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Data on the Aging of Stem Cells From Supercentenarian Blood


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#1 reason

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Posted 24 April 2014 - 11:49 AM


Researchers may gain some insight into the aging of stem cells and the relevance (or irrelevance) of nuclear DNA damage to aging from the analysis of blood and tissue donated by a supercentenarian:

Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells. Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulate genetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.

In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine if, over a long lifetime, mutations accumulate in healthy white blood cells. The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other. Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions." Whether stem cell exhaustion is likely to be a cause of death at extreme ages needs to be determined in future studies.

Link: http://www.eurekaler...l-hog041814.php


View the full article at FightAging
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#2 xEva

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Posted 24 April 2014 - 11:04 PM

Yet another bit in support for the idea that telomeres attrition drives aging and death.

 

 "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other. Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions." 



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#3 ceridwen

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Posted 25 April 2014 - 12:00 AM

That is really bad news for anti ageing. How could that be prevented? I am dying of dementia has that happened to my stem cells? Could increasing telomerase stop the loss of stem cells before something like this hits the rest of you? You must save your stem cells before it is too late so that you can get them replaced when you need to

#4 Turnbuckle

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Posted 25 April 2014 - 11:07 AM

Interesting, but it is just one person, after all.



#5 xEva

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Posted 25 April 2014 - 09:08 PM

Interesting, but it is just one person, after all.

 

 

beats 6 rats on c60oo :)



#6 niner

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Posted 25 April 2014 - 09:19 PM

Well, that depends on what you're looking at.  I don't really buy the "telomeres are the most important cause of aging" story that is floating about.  It's a cause, but (imho) not THE cause.  It's also something that we have agents for- the elderly would probably get significant benefit from cycloastragenol, for example.  Young people are unlikely to benefit.



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#7 xEva

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Posted 26 April 2014 - 12:35 AM

I would not agree that it's just "floating about". The evidence for it is pretty strong and comes from many different fronts. The main objection against telomeres as THE cause was the fact that mice are born with significantly longer telomeres than humans yet live much shorter lives -- until it was shown that their telomeres attrition rate was 100 times faster than human. If you plug in the numbers and calculate, the results match the lifespan data for both species. How about that?

 

While I would agree that telomeres is not the only cause, I'd estimate it at... from 2/3 to 3/4 of the whole. What would be your estimate?

 

 

.


Edited by xEva, 26 April 2014 - 12:48 AM.


#8 omega_tyrant

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Posted 26 April 2014 - 12:40 AM

I think this could put a huge dent in people's plans for reversing aging. Perhaps this is the reason why there is an upper limit  for lifespan of 115-120. Perhaps the longest living people die at that age because stem cells just exhaust themselves at that time. Perhaps there is simply no way around this? How do you rejuvenate the cells that rejuvenate our bodies?



#9 thedarkbobo

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Posted 26 April 2014 - 07:11 AM

It looks to me like another data supporting telomeres lengthening as a potential must-have for longer lifespan. Also, preventing DNA mutations?

Its all Sci-fi to me, as I'm a non-biology-doctor person :)



#10 niner

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Posted 26 April 2014 - 01:44 PM

I would not agree that it's just "floating about". The evidence for it is pretty strong and comes from many different fronts. The main objection against telomeres as THE cause was the fact that mice are born with significantly longer telomeres than humans yet live much shorter lives -- until it was shown that their telomeres attrition rate was 100 times faster than human. If you plug in the numbers and calculate, the results match the lifespan data for both species. How about that?
 
While I would agree that telomeres is not the only cause, I'd estimate it at... from 2/3 to 3/4 of the whole. What would be your estimate?


Well, pulling a number out of a semi-educated cocked hat, I'll say one fifth. The reason for this lower estimate is that if you gave everyone double the telomere length at birth, I don't see a maximum lifespan of 240 years-- mitochondrial dysfunction, glycation, the clogging of lysosomes and the systemic deposition of amyloid would have killed you... probably before you hit 120.

If we address mitochondrial dysfunction in a major way, it may have a side effect of preserving telomeres, since oxidative stress is a big telomere killer.

#11 Turnbuckle

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Posted 26 April 2014 - 03:27 PM

I doubt that telomere length has much primary effect on aging--

 

 

Individuals had relative telomere length measured twice with a 10-year interval, and were then followed for mortality and morbidity for a further 10 years after the second measurement. We found change in telomere length to be more dynamic than previously believed, as we observed both shortening (in 56%) and lengthening (in 44%) among participants. Contrary to previous beliefs, we found telomere length change to be unaffected by lifestyle factors. Instead, we found the strongest association between past telomere length and age with change in telomere length over 10 years. Also, we found no association between change in telomere length and risk of all-cause mortality, cancer, chronic obstructive lung disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease.

 

http://www.plosgenet...al.pgen.1004191

 

 

More likely short telomeres are associated with faulty mitochondria and the excess ROS produced by faulty mitochondria is the primary cause of cellular aging--

 

We found that mitochondrial function deteriorated while cells approached senescence, leading to increased ROS production. Delaying mitochondrial dysfunction led to postponed replicative senescence and slowing of telomere shortening. Prematurely senescing cells sorted out of young cultures displayed mitochondrial dysfunction, increased oxidative stress, and short telomeres. We propose that replicative telomere-dependent senescence is not "clocked," but rather is a stochastic process triggered largely by random mitochondrial dysfunction.

 

http://www.plosbiolo...al.pbio.0050110

 

 

Now the stem cells wearing out is certainty another possibility. And this was my theoretical worry about C60--that if it stimulated stem cells into differentiation into somatic cells (by its effect on mitochondria), this would produce a healthy effect in the sort run, but could result in the depletion of stem cells in the long run.

 

 


Edited by Turnbuckle, 26 April 2014 - 03:36 PM.

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#12 Avatar of Horus

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Posted 27 April 2014 - 05:38 AM

That is really bad news for anti ageing. How could that be prevented? I am dying of dementia has that happened to my stem cells? Could increasing telomerase stop the loss of stem cells before something like this hits the rest of you? You must save your stem cells before it is too late so that you can get them replaced when you need to

I think this could put a huge dent in people's plans for reversing aging. Perhaps this is the reason why there is an upper limit  for lifespan of 115-120. Perhaps the longest living people die at that age because stem cells just exhaust themselves at that time. Perhaps there is simply no way around this? How do you rejuvenate the cells that rejuvenate our bodies?

 
One possibility can be the induced pluripotent stem cells, which method rejuvenates the cells, including the telomeres, for example see this topic:
'Rejuvenated' stemcells coaxed from centenarian
http://www.longecity...om-centenarian/
 

I doubt that telomere length has much primary effect on aging--
 

Individuals had relative telomere length measured twice with a 10-year interval, and were then followed for mortality and morbidity for a further 10 years after the second measurement. We found change in telomere length to be more dynamic than previously believed, as we observed both shortening (in 56%) and lengthening (in 44%) among participants. Contrary to previous beliefs, we found telomere length change to be unaffected by lifestyle factors. Instead, we found the strongest association between past telomere length and age with change in telomere length over 10 years. Also, we found no association between change in telomere length and risk of all-cause mortality, cancer, chronic obstructive lung disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease.
 
http://www.plosgenet...al.pgen.1004191

 
More likely short telomeres are associated with faulty mitochondria and the excess ROS produced by faulty mitochondria is the primary cause of cellular aging--
 

We found that mitochondrial function deteriorated while cells approached senescence, leading to increased ROS production. Delaying mitochondrial dysfunction led to postponed replicative senescence and slowing of telomere shortening. Prematurely senescing cells sorted out of young cultures displayed mitochondrial dysfunction, increased oxidative stress, and short telomeres. We propose that replicative telomere-dependent senescence is not "clocked," but rather is a stochastic process triggered largely by random mitochondrial dysfunction.
 
http://www.plosbiolo...al.pbio.0050110

...

 


I have encountered 3 main views regarding the functional connections between telomeres/TERT and mitochondria:
one is similiar to what was quoted, namely that:

Mitochondrial dysfunction leads to telomere attrition and genomic instability
http://onlinelibrary...02.00004.x/full
Summary
Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.

 

and the second is the opposite of the above, which can be summarized as: for example:

Telomeres and mitochondria in the aging heart
http://circres.ahajo...110/9/1226.full
Abstract
Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1B in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.


another study connected to this:

Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage
http://atvb.ahajourn...t/29/6/929.long
Abstract
Objective— The enzyme telomerase and its catalytic subunit the telomerase reverse transcriptase (TERT) are important for maintenance of telomere length in the nucleus. Recent studies provided evidence for a mitochondrial localization of TERT. Therefore, we investigated the exact localization of TERT within the mitochondria and its function.
Methods and Results— Here, we demonstrate that TERT is localized in the matrix of the mitochondria. TERT binds to mitochondrial DNA at the coding regions for ND1 and ND2. Binding of TERT to mitochondrial DNA protects against ethidium bromide–induced damage. TERT increases overall respiratory chain activity, which is most pronounced at complex I and dependent on the reverse transcriptase activity of the enzyme. Moreover, mitochondrial reactive oxygen species are increased after genetic ablation of TERT by shRNA. Mitochondrially targeted TERT and not wild-type TERT revealed the most prominent protective effect on H2O2-induced apoptosis. Lung fibroblasts from 6-month-old TERT-/- mice (F2 generation) showed increased sensitivity toward UVB radiation and heart mitochondria exhibited significantly reduced respiratory chain activity already under basal conditions, demonstrating the protective function of TERT in vivo.
Conclusion— Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress–induced damage.


It is possible that both of these above are true to a degree, but that cells can be immortalized with TERT can suggest that the more important process in this regard is the second one.

And the third is that the TERT has no role outside telomere maintenance, maintained by, for example, the SENS:
http://www.sens.org/...ate-cure-cancer
but this seems to be under reexamination at present:
http://sens.org/educ...ions-telomerase


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#13 niner

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Posted 27 April 2014 - 01:23 PM

I have encountered 3 main views regarding the functional connections between telomeres/TERT and mitochondria:
one is similiar to what was quoted, namely that:

Mitochondrial dysfunction leads to telomere attrition and genomic instability
http://onlinelibrary...02.00004.x/full
Summary
Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.

 
and the second is the opposite of the above, which can be summarized as: for example:

Telomeres and mitochondria in the aging heart
http://circres.ahajo...110/9/1226.full
Abstract
Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1B in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.

Thanks for pulling together these interesting references, Avatar. I think this apparent contradiction can be explained: In the second paper, the mice were completely lacking telomerase. This resulted in rapid loss of telomeres, inducing the various forms of dysfunction they describe. In a human, the loss of telomeres is much slower, and until the telomeres reach a critical length, they will not give rise to any of the problems seen in the telomerase -/- mouse. On the other hand, mitochondrial dysfunction begins at a much earlier age, as the seeds of it are sown beginning at conception. Thus, from a relatively early age, you have an ever-increasing number of cells in which dysfunctional mitochondria are not only damaging other cellular components but also ablating telomeres. Eventually the telomere damage will begin to contribute to overall decline, but it occurs late in the game.

It is possible that both of these above are true to a degree, but that cells can be immortalized with TERT can suggest that the more important process in this regard is the second one.

Maybe cells that are rapidly proliferating in culture can be (apparently) immortalized with constitutively active TERT, but in the slowly proliferating in vivo case, I think mitochondrial damage will lead to problems before telomere loss does. A lot of important human cells are very long-lived, so loss of telomeres from replication isn't a problem for them.
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#14 Turnbuckle

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Posted 27 April 2014 - 01:44 PM

An interesting opinion piece addressing three causes of aging: telomere shortening, mitochondria dysfunction, and stem cell depletion--

 

Axis of ageing: telomeres, p53 and mitochondria

 

Abstract
Progressive DNA damage and mitochondrial decline are both considered to be prime instigators of natural ageing. Traditionally, these two pathways have been viewed largely in isolation. However, recent studies have revealed a molecular circuit that directly links DNA damage to compromised mitochondrial biogenesis and function via p53. This axis of ageing may account for both organ decline and disease development associated with advanced age and could illuminate a path for the development of relevant therapeutics.
 
 
 

 

 

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#15 xEva

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Posted 28 April 2014 - 03:24 AM

On the other hand, mitochondrial dysfunction begins at a much earlier age, as the seeds of it are sown beginning at conception. Thus, from a relatively early age, you have an ever-increasing number of cells in which dysfunctional mitochondria are not only damaging other cellular components but also ablating telomeres.

 

Interesting, any references for this?

 

This description does not match what I see. And what I see is that 'young' people (before ~35, if one got decent genes) appear to have remarkable capacity for healing and damage repair  -- until they hit 40 or so, following which things begin to deteriorate noticeably, and then just keep gettting progressively worse. This fits short telomeres as the cause. 

 

In the view you propose, aging happens gradually from the moment of conception (!) Sorry, but I just don't see it.  What I see is that healthy young people are.. well, young.  


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#16 Turnbuckle

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Posted 28 April 2014 - 09:07 AM

This paper proposes that mitochondria age first and it is the build-up of defective mitochondria in some cells and organs that kills the organism. The authors developed a mutant strain of mice with a defective mitochondrial repair mechanism--

 

To test the causative role of mtDNA mutations in aging we have developed the mtDNA mutator mouse that accumulates high levels of point mutations due to a proofreading deficiency of the mitochondrial DNA polymerase (POLG) [12]. Subsequently, a very similar model was developed by another group [13]. The two mouse models show basically the same phenotypes, differing only in the time of onset of phenotypes. In our hands, mtDNA mutator mice are born in Mendelian proportions, without any visible defects, but after 6-7 months they start to display a range of premature aging phenotypes, such as a weight loss, reduced subcutane-ous fat, alopecia, kyphosis, osteoporosis, anaemia, reduced fertility, heart disease, sarcopenia, progressive hearing loss and decreased spontaneous activity [12]. Their lifespan is also greatly reduced compared with wild-type littermate controls and they die at around 46 weeks of age.

 

...

 

So what have we learned from the mtDNA mutator mouse? Are mtDNA mutations relevant in normal aging? Clearly wt mice never accumulate the same level of point mutations as mtDNA mutator mouse. They do, however, acquire mitochondrial dysfunction with old age, as do the mtDNA mutator mice. This indicates mitochondrial dysfunction as not only being correlated to aging, but also causative. Results from mtDNA mutator mice clearly show that mutations in mtDNA can cause problems that resemble premature aging...

 

http://www.ncbi.nlm....les/PMC2815752/

 

 

 

And another paper of interest--The Role of the Mitochondrial Genome in Ageing and Carcinogenesis

 

The second result was perhaps less spectacular than those obtained with the mutator mouse but is very important for solving the problem of whether and how low levels of mitochondrial DNA mutations can affect the functioning of cells. Dufour et al. [91] found that a mitochondrial respiratory chain deficiency in neurons which was caused by a nuclear mutations when present in only 20% of the mitochondria caused degeneration of adjacent neurons. This points to a solution of the problem that the levels of mutations found in aging tissues are too low.

 

 


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#17 niner

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Posted 29 April 2014 - 12:27 AM

 

On the other hand, mitochondrial dysfunction begins at a much earlier age, as the seeds of it are sown beginning at conception. Thus, from a relatively early age, you have an ever-increasing number of cells in which dysfunctional mitochondria are not only damaging other cellular components but also ablating telomeres.

 
Interesting, any references for this?
 
This description does not match what I see. And what I see is that 'young' people (before ~35, if one got decent genes) appear to have remarkable capacity for healing and damage repair  -- until they hit 40 or so, following which things begin to deteriorate noticeably, and then just keep gettting progressively worse. This fits short telomeres as the cause. 
 
In the view you propose, aging happens gradually from the moment of conception (!) Sorry, but I just don't see it.  What I see is that healthy young people are.. well, young.

 


I agree that it looks like aging isn't happening until people reach well into adulthood, but that's because the damage has not yet reached the threshold level at which it begins to cause functional decline.

Molecular damage is a function of metabolism-- Mitochondria generate ROS as a consequence of oxidative phosphorylation, so as long as you are respirating, you will have some level of oxidative damage. Glycation of proteins occurs when sugars are present in the system, and since glucose is the primary fuel for most people, and glucose is maintained at a relatively high concentration in plasma, we are glycating steadily the entire time we are alive. But humans have enough molecular reserves to maintain a youthful organism for a long time, until the damage finally reaches a level that becomes apparent to the naked eye. If you look at the molecular level, you will find evidence of aging damage even in the youngest tissues. If skin is imaged in the UV, you can see evidence of photodamage in children as young as five. When my children were only a few years old, their skin was incredibly soft and smooth. Today they are 12 and 14, and their skin, while still youthful, is clearly on the way to being adult skin. They are accruing aging damage before my eyes.

Aubrey de Grey and Michael Rae address the concept of the threshold level of aging damage on page 196 of Ending Aging.


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#18 xEva

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Posted 29 April 2014 - 09:50 PM

Aubrey de Grey and Michael Rae address the concept of the threshold level of aging damage on page 196 of Ending Aging.

 

 

You must mean this:

 

"...remember that the molecular damage underlying aging begins accruing while we are still in our mothers' wombs, yet we remain youthful well into our thirties: it takes many decades of these insults before the amount of damage is sufficient to exert a functional impact on our bodies."

 

That's his opinion. He is talking about AGEs induced cross-linking, but I see no evidence of it in healthy children or even healthy adults <35.

 

In healthy, young people, there is no molecular damage that is not subject to built-in repair mechanisms. It's only when the rate of damage outruns the rate of repairs that "aging" becomes temporarily visible in young people. But from what I've seen, as long as a person is still young and healthy, the damage is repaired soon after the damaging influence is removed.

 

And aging is visible. You can see It plainly in children afflicted with various forms of progeria. The only "invisible aging" that goes on from the moment of conception, in healthy people, is telomere attrition -- but you downplay its importance.  

 

The correlation between age and telomere length, as well as between short telomeres and all-cause mortality, is strong and undeniable. Even the papers from which Turnbuckle quoted (out of context) agree with this. 

 

Turnbuckle gave the quote about individual dynamic changes in telomere length, which speaks more of the problems associated with the testing method itself than the lack of association between the telomere length and lifestyle, age or fitness. This problem with the test waacknowledged in that paper (basically, measuring telomeres in leukocytes in order to assess the fitness of an individual appears pretty useless -- unless it is done repeatedly in a stretch of time, for only then more or less accurate picture can be obtained -- but then it should confirm the person's age, so why bother.)

 

 

And so the argument here boils down to what's primary, damaged mitochondria that drive the telomere attrition rate by their inordinate ROS production -- or short telomeres that induce the cell cycle arrest and thus prevent access to nuclear encoded proteins needed for repair and maintenance of mitochondria. Sort of the chicken or the egg problem.

 

Well, I can see how damaged mitochondria can accelerate the telomere attrition rate. Still, as long as telomeres are not yet critically short, given a chance, mitochondria should be able to repair. That's why I think that telomeres are primary in this game. And Vince from anti-aging firewalls seems to agree here :

 

Recapitulating the steps of what happens:

  1. Telomere dysfunction =>
  2. DNA damage response =>
  3. p53 levels go up =>
  4. High p53 inhibits the expression of both PGC-1a and PGC-1b
  5. Genes for nuclear encoded mitochondrial proteins will NOT be expressed, as a result

Edited by xEva, 29 April 2014 - 09:56 PM.


#19 niner

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Posted 30 April 2014 - 12:24 AM

 

Aubrey de Grey and Michael Rae address the concept of the threshold level of aging damage on page 196 of Ending Aging.

 
You must mean this:
 

"...remember that the molecular damage underlying aging begins accruing while we are still in our mothers' wombs, yet we remain youthful well into our thirties: it takes many decades of these insults before the amount of damage is sufficient to exert a functional impact on our bodies."

 

That's his opinion. He is talking about AGEs induced cross-linking, but I see no evidence of it in healthy children or even healthy adults <35.

 

Aubrey and Michael's opinion is based on an awful lot of science, and is worth more than most people's on the topic of the molecular causes of aging.

The reason you see no evidence of aging in healthy children or healthy adults under 35 is because you are just looking with your eyes. If you look for damage using the appropriate analytical tools, you will see it. If you don't see aging in adults in their early 30's, you must be hanging out with some awfully healthy people. Really, 35? That is seriously on the downhill slope, imho.
 

In healthy, young people, there is no molecular damage that is not subject to built-in repair mechanisms. It's only when the rate of damage outruns the rate of repairs that "aging" becomes temporarily visible in young people. But from what I've seen, as long as a person is still young and healthy, the damage is repaired soon after the damaging influence is removed.
 
And aging is visible. You can see It plainly in children afflicted with various forms of progeria. The only "invisible aging" that goes on from the moment of conception, in healthy people, is telomere attrition -- but you downplay its importance.  

The correlation between age and telomere length, as well as between short telomeres and all-cause mortality, is strong and undeniable. Even the papers from which Turnbuckle quoted (out of context) agree with this.


What is the evidence that we are clearing damage as fast as it is created at any point in our lives? We certainly aren't clearing crosslinks in the extracellular matrix anywhere close to the rate we are creating them.

I downplay the importance of telomere shortening until they are short enough to cause a problem. The P53 response that Watson wrote about in Vince's blog is a response to critically short telomeres, I'd think. The kind of shortening you see early in life, when you might have lost a thousand bases, how is that going to hurt anything? It's not kicking off a DNA damage response as far as I'm aware.
 

And so the argument here boils down to what's primary, damaged mitochondria that drive the telomere attrition rate by their inordinate ROS production -- or short telomeres that induce the cell cycle arrest and thus prevent access to nuclear encoded proteins needed for repair and maintenance of mitochondria. Sort of the chicken or the egg problem.
 
Well, I can see how damaged mitochondria can accelerate the telomere attrition rate. Still, as long as telomeres are not yet critically short, given a chance, mitochondria should be able to repair. That's why I think that telomeres are primary in this game.

 

The problem is that mitochondria are self-damaging. They don't need telomeres to damage them, and in addition to that, they create damaging ROS as part of their normal operation. These ROS damage various molecular components, including telomeres, but the mitochondria are right in the line of fire, and suffer because of it. Here is an overview of the way in which mitochondria cause aging damage from an old post by Reason at FightAging.



#20 xEva

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Posted 30 April 2014 - 08:58 AM

The idea that aging 'starts in a womb' is very old; and the problem with old ideas is that we get accustomed to them to the point that we stop questioning their validity. It took hold well before telomeres became known, or when there was no reasonable explanation why we should experience a noticeable change at a certain age. Now that telomeres explain this 'downhill from now on' observation, I see no reason to pretend that aging is invisible until "the amount of damage is sufficient to exert a functional impact on our bodies". To the contrary, we are able to accurately judge the degree of aging, fitness and health of an individual at a glance. Millions of years of evolution taught us this invaluable for our species' survival skill.
 

The reason you see no evidence of aging in healthy children or healthy adults under 35 is because you are just looking with your eyes. If you look for damage using the appropriate analytical tools, you will see it. If you don't see aging in adults in their early 30's, you must be hanging out with some awfully healthy people. Really, 35? That is seriously on the downhill slope, imho.


Eyes can see plenty. Again, the only undeniable, plainly seen aging in children is when they have progeria or are otherwise chronically sick. 
 
35 is "seriously on the downhill slope"? Really? Even de Grey in the quote you first referred to says "yet we remain youthful well into our thirties". While this may not apply to an average fat American on a junk food diet, there is plenty of healthy people well into their 30s who look (and function) indistinguishable (if not better) from those who have just reached adulthood, which is 22-25.

So it would appear that we --well, the healthy lot of us-- enjoy lack of aging for about 10-15 years after we reach adulthood and then.. what happens then? Why sudden change? According to your/de Grey model, this change should happen gradually. Instead, it arrives quite noticeably at around 40 or so (earlier for fat Americans). After that date, but not before it, aging does accrue gradually, snowballing toward the end. More and more cells running out of telomeres, which hampers their and their organs' ability to repair, fits this description very well.

 

What is the evidence that we are clearing damage as fast as it is created at any point in our lives?


What is the evidence that we don't, as long as we "remain youthful"? Your/de Grey argument that aging is "invisible until..." is an old speculation unsupported by actual evidence. Please show a study that shows 'aging', other than telomere attrition, in a fetus.
 
 

I downplay the importance of telomere shortening until they are short enough to cause a problem. The P53 response that Watson wrote about in Vince's blog is a response to critically short telomeres, I'd think. The kind of shortening you see early in life, when you might have lost a thousand bases, how is that going to hurt anything? It's not kicking off a DNA damage response as far as I'm aware.


I'm glad we agree that shortening telomeres don't cause a problem until they get too short, and that's why we don't see it early in life, when a loss of a thousand bases certainly doesn't hurt anything. I believe the problem starts manifesting when we get about 40 or so (earlier for fat, spoiled Americans :)). According to you, at what age do we reach this problem?
 
 

The problem is that mitochondria are self-damaging. They don't need telomeres to damage them, and in addition to that, they create damaging ROS as part of their normal operation. These ROS damage various molecular components, including telomeres, but the mitochondria are right in the line of fire, and suffer because of it.


No one claimed that mitochondria "need telomeres to damage them". I merely pointed out that, according to the literature, so nicely summarized on Vince's blog, critically short telomeres induce cell cycle arrest and in doing so prevent access to nuclear coded mitochondrial proteins, without which they can't repair. Speaking of which, you seem to also downplay mitochondrial repair mechanisms -- why? They exist and function just fine. They mostly work during fasting though. I don't recall you or Turnbuckle speaking highly of fasting. Maybe that's why you guys seem unaware of how well the body is capable of fixing itself when given a chance -?

Edited by xEva, 30 April 2014 - 09:26 AM.


#21 xEva

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Posted 30 April 2014 - 10:08 PM

Here is an overview of the way in which mitochondria cause aging damage from an old post by Reason at FightAging.


I saw this review, as well as de Grey paper on which it is based, where the same sad scenario is described. Unfortunately, de Grey missed an important mechanism of mitochondrial quality control, and, in many years that passed since, I have not seen an update or correction, even though the information existed back when his paper was first published and has remained essentially unchanged. 
 
First, the pertinent points, with my bolding of troublesome statements:
  • The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.
  • BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.
That a damaged mitochondrion "will never get broken down by a lysosome" is simply not true. Missing in this picture is what goes on during a fast, when a cell is starving -- and this omission is not particularly surprising, since an openly negative attitude toward fasting by the key members is well known on this board. I don't recall de Grey ever mentioning fasting, while Rae never missed an opportunity to pooh-pooh it whenever the subject came up -- and it came up many times, since it has long been known that autophagy is crucial for cellular upkeep and repair, and nothing upregulates autophagy quite as well as fasting. Despite this, I remember way back when the board was still on the old server and went by a different name, one of the ImmInst's 'founding fathers' (don't recall now exactly who) loudly declared that fasting was "uncivilized". And so in such a setting, it's no wonder that many people here have, to put it mildly, incomplete knowledge (coupled with the unwavering belief that what we don't know can't possibly be important :)).
 
Here is a brief description of what's missing in de Grey scenario: When a cell is starving, all forms of macroautophagy are greatly upregulated. But even before autophagy is unleashed in a starving cell in earnest, soon after the scarcity of nutrients is sensed, mitochondria begin to fuse into large thread-like aggregates. (Apparently, mitochondria were first observed in a starving cell, hence the origin of the name: mitochondria means thread-like -- this usually comes as a surprise to people who are accustomed seeing illustrations depicting unitary, barrel-shaped objects). 
 
Now, there are two relevant reasons why mitochondria fuse into large, thread-like aggregates when nutrients become scarce.  First, this helps them to generate more energy for the cell, thus increasing ATP output for a given input. The second reason is crucial here: this prevents them from being gobbled up when indiscriminate autophagy starts raging in a starving cell. And when indiscriminate autophagy is raging in a cell, just about any protein 'lying around unattended' or any organelle small enough to fit into an autophagasome 'mouth' gets recycled. Please note: in the conditions of starvation, no additional tags or special signaling is required. Now note this: because damaged mitochondria are unable to fuse with the healthy ones, they remain in unitary form and thus become easy pickings for autophagasomes.

This is how damaged mitos get recycled in a starving cell that's been missing in de Grey paper and  => Reason's review. 
 
And BTW, this is just one of many beneficial things that go on during a fast that explains how "not eating for a stretch" can both heal and rejuvenate.

Edited by xEva, 30 April 2014 - 10:36 PM.


#22 niner

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Posted 01 May 2014 - 03:45 AM

Ok, I knew you were into fasting, but I didn't know that you felt under attack about it from anyone here.  You never got attacked by me, at least.  There's a lot of zealotry in this field- I mostly see it among vegans and CRonies.  (Some of them, anyway).  I don't think that you are a fasting zealot, but your ideas about the molecular damage that underlies aging are clearly influenced by your fasting practice.  That's ok, providing they are correct. 
 
Rather than muddy the waters with mitochondria and telomeres, lets just talk about glycation.  I presume you agree that glycation is a significant form of aging damage-- The crosslinking of proteins in the extracellular matrix (ECM) results in the loss of elasticity in skin, the vasculature, and other tissues.  The glycation of our tissues is like clockwork, gradually getting worse as we age, and the flexibility of skin can even be used to estimate age reasonably accurately.   The structural proteins in the ECM are turned over very slowly, which results in crosslinks building up over time.  Is it your position that fasting induces sufficiently rapid turnover of ECM tissues that crosslinks are eliminated? 
 
Here's a paper that looks at age-related glycation in the intervertebral disc:
 

Soud Lek. 2007 Oct;52(4):60-4.
Contents of pentosidine in the tissue of the intervertebral disc as an indicator of the human age.
Pillin A1, Pudil F, Bencko V, Bezdícková D.

The study deals with the post-translational modifications of proteins - glycation of the tissue of the intervertebral disc and determination of one of advanced glycation end's products - pentosidine in the relation to the age. Pentosidine was detected in the hydrolysate of the intervertebral discs from persons between the ages of 16 and 95 years. 142 samples were analysed by high performance liquid chromatography, and the detected amounts of pentosidine were processed statistically. The coefficient of correlation of dependence of the amount of pentosidine on the age amounts to r = 0.92. The results of the work testify to the fact that it is possible to use the detection of pentosidine in the tissue of the intervertebral disc for the estimation of the age. Nevertheless subsequent experiments should be done under different conditions post-mortem decomposition.

PMID: 18189072


There is clearly a very high correlation between age and glycation. That is entirely consistent with crosslinks being accrued at a constant rate, and given that they are formed as a function of blood glucose concentration, I can't see how they would not be formed beginning in the womb. Would it be your position that crosslinks are cleared if people fast long enough? If that's the case, do people who practice fasting reach old age with child-like collagen? It sounds like you are saying that all the forms of aging damage that we know of, with the exception of telomere attrition can be repaired by extreme fasting. Is there any published evidence that this is the case?

#23 xEva

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Posted 02 May 2014 - 01:38 AM

There is hardly any studies of fasting, since there is no money in it => no published evidence of any sort. Most studies were done in the 70s, usually on obese people. But there are plenty of anecdotal reports of skin improvement following a fast. A fast improves everything and skin is the most visible, of course.

Re glycation, I would assume that clearance of cross-linking is sped up during a fast -- after all, the body is looking for stuff to eat. But I also think that improvement in appearance of skin and eyes --they become luminous and clear and the whites acquire a slight bluish hue-- is due to clearance of extracellular fluid. In a very old Russian paper, I remember, they looked at plasma and marveled how crystal-clear it becomes. I imagine, removing extraneous proteins should have an overall positive effect on ECM, skin and connective tissue. It certainly looks like it.

Edited by xEva, 02 May 2014 - 02:20 AM.


#24 niner

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Posted 02 May 2014 - 02:23 AM

and I don't know about glycation in a fetus. ..I certainly do not consider a fetus aging nor do I see 'aging' in children and even in healthy adults <35. Skin is perfect, no wrinkles whatsoever and no sagging godforbid of any sort. Where is aging? Somewhere deep deep down on the molecular level? Why there is no sign of it on the surface? In my understanding, aging is plainly visible, just as radiant health is plainly visible.


Yes, I'm talking about aging damage at the molecular level. You can't see it with your eyes, you need instrumentation. Aging doesn't become visible to the eyes until the molecular damage exceeds the reserve capacity of the body. That takes a while, though with enough sun exposure, a light complected person can wreck their skin by their mid twenties. Photodamage is different than intrinsic aging, but it is the number one cause of visible skin aging. For most people, the vast majority of their photodamage occurs by the time they are 18, although it may take more time to fully manifest as visible problems.

How long would a person need to fast in order to see improvement in skin? Would this also extend to vasculature and other tissues?

#25 xEva

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Posted 02 May 2014 - 04:13 AM

Even short fasts (couple of days) improve complexion. A good length is couple of weeks. But one should not go for a fast this long off the bat, especially if a person is older. It is best to start with weekly 24-36h fasts, then try a longer fast.

#26 Brett Black

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Posted 03 May 2014 - 03:22 AM

To the contrary, we are able to accurately judge the degree of aging, fitness and health of an individual at a glance.

What's your definition of biological aging?

Here's a study that may have some relevance:

1. J Gerontol A Biol Sci Med Sci. 1998 Sep;53(5):M347-50.

Longevity and gray hair, baldness, facial wrinkles, and arcus senilis in 13,000
men and women: the Copenhagen City Heart Study.

Schnohr P(1), Nyboe J, Lange P, Jensen G.

Author information:
(1)Epidemiological Research Unit, National University Hospital, Copenhagen, Denmark.
PeterSchnohr@dadlnet.dk

BACKGROUND: We have previously reported that men who look older than their
contemporaries have a significantly higher risk for myocardial infarction. The
purpose of this study was to investigate whether persons with pronounced aging
signs such as graying of hair, baldness, or facial wrinkles are prone to a
shorter life span compared to their contemporaries.

METHODS: In the Copenhagen City Heart Study comprising a random sample of 20,000
men and women, we also recorded, in addition to cardiovascular risk factors, data
on signs of aging: extent of gray hair, baldness, facial wrinkles, and arcus
senilis (corneal arcus). During 16 years of follow-up, 3,939 persons (1,656 women
and 2,283 men) had died. The Cox regression model for proportional hazards, which
included age as an explanatory variable, was used for descriptive analysis of the
correlation between these aging signs and all-cause mortality.

RESULTS: We found no correlation between the mortality and the extent of graying
of the hair, or baldness or facial wrinkles in either of the sexes, irrespective
of age. A single exception was observed in a small subgroup of men with no gray
hair. They had a slightly, but significantly, lower mortality than the rest
[relative risk (RR) = .81, 95% confidence interval (CI) .67-.98; p < .05]. The
presence of arcus senilis was significantly correlated with a shorter life span
in women (RR = 1.25, 95% CI 1.08-1.46; p < .01). For men the same tendency was
found, but the correlation was not statistically significant.

CONCLUSION: We conclude that the degrees of graying of the hair, baldness, and
facial wrinkles are not predictive of a shorter life span in men and women in the
Copenhagen City Heart Study.


PMID: 9754140 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm..../pubmed/9754140

 
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#27 Brett Black

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Posted 03 May 2014 - 04:05 AM

Interesting, any references for this?
 
This description does not match what I see. And what I see is that 'young' people (before ~35, if one got decent genes) appear to have remarkable capacity for healing and damage repair  -- until they hit 40 or so, following which things begin to deteriorate noticeably, and then just keep gettting progressively worse. This fits short telomeres as the cause. 
 
In the view you propose, aging happens gradually from the moment of conception (!) Sorry, but I just don't see it.  What I see is that healthy young people are.. well, young.  

Fetuses can heal wounds without forming scars, and children can regenerate amputated fingertips and perfectly heal bone fractures; capabilities that are lost by early adulthood.

Edited by Brett Black, 03 May 2014 - 04:09 AM.


#28 xEva

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Posted 03 May 2014 - 03:25 PM

What's your definition of biological aging?

Here's a study that may have some relevance:

 
I don't have a "definition of biological aging" other than what can by assessed at a glance. In this definition children and young adults are clearly not old. And then why reject the obvious and instead look for invisible signs of molecular damage and, based on this, uphold the absurdity that a newborn 'is already aged'. In such a definition only freshly synthesized molecules can be qualified as 'young'.

As for the study you linked, "pronounced aging signs" have no relevance to my endorsement of a novel idea that modern healthy humans enjoy lack of aging for 10-15 years after reaching adulthood. 'Lack of aging' obviously precludes presence of any visible aging signs.

 

Fetuses can heal wounds without forming scars, and children can regenerate amputated fingertips and perfectly heal bone fractures; capabilities that are lost by early adulthood.


Yes, thank you Brett. And I recall years ago there was a 60+ y.o. man who regenerated severed fingertip, albeit with the help of "pixie dust" which was.. ECM powder derived from pig bladder -? The info is still floating around the Net.



I read up on telomeres in the last few days, and I'm sorry to say that with them SENS appears to be missing the boat, just like it did with fasting. Even if telomere attrition is not THE driving force but merely yet another symptom of aging, as long as this symptom can be helped --and it looks like there are ways-- IMO it would be stupid not to go for it.

#29 Brett Black

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Posted 04 May 2014 - 04:30 AM

xEva,

I don't have a "definition of biological aging" other than what can by assessed at a glance. In this definition children and young adults are clearly not old. And then why reject the obvious and instead look for invisible signs of molecular damage and, based on this, uphold the absurdity that a newborn 'is already aged'.


The SENS hypothesis is that "biological aging" (which is defined as the gradual accumulation of molecular-level damage) is an unavoidable side-effect of normal human metabolism. Since normal human metabolism extends right back to birth (at least), the hypothesis predicts that aging (molecular-level damage) will be occurring even at the earliest stages of life. This forms the rationale for SENS to look for such "invisible signs", even potentially in young macroscopically healthy-looking humans.

In the above quote, you appear to be equating "aging" with "old", but I don't think SENS or Aubrey De Grey or niner equate these two. In many of his presentations Aubrey makes the point that before about age 40, most humans do not experience any signifucant age-related dysfunction. He suggests that this is due to the human body being able to tolerate a certain level of molecular-level damage before dysfunction becomes subjectively noticeable. In other words, I believe De Grey(and probably niner too) suggests that whilst aging (molecular-level damage) occur from at least birth, it is only once a certain level of such damage has accumulated that a person would then be defined as "old"(ie suffering sufficient age-related dysfunction.)

I read up on telomeres in the last few days, and I'm sorry to say that with them SENS appears to be missing the boat, just like it did with fasting. Even if telomere attrition is not THE driving force but merely yet another symptom of aging, as long as this symptom can be helped --and it looks like there are ways-- IMO it would be stupid not to go for it.


My impression is that Aubrey De Grey isn't dogmatic about SENS. I could be wrong, but I seem to recall hearing him readily express the possibility that SENS could be wrong/flawed. Therefore, if sufficiently countervailing evidence is brought to his attention he may alter his stance.

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#30 Brett Black

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Posted 04 May 2014 - 06:04 AM

In healthy, young people, there is no molecular damage that is not subject to built-in repair mechanisms. It's only when the rate of damage outruns the rate of repairs that "aging" becomes temporarily visible in young people. But from what I've seen, as long as a person is still young and healthy, the damage is repaired soon after the damaging influence is removed.

The largest age-related cause of death has origins in molecular damage/events that are already visible in early childhood, just as SENS suggests:

1. Am J Clin Nutr. 2000 Nov;72(5 Suppl):1307S-1315S.

Origin of atherosclerosis in childhood and adolescence.

McGill HC Jr(1), McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP.

Author information:
(1)University of Texas Health Science Center at San Antonio, Texas, USA.
hmcgill@icarus.sfbr.org

Atherosclerosis begins in childhood as deposits of cholesterol and its esters,
referred to as fatty streaks, in the intima of large muscular arteries.
In some
persons and at certain arterial sites, more lipid accumulates and is covered by a
fibromuscular cap to form a fibrous plaque. Further changes in fibrous plaques
render them vulnerable to rupture, an event that precipitates occlusive
thrombosis and clinically manifest disease (sudden cardiac death, myocardial
infarction, stroke, or peripheral arterial disease). In adults, elevated
non-HDL-cholesterol concentrations, low HDL-cholesterol concentrations,
hypertension, smoking, diabetes, and obesity are associated with advanced
atherosclerotic lesions and increased risk of clinically manifest atherosclerotic
disease. Control of these risk factors is the major strategy for preventing
atherosclerotic disease. To determine whether these risk factors also are
associated with early atherosclerosis in young persons, we examined arteries and
tissue from approximately 3000 autopsied persons aged 15-34 y who died of
accidental injury, homicide, or suicide. The extent of both fatty streaks and
raised lesions (fibrous plaques and other advanced lesions) in the right coronary
artery and in the abdominal aorta was associated positively with
non-HDL-cholesterol concentration, hypertension, impaired glucose tolerance, and
obesity and associated negatively with HDL-cholesterol concentration.
Atherosclerosis of the abdominal aorta also was associated positively with
smoking. These observations indicate that long-range prevention of
atherosclerosis and its sequelae by control of the risk factors for adult
coronary artery disease should begin in adolescence and young adulthood.

PMID: 11063473 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm....pubmed/11063473

SENS also provides both a framework (the LysoSENS approach):
http://sens.org/rese...ular-aggregates

and now even the possible beginnings of an actual practical treatment for atherosclerosis based on this approach:
http://www.sens.org/...atherosclerosis

Edited by Brett Black, 04 May 2014 - 06:06 AM.


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