32 replies to this topic

[VidX]

Short version:

Engeneered mice with the "telomerase switch".
Lacks telomere lenght, shows all signs of aging prematurely
The switch is turned "On" - mice is "young" again in a few months.
Does not extend MLS

http://www.dailymail...mark-trial.html

Edited by VidX, 29 November 2010 - 01:28 PM.

[Shoe]

One thing I don't understand here: how come lifespan was not increased?

[Elus]

One thing I don't understand here: how come lifespan was not increased?

Aubrey's comments on facebook:

"Spectacularly oversold. The mice are broken in one very well-understood way (no telomerase, so eventually over-short telomeres), and they have been constructed so that that problem can be fixed with a drug, and lo, lots of the downstream consequences of the problem are also fixed. Duh.

Sorry..."

[stephen_b]

Here's the link to the abstract of the study published in Nature, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.

It sounds to me like it's the press doing the overselling.

My question is: what did they use as a telomerase activator?

An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses1. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk1, 3 and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.

[VidX]

I guess what may be relevant in context of aging is that a SINGLE gene produces huge consequences, depending on it's expression/inhibition.

[greensweater]

Stephen, I don't have access to the full article, and read the abstract from my iPhone, but if I read it correctly there is not a telomerase activator in the sense that would be beneficial to us, it seems they used an inducible promotor, meaning in the absence of this substance, transcription of telomerase would not take place, and in it's presence, transcription (and thus translation) of telomerase would take place, but not (presumably) at supraphysiological levels.

[missminni]

Posted: November 29, 2010

Aging Reversal May Work in Mice, but Still Far Off for Humans

Scientists have reversed some of the effects of aging in mice­, restoring the sense of smell, brain function, and fertility in test animals that were transformed from the physiological equivalent of frail 80-year-olds to strapping young adults, the Wall Street Journal reports. But the findings, published in the journal Nature, may not hold the key to the fountain of youth for humans: The process of tweaking a gene to halt aging could cause cancer, and it's not yet known whether the technique would even work in people. In the experiment, scientists took genetically-engineered mice—that aged prematurely and had atrophied organs—and injected them with a drug to activate the anti-aging enzyme telomerase. This enzyme makes DNA units called telomeres, which function like caps at the end of chromosomes to keep them from unraveling. Low levels of telomerase is thought to be one factor in what makes people age, so reactivating telomerase could potentially "turn back the clock" on some side effects of aging, the Journal reports. By the end of the experiment, the mice's telomerase levels increased and their telomeres lengthened, which could explain why they regained so much of their function.

It might be a while but it's really exciting news.

[Elus]

Posted: November 29, 2010

Aging Reversal May Work in Mice, but Still Far Off for Humans

Scientists have reversed some of the effects of aging in mice­, restoring the sense of smell, brain function, and fertility in test animals that were transformed from the physiological equivalent of frail 80-year-olds to strapping young adults, the Wall Street Journal reports. But the findings, published in the journal Nature, may not hold the key to the fountain of youth for humans: The process of tweaking a gene to halt aging could cause cancer, and it's not yet known whether the technique would even work in people. In the experiment, scientists took genetically-engineered mice—that aged prematurely and had atrophied organs—and injected them with a drug to activate the anti-aging enzyme telomerase. This enzyme makes DNA units called telomeres, which function like caps at the end of chromosomes to keep them from unraveling. Low levels of telomerase is thought to be one factor in what makes people age, so reactivating telomerase could potentially "turn back the clock" on some side effects of aging, the Journal reports. By the end of the experiment, the mice's telomerase levels increased and their telomeres lengthened, which could explain why they regained so much of their function.

It might be a while but it's really exciting news.

Not really exciting news. Extremely overhyped, in my opinion. Check out Aubrey's response I posted.

Edited by Elus, 30 November 2010 - 01:35 AM.

[VidX]

Talking about a significance of the study, IMO it's kind of a blow to the "wear and tear" viewpoint/approach.. quite an obvious one.

Edited by VidX, 30 November 2010 - 04:09 PM.

[Elus]

Talking about a significance of the study, IMO it's kind of a blow to the "wear and tear" viewpoint/approach.. quite an obvious one.

Not really. Telomeres that are critically short result in DNA mutations which express misformed proteins or no proteins, and therefore fixing the telomere length led to mitigation of damaged DNA, allowing DNA repair mechanisms to restore function in the DNA, leading to renewed expression of the correct proteins and regulation of pathways that are in healthy individuals.

Nowhere do these findings imply that damage isn't of critical importance to aging. The fact that this study was done in sick mice is very disappointing. How about we do it in healthy mice and see the effects then? I would be willing to bet that the effect would be close to none.

Edited by Elus, 30 November 2010 - 05:00 PM.

[VidX]

Not really. Telomeres that are critically short result in DNA mutations which express misformed proteins or no proteins, and therefore fixing the telomere length led to mitigation of damaged DNA, allowing DNA repair mechanisms to restore function in the DNA, leading to renewed expression of the correct proteins and regulation of pathways that are in healthy individuals.

Nowhere do these findings imply that damage isn't of critical importance to aging. The fact that this study was done in sick mice is very disappointing. How about we do it in healthy mice and see the effects then? I would be willing to bet that the effect would be close to none.

What I meant is that if a single variable can influence so many events - the question is - wouldn't it be futile to try to "fix" all kind of "damage" that arises with an exponential varity, as the age advances, if it's getting obvious - it's not the "damage" that brings the organism down, but rather a "damage" in the genome (or a change/shift/ or maybe lack of certain change/shift, still to be researched..)..
Obviously - we should try to fix as much as possible in order to prolong the best possible homeostasis, but eventualy it probably will be dommed to fail, in the context of an age reversal..
An epigenomic level "work" is probably where it's at, eventually..

Edited by VidX, 30 November 2010 - 05:21 PM.

[Elus]

What I meant is that if a single variable can influence so many events - the question is - wouldn't it be futile to try to "fix" all kind of "damage" that arises with an exponential varity, as the age advances, if it's getting obvious - it's not the "damage" that brings the organism down, but rather a "damage" in the genome (or a change/shift/ or maybe lack of certain change/shift, still to be researched..)..
Obviously - we should try to fix as much as possible in order to prolong the best possible homeostasis, but eventualy it probably will be dommed to fail, in the context of an age reversal..
An epigenomic level "work" is probably where it's at, eventually..

Damage in the genome causes cancer, which is the only type of genomic damage that we need to worry about. Cells that undergo other types of genomic damage undergo apoptosis - programmed cell death. All of your other cells still contain intact copies of your DNA, so you don't need to worry about DNA damage in single cells unless it relates to cancer. Do you see what I'm getting at?


Metabolism is extremely complex. If you influence just a single variable, there are many different effects. I agree. We should not tamper with metabolism because we understand so little about it.

However, the metabolic byproducts, i.e. damage that accumulates within and outside of cells, are fairly well categorized and understood. If we can get rid of the damage, and thereby let metabolism do its job, we don't have to intervene in any process. We just have to clean up the damage.

The reason antique cars are still running is not because people have changed how they work. Instead, they simply replace and clean up the car periodically to keep it in working order. We'll do the same with our body on the cellular level.

[missminni]

Posted: November 29, 2010

Aging Reversal May Work in Mice, but Still Far Off for Humans

Scientists have reversed some of the effects of aging in mice­, restoring the sense of smell, brain function, and fertility in test animals that were transformed from the physiological equivalent of frail 80-year-olds to strapping young adults, the Wall Street Journal reports. But the findings, published in the journal Nature, may not hold the key to the fountain of youth for humans: The process of tweaking a gene to halt aging could cause cancer, and it's not yet known whether the technique would even work in people. In the experiment, scientists took genetically-engineered mice—that aged prematurely and had atrophied organs—and injected them with a drug to activate the anti-aging enzyme telomerase. This enzyme makes DNA units called telomeres, which function like caps at the end of chromosomes to keep them from unraveling. Low levels of telomerase is thought to be one factor in what makes people age, so reactivating telomerase could potentially "turn back the clock" on some side effects of aging, the Journal reports. By the end of the experiment, the mice's telomerase levels increased and their telomeres lengthened, which could explain why they regained so much of their function.

It might be a while but it's really exciting news.

Not really exciting news. Extremely overhyped, in my opinion. Check out Aubrey's response I posted.

I read it and realized the over hype. But I still think it's exciting going forward.

How about we do it in healthy mice and see the effects then? I would be willing to bet that the effect would be close to none.]

Just curious, why ?

[Elus]

Just curious, why ?

I would guess that mice who are healthy would not benefit from telomere extension in terms of youthfulness. Why?

1. The mice in the study had artificially short telomeres. This is not comparable to old people who have artificially short telomeres. There is far more awry in an old person's body than telomere length. These include things like plaques between cells, mitochondrial mutations which create reactive oxygen species hotspots (due to lack of NAD+, so they shuttle their electrons elsewhere), lipofuscin accumulation with the cells, etc. All of these things cannot be dealt with even in healthy individuals because our body lacks the mechanism to remove those types of damage. Telomere extension will do nothing for this damage.

2. Mice telomeres differ in several respects from human telomeres. I heard Aubrey mention this, but you'd need to consult him for more info (PM him on FB or here)


Telomere extension may confer an anti-cancer advantage, I admit. This study has not yet confirmed that this really does help prevent cancer, but the fact that none of the mice had cancer when their telomeres extended is promising. However, those of us who are already in middle age, and who have small cancers in our bodies may be at a greater risk because telomere extension could give those cancers the power to proliferate.

[missminni]

Just curious, why ?

I would guess that mice who are healthy would not benefit from telomere extension in terms of youthfulness. Why?

1. The mice in the study had artificially short telomeres. This is not comparable to old people who have artificially short telomeres. There is far more awry in an old person's body than telomere length. These include things like plaques between cells, mitochondrial mutations which create reactive oxygen species hotspots (due to lack of NAD+, so they shuttle their electrons elsewhere), lipofuscin accumulation with the cells, etc. All of these things cannot be dealt with even in healthy individuals because our body lacks the mechanism to remove those types of damage. Telomere extension will do nothing for this damage.


2. Mice telomeres differ in several respects from human telomeres. I heard Aubrey mention this, but you'd need to consult him for more info (PM him on FB or here)

Telomere extension may confer an anti-cancer advantage, I admit. This study has not yet confirmed that this really does help prevent cancer, but the fact that none of the mice had cancer when their telomeres extended is promising. However, those of us who are already in middle age, and who have small cancers in our bodies may be at a greater risk because telomere extension could give those cancers the power to proliferate.

I understand what you're saying about it not being comparable to old people etc...however in the experiment, the mice who were genetically manipulated to be sans telomeres were balding and suffering from age related deterioration that was totally reversed.
Since they were physically aging wouldn't there have been plaque between cells and mitochondrial mutations present in them as well ? Isn't that part of the aging process? I don't have a science background, so if my assumption is really off base, forgive me.
The cancer issue isn't necessarily insurmountable.
I'm just excited that the concept of age REVERSAL actually has legs!

[maxwatt]

According to a Wall Street Journal write-up, the authors are planing to test it next in genetically normal mice. I think the first step they accomplished was to show their substance induces telomerase expression and that this reverses the effects of its being absent. Next step is to see how this affects your average healthy strain of lab mouse. In the meantime the self-experimenters will be trying it and we may learn something of the effects in humans before the next mouse study gets published.

[nowayout]

However, the metabolic byproducts, i.e. damage that accumulates within and outside of cells, are fairly well categorized and understood. If we can get rid of the damage, and thereby let metabolism do its job, we don't have to intervene in any process. We just have to clean up the damage.

I am not so sure this is in any way on the horizon. To get an idea of what we are up against, here is a discussion of the type of damage accumulating in just one tissue, the testis. I find it hard to believe that simply preserving telomeres, normalizing apoptosis, and cleaning up the crud, are going to fix all this:

Ultrastructure of the aging human testis

1. Ricardo Paniagua1,*,
2. Manuel Nistal2,
3. Francisco J. Sáez,
4. Benito Fraile1

Abstract

The ultrastructure of the progressive testicular involution with advancing age in men is reviewed. There is no definite age at which testicular involution begins, and the onset and severity of testicular lesions are subjected to pronounced individual variations. Hormone studies also indicate great individual variations, and subtle changes in both the testis and the pituitary develop progressively with age. Testicular size, sperm quality, and numbers of all germ cell types, Sertoli cells, and Ley dig cells decrease with age. The volume occupied by the seminiferous tubules decreases, whereas that occupied by the testicular interstitium remains constant. The most frequent histological pattern of the aging testis is a mosaic of different seminiferous tubule lesions, varying from tubules with complete, although reduced, spermatogenesis, to completely sclerosed tubules. The tubules with complete spermatogenesis may show numerous .morphological abnormalities in the germ cells, including multinucleation. Abnormal germ cells degenerate causing Sertoli cell vacuolation. These vacuoles correspond to dilations of the extracellular spaces resulting from the premature exfoliation of germ cells. Degenerating cells that are phagocytosed by the Sertoli cells give rise to an accumulation of lipid droplets in the Sertoli cell cytoplasm. The loss of germ cells begins with the spermatids, but progressively affects the earlier germ cell types, and tubules with maturation arrest at the level of the spermatocytes or spermatogonia are observed. The Sertoli cells show morphological abnormalities such as dedifferentiation, mitochondrial metaplasia, and multinucleation. Germ cell loss is associated with thickening of the tunica propria. When all seminiferous epithelial cells have disappeared, only an intensely collagenized tunica propria with myoid cells remains (sclerosed tubules). The Ley dig cells progressively dedifferentiate with a decrease in the quantity of both smooth endoplasmic reticulum and mitochondria, together with an accumulation of lipid droplets, crystalline inclusions, and residual bodies, and formation of multinucleate cells. The development of tubular involution with age is similar to that observed after exprimental ischemia, suggesting that vascular lesions may play an important role in age-related testicular atrophy.

Edited by viveutvivas, 30 November 2010 - 08:22 PM.

[missminni]

According to a Wall Street Journal write-up, the authors are planing to test it next in genetically normal mice. I think the first step they accomplished was to show their substance induces telomerase expression and that this reverses the effects of its being absent. Next step is to see how this affects your average healthy strain of lab mouse. In the meantime the self-experimenters will be trying it and we may learn something of the effects in humans before the next mouse study gets published.

and what is "their substance"?

[VidX]

Damage in the genome causes cancer, which is the only type of genomic damage that we need to worry about. Cells that undergo other types of genomic damage undergo apoptosis - programmed cell death. All of your other cells still contain intact copies of your DNA, so you don't need to worry about DNA damage in single cells unless it relates to cancer. Do you see what I'm getting at?


Metabolism is extremely complex. If you influence just a single variable, there are many different effects. I agree. We should not tamper with metabolism because we understand so little about it.

However, the metabolic byproducts, i.e. damage that accumulates within and outside of cells, are fairly well categorized and understood. If we can get rid of the damage, and thereby let metabolism do its job, we don't have to intervene in any process. We just have to clean up the damage.

The reason antique cars are still running is not because people have changed how they work. Instead, they simply replace and clean up the car periodically to keep it in working order. We'll do the same with our body on the cellular level.

Well maybe not the damage in genome, but a certain "shift" (or lack of it, or just lack of epigenic instructions/blueprints, from a certain phase. Instructions, that would enable us to sustain health/youth.) maybe what it's all about. As the experiments with fruit flies show - it's not the change or mutations of new genes, that enables them to live a lot longer, but the change of expression patterns of the same ones, is what's important. So basically, if the certain kind of "pattern" that grants us health in an early adulthood starts to "blur" (because of lack evolutionary pressure) and we start going downhill - the manifestation of that "blurring" is a wide variety of what we call "damage" (not like damage is the CAUSE, but more likely - a RESULT. At least I start to get get such an impression.). And to "fix" all of these "damages" (and they go up in number faster and faster) may be quite an unlikely scenario, as like you say - if metabolism is extremly complex - so probably is the "damage" that happens to it.


The same study showed that a significant part of "change" happens in expression of genes, that are responsible for energy metabolism, so some kind of a mitochondrial intervention may be one of the succesfull apprach "Fix-damage" style (if there's a mechanism - a lot of stuff may go wrong, but there may be a common variable, like Oil, that lubes it, and if it dires out - the whole mechanism starts to overheat, etc.. And mitochondria COULD be such an "oil", an universal variable in a whole organism, that could add up to the overall effectiveness of the function of parts that depend on it..). Just a guess.


Anyway - we can witness that just one, single intervention can make it or break it. So maybe it's not the actual mechanism of aging that's so complex, but it's manifestation (you know - like with that equation of a fractal, that's very simple from a first look, but it can produce an amazingly complex looking structures.).

Well it's just my rambling, in part to just better arrange the thoughts in my own head.

[greensweater]

According to a Wall Street Journal write-up, the authors are planing to test it next in genetically normal mice. I think the first step they accomplished was to show their substance induces telomerase expression and that this reverses the effects of its being absent. Next step is to see how this affects your average healthy strain of lab mouse. In the meantime the self-experimenters will be trying it and we may learn something of the effects in humans before the next mouse study gets published.

and what is "their substance"?

Read my previous post, and this, http://en.wikipedia.org/wiki/Operon

The substance they used does not matter. It would not cause expression of telomerase in a normal mouse or human.

[maxwatt]

According to a Wall Street Journal write-up, the authors are planing to test it next in genetically normal mice. I think the first step they accomplished was to show their substance induces telomerase expression and that this reverses the effects of its being absent. Next step is to see how this affects your average healthy strain of lab mouse. In the meantime the self-experimenters will be trying it and we may learn something of the effects in humans before the next mouse study gets published.

and what is "their substance"?

There was no substance.

we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter.

I took a closer look. Grant's point is well taken. Sounds like they corrected the genetic defect in homozygous TERT-ER mice with a knock-in allele rather than with the latest supplement. Gene therapy. The question remains if in normal mice they can lengthen telomeres, and if that would make them youthful. We know now of some substances, including cycloastrogenol and purslane, that activate telomerase and perhaps lengthen some telomeres, but there is no certain proof this does. There is a study showing that the shortest telomeres may become on average less short. This might be sufficient, as the shortest telomeres are thought most critical in determining the adequacy of cellular function. But we have too long a string of "maybe's" here to be certain of anything.

Something else to consider: in some autoimmune conditions, such as psoriasis, expression of telomerase is elevated, but apparently in vain: the afflicted immune cells still have abnormally short telomeres. This is not a simple situation. Something that increases telomerase where it is already elevated, perhaps as the body is attempting to correct a problem with short telomeres, is likely futile. Even worse it may aggravate the situation.

[Elus]

Well maybe not the damage in genome, but a certain "shift" (or lack of it, or just lack of epigenic instructions/blueprints, from a certain phase. Instructions, that would enable us to sustain health/youth.) maybe what it's all about. As the experiments with fruit flies show - it's not the change or mutations of new genes, that enables them to live a lot longer, but the change of expression patterns of the same ones, is what's important. So basically, if the certain kind of "pattern" that grants us health in an early adulthood starts to "blur" (because of lack evolutionary pressure) and we start going downhill - the manifestation of that "blurring" is a wide variety of what we call "damage" (not like damage is the CAUSE, but more likely - a RESULT. At least I start to get get such an impression.). And to "fix" all of these "damages" (and they go up in number faster and faster) may be quite an unlikely scenario, as like you say - if metabolism is extremly complex - so probably is the "damage" that happens to it.


The same study showed that a significant part of "change" happens in expression of genes, that are responsible for energy metabolism, so some kind of a mitochondrial intervention may be one of the succesfull apprach "Fix-damage" style (if there's a mechanism - a lot of stuff may go wrong, but there may be a common variable, like Oil, that lubes it, and if it dires out - the whole mechanism starts to overheat, etc.. And mitochondria COULD be such an "oil", an universal variable in a whole organism, that could add up to the overall effectiveness of the function of parts that depend on it..). Just a guess.


Anyway - we can witness that just one, single intervention can make it or break it. So maybe it's not the actual mechanism of aging that's so complex, but it's manifestation (you know - like with that equation of a fractal, that's very simple from a first look, but it can produce an amazingly complex looking structures.).

Well it's just my rambling, in part to just better arrange the thoughts in my own head.

Good thoughts.

I'm not convinced that the solution is that easy given the presence of lesions that our cells are uncapable of repairing even with youthful machinery. How would undegradable amyloids be cleared if the "youthful pattern" you speak of were restored? The body just isn't equipped with the machinery to deal with that kind of type of thing.


If one simple variable or gene really were the one root cause of aging, we should have probably seen at least a few immortal people (That would be my guess) who happen to have acquired this mutation by chance.


I'd love to be wrong!

[Elus]

I am not so sure this is in any way on the horizon. To get an idea of what we are up against, here is a discussion of the type of damage accumulating in just one tissue, the testis. I find it hard to believe that simply preserving telomeres, normalizing apoptosis, and cleaning up the crud, are going to fix all this:

Ultrastructure of the aging human testis

1. Ricardo Paniagua1,*,
2. Manuel Nistal2,
3. Francisco J. Sáez,
4. Benito Fraile1

Abstract

The ultrastructure of the progressive testicular involution with advancing age in men is reviewed. There is no definite age at which testicular involution begins, and the onset and severity of testicular lesions are subjected to pronounced individual variations. Hormone studies also indicate great individual variations, and subtle changes in both the testis and the pituitary develop progressively with age. Testicular size, sperm quality, and numbers of all germ cell types, Sertoli cells, and Ley dig cells decrease with age. The volume occupied by the seminiferous tubules decreases, whereas that occupied by the testicular interstitium remains constant. The most frequent histological pattern of the aging testis is a mosaic of different seminiferous tubule lesions, varying from tubules with complete, although reduced, spermatogenesis, to completely sclerosed tubules. The tubules with complete spermatogenesis may show numerous .morphological abnormalities in the germ cells, including multinucleation. Abnormal germ cells degenerate causing Sertoli cell vacuolation. These vacuoles correspond to dilations of the extracellular spaces resulting from the premature exfoliation of germ cells. Degenerating cells that are phagocytosed by the Sertoli cells give rise to an accumulation of lipid droplets in the Sertoli cell cytoplasm. The loss of germ cells begins with the spermatids, but progressively affects the earlier germ cell types, and tubules with maturation arrest at the level of the spermatocytes or spermatogonia are observed. The Sertoli cells show morphological abnormalities such as dedifferentiation, mitochondrial metaplasia, and multinucleation. Germ cell loss is associated with thickening of the tunica propria. When all seminiferous epithelial cells have disappeared, only an intensely collagenized tunica propria with myoid cells remains (sclerosed tubules). The Ley dig cells progressively dedifferentiate with a decrease in the quantity of both smooth endoplasmic reticulum and mitochondria, together with an accumulation of lipid droplets, crystalline inclusions, and residual bodies, and formation of multinucleate cells. The development of tubular involution with age is similar to that observed after exprimental ischemia, suggesting that vascular lesions may play an important role in age-related testicular atrophy.

My guess is that these types of damage fit into the seven Aubrey outlines in one way or another. Unfortunately, I don't have sufficient knowledge to tell you how these things fit into that framework, but I'm sure things like that would have been brought up when Aubrey provided that $20,000 prize for any paper that could demolish SENS (No one was able).

I will look into this further. Perhaps we should get Aubrey to comment briefly?

[VidX]

Good thoughts.
I'm not convinced that the solution is that easy given the presence of lesions that our cells are uncapable of repairing even with youthful machinery. How would undegradable amyloids be cleared if the "youthful pattern" you speak of were restored? The body just isn't equipped with the machinery to deal with that kind of type of thing.

If one simple variable or gene really were the one root cause of aging, we should have probably seen at least a few immortal people (That would be my guess) who happen to have acquired this mutation by chance.
I'd love to be wrong!

Exactly - amyloids appear/accumulate in a significant amounts at an advanced age (correct me if I'm wrong) so this one fact may explain why there isn't an effective mechanism that clears out that junk (as evolutionary pressure is far away in the "back", during that time). Though I'm not sure what would happen if various gene pathways would be "retuned" to an optimal performance/phenotype of youth (I mean - whether these would be cleared somehow). I have no idea at the moment...

I still find this study to be interesting, as the overall concept suggests that various kind of "tweaking" is completely feasible. And that "damage" approach may be good for some limited time (and I hope it will work, and long enough to create a "bridge" to a more advanced therapies) as it may turn out that "damage" itself is a result (like any other dissease/pathology) of an "unlucky" (for us) code, that's written in our epigenomic blueprints, that needs to be corrected/influenced somehow to a sufficient degree.

Edited by VidX, 01 December 2010 - 03:38 AM.

[niner]

I am not so sure this is in any way on the horizon. To get an idea of what we are up against, here is a discussion of the type of damage accumulating in just one tissue, the testis. I find it hard to believe that simply preserving telomeres, normalizing apoptosis, and cleaning up the crud, are going to fix all this:

The ultrastructure of the progressive testicular involution with advancing age in men is reviewed. There is no definite age at which testicular involution begins, and the onset and severity of testicular lesions are subjected to pronounced individual variations. Hormone studies also indicate great individual variations, and subtle changes in both the testis and the pituitary develop progressively with age. Testicular size, sperm quality, and numbers of all germ cell types, Sertoli cells, and Ley dig cells decrease with age. The volume occupied by the seminiferous tubules decreases, whereas that occupied by the testicular interstitium remains constant. The most frequent histological pattern of the aging testis is a mosaic of different seminiferous tubule lesions, varying from tubules with complete, although reduced, spermatogenesis, to completely sclerosed tubules. The tubules with complete spermatogenesis may show numerous .morphological abnormalities in the germ cells, including multinucleation. Abnormal germ cells degenerate causing Sertoli cell vacuolation. These vacuoles correspond to dilations of the extracellular spaces resulting from the premature exfoliation of germ cells. Degenerating cells that are phagocytosed by the Sertoli cells give rise to an accumulation of lipid droplets in the Sertoli cell cytoplasm. The loss of germ cells begins with the spermatids, but progressively affects the earlier germ cell types, and tubules with maturation arrest at the level of the spermatocytes or spermatogonia are observed. The Sertoli cells show morphological abnormalities such as dedifferentiation, mitochondrial metaplasia, and multinucleation. Germ cell loss is associated with thickening of the tunica propria. When all seminiferous epithelial cells have disappeared, only an intensely collagenized tunica propria with myoid cells remains (sclerosed tubules). The Ley dig cells progressively dedifferentiate with a decrease in the quantity of both smooth endoplasmic reticulum and mitochondria, together with an accumulation of lipid droplets, crystalline inclusions, and residual bodies, and formation of multinucleate cells. The development of tubular involution with age is similar to that observed after exprimental ischemia, suggesting that vascular lesions may play an important role in age-related testicular atrophy.

My guess is that these types of damage fit into the seven Aubrey outlines in one way or another. Unfortunately, I don't have sufficient knowledge to tell you how these things fit into that framework, but I'm sure things like that would have been brought up when Aubrey provided that $20,000 prize for any paper that could demolish SENS (No one was able).

Elus, I think that you are essentially correct. If you look at the numerous pathologies of the aging testis described above, and track down why each has occurred, you likely will find more fundamental causes, and examining them for cause will likely reveal causes that are even more fundamental. Eventually, I suspect you would reach the "ultimate" causes, and I would expect them to be close to Aubrey's seven. Perhaps there will be a few others, and the magnitude of some of the seven might be smaller (or larger) than we think.

My main point is that a wide variety of seemingly unrelated problems could all be due to a small number of causes.

[Gern]

Elus, I think that you are essentially correct. If you look at the numerous pathologies of the aging testis described above, and track down why each has occurred, you likely will find more fundamental causes, and examining them for cause will likely reveal causes that are even more fundamental. Eventually, I suspect you would reach the "ultimate" causes, and I would expect them to be close to Aubrey's seven. Perhaps there will be a few others, and the magnitude of some of the seven might be smaller (or larger) than we think.

My main point is that a wide variety of seemingly unrelated problems could all be due to a small number of causes.

This is the essence of root cause analysis, something quality people do all the time. There are numerous techniques for root cause analysis from simple ones like "5 whys" which you more or less described above, to mapping networks of causes. The scientific method does not lend itself well to root cause analysis, it tends instead to try to isolate things and quantify. The need to specialize and focus on a single phenomena is fundamentally at odds with the concept of tracking a complex network of aging symptoms and causes back through a vast network of independent systems to some root cause.

I was surprised how easily this was dismissed. IMHO to dismiss this research because the mice were aging unnaturally is as foolish as the articles exaggerating it's importance. Unless someone has solid evidence that shortening telomeres are not one of the key mechanism resulting in age related decline. We have at least some evidence to suggest that just a mild reduction in short telomeres can have a dramatic age reversal effect on a hand full of systems (immunity, skin, eyesight, etc).

Setting that aside, to me what's interesting about this research is kind of being lost in all the discussion about telomeres; that the body can repair fairly severe damage of a type that is similar, if not identical, to age related decline. So what is stopping an old body from repairing the same damage that a young body can repair?

Edited by Gern, 02 December 2010 - 01:16 AM.

[Elus]

Lengthen telomeres in healthy mice and extend their lifespan. Then I will concede that telomeres really do play a role in determining maximum lifespan.

Also, lol'd at this comment:

Gets Hit With A Hammer Once A Day Mice get better when we lock up all the hammers. "Now for humans!" Let's ban hammers from the shelves of all hardware stores! Together we can do this!

Edited by Elus, 02 December 2010 - 03:06 AM.

[Gern]

Lengthen telomeres in healthy mice and extend their lifespan. Then I will concede that telomeres really do play a role in determining maximum lifespan.

I didn't see that as the point of the article. The research wasn't about mice living longer, it was about reversing what appear to be the signs of aging. Living longer and being health longer are not necessarily the same thing. So the only question with respect to this research is: what is the evidence that lengthening or shortening telomeres can affect the health of the organism? So far I don't see anyone contesting that shortening telomeres caused what appears to be a general decline in the health of those mice. What the research shows is that that decline in health is not a one way street. The body can repair that damage. So if we know telomeres shorten with age and we know short telomeres can cause a decline in health and we know lengthening those telomeres reverses the decline, then it is likely that at least some of the health related effects of aging are reversible. This is big news even if it does not result in living one day longer.

Think of it this way, in a world where we are subjected daily to ads for herbal supplements to improve prostate health, telling you that you too can have "better stream and flow," when that is just one small affect of aging, the news that telomere lengthening could result in a more widespread reversal of the symptoms of aging is huge.

[Elus]

Lengthen telomeres in healthy mice and extend their lifespan. Then I will concede that telomeres really do play a role in determining maximum lifespan.

I didn't see that as the point of the article. The research wasn't about mice living longer, it was about reversing what appear to be the signs of aging. Living longer and being health longer are not necessarily the same thing. So the only question with respect to this research is: what is the evidence that lengthening or shortening telomeres can affect the health of the organism? So far I don't see anyone contesting that shortening telomeres caused what appears to be a general decline in the health of those mice. What the research shows is that that decline in health is not a one way street. The body can repair that damage. So if we know telomeres shorten with age and we know short telomeres can cause a decline in health and we know lengthening those telomeres reverses the decline, then it is likely that at least some of the health related effects of aging are reversible. This is big news even if it does not result in living one day longer.

Think of it this way, in a world where we are subjected daily to ads for herbal supplements to improve prostate health, telling you that you too can have "better stream and flow," when that is just one small affect of aging, the news that telomere lengthening could result in a more widespread reversal of the symptoms of aging is huge.

Short telomeres have not been shown to be the cause of ill health in old individuals. The research shows we can lengthen artificially engineered short telomeres in mice.


This research does not suggest that lengthening telomeres in old individuals will lead to a reversal of aging symptoms.

Edited by Elus, 08 December 2010 - 02:47 AM.

[Gern]

Lengthen telomeres in healthy mice and extend their lifespan. Then I will concede that telomeres really do play a role in determining maximum lifespan.

I didn't see that as the point of the article. The research wasn't about mice living longer, it was about reversing what appear to be the signs of aging. Living longer and being health longer are not necessarily the same thing. So the only question with respect to this research is: what is the evidence that lengthening or shortening telomeres can affect the health of the organism? So far I don't see anyone contesting that shortening telomeres caused what appears to be a general decline in the health of those mice. What the research shows is that that decline in health is not a one way street. The body can repair that damage. So if we know telomeres shorten with age and we know short telomeres can cause a decline in health and we know lengthening those telomeres reverses the decline, then it is likely that at least some of the health related effects of aging are reversible. This is big news even if it does not result in living one day longer.

Think of it this way, in a world where we are subjected daily to ads for herbal supplements to improve prostate health, telling you that you too can have "better stream and flow," when that is just one small affect of aging, the news that telomere lengthening could result in a more widespread reversal of the symptoms of aging is huge.

Short telomeres have not been shown to be the cause of ill health in old individuals.[/i]

I didn't suggest that it did, only that damage similar to that caused by aging can be reversed.

However, there are a number of studies that correlate short telomeres with various diseases of old age. Though it is not possible to say whether they are the cause.

These mice in this research have artificially short telomeres which appear, according to the authors, to cause ill health that appears similar to the ill health of old individuals. That seems to me like it has been shown, at the very least, that either short telomeres, or whatever caused the short telomeres, causes ill health. I'm not sure what would constitute proof that the aging in these mice was the same as normal aging, or even if any such proof is possible.

Edited by Gern, 21 December 2010 - 01:39 AM.