35 replies to this topic

[Vitamin_User]

I was looking at Crack Aging's Cylcoastragenol for telomere lengthening.

 

There is a disclaimer saying the product is not recommended for people under 30.

As a 21 year old,  what are the drawbacks for taking the product? Why is it not recommended?

[YOLF]

So Cyclo only fixes the shortest telomeres of cells, a phenomena which might not be all that prevalent in the young. Astragaloside IV actually elongates telomeres broadly. I would look into using that. It's less expensive too and probably still has a dose dependent result at your age. 

 

I've been watching people who take cyclo for as long as it's been around. It doesn't seem to make them look younger than I'd expect... it's more of a healthy aging thing I guess. They are definitely very healthy for their ages.

Edited by YOLF, 09 September 2018 - 01:39 AM.

[Vitamin_User]

Thanks for this info,  Yolf. I'll look into astragaloside IV.

[marcobjj]

So Cyclo only fixes the shortest telomeres of cells, a phenomena which might not be all that prevalent in the young. Astragaloside IV actually elongates telomeres broadly. I would look into using that. It's less expensive too and probably still has a dose dependent result at your age. 

 

I've been watching people who take cyclo for as long as it's been around. It doesn't seem to make them look younger than I'd expect... it's more of a healthy aging thing I guess. They are definitely very healthy for their ages.

 

Astragaloside IV elongating telomeres was based on a N=1 study that someone posted here. I wouldn't put much stock into it. Cycloastragenol works on all cells it just doesn't produce enough telomerase to increase the mean average length.

[YOLF]

Astragaloside IV elongating telomeres was based on a N=1 study that someone posted here. I wouldn't put much stock into it. Cycloastragenol works on all cells it just doesn't produce enough telomerase to increase the mean average length.

I remember getting my information from a comparison that was done between Cyclo and  A IV from original geron documents. They are definitely functional equivalents that act on two different  IIrc the same study compared the performance to that of a ginseng extract and some other things. A IV was originally trialed by geron with chitosan for better absorption and then later, they used smaller mesh size and enteral capsules to improve the delivery of Cyclo, but both are more alkali stable.

 

Before you click the needs references button, keep in mind that information can come and go as websites get remodelled, though I remember these well enough not to even bother looking. I was obsessed in those days given the sheer expense of Cycloastragenol. 

 

Anyways, you might consider using quercetin or the kojic acid and quercetin conjugate... whatever that was called. It will kill off senescent cells very effectively and slow aging. Not sure how the price compares to standard quercetin though, but limiting the toxicity of senescent cells early should slow telo attrition.

[marcobjj]

that doesn't make sense at all. Why would they go through the process of breaking down Astragaloside IV to obtain Cycolastragenol if it's a weaker telomerase activator? It would only add cost. 

Edited by marcobjj, 29 September 2018 - 06:28 AM.

[YOLF]

Because they found two that had activity and produced two different results, thus the assertion that A IV and Cyclo elongate telos by different means when compared to the telo elongation mechanisms which we know. 

 

Resveratrol, quercetin, and apigenin(probably) aren't telomerase extenders specifically, though they may make telos longer on average b/c their action gets rid of the shortest telo'd cells.

[Turnbuckle]

The telomerase activator TA-65 modestly improves organ health in mice but does not lengthen life span. See this figure. Telomere length does not have an impact on cells until it gets below a certain cutoff, and that doesn't happen to any degree until you're around sixty. See this figure. The associated paper suggests that the lowest telomere lengths will ultimately limit human lifespan, but human lifespan has not yet reached that point where it would be significant--

 

In conclusion, at present, most individuals are not reaching the LTL brink during their life course, but our findings suggest that further extension in human longevity will be increasingly constrained by telomere length.

https://www.ncbi.nlm...es/PMC5425118/ 

 

 

[YOLF]

I'm not sure how accurate that statement is to this conversation. They were only looking a leukocytes and it's about more than lifespan, it's about maintaining youth. Lifespan as an endpoint won't be as successful at giving us long lifespans as concentrating on sustaining youth. If you want to live a long time, it is likely that you will need to keep your telos long.

[QuestforLife]

That's an interesting point of view Turnbuckle, but I think it's out of date.

It's not about a cell being fine then suddenly getting short telomeres and causing irreversible senescence. Look at cells in vitro: they slow down their divisions long before the culture becomes senescent. And even when the culture won't grow anymore, many cells in it are not senescent yet. This is like how it is in the body: cells are gradually slower to be replaced and they produce and then break down all the vital proteins more slowly too. This is a large part of what aging is all about.

So yes there is a hard limit on human lifespan based on telomeres that only a few supercentenarian people reach, but having older cells with shorter telomeres means a shock (such as infection, injury, etc.) is much more likely to knock you off far before this limit.

[Turnbuckle]

That's an interesting point of view Turnbuckle, but I think it's out of date.

 

 

 

The paper I linked to above (corrected link) is from a year ago. So if it's out of date, do you have a later reference?

[YOLF]

It's not always about the latest paper, but the latest and most informed/correct thinking. This study is just a reiteration of work that was previously done or is a replication study for things that were already obvious. It's scope is limited and I think you said that by quoting it without realizing it. I imagine that it's not uncommon to see a paper published with old information for business purposes rather than to tell the world about the latest discovery either. Maybe they just launched some fundraising for a different type of product which required that understanding and they wanted to make the data look fresher.

[Turnbuckle]

It's not always about the latest paper, but the latest and most informed/correct thinking. This study is just a reiteration of work that was previously done or is a replication study for things that were already obvious. It's scope is limited and I think you said that by quoting it without realizing it. I imagine that it's not uncommon to see a paper published with old information for business purposes rather than to tell the world about the latest discovery either. Maybe they just launched some fundraising for a different type of product which required that understanding and they wanted to make the data look fresher.

 

 

Fine, you reject this old thinking. Then please link to the fresh thinking you subscribe to. Something in the past couple of years.

[QuestforLife]

Well here is the current thinking on telomeres and gene expression changes (long before arrest) if you want to understand the subject.

 

2014

http://genesdev.cshl...tent/28/22/2464

2016

https://journals.plo...al.pbio.2000016

2018

https://www.ncbi.nlm...pubmed/29197683

 

For the last one you'll need Sci-hub, and it's more about how HTERT is periodically activated in immune cells, but it follows on nicely from the previous work.

 

And he's a basic review article from 2014 on the Telomere Position Effect:

 

https://www.ncbi.nlm...les/PMC4233237/

 

But really? references are required for this statement: 'Look at cells in vitro: they slow down their divisions long before the culture becomes senescent. And even when the culture won't grow anymore, many cells in it are not senescent yet. This is like how it is in the body: cells are gradually slower to be replaced and they produce and then break down all the vital proteins more slowly too.'

 

This is basic text book stuff.

 

Edited by QuestforLife, 01 October 2018 - 11:10 AM.

[Turnbuckle]

For the last one you'll need Sci-hub, and it's more about how HTERT is periodically activated in immune cells, but it follows on nicely from the previous work.

 

 

 

The last one is not yet published and is not available on Sci-hub. And nothing you posted indicates that longer telomeres translates to longer life. The telomere aging theory sounded nice years ago, but it's just the latest theory to go down in flames. Like antioxidants. And both will still be sold long into the future no matter the lack of evidence that they extend life.

[QuestforLife]

The last one is not yet published and is not available on Sci-hub. And nothing you posted indicates that longer telomeres translates to longer life. The telomere aging theory sounded nice years ago, but it's just the latest theory to go down in flames. Like antioxidants. And both will still be sold long into the future no matter the lack of evidence that they extend life.

 

I managed to get it off Sci-hub, so not sure what's happening there.

 

I never said telomeres are all there is to it, but the telomere theory of aging is far from dead. It is rightly included as a primary driver of aging in the widely acclaimed Hallmarks of Aging Paper.

 

https://www.cell.com...8674(13)00645-4

 

It is complicated drawing a line between the aging of cells and the aging of organisms, but I'm pretty confident extending telomeres will be a very important part of complete rejuvenation. 

[Turnbuckle]

Again, I don't agree that lengthening telomeres by itself will lengthen lifespan. There is no experimental evidence for it, and there's the obvious example of rats that have telomeres much longer than humans--long enough for several rat lifetimes--and yet die anyway. And there is the scatter nature of telomere length vs age plots. I posted a couple of them 5 years ago here. And finally the seeming inverse relationship between telomeric age (poorly correlated with chronological age) and epigenetic age (well correlated with chronological age) that I explained in Reversing the Clocks as the result of extended telomeres preventing the apoptosis of epigenetically old cells.

 

[QuestforLife]

Okay, let me take these points one at a time.
 

Again, I don't agree that lengthening telomeres by itself will lengthen lifespan. There is no experimental evidence for it, and there's the obvious example of rats that have telomeres much longer than humans--long enough for several rat lifetimes--and yet die anyway.

Rats and mice have longer telomeres than humans true, but their rate of shortening is much, much greater - hence their shorter lives. As I've been trying to argue above, it's not (only) about the final irreversible senescence, but the long road to get there as cells slow down as telomeres shorten.



https://www.cell.com...3X?showall=true

And there is evidence of extending telomeres extending life, even in mice with long (average) telomeres already.



https://www.ncbi.nlm...les/PMC3494070/
 

And there is the scatter nature of telomere length vs age plots. I posted a couple of them 5 years ago here.

Agreed our ability to measure telomere length is poor - as so far we've just used leukocyte telomere lengths, and have often only looked at average lengths, which doesn't tell us that much - but this doesn't mean telomere lengths are unimportant.
 

And finally the seeming inverse relationship between telomeric age (poorly correlated with chronological age) and epigenetic age (well correlated with chronological age) that I explained in Reversing the Clocks as the result of extended telomeres preventing the apoptosis of epigenetically old cells.

Having long telomeres will obviously mean cells can divide more times, so you'd expect them to accumulate more methylation changes before that cell line can no longer divide. However: 1) we don't know if these changes are harmful or not, 2) stem cells get short telomeres too, 3)the more recent PhenoAge clock, which is correlated with health outcomes rather than chronological age has a positive (although weak) correlation with leukocyte telomere length, as you'd expect, rather than the negative correlation between LTL and the Horvath clock.



http://www.aging-us....cle/101414/text

 

Edited by QuestforLife, 01 October 2018 - 03:06 PM.

[Turnbuckle]

Rodent telomeres shorten faster than in humans, but they have enough length for several lifetimes to begin with, as has been demonstrated with telomerase knockout mice. In mammals generally, telomere length inversely correlates with lifespan. The longer the lifespan the shorter the telomeres. So the question remains: within a species, do longer telomeres correspond with longer lifespan for individuals? In a study of 100,000 humans, telomere length was found to fall during the first part of life, but remained steady or increased thereafter (especially with women). See Fig 7 in this paper--Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

 

In women telomeres were about the same at 40 as at 90. Men showed more of a decline, and if one were to only look at them, a case might be made.

 

We can't say telomere shortening explains aging in men but it's something different in women. Nor can telomeres be looked at in isolation. Aging results from the interactions of a number of things: telomere shortening, senescence, apoptosis, declining stem cell pools, epigenetic aging, and mitochondrial aging.

 

Telomere shortening provides a timer for cells to prevent them from aging past a certain number of replications. This is good because it puts a limit on tumor size, and it stops cells that are epigenetically old (on average) from reproducing.

 

Epigenetic aging is the ultimate source of aging as most people experience it, as the rate of epimutations is far higher than the rate of mutations of the underlying DNA. Cells become detuned for their assigned functions and organ function declines. So old cells being shut down by telomere shortening and senescence is good, not bad, as they are typically epigenetically old. Intervention to lengthen telomeres will allow epigenetically old cells to continue to divide and become even more dysfunctional.

 

Senescent cells are bad if they stick around, but as long as apoptosis is functioning correctly, they will be eliminated and replaced with new cells derived from still dividing somatic cells or (preferably) from stem cells. Millions of cells have to be replaced every second, so here are two more sources of aging--the failure of apoptosis to act correctly, and the depletion of stem cell pools.

 

And finally, mitochondrial morphology guides stem cell behavior (fission vs fusion), mito function triggers apoptosis (through cytochrome c release), and failure of mito QC reduces energy supplies across the board.

 

Edited by Turnbuckle, 01 October 2018 - 05:48 PM.

[marcobjj]

Here's the conclusion of the study you just linked above, Turnbuckle. (It's the opposite of what you;re claiming)

 

 

 

 It was found that overall, telomere length decreased for both men and women with increasing age. Telomere length decreased more for men than women from age 50 to 75, but TL increased modestly for the age 80 to 90 group for both men and women. The variation of TL among individuals increased with age, but the variation of TL measurements within an individual did not.

 

 

 

 

 

[Turnbuckle]

Here's the conclusion of the study you just linked above, Turnbuckle. (It's the opposite of what you;re claiming)

 

 

Look again at Fig 7. For women it's about the same at 40 as it is at 90.

[marcobjj]

The graph shows a clear downtrend. You just don't know how to read a it, and are confused by statistical noise.

 

You don't get to cherry pick two points on a graph that better suit your argument, and it's even worse when they go against the Author's conclusion.

 

 

[Turnbuckle]

The graph shows a clear downtrend. You just don't know how to read a it, and are confused by statistical noise.

 

You don't get to cherry pick two points on a graph that better suit your argument, and it's even worse when they go against the Author's conclusion.

 

 

There more than 110,000 individuals represented here, so it will be difficult to get better statistics that this. With women, it's clear that telomere length is not well correlated with age past the age of about 40. With men it's a different story, but it's very unlikely that men and women age differently at such a basic level.

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[marcobjj]

It doesn't have to be a straight line to prove a downtrend. I think anybody with an IQ above, say, 95 can figure that out. (including the authors).

[Turnbuckle]

It doesn't have to be a straight line to prove a downtrend. I think anybody with an IQ above, say, 95 can figure that out. (including the authors).

 

 

Were the authors smart enough to figure that out, marc? Seems not, as they said--

 

 In our data, the declining trend with age was highly dimorphic in men and women, with a continuing decline in men but not women after the age of 50.

 

[marcobjj]

Because their final conclusion is that "It was found that overall, telomere length decreased for both men and women with increasing age".  You can cherry pick points on a graph and excerpts on their paper all you want. You sound very dishonest.

Edited by marcobjj, 01 October 2018 - 09:13 PM.

[Turnbuckle]

Because their final conclusion is that "It was found that overall, telomere length decreased for both men and women with increasing age".  You can cherry pick points on a graph and excerpts on their paper all you want. You sound very dishonest.

 

 

From the beginning to the end, yes, there is a decline, but quite obviously past the age of forty, telomere length is not correlated to age for women. You could never base an insurance premium only knowing a woman's telomere length, however you could for anyone if you had their epigenetic age, which is highly correlated with chronological age. Horvath's clock appears to be excellent--

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[QuestforLife]

Remember the Horvath clock is 'just' based on mathematically matching changes in certain methylation sites to the chronological age of many tissue donors - so it is not surprising you get a very good (~0.98) correlation with age. There are many, many times more methylation sites than are used by Horvath however, so you could pick ones to give you no relationship at all, or even an inverse one. This is a brilliant clock, no question, but its not functionally connected to health or youth other than by mathematics (as far as we yet know). It may be connected to aging directly but the mechanism for this has not yet been uncovered. I can't stress this enough - this is just methylation changes. Nothing about acetylation or deacetylation of histones, nothing about spicing factors, nothing about gene expression, nothing about genomic stability. It is very unlikely that methylation changes, on their own, are the driving factor behind all these other things that are definitely connected to aging.  

 

(Leukocyte) telomere length is correlated very, very closely to the health of the (leukocyte) cell for all the reasons I've explained above, and more tenuously to health of the individual (correlation is stronger for cardiovascular health as you'd expect given they're from the blood). The correlation with chronological age is ~0.70, so not bad, but worse in the very old, and with females, as pointed out. So not a brilliant clock, but still very much connected to the aging of cells, and therefore organisms.

 

So let's not get confused between how good a clock is and the mechanisms of aging.

Edited by QuestforLife, 02 October 2018 - 08:20 AM.

[QuestforLife]

Rodent telomeres shorten faster than in humans, but they have enough length for several lifetimes to begin with, as has been demonstrated with telomerase knockout mice.

 

 

You're still not getting it - it's not about cellular arrest due to depleted telomeres; it's about shortening telomeres causing the cell to slow down its replication and produce and break down all the vital proteins more slowly too. The length of the telomere is probably irrelevant, it's the change in telomere length over a lifespan that matters. And mouse telomeres get shorter much faster than humans.

 

Even if your telomeres shortened till 60, say, then stayed the same for the rest of your life (I don't believe they do, but acknowledge average telomere lengths in leukocytes have a lot of scatter in them) then you'd still have only partially functional cells for all of that time, which would be a cause of the diseases of aging.

[Turnbuckle]

You're still not getting it - it's not about cellular arrest due to depleted telomeres; it's about shortening telomeres causing the cell to slow down its replication and produce and break down all the vital proteins more slowly too. The length of the telomere is probably irrelevant, it's the change in telomere length over a lifespan that matters. And mouse telomeres get shorter much faster than humans.

 

Even if your telomeres shortened till 60, say, then stayed the same for the rest of your life (I don't believe they do, but acknowledge average telomere lengths in leukocytes have a lot of scatter in them) then you'd still have only partially functional cells for all of that time, which would be a cause of the diseases of aging.

 

 

You like most people are mixing up cause and effect. Telomere shortening is the result of cellular aging, not the cause of it. Telomere shortening is good as it tells old cells to shut down and commit suicide, making room for new cells. And that fits hand in glove with the replacement of those cells with new cells derived from stem cells. The key to longevity is thus the replacement of old cells with young cells minted from stem cells, not keeping old cells alive past their expiration date.