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New discovery in telomere biology: It is not telomere length that matters, but telomere structure.

telomere length

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#1 Phoebus

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Posted 28 July 2018 - 01:34 PM


https://newsroom.uns...d-heart-disease

 

 

Telomere shortening causes chromosomes ends to resemble broken DNA. However, it has remained a mystery why telomeres change from healthy to unhealthy with age. This research has identified the underlying cause.

 

“We knew that telomeres regulate cellular ageing, but our new data explain the trigger that makes telomeres unhealthy,’’ Dr Cesare said. “Telomeres normally form a loop structure, where the chromosome end is hidden. We found that when the telomere-loop unfolds, the chromosome end is exposed and the cell perceives this as broken DNA.’’

 

Dr Cesare further explained: “It is not telomere length that matters, but telomere structure. The telomere-loop becomes harder to form as telomeres get short.”

 

Additionally, the team identified that telomeres can also change structure in response to some chemotherapeutic agents, which helps kill cancer cells.

 

The results of this study have also proven how important technological advances are in the field of research. Dr Cesare first developed his theories about telomere-loops in 2002 when studying for his PhD. However, the technology was not available at the time to easily visualise telomere-loops using microscopy. 

 


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#2 Oakman

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Posted 28 July 2018 - 05:20 PM

Goo find! This looks to be very significant research. Previously, there have been those that took telomere length as the holy grail to longevity, but this never reliably played out in practice. This gives new insight into telomeres and longevity that may, eventually, lead to therapies to 'close the loop' on telomeres and see if that can contribute to true, healthy longevity. 


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#3 QuestforLife

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Posted 31 July 2018 - 09:39 AM

This is THE paper if you want to understand telomeres.

 

http://journals.plos...al.pbio.2000016

 

Pay particular interest to Figures 4 and 5: when the telomere is long enough it curls back and tucks into a region of telomere in chromosome 5 that is separate to the rest of the telomere. This means that along with histone curling, the HTERT gene (and probably other genes) are inhibited from being expressed. As the telomere shortens it reaches a point at which it can only tuck back into itself rather than the isolated bit of telomere upstream. This causes more DNA to become exposed and gene expression to change. It is clear that the telomere interacts with histones that are inhibiting gene expression, see figure 4g.

 

It is a mistake of many commentators and even researchers to concentrate on replicative senescence, i.e. when a telomere is completely exhausted and the DNA damage response is activated. It is clear that there is a whole range of gene expression changes that occur before this point as the telomere shortens, and that this has far more relevance to aging that simply the DDR response. From this perspective we can see that cellular senescence is a gradual, analogue change as telomeres shorten, rather than the binary 'cell works perfectly/cell is arrested' dichotomy.

 

For example, mice have long telomeres (but short lifespans) and do not normally experience replicative senescence, and this is often pointed out as a flaw in the telomere theory of aging. But they DO experience shortening of telomeres, at 100x the rate of the shortening in humans. In fact this paper shows it is the rate of increase in the short telomeres in mice (<15kb) that is linked to mortality rather than the average length of telomeres.

 

https://www.cell.com...(12)00263-X.pdf

 


Edited by QuestforLife, 31 July 2018 - 09:41 AM.

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#4 Nate-2004

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Posted 31 July 2018 - 02:28 PM

This headline is misleading since the article implies that it is both length and structure that matter. Length lends to shape and its ability to loop but if shape is affected first then it's perceived as damaged. Rate of shortening may matter too though. It may be more important to greatly slow that rate of shortening than to try and lengthen no? 

 

In Turnbuckle's stem cell protocol I was using the liposomal glutathione, liposomal astragalus and vitamin c to slow this rate of attrition while attempting to stimulate symmetric division. I don't know that astragalus really does anything, there's so little evidence or even research on it, especially the liposomal variety.

 

How does telomerase play a role in its shape I wonder?


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#5 QuestforLife

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Posted 31 July 2018 - 05:33 PM

You've answered your own question Nate, the telomere has to have sufficient length to form the T-loop, and as I have pointed out its length determines where the T-loop ties in, which has implications for gene expression separate to final cellular arrest when the telomere is gone.

There are other factors too, like the availability of shelterin proteins like TRF2, which in particular is important in binding the T loop together. So there might be some scope to help here.

Sadly astralagus extracts only seem to be able to do anything whilst the cell is dividing. So in leukocytes it helps out a little whilst the population expands to deal with a threat, but only so long as you keep taking it.

I've taken plenty of the liposomal astralagus extract in the past - my LifeLength measurements came back as only being in the normal range however. I have no prior baseline however, so maybe it did something.
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#6 hav

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Posted 31 July 2018 - 06:34 PM

The paper to which OP refers is here:

 

Telomere-loop dynamics in chromosome end protection

 

Howard


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#7 Turnbuckle

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Posted 01 August 2018 - 11:44 AM

the trigger that makes telomeres unhealthy

 

 

Regardless of the details, telomere shortening is a good thing when it coincides with high epigenetic age, thus it shouldn't be considered unhealthy. By halting the proliferation of epigenetically old cells and rendering them senescent, such cells can be removed by apoptosis and replaced with new cells (assuming you still have sufficient pools of active stem cells). This process can potentially be hurried along by senolytic therapies.


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#8 Nate-2004

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Posted 01 August 2018 - 12:39 PM

Sadly astralagus extracts only seem to be able to do anything whilst the cell is dividing. So in leukocytes it helps out a little whilst the population expands to deal with a threat, but only so long as you keep taking it.

I've taken plenty of the liposomal astralagus extract in the past - my LifeLength measurements came back as only being in the normal range however. I have no prior baseline however, so maybe it did something.

 

Wait first off how do you know the extracts only do something when the cell is dividing? Any more info on that? Source?

 

I assume that if what you're saying is true, for whatever reason, then taking it with Stearic and/or sulforaphane (assuming the protocol works) and C60 should help with symmetric divisions right?



#9 QuestforLife

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Posted 01 August 2018 - 01:28 PM

Wait first off how do you know the extracts only do something when the cell is dividing? Any more info on that? Source?

 

I assume that if what you're saying is true, for whatever reason, then taking it with Stearic and/or sulforaphane (assuming the protocol works) and C60 should help with symmetric divisions right?

 

Well this conclusion is based on the observation that when the cell divides the chromosomes are split in two and lose all histone modifications and methylation patterns. Once the chromosomes strands have copied the other half they then have methylation patterns re-established by DNA methyltransferases.

 

https://www.ncbi.nlm...les/PMC2848124/

 

Similarly during DNA replication the telomere loop unwinds, and this along with the loss of methylation and unwinding from histones means HTERT is temporarily uninhibited. This allows a window by which to extend telomeres with activators (see The Shay and Wright paper I posted up-thread).

 

This is my interpretation for why TA-65 and similar compounds seem to be able to boost telomerase in human somatic cells by ~300% in vitro (where cells are constantly stimulated and fed to grow and divide):

 

https://www.research...rring_Compounds

 

but only seem to have a small effect in vivo, when cellular division cannot be guaranteed (as well as other problems like bioavailability and tissue distribution common to many supplements):

 

https://www.ncbi.nlm...les/PMC5178008/

 

In answer to your second question, yes taking the telomerase booster during the Stem Cell protocol should help. And as you may have noticed from the 'Naturally occurring compounds' reference Sulphoraphane activates telomerase moderately because it's a HDAC inhibitor.


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#10 marcobjj

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Posted 28 July 2020 - 01:48 AM

 

 

For example, mice have long telomeres (but short lifespans) and do not normally experience replicative senescence, and this is often pointed out as a flaw in the telomere theory of aging. But they DO experience shortening of telomeres, at 100x the rate of the shortening in humans. In fact this paper shows it is the rate of increase in the short telomeres in mice (<15kb) that is linked to mortality rather than the average length of telomeres.

 

https://www.cell.com...(12)00263-X.pdf

 

mice do not have long telomeres. All lab rates come from one source in Bar Harbor , Maine are are mutants.

 

 

 

https://www.youtube....h?v=ve4q-1D_Ajo

 

 

https://www.youtube....h?v=8ygLNOt43So


Edited by marcobjj, 28 July 2020 - 01:53 AM.

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#11 Turnbuckle

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Posted 28 July 2020 - 09:48 AM

mice do not have long telomeres. All lab rates come from one source in Bar Harbor , Maine are are mutants.

 

 

 

https://www.youtube....h?v=ve4q-1D_Ajo

 

 

https://www.youtube....h?v=8ygLNOt43So

 

True.

 

Established inbred mouse strains have long, hypervariable telomere lengths, ranging from 30 to 150 kb (12). In contrast, the wild-derived mouse species Mus spretus, has telomeres ranging from 8 to 10 kb (11,14–16). Because M.spretus is evolutionarily quite distinct from Mus musculus inbred strains, it was unclear whether the short telomere in M.spretus represented a unique exception to the generally long telomeres in mice.
 
To assess whether long telomere length is an important component of mouse chromosomes, we examined telomere length in a number of wild-derived inbred mouse strains. Wild-derived inbred mice have been inbred within the last 20–30 years, while the more established inbred strains were derived more than 60 years ago (17). Our results indicate that recently inbred mouse strains have telomere lengths considerably shorter than those found in established inbred mouse strains. This suggests that there is no requirement for long, hypervariable telomeres in mice. Additionally, mice with short telomere lengths show no significant reduction in lifespan, indicating that while telomere length may play a role in human cellular senescence it is not a natural determinant of organismal lifespan.
 

 

 

Also --

 

Our study highlights the error in the notion that activation of telomerase (as advocated by some) will cure aging. Instead, our study shows that an anti-aging therapy based on telomerase expression would be accompanied by continued aging.

https://www.scienced...80202140852.htm

 

 

 


Edited by Turnbuckle, 28 July 2020 - 09:56 AM.


#12 QuestforLife

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Posted 28 July 2020 - 03:09 PM

mice do not have long telomeres. All lab rates come from one source in Bar Harbor , Maine are are mutants.



https://www.youtube....h?v=ve4q-1D_Ajo


https://www.youtube....h?v=8ygLNOt43So

That's fascinating. I wonder if the effect of inbreeding is generally for longer telomeres.

I've speculated elsewhere that inter generational telomere shortening may be behind the evolution of new species.

https://www.longecit...ge/#entry878926

In the case of mice I would not expect changes in telomere length to have much effect on aging as the rate of shortening in their species is so great. But Blasco did recently show that mice born with longer telomeres - by culturing embryonic stem cells for longer before creating baby mice, rather than through telomerase activation during adult life - did result in healthier and longer lived mice, see : https://www.nature.c...467-019-12664-x

Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects


Edited by QuestforLife, 28 July 2020 - 03:10 PM.


#13 QuestforLife

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Posted 28 July 2020 - 06:36 PM

One other thing. I've made comments before about maybe wanting to be cautious about senolytics, due to the far superior regenerative ability of mice compared to humans. This new work on inbred lab mice adds weight to this argument.





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