might be 5% uptake, or it might be 60% uptake, or anywhere in between. A lot of work has gone into trying to make things more reliable over the past decade, but for many years yet there will be questions as to whether any particular formulation works well enough to build upon. That said, the error bars are large in these measurements, and further data is definitely called for.

First Data from Anti-Aging Gene Therapy

Last year, Elizabeth Parrish, the CEO of Seattle-based biotech firm BioViva, hopped a plane to Colombia, where she received multiple injections of two experimental gene therapies her company had developed. One is intended to lengthen the caps of her chromosomes (called telomeres) while the other aims to increase muscle mass. The idea is that together these treatments would "compress mortality," by staving off the diseases of aging - enabling people to live healthier, longer. Last week, BioViva reported the first results of Parrish's treatment: the telomeres of her leukocytes grew longer, from 6.71 kb in September 2015 to 7.33 kb in March 2016. The question now is: What does that mean? The company announced Parrish's response as success against human aging, having "reversed 20 years of normal telomere shortening." Over the phone, Parrish was more measured in discussing the implications of the finding, which has not yet undergone peer review. "The best-case scenario would be that we added 20 years of health onto the leukocytes, and the immune system might be more productive and catch more of the bad guys. But we have to wait and find out. The proof will be in the data."

Much more data are needed before claiming success against aging, said Dana Glei, a senior research investigator at Georgetown University. "We haven't established a causal link between telomere length and health. If it's like gray hair, dying your hair won't make you live longer." An n of one won't give us the answer, but Parrish's personal trial is the start of what BioViva hopes to accomplish: the first clinical studies using a gene therapy to stall aging and increase health span. The company's approach is backed by preclinical evidence - in particular, that from María Blasco's group at the Spanish National Cancer Research Centre (CNIO). In 2012, Blasco's team reported the results of a telomerase gene therapy in mice. The enzyme telomerase, encoded by the TERT gene, lengthens telomeres. "We demonstrated that AAV9-Tert gene therapy was sufficient to delay age-related pathologies and extend both median and maximum longevity in mice," said Blasco, who is not involved with BioViva. "Many pathologies were delayed, including cancer."

There is another potential weakness of the BioViva data: measurement error. The 9 percent difference between Parrish's before and after telomere lengths is within the measurement error of most laboratories. Houston-based SpectraCell Laboratories conducted the telomere length assay for BioViva. Jonathan Stein, the director of science and quality at SpectraCell, said that most telomere-length assays have a variance of 8 percent, and his firm's test is in line with that number.

The other gene therapy Parrish received - the gene encoding the follistatin protein - is supported by human data, at least in the context of people with muscle disorders. (There are not yet data demonstrating the effects of follistatin gene therapy on aging-related muscle loss.) Follistatin inhibits myostatin, which puts the breaks on muscle growth and therefore makes it an attractive therapy for muscular dystrophies. Early clinical trials on six people with Becker muscular dystrophy, for instance, showed that four of them could walk longer distances after the follistatin gene therapy. Parrish said she expects MRI data on her muscles' response to the treatment in about a month. Working with regulatory agencies has been a sticking point for BioViva, hence Parrish's trip to Colombia. Her controversial move - to skirt oversight by the US Food and Drug Administration by receiving the gene therapies outside the country - prompted a member of the company's advisory board, the University of Washington's George Martin, to resign. Parrish said she is now traveling the globe to find a regulatory partner willing to approve human clinical trials. "When I started looking into this, it seemed like a crazy science," she said. "But it's a crazy science whose time has come."

If you read around online discussions of BioViva's work, you'll find opinions to be fairly polarized. It is clearly the case that a fair number of people in the sciences really, really don't like it when anyone departs from the standard regulatory script of spending a lot of money and time keeping various government agencies happy, and set off to do something adventurous and entirely legal in another jurisdiction that regulators disallow in their own. This might be something like crabs in a bucket, perhaps, but the scientific community has always fiercely attacked those who deviate from the orthodoxy. Maintaining the scientific method in the face of those who are in fact out to undercut its foundations is a constant battle, and this is understandable. Yet the present system of regulation is not the embodiment of the scientific method, and certainly not the only way to conduct technological development resulting from science. Someone has to be the first human subject after animal studies have proven promising, and medicine has a long and noble history of self-experimentation to prove safety and capability, or even for the purposes of discovery. Many of the people who did this, and in some cases suffered for it, and as a result succeeded in producing new and useful medicine are regarded as brave pioneers. Rightfully so, I think.

What do regulators add to this picture other than barriers and objections? It doesn't require a regulator to design and carry out ethical studies in human medicine, and the present state of medical regulation is so ridiculously overblown, costly, and constrained that if everyone went by the FDA book, it would be a decade or more before anyone could legally access gene therapies intended to compensate for aspects of aging. Even that would only happen after the expenditure of billions of dollars, ensuring that only very large entities could control and deliver this sort of therapy: Big Pharma and government work hand in hand to the tune of their perverse incentives, limiting rather than expanding opportunities for progress. If you want a dynamic market of many small competing groups, innovative and rapid, then the heavy hand of regulation has to go. At present the only realistic way to go about this is to embrace the medical tourism marketplace and transparency in development: fund small trials, make all the data public, license the technology widely, and let educated patients decide on their options.

Freedom to choose and differences of opinion on the utility of specific therapies are important. For my money, I'm happy to let someone else go first in the case of telomerase gene therapy, which seems riskier than myostatin or follistatin gene therapies given the current state of evidence. I would be made more comfortable by trials in something other than mice, a species that is quite different from us in terms of its telomere dynamics and thus cancer risk profile following this sort of treatment. While telomerase gene therapy actually reduces cancer risk in mice in some cases, perhaps by spurring greater immune activity, along with extending life and reducing incidence of disease, there is no guarantee that the various changes involved will balance in the same way in humans. The falling cost and increasing reliability of gene therapy these days means that there are enough interested people for this to move straight to human testing, however - which isn't unusual in many areas of medicine, I should add.

Even if the economics were different, it is clear that telomerase gene therapies would still be heading for human trials one way or another. There are research groups with enough data in mice and the interest to move forward: telomerase therapies appear to be in essence another way to spur greater activity in old stem cells, and thus improve health and extend life, and all such approaches are gathering attention these days. The established research groups may well continue to work within the regulatory gauntlet while those less impeded forge ahead much more rapidly. This will be a repeat of the development of the stem cell industry over the past two decades, parallel lines inside and outside the gilded cage of regulatory capture. It was just about a decade between the availability of stem cell therapies via medical tourism and the capitulation of the FDA allowing the first classes of treatment in the US, and it certainly would have been longer without the pressure of having these treatments available so widely elsewhere in the world.

View the full article at FightAging

[xEva]

and mice have been noted to maintain telomere length better than humans.

I must have missed this study. I saw the one by Blasco where her groups showed that mice telomeres shorten 100 times faster than humans. This does not fit with them "maintaining telomere length better".

So, could you please post the link to that paper -?

[corb]

 

and mice have been noted to maintain telomere length better than humans.

I must have missed this study. I saw the one by Blasco where her groups showed that mice telomeres shorten 100 times faster than humans. This does not fit with them "maintaining telomere length better".

So, could you please post the link to that paper -?

 

 

Mice (the labs ones, the wild ones have around 10KBP) have long telomeres. Up to 150 KBP. Human telomeres are around 7-8 KBP at birth.

So let's do the math 100 faster attrition / 20 longer length. So the speed per se is not a good predictor of aging, because by that math mice should live to their teens.

 

Now if you read this study:

http://www.ncbi.nlm....les/PMC2259034/

 

Notice that at the age of 1 year mice only lose 3% of their telomere length. That's nothing. People in their 30-40s already supposedly have less that 40% of their telomeres left at that point (the midpoint) in their lives.

So what can we get from this?

I don't think we can get anything. Telomere length and telomere attrition and so on comparison between species is a useless endeavor and I'm yet to read something that points at another conclusion. That was pretty much my point.