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liz parrish bioviva

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#151 Logjam

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Posted 28 April 2016 - 12:23 AM

@corb The dog study I posted is interesting nonetheless.  It posits that length of life is proportional to dog breed telomere length.  That's probably an interesting data point.

 

Poodles and labradors live the longest.  http://www.cell.com/...1247(12)00418-4

 

We'll never know for sure, but that's an interesting datapoint.  I'm reasonably sure that there are things that are actually downstream of telomere length, but not that lengthening them will undo it.  That's different than correlation not-eq causation.  it's just not totally reversible, then.



#152 marcobjj

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Posted 28 April 2016 - 01:44 AM

 

 

 

Cancers use other mechanisms to lengthen their telomeres on top of the telomerase in stem cells

 

All of the other mechanisms used to achieve immortality involve maintaining and lengthening telomeres. only through alternative pathways.

 

 

"

Telomerase-negative immortalized human cells maintain their telomeres by a mechanism known as alternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat binding factors 1 and 2. Immunostaining showed that APBs also contain replication factor A, RAD51, and RAD52, proteins involved in DNA synthesis and recombination. During immortalization, APBs appeared at exactly the same time as activation of ALT. APBs were found in ALT tumors and cell lines but not in mortal cell strains or in telomerase-positive cell lines or tumors."

 

 

http://cancerres.aac.../4175.full.html

 

http://www.ncbi.nlm....pubmed/10485449



#153 marcobjj

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Posted 28 April 2016 - 01:53 AM

You'd think, if the epigenetic clock has found that immortalized cells continued to age it would rather disprove the clock and not immortality. "Immortal" and getting older at the same time is a paradox. We know for a fact that cancer cells are immortal. Since the Hovarth clock and it's variations have shown to estimate chronological age with reliability, they are possibly not much more than timestamps.



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#154 Logjam

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Posted 28 April 2016 - 02:22 AM

Can we agree this could be a bad idea?  http://www.telegraph...te-human-sperm/

 

Testicles are balls of hTert.  So much so that older sperm actually have _longer_ telomeres.


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#155 corb

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Posted 28 April 2016 - 02:52 AM

You'd think, if the epigenetic clock has found that immortalized cells continued to age it would rather disprove the clock and not immortality. "Immortal" and getting older at the same time is a paradox. We know for a fact that cancer cells are immortal. Since the Hovarth clock and it's variations have shown to estimate chronological age with reliability, they are possibly not much more than timestamps.

 

It's not really a paradox.
For a cell line to be deemed "immortalized", all it needs to display is the ability to do mitosis unaffected by programmed cell death.

As far as I know cell lines are not meant for public "consumption", they're just for experiments.
They have a very low genomic stability and suffer from plenty of problems like aneuploidy.

 

So it's not just their epigenetics changing.

 

Granted that's in vitro. In a live organism I suppose the immune system would take care of any such problems. Autoimmune diseases sure are fun, hey! :~



#156 marcobjj

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Posted 28 April 2016 - 03:12 AM

 

 

 

Granted that's in vitro. In a live organism I suppose the immune system would take care of any such problems. Autoimmune diseases sure are fun, hey! :~

 

 

do you have any? because you're carrying your share of Aneuploid cells, like everyone else does. That's not what autoimmune diseases are.



#157 xEva

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Posted 29 April 2016 - 03:02 PM

 

 

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.

 

 
I'm afraid you misunderstand. The 2008 Blasco study you cite speaks about the longest telomeres, while it is the critically short telomeres that matter. The Rate of Increase of Short Telomeres Predicts Longevity in Mammals, 2012
 
Then there is a question of the telomere length at birth. Where did you get your numbers? I took mine from the same 2012 Blasco paper and it gives "50 kb in young ..mice, compared with15 kb in young humans". if we go with these numbers then:

 

 M = H * (50kb/15kb)/100 = H * 0.033

 
where M and H stand for mouse and human lifespans. This gives us the mouse lifespan of 0.033 that of the human. If we take 80 years for a human lifespan then 80 * 0.033 gives us  2.6 years for a mouse, which is about right, depending on the strain.

 

 Here is the summary from the paper:

Highlights
- Mouse telomeres shorten ∼100 times faster than human telomeres
- The increase in the percentage of short telomeres predicts individual mouse longevity
- Longitudinal telomere length studies are necessary to predict mammalian longevity
 
Summary
Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice. We found that mouse telomeres shorten ∼100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity.

 

 

 


Edited by xEva, 29 April 2016 - 03:04 PM.

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#158 corb

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Posted 29 April 2016 - 04:27 PM

Pretty much every paper I've read on telomerase in mice cites them as having longer telomeres than us and also more expression of telomerase.

This is from the first hit on google. Their telomeres also shorten in a linear fashion something which doesn't happen in humans.

 

 

Although telomeres are present in all eukaryotes, telomere length varies widely among eukaryotic organisms. This affects how useful particular model systems are for studying telomere length as it relates to human aging. For example, yeast organisms have telomeres that are as short as 300 base pairs (9). Consequently, yeast cells are more amenable to studies of telomere structure and dynamics. Telomeres in inbred mice are much longer (20,000–150,000 base pairs) than telomeres in humans, and mice have a higher baseline expression of telomerase (1, 10). In terms of comparing mouse aging with human aging, mice also have a higher rate of somatic expansion and a shorter lifespan.

http://epirev.oxford...rev.mxs008.full



#159 xEva

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Posted 29 April 2016 - 05:33 PM

Pretty much every paper I've read on telomerase in mice cites them as having longer telomeres than us and also more expression of telomerase.
This is from the first hit on google. Their telomeres also shorten in a linear fashion something which doesn't happen in humans.
 

Although telomeres are present in all eukaryotes, telomere length varies widely among eukaryotic organisms. This affects how useful particular model systems are for studying telomere length as it relates to human aging. For example, yeast organisms have telomeres that are as short as 300 base pairs (9). Consequently, yeast cells are more amenable to studies of telomere structure and dynamics. Telomeres in inbred mice are much longer (20,000–150,000 base pairs) than telomeres in humans, and mice have a higher baseline expression of telomerase (1, 10). In terms of comparing mouse aging with human aging, mice also have a higher rate of somatic expansion and a shorter lifespan.

http://epirev.oxford...rev.mxs008.full

 

 
 Apparently neither longer telomeres at birth nor "more expression of telomerase" in various mutant strains prevent mice from running of their  telomeres quickly, which in the end determines their short lifespans. 

The numbers in bold are for the inbread mice. And you should have continued the quote, for it speaks of importance of telomeres in predicting animal longevity:
 

"These studies provide strong evidence that a minimum telomere length is necessary for maintenance of viability and proper development in vertebrates. Nonetheless, they belie the difficulty in using model organisms to study telomere length because the telomerase-deficient mouse displays phenotypic characteristics that are far from normal mouse or human aging."

 



#160 corb

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Posted 29 April 2016 - 06:43 PM

The first paper I pointed out to you couple posts back says it clearly - they only lose 3% of their telomere length while they are still healthy.

 

Also inbred lab mice almost all die from cancer which is in a way the opposite - to me it seems like the longer telomeres of the inbred strains pretty much seal their fate, the failsafe has been removed and they perish exactly as you would expect them to in that case.

 

Look at this interesting comparison.

 

http://www.ncbi.nlm....cles/PMC113886/

 

 

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.

 

 

Additionally, we found no correlation between telomere length and longevity in closely related mouse strains. In fact, the strain with the shortest telomeres of those we studied, P.leucopus, had the longest lifespan.

 

This paper is better than the dog breeds one telomere length and lifespans study imho.
The mice they studied are in some cases even the same mice, only difference is they are inbred or wild. So potatoes to potatoes comparison. Can't get more relevant to this thread than that.

 

 



#161 xEva

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Posted 29 April 2016 - 08:42 PM

Not sure there is a point to yet again to point out to you that the Blasco paper of 2008 (the one you refer to as "The first paper I pointed out to you couple posts back") did not deal with the shortest telomeres. Her paper of 2012 did. That's the one which states that mouse telomeres shorten 100x faster than human's.  Yes, both papers are by the same group lead by Maria Blasco and both are linked above.

 

You keep ignoring the distinctions between telomeres and critically short telomeres, and when they are pointed out to you --repeatedly-- you keep linking out-of-context quotes which, superficially, seem to support your position -- until one follows the links and reads the quotes in their context. ..which invariably supports the opposite view that telomeres do matter. A lot. Specifically, what matters is the accumulation of the critically short telomeres.  

 



#162 Logjam

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Posted 29 April 2016 - 08:50 PM

Critically short telomeres may be the most destructive, but that doesn't mean that aging gene expression is not a function of shorter telomeres.

 

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

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

 

"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.


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#163 corb

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Posted 29 April 2016 - 09:45 PM

Not sure there is a point to yet again to point out to you that the Blasco paper of 2008 (the one you refer to as "The first paper I pointed out to you couple posts back") did not deal with the shortest telomeres. Her paper of 2012 did. That's the one which states that mouse telomeres shorten 100x faster than human's.  Yes, both papers are by the same group lead by Maria Blasco and both are linked above.

 

You keep ignoring the distinctions between telomeres and critically short telomeres, and when they are pointed out to you --repeatedly-- you keep linking out-of-context quotes which, superficially, seem to support your position -- until one follows the links and reads the quotes in their context. ..which invariably supports the opposite view that telomeres do matter. A lot. Specifically, what matters is the accumulation of the critically short telomeres.  

 

The thing is I'm discussing specifically the tert therapy. You're going on some sort of an aging theory tangent I'm not interested in.

 

A cell with critically short telomeres would simply be a senescent cell.
In the end of the day a senescent cell is only bad if it's not removed.

So looking at the mice with megatelomeres, I don't think they have a problem with telomere length or maintenance - to me it seems they have a problem with senescent cell turnover, (and pretty much every other of the processes that cause aging) if anything.

 

That's what I'm trying to point out really - it's really not as simple as adding telomerase to a cell. Let a lone a single component.

And it doesn't matter when you get it, because those mice have their telomeres elongated from birth.

As I said in the start I don't think this will be even close to being a silver bullet.

 

For the sake of Mrs. Parish I hope the expected increase in caner risk doesn't pan out, but ... we'll see I guess.
 


Edited by corb, 29 April 2016 - 09:51 PM.

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#164 Rocket

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Posted 29 April 2016 - 10:57 PM

 

 

 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.

 

A lump of uranium is composed of atoms that decay completely and totally at random, and yet the decay of the lump of mass is precisely and perfectly predicted by mathematics. 

 

Is the fact that the decay is so predictable evidence that the atoms are "encoded" to decay per a program? No. It's random, and probabilistic. It's statistical. It's quantum mechanics.

 

Your conclusion... your argument, about aging, is therefore unfounded.


Edited by Rocket, 29 April 2016 - 10:59 PM.

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#165 marcobjj

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Posted 30 April 2016 - 12:56 AM

Youre talking quantum mechanics, smartass. Try replicating the double slit experiment with mice, see if they can re-materialize on the other side. Theres a reason why the Unification QM and relativity is such a hot topic in physics. Because the subatomic level operates under completely different rules than the multi-cellular level.
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#166 xEva

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Posted 30 April 2016 - 01:16 AM

  lol Liz provokes some weird discussions here!  :laugh:
 

So looking at the mice with megatelomeres, I don't think they have a problem with telomere length or maintenance - to me it seems they have a problem with senescent cell turnover, (and pretty much every other of the processes that cause aging) if anything.

That's what I'm trying to point out really

 
there you go again! Where are those mice with megatelomeres? And you don't need to think whether they have problems with telomere length or maintenance, 'cause there should be studies to this effect. Why would not you cite them and make sure the quote you pick matches the rest of the context. My point is, there is no such mice, except when it does not count, witch is at birth.

 

I like your point about the senescent cells though. Though it looks like short telomeres is what can make a cell senescent. Hence the rationale for the Liz therapy.

 

 

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.

 
A lump of uranium is composed of atoms that decay completely and totally at random, and yet the decay of the lump of mass is precisely and perfectly predicted by mathematics. 
 
Is the fact that the decay is so predictable evidence that the atoms are "encoded" to decay per a program? No. It's random, and probabilistic. It's statistical. It's quantum mechanics.
 
Your conclusion... your argument, about aging, is therefore unfounded.

 

@Rocket: "therefore unfounded"? From where exactly does that therefore follow? (it's a rhetoric question :))

 

I rather agree with marcobjj. Aging is genetically encoded, and only partially environmental.


Edited by xEva, 30 April 2016 - 01:18 AM.

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#167 corb

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Posted 30 April 2016 - 03:51 AM

  lol Liz provokes some weird discussions here!  :laugh:
 

So looking at the mice with megatelomeres, I don't think they have a problem with telomere length or maintenance - to me it seems they have a problem with senescent cell turnover, (and pretty much every other of the processes that cause aging) if anything.

That's what I'm trying to point out really

 
there you go again! Where are those mice with megatelomeres? And you don't need to think whether they have problems with telomere length or maintenance, 'cause there should be studies to this effect. Why would not you cite them and make sure the quote you pick matches the rest of the context. My point is, there is no such mice, except when it does not count, witch is at birth.

 

I like your point about the senescent cells though. Though it looks like short telomeres is what can make a cell senescent. Hence the rationale for the Liz therapy.

 

I did. In the previous post to the one you're quoting.

Certain inbred animals such as mice and chickens are known to have megatelomeres. Telomeres in the 100K range and above.

Unfortunately this http://www.ncbi.nlm....cles/PMC113886/ paper is the ONLY study of telomere length in mice that looks at the full spectrum of mice strains that is available on the open net as far as I know. I guess it's just not an interesting enough topic for the scientific community. Or maybe the are studies buried behind some publisher's paywalls, I don't know.

 

Now since someone in the thread said aneuploidy are not scary. And specifically said it's not scary in the case of telomerase activated cells.
This is for you: http://www.ncbi.nlm....les/PMC4491997/

 

 

Here, described experiments indicate that telomerase has a conserved function in alleviating replication stress at telomeres that occurs in response to aneuploidy induction in mammalian cells. The findings could be of particular importance for the transformation of tissue stem cells that are known to express high levels of telomerase (Morrison et al, 1996; Ritz et al, 2005) and represent an important cell type of origin for the evolution of cancer in both humans and mice

 

Does that tert therapy still sound like a good idea to you now?



#168 xEva

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Posted 30 April 2016 - 09:31 AM

I did. In the previous post to the one you're quoting.


This is just the thing about your refs. That one is of 2000, in other words, long BEFORE it was noted that average telomere length is not a good predictor of longevity or that different species telomeres shorten at different rates. It was about a decade later when it was established that, for the aging animals, it's the accumulation of short telomeres that matter -- something you to have trouble accepting. It appears that,  once you form your opinion, no new developments can change it. 
 
 

Certain inbred animals such as mice and chickens are known to have megatelomeres. Telomeres in the 100K range and above.
Unfortunately this http://www.ncbi.nlm....cles/PMC113886/ paper is the ONLY study of telomere length in mice that looks at the full spectrum of mice strains that is available on the open net as far as I know. I guess it's just not an interesting enough topic for the scientific community. Or maybe the are studies buried behind some publisher's paywalls, I don't know.

 
Again, it's not that it's not interesting. It's that this 2000 paper has long become water under the bridge.

 

Now since someone in the thread said aneuploidy are not scary. And specifically said it's not scary in the case of telomerase activated cells.
This is for you: http://www.ncbi.nlm....les/PMC4491997/
 

Here, described experiments indicate that telomerase has a conserved function in alleviating replication stress at telomeres that occurs in response to aneuploidy induction in mammalian cells. The findings could be of particular importance for the transformation of tissue stem cells that are known to express high levels of telomerase (Morrison et al, 1996; Ritz et al, 2005) and represent an important cell type of origin for the evolution of cancer in both humans and mice

 
Does that tert therapy still sound like a good idea to you now?

 

 
Yeas it does! Did you have a chance to read the paper posted by Logjam above?


"Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response."

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


Edited by xEva, 30 April 2016 - 09:34 AM.


#169 Rocket

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Posted 30 April 2016 - 04:36 PM

  lol Liz provokes some weird discussions here!  :laugh:
 

So looking at the mice with megatelomeres, I don't think they have a problem with telomere length or maintenance - to me it seems they have a problem with senescent cell turnover, (and pretty much every other of the processes that cause aging) if anything.

That's what I'm trying to point out really

 
there you go again! Where are those mice with megatelomeres? And you don't need to think whether they have problems with telomere length or maintenance, 'cause there should be studies to this effect. Why would not you cite them and make sure the quote you pick matches the rest of the context. My point is, there is no such mice, except when it does not count, witch is at birth.

 

I like your point about the senescent cells though. Though it looks like short telomeres is what can make a cell senescent. Hence the rationale for the Liz therapy.

 

 

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.

 
A lump of uranium is composed of atoms that decay completely and totally at random, and yet the decay of the lump of mass is precisely and perfectly predicted by mathematics. 
 
Is the fact that the decay is so predictable evidence that the atoms are "encoded" to decay per a program? No. It's random, and probabilistic. It's statistical. It's quantum mechanics.
 
Your conclusion... your argument, about aging, is therefore unfounded.

 

@Rocket: "therefore unfounded"? From where exactly does that therefore follow? (it's a rhetoric question :))

 

I rather agree with marcobjj. Aging is genetically encoded, and only partially environmental.

 

So you're saying we're "programmed" to accumulate AGEs? Lipofuscin? What about mitochondria generating ROS? Is that programmed?

 

Exactly what aspects of aging are programmed?
 


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#170 xEva

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Posted 30 April 2016 - 06:54 PM

 

So you're saying we're "programmed" to accumulate AGEs? Lipofuscin? What about mitochondria generating ROS? Is that programmed?

 

Exactly what aspects of aging are programmed?
 

 

That aging is genetically programmed is evident in the fact that similar in size animals, with similar metabolic rates, age differently. There are many examples, a good common one is lab mice vs naked mole-rats, with about 10-fold difference in lifespans. 

 

If the rate of accumulation of  AGEs, lipofuscin and mitochondial ROS generation are driven by random  environmental assaults, why would not these similar in size animals, age at the same rate and have similar lifespans? Then there is a group of animals with negligible senescence. Why don't they age at the same rate as the rest, if they are the subject of exactly the same environmental stresses? 

 

It's evident that the main difference between the fast-aging animals and the ones that age slowly lies in the ability of their tissues to self-repair. In most aging species this ability is high at birth and diminishes with age. This ability is maintained throughout life in species with negligible senescence.

 

A paper came out a year ago that showed, for the first time, that the expression of one of the "repair genes", a heat-shock protein in that case, goes down in a nematode couple of hours after it reaches sexual maturity (which is heralded by a specific change in the expression of relevant genes). This seems a good model of programmed aging in other species. The program here consists of downregulation of repairs, on all levels, which with time leads to gradual accumulation of various forms of damage.

 

 

:) Yeah, I too went the full circle, starting with programmed aging, just because it felt right, though I knew close to nothing about biology and physiology at the time. Then I joined the ranks of random damage accumulation supporters. And now I'm back to programmed aging, knowing helluvalot this time.

 

IMO whatever ups our failing inherent repair mechanisms is good. Tert therapy is one of those things, no? 


Edited by xEva, 30 April 2016 - 07:00 PM.

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#171 Rocket

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Posted 30 April 2016 - 09:37 PM

 

 

So you're saying we're "programmed" to accumulate AGEs? Lipofuscin? What about mitochondria generating ROS? Is that programmed?

 

Exactly what aspects of aging are programmed?
 

 

That aging is genetically programmed is evident in the fact that similar in size animals, with similar metabolic rates, age differently. There are many examples, a good common one is lab mice vs naked mole-rats, with about 10-fold difference in lifespans. 

 

If the rate of accumulation of  AGEs, lipofuscin and mitochondial ROS generation are driven by random  environmental assaults, why would not these similar in size animals, age at the same rate and have similar lifespans? Then there is a group of animals with negligible senescence. Why don't they age at the same rate as the rest, if they are the subject of exactly the same environmental stresses? 

 

 

Wow, you're all over the place. So disorganized.

 

AGE accumulation is a biochemical and metabolic phenomena, not random nor controlled by environment. It's unavoidable!  ROS generation is also not random... it's a consequence of our human chemical constitution.

 

Furthermore, do a little research on AGE accumulation and its effects on normal tissue function......... i.e. stem cell activity, maintenance/healing.  AGE accumulation leads to the aging phenotype.

 

As for negligible senescent animals..... Do you think the biochemistry of a lobster or rockfish is comparable to a mouse or a human?

 

 



#172 Logjam

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Posted 30 April 2016 - 09:52 PM

AGE accumulates on its own and may make tissue less flexible or generally interfere and cause damage directly, but RAGE receptors are seemingly designed to increase the harm AGEs cause by increasing ROS in mammals by design and on purpose like a self-destruct mechanism with AGEs as the enabler.  See http://journals.plos...al.pone.0086903.
 

ALT-711 is reasonably believed to reduce AGE, and here it reduces ROS—probably by blunting methylglyoxal or CML—http://www.ncbi.nlm....pubmed/19158353.

 

I don't think we need to argue over whether aging is programmed or random accumulated damage.  It appears to be both.  AGE formation is pretty much random—involving no enzymes at least—but RAGE is a receptor designed to sense the existence of AGEs and inflict self-harm beyond the damage it causes directly.

 

Lobsters don't have RAGE receptors by design, so the random process of AGE/glycation doesn't kill them via said receptor designed into mammals like us.  Lobsters only die when they get too big for their own bodies or when we boil them alive.

 

I really don't see the point in arguing about whether it's random or not.  Random processes appear to feed into designed processes in this case.

 

Obviously we should try to block AGE.  Everyone talks about that.

 

The interesting part is that AGE is not just a harmful product that makes tissues less flexible.  Cells have receptors to sense it and begin a self-destruct process by design.

 

So it's both.  Random.  By design.  Both.

 

Should we try to blunt the self-destruct process too by blocking RAGE receptors?  What could be the constructive purpose of RAGE receptors?

 

 

 

 

So you're saying we're "programmed" to accumulate AGEs? Lipofuscin? What about mitochondria generating ROS? Is that programmed?

 

Exactly what aspects of aging are programmed?
 

 

That aging is genetically programmed is evident in the fact that similar in size animals, with similar metabolic rates, age differently. There are many examples, a good common one is lab mice vs naked mole-rats, with about 10-fold difference in lifespans. 

 

If the rate of accumulation of  AGEs, lipofuscin and mitochondial ROS generation are driven by random  environmental assaults, why would not these similar in size animals, age at the same rate and have similar lifespans? Then there is a group of animals with negligible senescence. Why don't they age at the same rate as the rest, if they are the subject of exactly the same environmental stresses? 

 

 

Wow, you're all over the place. So disorganized.

 

AGE accumulation is a biochemical and metabolic phenomena, not random nor controlled by environment. It's unavoidable!  ROS generation is also not random... it's a consequence of our human chemical constitution.

 

Furthermore, do a little research on AGE accumulation and its effects on normal tissue function......... i.e. stem cell activity, maintenance/healing.  AGE accumulation leads to the aging phenotype.

 

As for negligible senescent animals..... Do you think the biochemistry of a lobster or rockfish is comparable to a mouse or a human?

 

 


Edited by Logjam, 30 April 2016 - 10:16 PM.

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#173 xEva

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Posted 30 April 2016 - 11:07 PM

Wow, you're all over the place. So disorganized.
 
AGE accumulation is [...] unavoidable!  ROS generation is also not random... it's a consequence of our human chemical constitution.


really? a consequence of our human chemical constitution? :laugh:
Well, thanks! That explains it all.

 

Furthermore, do a little research on AGE accumulation and its effects on normal tissue function......... i.e. stem cell activity, maintenance/healing.  AGE accumulation leads to the aging phenotype.
 
As for negligible senescent animals..... Do you think the biochemistry of a lobster or rockfish is comparable to a mouse or a human?

 
Oh! so you're saying that AGEs is actually responsible for aging?! Explain please why does not it accumulate in animals with negligible senescence.
 
And if you don't like lobster or rockfish, take an albatross, a whale, or a turtle.
 
Better yet, explain why a lab mouse and a naked mole-rat have such vastly different lifespans. According to you, due to their very similar ratty "chemical constitutions" they should have the same levels of AGEs and ROS in the same timeframe. Why don't they?
 

 

So it's both.  Random.  By design.  Both.

 

Well, it depends. There was a good article posted recently on this very topic. You guys should read it. It discussed a wide variation in how different animals age, if at all. Exactly this wide difference in aging phenotypes among various species proves that aging is controlled genetically. Think about it. If it were otherwise, everyone would age at about the same rate, depending on their metabolic rate and exposure to environmental stresses. And, while overall, various species of about the same size would have about the same lifespans, at the same time, there would be a wide variation in natural lifespan among individuals of the same species (depending on their individual "rate of living"). Instead, an aging species lifespan is tightly controlled genetically. But read for yourselves: Principles of alternative gerontology, 2016


Edited by xEva, 30 April 2016 - 11:14 PM.

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#174 Logjam

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Posted 01 May 2016 - 11:28 PM

"Mortality of an organism is clearly associated with terminal specialisation in sexual reproduction."

 
And:
 
"Destructive effects of stochastic events are visible only when allowed by the specific life program of an organism."
 

So it's both, but some of the stochastic events are better prevented by the asexual programs.  Or it may be more correct to say that sexual programs work better when destruction is deliberately permitted.  Eventually you do get hit by some sort of bus, though—whether that be an actual bus or a retrovirus that messes up your program.  Much later in the program, all it takes is pneumonia.  Stochastic events act as part-of/input-to a genetic algorithm to select for a better program when you get to step #3 and create a new program via sexual reproduction and genetic recombination.  We're all the program.  Duh.

 

I'm really not sure why people argue over whether death is programmed.  Life in general is programmed, centered about sexuality, reproduction, and child rearing for the next stochastic experiment (said: "baby:")

  1. You're born.
  2. You hit puberty (menses or lots more muscle/hair/deeper voice).
  3. You reproduce.
  4. You hit menopause ("F" program only).
  5. You help raise grandkids (more recent to the species).
  6. You die.

The male program is slightly more flexible—lacking step #4—probably because women having babies too late is provably really bad for the species, so that's programmed to stop.  Whether menopause is "strongly" caused by stochastic events or actually programmed to happen after N days is an interesting question.

 

This is the same program in every human population.  #1 obviously never occurs after #2 or #3.  But #4 always happens around the same time in women according to a program of gene expression.  I really wonder why people doubt this sometimes.

 

If you don't buy this theory, ya'll are trying to beat #6 without noticing it's always steps #1-5 in that order prior to #6.  In a computer program it would look like this:

 

Human logjam = new Human(T_MALE);

logjam->puberty();

logjam->bowchikabowwow();

logjam->playwithgrandkids();

delete logjam;

 

Now in real life it's much more complicated and not declarative like that.  According to that paper, stochastic events make it look random.  Instead it looks more like:

 

Human logjam = new Human(T_MALE);

logjam->puberty();

logjam->bowchikabowwow();

logjam->stochastic->decline(TD_PHYSICAL);

logjam->playwithgrandkids();

logjam->stochastic->decline(TD_PHYSICAL);

logjam->stochastic->decline(TD_MENTAL);

 

Then it takes an increasingly small insult to wipe me out after each ->decline().  The ->decline() in lieu of actual declaratives is what makes it all look random, but it really probably isn't at all.  It takes a smaller and smaller "stochastic bus" until it's "just" pneumonia, and then you die.  Pneumonia was always in your nostrils, but stochastic->decline didn't do enough to let the pneumonia bus through.

 

To make it even more confusing, all the systems are connected through feedback loops and the train eventually leaves the station on your death.  The fact that you're metabolically alive is powering several feedback loops—esp. endocrine—that are killing you with the same ATP you need to stay alive.

 

That kind of unifies why caloric restriction can work (fewer stochastic events and a slower clock), but only does so much.  Entropy and stochastic events happen no matter what.  They're part of the (input to the) program.  Things like RAGE receptors may have a purpose—to help us get hit by a bus.  Sometimes I have no better explanation.  You can argue that all of these mechanisms are to help a sick cell die, and sometimes that's true.  Some mechanisms are less convincingly so.

 

Telomeres may be a clock and a stopgap anti-cancer heuristic and very high upper bound on program length.  There is clearly statefulness in our program—and more than just general ordering—some steps never occur before other steps.  I don't believe you can achieve a sequence like that without a clock.  Telomeres may be one of those:

 

We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length.

 

It's also completely possible that the "metabolic memory" perpetuated by AGEs are one of many parts of a clocking mechanism, but they can't enforce program execution order nearly as well as a clock like (perhaps) a telomere—that's much too random.  The fact that a telomere looks sort of like the original programs like these: https://en.wikipedia...ki/Punched_tape shouldn't be lost on anyone in computer science.  They'd be functioning more like a complicated register that almost-monotonically decreases, but it's difficult for me not to see this analogy.

 

I do doubt making a telomere longer would directly cause cancer because telomere dysfunction is only 1 of hundreds of subsystems in human physiology that cause senescence — like p53, for example.  Telomere dysfunction itself causes termination via p53!  It's just an additional checkpoint to stop unnecessary replication (an upper bound in addition to everything else) in the event that a cancerous program materializes.  So longer telomeres might enable a few thousand more cell cycles but also yield gene expression that stops it more effectively if you believe that.

 

If cells replicated full time you'd be gray goo.  Telomere dysfunction only stops the bad programs that try to turn you into gray goo.  The idea that simply lengthening them somewhat through some sort of transient mechanism will cause cancer is far-fetched.  On the other hand, disallowing telomerase to be expressed chronically will kill lots of cancers because they'll need to lengthen telomeres to keep creating gray goo.  That's what Geron is actually working on doing after giving up on cycloastragenol awhile ago.

 

 

Wow, you're all over the place. So disorganized.
 
AGE accumulation is [...] unavoidable!  ROS generation is also not random... it's a consequence of our human chemical constitution.


really? a consequence of our human chemical constitution? :laugh:
Well, thanks! That explains it all.

 

Furthermore, do a little research on AGE accumulation and its effects on normal tissue function......... i.e. stem cell activity, maintenance/healing.  AGE accumulation leads to the aging phenotype.
 
As for negligible senescent animals..... Do you think the biochemistry of a lobster or rockfish is comparable to a mouse or a human?

 
Oh! so you're saying that AGEs is actually responsible for aging?! Explain please why does not it accumulate in animals with negligible senescence.
 
And if you don't like lobster or rockfish, take an albatross, a whale, or a turtle.
 
Better yet, explain why a lab mouse and a naked mole-rat have such vastly different lifespans. According to you, due to their very similar ratty "chemical constitutions" they should have the same levels of AGEs and ROS in the same timeframe. Why don't they?
 

 

So it's both.  Random.  By design.  Both.

 

Well, it depends. There was a good article posted recently on this very topic. You guys should read it. It discussed a wide variation in how different animals age, if at all. Exactly this wide difference in aging phenotypes among various species proves that aging is controlled genetically. Think about it. If it were otherwise, everyone would age at about the same rate, depending on their metabolic rate and exposure to environmental stresses. And, while overall, various species of about the same size would have about the same lifespans, at the same time, there would be a wide variation in natural lifespan among individuals of the same species (depending on their individual "rate of living"). Instead, an aging species lifespan is tightly controlled genetically. But read for yourselves: Principles of alternative gerontology, 2016

 

 


Edited by Logjam, 02 May 2016 - 12:27 AM.

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#175 Logjam

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Posted 02 May 2016 - 12:37 AM

Here's an example of when you'd need both telomere dysfunction and repression of p53 to get cancer:

http://www.sciencedi...09286740080762X

 

As expected, repressing p53 was helpful until you get cancer, and telomeres are only a last-ditch anti-cancer "catastrophe" mechanism—not the only one.

 

Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.

 

I still don't see how increasing the theoretical replicative potential of many cells—so that 1000000 cells each might replicate a few more times will cause cancer.  If they execute a bad program and replicate 12x instead of 11x that won't matter.

 

What matters is that it not figure out how to express large amounts of telomerase itself chronically.


Edited by Logjam, 02 May 2016 - 12:50 AM.

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#176 corb

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Posted 02 May 2016 - 01:08 AM

I'm really not sure why people argue over whether death is programmed.  Life in general is programmed, centered about sexuality

 

Because when some people hear program they think - "well obviously all we have to do to live longer or even indefinitely is to shutdown the aging program and we're golden smiley face 1one!11one." As if it's as easy as flipping a switch. I already said it in my first post, the quest for the silver bullet - biology unfortunately is not so simple.

We can delete genes. We can add genes. We can inhibit genes. We can hyperactivate genes. In the end of the day, exercise and diet beats all of it in the lifespan studies, and then you hit a wall - everything else we've tried pretty much either does worse or about as good as a diet - and most of the things that do about as good as a diet are SENS like options like parabiosis and senolysis.

 

Thinking like a computer scientist is part of the problem - a lot of the people that think it's easy just because it's "programmed" try to liken biology to computer code. But if you've been here enough you should freaking know better. Even if it's not unlike computer code, reverse engineering 3,500,000,000 lines of code won't be a cakewalk.

Let me put the question like this - how many pathways do you think we'll need to change if we go about life extension (not radical life extension, any life extension) with genetics? One? Ten? Ten thousand? If I had to guess I'd say ten thousand Is closer than one. We know that for certain, because lots of scientists basically spend their lives deleting and adding random fly and worm genes just to see what happens, if there was a switch, they would have found it by now. If anything a lot of the biggest "culprits" of aging  we've identified, we cannot remove them because we need them to live - scientists have already tried to do it. A mouse embryo without the component genes for NFkB for instance will simply not be viable, even if it was NFkB plays such a pivotal role in the immune system it wouldn't have been a very long lived mouse either way.

 

The other thing is if you at least have the basic knowledge about medicine you realize - it's not even possible to add and delete or even regulate a large number of genes on demand right now. We can't even regulate one or two without ruining into problems. And on a mouse - not on a person with family that can sue you if you f up! Heck it might never be possible to do it in an organism that has already matured. I honestly cannot imagine it even in a foreseeable far future, I'm not even considering the present day.

 

And then some other things that irk, for instance - have you considered that stochastic damage could be a clock of it's own? Telomeres alone obviously - since we've tried it already- cannot make a multi-cellular organism live indefinitely. Maybe you should start looking at other options. I've never ignored telomere length, I just consider lengthening them in vivo a dangerous way of doing it, TERT might not cause cancer, but it can feed it. A barrel of oil won't start a fire on it's own but you still put a fire hazard label on the thing. The AAV vector as it happens is a wonderful cancer risk.

http://www.nature.co...ll/ng.3407.html


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#177 corb

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Posted 02 May 2016 - 01:17 AM

 

Very nice paper by the way. I love their conclusion:

 

 

Instead of looking for mutants of simple and evolutionarily distant species with increased lifespans, gerontology should focus on finding factors alleviating the most life-disrupting effects of senescence.

The embodiment of the SENS methodology in a single sentence.
Rationality at the end of the day, will always triumph in science.


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#178 marcobjj

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Posted 02 May 2016 - 01:27 AM

I get the feeling there is a monetary motivation behind the anti-telomere crowd. Silver bullet model implies a lot of the supplement peddlers, the resveratrols, the c60 and the epitalon crowd among others going out of business.


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#179 Logjam

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Posted 02 May 2016 - 07:09 AM

I don't think anyone here is saying they know it's the silver bullet, but there are plenty of data to suggest it's worth seeing what happens when you get "telomere surgery."

 

In at least some experiments, the action of lengthening (not just happening to have longer telomeres) the telomeres has led to things like lower insulin resistance.  Yes, only in mice so far.  And yes, the data could be totally fudged—but I doubt it with the names on that paper.  It would be nice to see if anyone can replicate this over and over so we may suppose if the same thing may happen in less furry primates like us.  Liz is a primate.  Let's see what happens there too.

 

From one of the Blasco papers:

 

Glucose intolerance and insulin resistance are also well-established indicators of the aging progression (Bailey & Flatt, 1982; Guarente, 2006), and telomerase deficiency contributes to glucose intolerance in mice (Kuhlow et al, 2010). AAV9-mTERT treated mice of both aged groups showed significantly lower levels of fasting insulin compared with the AAV9-eGFP controls, which presented increased insulin levels with aging (Fig 2C), indicating an improved insulin sensitivity upon TERT treatment. AAV9-mTERT treated mice also showed a trend for an improved glucose uptake and a better homeostatic model assessment (HOMA (Heikkinen et al, 2007; Matthews et al, 1985)) compared to the AAV9-eGFP controls, although differences did not reach statistical significance (Supporting Information Fig S4D and E). We observed significantly higher IGF-1 levels in the 2 year old AAV9-mTERT treated mice compared to age-matched controls, which showed decreased IGF-1 levels compared to the 1 year old controls (Fig 2D). A decline in IGF-1 expression occurs with age progression (Hammerman, 1987), and high IGF-1 levels in the 2 year old AAV9-mTERT treated mice could suggest an improved health-span. Finally, we did not find significant differences in body fat content or in body weight of the different mouse cohorts (Supporting Information Fig S4F and G).

 

I'm not about to experiment with gene therapy, but taking cycloastragenol every other 6 months sounds like an OK idea for now if I want to be conservative and slow down telomere attrition.  It's basically food, not gene therapy.  It's definitely no more adventurous than substances like buckyballs that may indeed also work but also stay in your cells for a long, long time and are less understood.

 

Not all the benchmarks in that study reached statistical significance, but some apparently did.

 

If younger mice have better insulin sensitivity with longer telomeres that's one thing.  This actually says they have better insulin sensitivity after "telomere lengthening surgery."  That doesn't have the correlation-isn't-causation problem.  Yep, it actually says that if we get our telomeres to be longer (and we're mice), we'll instantly be "less diabetic."  Even if we can't get our islets to regenerate like they do when we're toddlers (that window closes when we're around 2 y/o), at least we'll need less insulin.  Anyway, mice don't live past toddler age if you don't scale them to mouse-years.  Now we just have to replicate in humans.  Mice and humans aren't quite the same, and ironically very much not so in the realm of endocrinology, but that probably has more to do with tumor suppressors and cell cycle regulators than overall IR.

 

Isn't this what Liz is trying, even if it's not a rigorous scientific experiment with controls?  She's turning on hTERT transiently, which is probably less safe than cycloastragenol, but not going to instantly cause cancer.  My problem with it is that there are epigenetic and chromatin factors downstream of telomere length for certain.  Progerin is one of those, for example.

 

The aforementioned study says she may now need less insulin, though, no?

 

Not everyone who thinks telomeres are 1 piece of the puzzle is a schmuck that is ignoring all other data.  We may achieve better health with the so-called silver bullet—even if it's one of many silver bullets—yes, even 1000s.  There are a few reasons to believe telomere length could be a sort of epigenetic controller and age register.  I'm not sure what I believe, but there's enough evidence to entertain that it's a factor.

 


Edited by Logjam, 02 May 2016 - 07:47 AM.

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#180 marcobjj

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Posted 03 May 2016 - 03:14 AM

 

I'm not about to experiment with gene therapy, but taking cycloastragenol every other 6 months sounds like an OK idea for now if I want to be conservative and slow down telomere attrition.  It's basically food, not gene therapy.  It's definitely no more adventurous than substances like buckyballs that may indeed also work but also stay in your cells for a long, long time and are less understood.

 

 

 

glad I'm not the only one who's noticed the cognitive dissonance between telomere skepticism and eating fullerene buckyballs for lunch, based on a single experiment half a decade ago no less.


Edited by marcobjj, 03 May 2016 - 03:20 AM.

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