266 replies to this topic

[xEva]

Last spring an idea about the causes of aging sprouted in my mind. As a result of a recent discussion, it finally consolidated. Below is my brief definition of aging and logical approach to it.

Aging is the progressive failure of the existing repair mechanisms to do their job.

I know many will disagree, as this discussion shows (but it has not convinced me), still, I claim that these repair mechanisms exist and work fine while we're young, which our youthfulness well into our 20s, and often late 30s, amply demonstrates.

This is a better definition, because it offers a tangible goal and pragmatic approach:

 

identify these mechanisms as well as the causes of their failure, and then find ways to upregulate them.

No need to invent anything new.

 

 

 thoughts?

[Danail Bulgaria]

Hi xEva!

 

Even though, that I have a different idea about "the causes of aging", and I have developed my own theory in my mind, that explains them, I must admit, that your theory is not bad at all.

 

I am sure, that I red somewhere a theory, that was dealing with the aging as a progressive decrease of the homeostasis. Since the homeostasis is provided by repair and regulatory mechanisms, then yes, "failure of the existing repair mechanisms" can cause the aging.

[Kevnzworld]

I agree to a point. There is a progressive decline in many bodily functions, not just the repair ones, all of which accelerate the aging process as it progresses. Immunosenescence is an obvious result of the deterioration of the body's repair mechanisms. Glands like the thymus shrink during the aging process. Declining hormone levels, NAD levels, CoQ10 production, muscle creatine levels all help contribute to the acceleration of aging as one gets older. Insulin resistance increases during aging which accelerates glycation. The body's repair mechanisms and it's ability to discard the cellular junk like lipofuscin decline, but may be helped if other bodily functions are supported. I believe that they are all interrelated.
Whether or not any of the " stop gap " replacement and support strategies that life extensionist's use to ameliorate this decline actually will work meaningfully is unknown , but I have to believe they may be semi effective, at least in terms of a 5-10% increase in healthy lifespan at minimum. ( bio identical hormone replacement, NR+ resveratrol , creatine, Metformin , IP6, maitake mushroom, thymus extract, amour thyroid extract etc ).

Edited by Kevnzworld, 01 December 2014 - 09:10 PM.

[niner]

This progressive failure of repair mechanisms idea is a hypothesis, not a theory, since it's not supported by any data, AFAIK.  On the other hand, it is contradicted by various published work, some of which is posted in the thread that xEva linked.  The idea would be right with a subtle modification-- that some of our repair mechanisms are inadequate, period.  I guess that's not really so subtle, though. 

 

I like to think of aging as a "snowball effect".  Some of you might not be familiar with this idiom, so allow me to explain:  Under certain weather conditions, snow acts kind of sticky.  If you make a small snowball and roll it down a hill, it picks up more and more snow as it rolls, becoming ever larger.  This has become a popular metaphor, which Wikipedia defines as:

 

 

Metaphorically, a snowball effect is a process that starts from an initial state of small significance and builds upon itself, becoming larger, and also perhaps potentially dangerous or disastrous, though it might be beneficial instead.

 

In the case of aging, initial small problems are insignificant, but they eventually feed back on other cellular and organismic systems in ways that become much worse.  One way this happens is by defective mitochondria becoming unable to trigger mitophagy, due to the very defect that makes it important to get rid of them.  They instead take over the cell, causing all manner of problems.  Another example is that damaged cells  may become senescent, and then the trouble really begins.  Not only do they lose the ability to kill themselves (apoptosis), but they become very bad cellular citizens, churning out inflammatory mediators that sicken other cells in the vicinity.  This "Senescence Associated Secretory Phenotype", or SASP, is a major problem in the elderly.  It doesn't become apparent until other forms of damage get bad enough for the cell to enter the senescent zombie state.  These kinds of "snowball effects" explain the accelerating decline that we observe late in life.

[xEva]

This progressive failure of repair mechanisms idea is a hypothesis, not a theory, since it's not supported by any data, AFAIK. On the other hand, it is contradicted by various published work, some of which is posted in the thread that xEva linked.  The idea would be right with a subtle modification-- that some of our repair mechanisms are inadequate, period.  I guess that's not really so subtle, though.

I hold it self-evident that the repair mechanisms exist and do an excellent job keeping us young for 25-35 years. It is only when they start failing that we begin to age, or "accumulate damage" in your and SENS definition. This goes in contrast to your position that damage starts accumulating in utero, which implies that a newborn is already "aged". I cannot disagree more. Damage does occur all the time but is continuously repaired. The efficiency of these repairs correlates with youth. Again, damage starts accumulating only when these repair mechanisms start failing.

And how can you say "not supported by any data"? Where is the evidence that water is wet? If it were not for these repair mechanisms, we all would age at about the same rate, yet there is a wide variation in the age at which people start getting visibly aged. That these repair mechanisms can be upregulated with fasting or CR, resulting in rejuvenation, is also evidence. If it were not for these repair mechanisms, rejuvenation due to a fast would not be possible in principle. And, as it was discussed in that thread, the best evidence are various in-born syndromes, from Xenoderma Pigmentosum to various forms of progeria, that show what happens when some of these repair mechanisms don't work.


And contradicts what published work? In that thread you posted the study that correlated skin damage with age. The median age of their cohort was 43-47. That work only confirmed what anyone can assess with a naked eye. Please link a study that shows that "damage accumulates" in a young cohort.

Edited by xEva, 02 December 2014 - 05:27 AM.

[xEva]

@ seivtcho, Kevnzworld: dysregulation of homeostasis, progressive decline in bodily functions, declining hormone levels, insulin resistance, accelerated glycation... -- where is the cause in all this? If we are to accept that the items on the list are the products of various cells' functions, working singularly and in concert, then it is not difficult to see that the lack of a timely repair of damage sustained by one component of the whole may cause some other component to stutter. ..and then it snowballs right, niner?

And niner, SENS' notion that "defective mitochondria [are] unable to trigger mitophagy, due to the very defect that makes it important to get rid of them" is WRONG. This was already discussed in the thread last spring.

[Kevnzworld]

@ seivtcho, Kevnzworld: dysregulation of homeostasis, progressive decline in bodily functions, declining hormone levels, insulin resistance, accelerated glycation... -- where is the cause in all this? If we are to accept that the items on the list are the products of various cells' functions, working singularly and in concert, then it is not difficult to see that the lack of a timely repair of damage sustained by one component of the whole may cause some other component to stutter. ..and then it snowballs right,

The cause is genetic, programmed. It can be modified or accelerated by poor lifestyle, as we all witness. Unfortunately it's doubtful that optimal lifestyle ( CR etc ) can decelerate the genetic process.
The stop gap measures that many of us employ, may be successful at squaring the curve by reducing the probabilities of an early demise from cancer or cardiovascular disease.
The other measures that many of us employ to activate AMPK, or boost NAD, maintain youthful hormone levels, reduce glycation, manage and suppress inflammation, exercise, CR, maintain healthy methylation, manage cholesterol and BP levels, maintain endogenous antioxidant levels and strategically taking exogenous polyphenols will probably square the curve by allowing existing repair mechanisms to work as efficiently as is genetically possible, while not letting them become overworked or prematurely exhausted by lifestyle factors.

Edited by Kevnzworld, 02 December 2014 - 06:29 PM.

[niner]

 

This progressive failure of repair mechanisms idea is a hypothesis, not a theory, since it's not supported by any data, AFAIK. On the other hand, it is contradicted by various published work, some of which is posted in the thread that xEva linked.  The idea would be right with a subtle modification-- that some of our repair mechanisms are inadequate, period.  I guess that's not really so subtle, though.

I hold it self-evident that the repair mechanisms exist and do an excellent job keeping us young for 25-35 years. It is only when they start failing that we begin to age, or "accumulate damage" in your and SENS definition. This goes in contrast to your position that damage starts accumulating in utero, which implies that a newborn is already "aged". I cannot disagree more. Damage does occur all the time but is continuously repaired. The efficiency of these repairs correlates with youth. Again, damage starts accumulating only when these repair mechanisms start failing.

And how can you say "not supported by any data"? Where is the evidence that water is wet? If it were not for these repair mechanisms, we all would age at about the same rate, yet there is a wide variation in the age at which people start getting visibly aged. That these repair mechanisms can be upregulated with fasting or CR, resulting in rejuvenation, is also evidence. If it were not for these repair mechanisms, rejuvenation due to a fast would not be possible in principle. And, as it was discussed in that thread, the best evidence are various in-born syndromes, from Xenoderma Pigmentosum to various forms of progeria, that show what happens when some of these repair mechanisms don't work.


And contradicts what published work? In that thread you posted the study that correlated skin damage with age. The median age of their cohort was 43-47. That work only confirmed what anyone can assess with a naked eye. Please link a study that shows that "damage accumulates" in a young cohort.

 

 

In the thread you linked, where you claimed that fasting would clean up damaged mitochondria that were not signalling mitophagy (evidence?) I posted a paper that looked at glycation in intervertebral discs in a population from 16 to 95.  In the paper that you criticize for having a median age in the 40's, bear in mind the definition of median-- Half the people were younger than that.

 

As for the evidence that water is wet, I think we see the nub of our disagreement.  You are considering aging as things that you can sense with your eyes, and I'm considering it as a process that occurs on the molecular level.  All the data seems to support the idea that damage accrues gradually, first as a consequence of metabolism in a healthy organism, and later at an accelerating rate due to the snowballing effects of that damage, which causes more damage.  (e.g. SASP)

 

The human body (or any animal) is designed to maintain homeostasis.  It does that very well for a long time, until one day, some homeostatic mechanism reaches the end of its travel, at which point things start going haywire.  That's when you start "seeing" the effects, but that doesn't mean that the damage wasn't building all the while.
 

Edited by niner, 02 December 2014 - 08:47 PM.

[Mind]

Kind-of a chicken and egg scenario the way I look at it. Why do repair mechanisms fail? Because of accumulated damage, perhaps. Things that the body cannot deal with, such as indigestible junk. I am unaware of repair mechanisms that remove all AGEs. AGEs, lipofuscin, amyloid beta, etc... all slowly build throughout life - from DAY ONE. If we had repair mechanisms to take care of this stuff, we wouldn't see any build up at all. My feeling is that the damage affects the repair mechanisms and these slowly degrade throughout life.

 

If supplements and hormones could restore youthfulness, we would have seen it already to a greater degree. There are plenty of test subjects around the world taking all manner of supplements/injections/treatments yet they are all getting grey and wrinkled. It seems they feel better (subjectively) and some markers of aging probably improve a bit, but we are not talking about a fountain of youth, only preserving healthspan a bit.

 

The easiest theory of aging to test with the least amount of money and which has good theoretical backing is the damage theory. That is where I will focus my energy, time, and money. Even if removing damage does not get to the true root of aging, it will likely improve healthspans.

 

By the way, I am not anti-hormone. My feeling is that if we remove damage, that is only one step in the process. If we really want to feel like a young human again, we will have to resett hormones to a youthful level as well.

 

[Kevnzworld]

We do know that hormones have many roles and control a lot of physiological processes, many of which are poorly understood. We know that aging accelerates as hormone production falls. This is especially evident in post menopausal and andropausal people. It's always been a mystery to me why doctors have historically been so willing to treat/ replace low thyroid hormone in aging people, but not the other hormones. ( now " low T " )
We know that estrogen/progesterone decline contributes to skin aging, mood changes, osteoporosis
Testosterone depletion leads to muscle atrophy, cardiovascular disease, insulin resistance
Pregnenalone is neuroprotective
DHEA protects immune function

My point as it relates to the thread topic is the question of why the body's ability to repair cellular damage decreases with age, it may in part be associated with hormonal decline and the resulting consequences of it.
Bio identical hormone replacement on a sophisticated level has only been in existence for a little over a decade.
Supplementation to specifically effect other testable blood markers of aging has only been a science for not much longer.
( HbA1C, CRP, homocysteine , fasting insulin, sophisticated hormone panels, etc ) the blood tests themselves are becoming more sophisticated.
It's impossible to know how this science properly applied will affect the longevity of those who have begun it in midlife.

Edited by Kevnzworld, 03 December 2014 - 01:20 AM.

[xEva]

In the thread you linked, where you claimed that fasting would clean up damaged mitochondria that were not signalling mitophagy (evidence?) I posted a paper that looked at glycation in intervertebral discs in a population from 16 to 95.  In the paper that you criticize for having a median age in the 40's, bear in mind the definition of median-- Half the people were younger than that.

First, it is not my claim that starvation greatly upregulates mactoautophagy of all kinds, including mitophagy. This is the state of the current knowledge, which I learned from reading countless papers on the topic (you get the latest scoop from the intro section and following the relevant refs). I stand by my knowledge and can only repeat here, for the convenience sake:

Here is, briefly, what's missing in de Grey scenario: When a cell is starving, all forms of macroautophagy are greatly upregulated. 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 of unitary mitochondria depicted as 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 is unleashed 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 autophagasome 'mouth' gets recycled. Please note: in the conditions of starvation, no additional tags or special signaling are required. Now note this: because damaged mitochondria are generally unable to fuse with the healthy ones, they remain in their unitary form and thus become easy pickings for autophagasomes.

Now, as far as I remember, the bulk of papers that deal with damaged mitochondria having difficulty fusing with healthy ones came out around 2005, which is after the de Grey paper on mitochondria but well before the post by Reason on this topic in FightAging (and before Ending Aging came out). That's one of the problems with SENS and their followers. They don't seem to be engaged in 'continuous education' and instead always refer to the ~8 year old Ending Aging as if it was something set in stone.


Regarding the studies you linked, I have already pointed out the problem with their cohorts. The nub of our disagreement lies in my claim that damage does not accumulate while we're young, which, it is generally agreed, for most people, is under 25. Therefore, to make your point, a convincing study should demonstrate that damage accumulates in the cohort <25. The ideal range would be 18-24. Would they find the correlation to be statistically significant?


Finally, your lofty sounding definition of damage as "a process that occurs on the molecular level" is impractical considering that the halflife of an average protein in a body spans from minutes to hours, though some last years. And, as I have already pointed out in the other thread, in a multicellular organism, at any given point in time cells get damaged, die and are replaced, which is especially true of epithelia. So, when you talk about the molecular damage, what is your precise definition of it? How would you capture it in practice, if the very process of life involves continuous creation and destruction?

Edited by xEva, 03 December 2014 - 02:18 AM.

[niner]

 

In the thread you linked, where you claimed that fasting would clean up damaged mitochondria that were not signalling mitophagy (evidence?) I posted a paper that looked at glycation in intervertebral discs in a population from 16 to 95.  In the paper that you criticize for having a median age in the 40's, bear in mind the definition of median-- Half the people were younger than that.

First, it is not my claim that starvation greatly upregulates mactoautophagy of all kinds, including mitophagy. This is the state of the current knowledge, which I learned from reading countless papers on the topic (you get the latest scoop from the intro section and following the relevant refs). I stand by my knowledge and can only repeat here, for the convenience sake:

Here is, briefly, what's missing in de Grey scenario: When a cell is starving, all forms of macroautophagy are greatly upregulated. 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 of unitary mitochondria depicted as 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 is unleashed 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 autophagasome 'mouth' gets recycled. Please note: in the conditions of starvation, no additional tags or special signaling are required. Now note this: because damaged mitochondria are generally unable to fuse with the healthy ones, they remain in their unitary form and thus become easy pickings for autophagasomes.

Now, as far as I remember, the bulk of papers that deal with damaged mitochondria having difficulty fusing with healthy ones came out around 2005, which is after the de Grey paper on mitochondria but well before the post by Reason on this topic in FightAging (and before Ending Aging came out). That's one of the problems with SENS and their followers. They don't seem to be engaged in 'continuous education' and instead always refer to the ~8 year old Ending Aging as if it was something set in stone.


Regarding the studies you linked, I have already pointed out the problem with their cohorts. The nub of our disagreement lies in my claim that damage does not accumulate while we're young, which, it is generally agreed, for most people, is under 25. Therefore, to make your point, a convincing study should demonstrate that damage accumulates in the cohort <25. The ideal range would be 18-24. Would they find the correlation to be statistically significant?


Finally, your lofty sounding definition of damage as "a process that occurs on the molecular level" is impractical considering that the halflife of an average protein in a body spans from minutes to hours, though some last years. And, as I have already pointed out in the other thread, in a multicellular organism, at any given point in time cells get damaged, die and are replaced, which is especially true of epithelia. So, when you talk about the molecular damage, what is your precise definition of it? How would you capture it in practice, if the very process of life involves continuous creation and destruction?

 

 

Would you happen to have the reference for the paper that says damaged mitochondria don't engage in the starvation-driven fusion?  I looked but didn't see it.  I'm not anti-fasting, and if a non-lethal fast can rejuvenate mitochondria, I'm interested.  If this does turn out to be the case, it doesn't mean that SENS is wrong, nor does it mean that a method to repair mitochondria that was easier than fasting would be a bad thing, particularly for the frail elderly.

 

Now, regarding cohorts, what's wrong with 16-95?  16 is pretty young...   The correlation between chronological age and AGE content for the entire cohort was extremely good.  That's probably why you can determine a person's age by the amount of time it takes for skin on the top of the hand to return to normal after it's pinched and pulled up. 

 

I'm not sure why damage being something that occurs on the molecular level sounds "lofty".  What other level can it occur on?  All of biology occurs on the molecular level!  And yes, many proteins are turned over rapidly.  They are not the problem.  The problem is the long-lived ones.  And yes, when cells are damaged, they die and are replaced.  Except when they refuse to die, and turn into senescent zombies that spew cytokines and injure other tissue in the vicinity.

 

I've already posted a couple papers describing how the precise nature of damage is characterized.  You measure it with assays that quantify the damaged molecules, which have a different atomic arrangement than the undamaged molecules.  Life involves continuous creation and destruction, except for the very molecules and cells that are the problem.  They stick around for a long time, get damaged, and are not replaced.  That's not the end of the story on aging, but it's a big part of it.

[xEva]

Would you happen to have the reference for the paper that says damaged mitochondria don't engage in the starvation-driven fusion?  I looked but didn't see it.  I'm not anti-fasting, and if a non-lethal fast can rejuvenate mitochondria, I'm interested.  If this does turn out to be the case, it doesn't mean that SENS is wrong, nor does it mean that a method to repair mitochondria that was easier than fasting would be a bad thing, particularly for the frail elderly.
 
Now, regarding cohorts, what's wrong with 16-95?  16 is pretty young...   The correlation between chronological age and AGE content for the entire cohort was extremely good.  That's probably why you can determine a person's age by the amount of time it takes for skin on the top of the hand to return to normal after it's pinched and pulled up. 
 
I'm not sure why damage being something that occurs on the molecular level sounds "lofty".  What other level can it occur on?  All of biology occurs on the molecular level!  And yes, many proteins are turned over rapidly.  They are not the problem.  The problem is the long-lived ones.  And yes, when cells are damaged, they die and are replaced.  Except when they refuse to die, and turn into senescent zombies that spew cytokines and injure other tissue in the vicinity.
 
I've already posted a couple papers describing how the precise nature of damage is characterized.  You measure it with assays that quantify the damaged molecules, which have a different atomic arrangement than the undamaged molecules.  Life involves continuous creation and destruction, except for the very molecules and cells that are the problem.  They stick around for a long time, get damaged, and are not replaced.  That's not the end of the story on aging, but it's a big part of it.

I will look for the papers on mitochondrial fission and fusion.

Regarding the cohorts, I agree that 16 is pretty young. The problem is in 25-92 part. Again: the nub of our disagreement lies in whether damage accumulates in young adults, which is generally 18-24 (make 16-24, if you like). That damage accumulates in 25-92 cohort is a given. Inclusion of the 16-24 in the larger cohort only strengthens the obviously existing 25-92 correlation. It does nothing for the 16-24 correlation, if there is such a thing. Well, is there?


And yes, all of biology occurs on the molecular level. It is precisely its all-encompassing nature that makes the 'molecular damage' definition impractical. A snapshot of the molecular damage is useless, exactly because of the dynamic nature of life processes. When will a given protein be replaced? When is the right time to replace it? When can we say that a level of a given protein constitutes 'accumulation of damage'? One answer could be, when it starts interfering with some function. ..but then it leaves out the question of illness and recovery from it.. See, that's why I prefer the obvious, mundane definition of aging. It can be assessed accurately at a glance from how a person looks and functions (walks, talks, reacts, acts).

Edited by xEva, 03 December 2014 - 05:13 AM.

[xEva]

Kind-of a chicken and egg scenario the way I look at it. Why do repair mechanisms fail? Because of accumulated damage, perhaps. Things that the body cannot deal with, such as indigestible junk. I am unaware of repair mechanisms that remove all AGEs. AGEs, lipofuscin, amyloid beta, etc... all slowly build throughout life - from DAY ONE. If we had repair mechanisms to take care of this stuff, we wouldn't see any build up at all. My feeling is that the damage affects the repair mechanisms and these slowly degrade throughout life.
 
If supplements and hormones could restore youthfulness, we would have seen it already to a greater degree. There are plenty of test subjects around the world taking all manner of supplements/injections/treatments yet they are all getting grey and wrinkled. It seems they feel better (subjectively) and some markers of aging probably improve a bit, but we are not talking about a fountain of youth, only preserving healthspan a bit.

 
Why the repair mechanisms start failing at a certain age is of course the 'million dollar question'. Though I definitely have misgivings about your proposal that damage accumulates because the repair mechanisms themselves get damaged   This looks to me not like the chicken and the egg problem but a sort of a circular definition.

And I believe that the body is capable of fixing all kinds of damage, including AGEs.  ..and there are a lot of things SENS and their followers are not aware of. Again, there is no evidence that AGEs, lipofuscin, amyloid beta, etc. accumulate in a young organism, only that this sort of damage does occur from day one. I disagree that it builds up.

And I agree that supplements and hormones can only temporarily ameliorate the problem but not solve it. ..though I don't see how this relates to the topic at hand. In his posts Kevnzworld referred to already aged people, while my focus is on young adults. When people in their mid twenties start showing the signs of aging, their hormonal levels are still pretty high, which implies that the declining hormonal levels that generally become obvious decade-two later is not the cause but the consequence of this process.

 

The easiest theory of aging to test with the least amount of money and which has good theoretical backing is the damage theory. That is where I will focus my energy, time, and money. Even if removing damage does not get to the true root of aging, it will likely improve healthspans.

 
We agree on the problem, though I claim that damage starts accumulating only at a time we associate with the onset of aging. My biggest issue with SENS is the manner in which they propose to deal with the problem. What they propose I find impractical and theoretically unsound.  I believe, the best way to tackle the problem is to work with the existing repair mechanisms. And I realize the difficulty I have convincing other people. I had the privilege of seeing true, obvious, undeniable rejuvenation, in myself and others, that occurs entirely due to upregulation of those repair mechanisms, not because of plastic surgery or whatnot.
 
See, if I had research money, I would invest it in the study of fasting. This is how those repair mechanisms can be naturally approached. No pharma will do it, 'cause there is no money in it. How does fasting manage to do what it does, why its effects seem to decline with age (in how long they last), how to make it a safe and enjoyable practice, how to make it more effective, etc, etc. Right now, fasting is the only thing that works, but since no one studies it there are too many open questions.

[Kevnzworld]

And I believe that the body is capable of fixing all kinds of damage, including AGEs. ..and there are a lot of things SENS and their followers are not aware of. Again, there is no evidence that AGEs, lipofuscin, amyloid beta, etc. accumulate in a young organism, only that this sort of damage does occur from day one. I disagree that it builds up.

And I agree that supplements and hormones can only temporarily ameliorate the problem but not solve it. ..though I don't see how this relates to the topic at hand. In his posts Kevnzworld referred to already aged people, while my focus is on young adults. When people in their mid twenties start showing the signs of aging, their hormonal levels are still pretty high, which implies that the declining hormonal levels that generally become obvious decade-two later is not the cause but the consequence of this process.

I agree that there is no current strategy available that " solves " the problem. It's genetic and preprogrammed. Temporary amelioration is all that's available currently, and I'll take that if it could add an additional decade or more to my functional lifespan .
Fasting, CR, voluntary or otherwise has been around as long as human existence. If that, in and of itself had any significant effect on lifespan , we would know that. It certainly positively effects healthspan.
Hormone decline begins in the early forties,( hardly aged ) and is genetic. It coincides with the beginning of the acceleration of the aging process. If we know that the broad spectrum of hormonal decline is associated with the progression of cardiovascular disease, osteopenia and osteoporosis , sexual function decline, skin aging, insulin resistance and metabolic disease, immune dysfunction etc....
It isn't a leap to speculate that it would also be associated with the decline of the bodies endogenous cellular repair mechanisms as well.
I agree with Niner, that aging isn't linear, it accelerates as it progresses. That doesn't meant that unrepaired cellular damage doesn't exist in a twenty yo, it just means that the ability of the body to clear cellular debris diminishes with age.
Will hormone replacement, CRON, targeted supplementation and substances that may rejuvenate mitochondria ( C60, PQQ ), Sirtuin activators/ NAD boosters, AMPK
activators etc " solve " either the disease of aging or one of its consequences, the progressive decline of cellular repair mechanisms?
Nope, just temporarily ameliorate it, but that isn't a reason to not employ any and all strategies that have shown some efficacy. The perfect shouldn't be the enemy of the adequate....

[Kalliste]

That is a crazy focus on fasting xEva. We know it's probably a good thing but I suspect that the best case scenario for us is that frequent PF at long enough intervals is only ever going to give you a few years of extra lifespan. I'm sure it's a good thing for healthspan, probably dramatically altering risk for cancer and CVD. And I'm sure that might require you to start doing it at an early age and continue it all your life several times/year.

In the end even with a perfect protocol for fasting, diet and exercise  you will die almost as soon as anyone else.

[niner]

And yes, all of biology occurs on the molecular level. It is precisely its all-encompassing nature that makes the 'molecular damage' definition impractical. A snapshot of the molecular damage is useless, exactly because of the dynamic nature of life processes. When will a given protein be replaced? When is the right time to replace it? When can we say that a level of a given protein constitutes 'accumulation of damage'? One answer could be, when it starts interfering with some function. ..but then it leaves out the question of illness and recovery from it.. See, that's why I prefer the obvious, mundane definition of aging. It can be assessed accurately at a glance from how a person looks and functions (walks, talks, reacts, acts).

 

It's not impractical at all.  You just think it's impractical because you aren't a molecular biologist.  The replacement rate of various proteins is well understood; it is precisely the long-lived ones that are a problem.  (ECM or neurons for example)   It all seems so confusing to you because, well, you aren't a molecular biologist.  It's fine if you want to personally view aging on the basis of things you can see with your eyes, but that doesn't qualify you to critique SENS or molecular definitions of aging.

[niner]

We agree on the problem, though I claim that damage starts accumulating only at a time we associate with the onset of aging. My biggest issue with SENS is the manner in which they propose to deal with the problem. What they propose I find impractical and theoretically unsound.  I believe, the best way to tackle the problem is to work with the existing repair mechanisms. And I realize the difficulty I have convincing other people. I had the privilege of seeing true, obvious, undeniable rejuvenation, in myself and others, that occurs entirely due to upregulation of those repair mechanisms, not because of plastic surgery or whatnot.
 
See, if I had research money, I would invest it in the study of fasting. This is how those repair mechanisms can be naturally approached. No pharma will do it, 'cause there is no money in it. How does fasting manage to do what it does, why its effects seem to decline with age (in how long they last), how to make it a safe and enjoyable practice, how to make it more effective, etc, etc. Right now, fasting is the only thing that works, but since no one studies it there are too many open questions.

 

You saw true, obvious, undeniable rejuvenation in yourself and others, but.. the effects decline with age?  So this rejuvenation only works in the young?  That's not very encouraging.  I think we need something that works in people of all ages, particularly those that need it the most.

[Kevnzworld]

We agree on the problem, though I claim that damage starts accumulating only at a time we associate with the onset of aging. My biggest issue with SENS is the manner in which they propose to deal with the problem. What they propose I find impractical and theoretically unsound. I believe, the best way to tackle the problem is to work with the existing repair mechanisms. And I realize the difficulty I have convincing other people. I had the privilege of seeing true, obvious, undeniable rejuvenation, in myself and others, that occurs entirely due to upregulation of those repair mechanisms, not because of plastic surgery or whatnot.

See, if I had research money, I would invest it in the study of fasting. This is how those repair mechanisms can be naturally approached. No pharma will do it, 'cause there is no money in it. How does fasting manage to do what it does, why its effects seem to decline with age (in how long they last), how to make it a safe and enjoyable practice, how to make it more effective, etc, etc. Right now, fasting is the only thing that works, but since no one studies it there are too many open questions.

You saw true, obvious, undeniable rejuvenation in yourself and others, but.. the effects decline with age? So this rejuvenation only works in the young? That's not very encouraging. I think we need something that works in people of all ages, particularly those that need it the most.

And eating is enjoyable, fasting,... not so much.
Seriously though, periodic fasting for an aging person that has sarcopenia or difficulty with nutrition and keeping on weight ( like my mom ), could be dangerous.
Though I began my quest in my early forties, I'm now 58 so my focus is on what I can employ going forward that gives me the best shot at hitting 100 while enjoying life in a reasonable fashion simultaneously.
Many of the strategies that one should employ are life and age specific

Edited by Kevnzworld, 03 December 2014 - 09:25 PM.

[xEva]

 

And yes, all of biology occurs on the molecular level. It is precisely its all-encompassing nature that makes the 'molecular damage' definition impractical. A snapshot of the molecular damage is useless, exactly because of the dynamic nature of life processes. When will a given protein be replaced? When is the right time to replace it? When can we say that a level of a given protein constitutes 'accumulation of damage'? One answer could be, when it starts interfering with some function. ..but then it leaves out the question of illness and recovery from it.. See, that's why I prefer the obvious, mundane definition of aging. It can be assessed accurately at a glance from how a person looks and functions (walks, talks, reacts, acts).

 
It's not impractical at all.  You just think it's impractical because you aren't a molecular biologist.  The replacement rate of various proteins is well understood; it is precisely the long-lived ones that are a problem.  (ECM or neurons for example)   It all seems so confusing to you because, well, you aren't a molecular biologist.  It's fine if you want to personally view aging on the basis of things you can see with your eyes, but that doesn't qualify you to critique SENS or molecular definitions of aging.

 

It would be better if you could focus on the content of my posts rather than sway into what you perceive as my 'confusion' or 'qualifications', which, frankly, looks like a classical case of transference.

I made it perfectly clear why the molecular damage definition of aging is impractical. It can only 'sound good' to people with shallow understanding of molecular biology and vague ideas of how it applies to human physiology in practice.

And what are you sayng, that SENS cannot be criticized?

Surely you don't want this site to turn into Ending Aging study class for True Believers 

[xEva]

You saw true, obvious, undeniable rejuvenation in yourself and others, but.. the effects decline with age?  So this rejuvenation only works in the young?  That's not very encouraging.  I think we need something that works in people of all ages, particularly those that need it the most.

Yes, that's right. What fasting does, in your snowballing analogy, is to slightly push the snowball back uphill. It does not stop the process of aging itself, which indeed is not linear but accelerates with years.

But I brought up fasting not as a method to address aging, but a method to get in touch, so to speak, with our inherent repair mechanisms. At the moment there is no other practical means to approach them, to study them in situ, how they are activated or upregulated.

Edited by xEva, 03 December 2014 - 10:03 PM.

[niner]

 

 

And yes, all of biology occurs on the molecular level. It is precisely its all-encompassing nature that makes the 'molecular damage' definition impractical. A snapshot of the molecular damage is useless, exactly because of the dynamic nature of life processes. When will a given protein be replaced? When is the right time to replace it? When can we say that a level of a given protein constitutes 'accumulation of damage'? One answer could be, when it starts interfering with some function. ..but then it leaves out the question of illness and recovery from it.. See, that's why I prefer the obvious, mundane definition of aging. It can be assessed accurately at a glance from how a person looks and functions (walks, talks, reacts, acts).

 
It's not impractical at all.  You just think it's impractical because you aren't a molecular biologist.  The replacement rate of various proteins is well understood; it is precisely the long-lived ones that are a problem.  (ECM or neurons for example)   It all seems so confusing to you because, well, you aren't a molecular biologist.  It's fine if you want to personally view aging on the basis of things you can see with your eyes, but that doesn't qualify you to critique SENS or molecular definitions of aging.

 

It would be better if you could focus on the content of my posts rather than sway into what you perceive as my 'confusion' or 'qualifications', which, frankly, looks like a classical case of transference.

I made it perfectly clear why the molecular damage definition of aging is impractical. It can only 'sound good' to people with shallow understanding of molecular biology and vague ideas of how it applies to human physiology in practice.

And what are you sayng, that SENS cannot be criticized?

Surely you don't want this site to turn into Ending Aging study class for True Believers 

 

I hate to sound mean, but you are critiquing SENS and the molecular model of aging in general without actually understanding it.  This is certainly not to say that SENS can't be criticized, but criticism needs to be based on an understanding of what SENS is all about.  Otherwise, it's just pointless.  It would be like me criticizing the detailed operation of the LHC or the judges' calls in Olympic Ice Dancing.  I don't know enough about either of those to provide valid criticism.
 

[xEva]

And yes, all of biology occurs on the molecular level. It is precisely its all-encompassing nature that makes the 'molecular damage' definition impractical. A snapshot of the molecular damage is useless, exactly because of the dynamic nature of life processes. When will a given protein be replaced? When is the right time to replace it? When can we say that a level of a given protein constitutes 'accumulation of damage'? One answer could be, when it starts interfering with some function. ..but then it leaves out the question of illness and recovery from it.. See, that's why I prefer the obvious, mundane definition of aging. It can be assessed accurately at a glance from how a person looks and functions (walks, talks, reacts, acts).

 
It's not impractical at all.  You just think it's impractical because you aren't a molecular biologist.  The replacement rate of various proteins is well understood; it is precisely the long-lived ones that are a problem.  (ECM or neurons for example)   It all seems so confusing to you because, well, you aren't a molecular biologist.  It's fine if you want to personally view aging on the basis of things you can see with your eyes, but that doesn't qualify you to critique SENS or molecular definitions of aging.

It would be better if you could focus on the content of my posts rather than sway into what you perceive as my 'confusion' or 'qualifications', which, frankly, looks like a classical case of transference.

I made it perfectly clear why the molecular damage definition of aging is impractical. It can only 'sound good' to people with shallow understanding of molecular biology and vague ideas of how it applies to human physiology in practice.

And what are you sayng, that SENS cannot be criticized?

Surely you don't want this site to turn into Ending Aging study class for True Believers 

 
I hate to sound mean, but you are critiquing SENS and the molecular model of aging in general without actually understanding it.  This is certainly not to say that SENS can't be criticized, but criticism needs to be based on an understanding of what SENS is all about.  Otherwise, it's just pointless.  It would be like me criticizing the detailed operation of the LHC or the judges' calls in Olympic Ice Dancing.  I don't know enough about either of those to provide valid criticism.

It is good that we have this forum to express our opinions on aging and yes, SENS and their approach to it. ..and yes that includes our opinions on the opinions of others

[Danail Bulgaria]

SENS are doing their best to stop the aging. They don't want to die too. This is why I respect them.

 

However I am also skeptic about some of their developments. For example they are researching enzymes, that manage to decompose the cholesterol. This is a nice idea, and I hope, that they will make it a reality. But when it becomes a reality it will be just the next drug against cholesterol. Why this exactly medication will stop the cholestero building up in the blood vessels, since the other existing methods didn't? So far against the cholesterol we have diets, statins and several other types of drugs, dialysis type of machines, that remove it directly from the blood, extravasal operative methods, stands, that are being placed every day on thousands of people all over the world, bypasses and other blood vessels transplantation methods, we have already even an artificial hearts manufactured today, and before and soon after the glorious rise of each one of these things we thought, that we will stop dying from cholesterol, and yet the people today still are dying mainly from heart failure and insults!!!! Why exactly the enzyme will stop the cholesterol like with a magic wand? SENS can't say, because they are not searching for the reason for the cholesterol build - up. They are attacking it as a fact.

[Rocket]

SENS are doing their best to stop the aging. They don't want to die too. This is why I respect them.

However I am also skeptic about some of their developments. For example they are researching enzymes, that manage to decompose the cholesterol. This is a nice idea, and I hope, that they will make it a reality. But when it becomes a reality it will be just the next drug against cholesterol. Why this exactly medication will stop the cholestero building up in the blood vessels, since the other existing methods didn't? So far against the cholesterol we have diets, statins and several other types of drugs, dialysis type of machines, that remove it directly from the blood, extravasal operative methods, stands, that are being placed every day on thousands of people all over the world, bypasses and other blood vessels transplantation methods, we have already even an artificial hearts manufactured today, and before and soon after the glorious rise of each one of these things we thought, that we will stop dying from cholesterol, and yet the people today still are dying mainly from heart failure and insults!!!! Why exactly the enzyme will stop the cholesterol like with a magic wand? SENS can't say, because they are not searching for the reason for the cholesterol build - up. They are attacking it as a fact.

Even children fed diets of high amounts of unhealthy fats suffer from the build up of plaque. I would say that "its" a fact of life itself and diet and exercise... Not a problem of aging in the same league as sarcopenia or a declining immune system.

[Kalliste]

 

SENS are doing their best to stop the aging. They don't want to die too. This is why I respect them.

However I am also skeptic about some of their developments. For example they are researching enzymes, that manage to decompose the cholesterol. This is a nice idea, and I hope, that they will make it a reality. But when it becomes a reality it will be just the next drug against cholesterol. Why this exactly medication will stop the cholestero building up in the blood vessels, since the other existing methods didn't? So far against the cholesterol we have diets, statins and several other types of drugs, dialysis type of machines, that remove it directly from the blood, extravasal operative methods, stands, that are being placed every day on thousands of people all over the world, bypasses and other blood vessels transplantation methods, we have already even an artificial hearts manufactured today, and before and soon after the glorious rise of each one of these things we thought, that we will stop dying from cholesterol, and yet the people today still are dying mainly from heart failure and insults!!!! Why exactly the enzyme will stop the cholesterol like with a magic wand? SENS can't say, because they are not searching for the reason for the cholesterol build - up. They are attacking it as a fact.

Even children fed diets of high amounts of unhealthy fats suffer from the build up of plaque. I would say that "its" a fact of life itself and diet and exercise... Not a problem of aging in the same league as sarcopenia or a declining immune system.

 

 

Just like its a fact of life that most children and many mothers die after birth from bacterial infections because real gentlemen doctors doesn't need to wash their hands between different child births, a real gentlemen is always fine and dandy I tell ye!
 

[niner]

SENS are doing their best to stop the aging. They don't want to die too. This is why I respect them.

 

However I am also skeptic about some of their developments. For example they are researching enzymes, that manage to decompose the cholesterol. This is a nice idea, and I hope, that they will make it a reality. But when it becomes a reality it will be just the next drug against cholesterol. Why this exactly medication will stop the cholestero building up in the blood vessels, since the other existing methods didn't? So far against the cholesterol we have diets, statins and several other types of drugs, dialysis type of machines, that remove it directly from the blood, extravasal operative methods, stands, that are being placed every day on thousands of people all over the world, bypasses and other blood vessels transplantation methods, we have already even an artificial hearts manufactured today, and before and soon after the glorious rise of each one of these things we thought, that we will stop dying from cholesterol, and yet the people today still are dying mainly from heart failure and insults!!!! Why exactly the enzyme will stop the cholesterol like with a magic wand? SENS can't say, because they are not searching for the reason for the cholesterol build - up. They are attacking it as a fact.

 

SENS isn't looking for "just another cholesterol drug".  They are trying to develop a method to get rid of a very special form of cholesterol, 7-ketocholesterol, that the body has no mechanism to degrade.  It builds up in the lysosomes until they swell and make the cell dysfunctional.  This process is at the root of atherosclerosis.  If SENS or anyone else succeeds at this endeavor it will have a huge effect on human health.

[Danail Bulgaria]

Yup. Not only SENS, virtually no one, who developed a method to fight with the cholesterol didn't want to do "just the next anti-cholesterol drug", but nevertheless, this was the result so far...

[Avatar of Horus]

Would you happen to have the reference for the paper that says damaged mitochondria don't engage in the starvation-driven fusion?  I looked but didn't see it.  I'm not anti-fasting, and if a non-lethal fast can rejuvenate mitochondria, I'm interested.  If this does turn out to be the case, it doesn't mean that SENS is wrong, nor does it mean that a method to repair mitochondria that was easier than fasting would be a bad thing, particularly for the frail elderly.
 ...

I will look for the papers on mitochondrial fission and fusion.
...

 
Here is a study with a similar subject: about serum starved cells:

Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis
Gu Y1, Wang C, Cohen A.   FEBS Lett. 2004 Nov 19;577(3):357-60. PMID: 15556609

Abstract
Mutations in mitochondrial DNA (mtDNA) cause excessive production of mitochondrial reactive oxygen species (ROS) and shorten animal life span. We examined the mechanisms responsible for removal of mitochondria with deleterious mtDNA mutations by autophagy. Incubation of primary cells and cell lines in the absence of serum promotes autophagy of mitochondria with deleterious mtDNA mutations but spares their normal counterparts. The effect of serum withdrawal on the autophagy of dysfunctional mitochondria is prevented by the addition of IGF-1. As a result of the elimination of mitochondria with deleterious mutations, excessive ROS production, characteristic of dysfunctional mitochondria, is greatly reduced. Mitochondrial autophagy shares a common mechanism with mitochondrial-induced cell apoptosis, including mitochondrial transition pore formation and increased ROS production.

→ source (external link)

[HighDesertWizard]

AFAIK, the best case against the Accumulated Damage way of thinking about aging has been made by Harold Katcher in...
 
Studies that shed new light on aging
 
AFAIK, Katcher's paper hasn't been adequately discussed at Longecity. Seems like this might be the thread to talk about it.
 
  
Abstract
 
I will first discuss how all aging models which assume that the aged cell has irreversibly lost its
youthful capabilities through such mechanisms as accumulated dysfunction, accumulated
damage and/or accumulation of toxic byproducts of metabolism have been shown to be incorrect.
I will then briefly discuss models of aging and propose an experiment that would distinguish
between those models and provide a basis for organismic rejuvenation.
Highlights

• The phenomenon of cellular rejuvenation tests 'wear and tear' theories of aging
• Evidence presented indicates that cellular age-phenotype depends on environment not chronology
• A simple experiment is proposed to distinguish aging theories. 

 

How about I jump start the discussion with this quote from the paper...

 

In spite of inconsistencies and improper assumptions, these current leading "evolutionary" theories of aging are widely accepted models yet, to call them “theories,” is normally a scientific assessment of their proven truth, which is not the case (Le Bourg, 2001). As this paper will show, the hypothesis that aging at the cellular level is the product of the accumulation of irreparable damage and/or un-eliminable toxic substances has been tested and rejected in numerous studies. Simply demonstrating that cells can be rejuvenated by exogenous factors is logically equivalent to demonstrating that cells are not irreparably damaged by aging, in direct contradiction to the assertion that aging is the result of irreparable damage. 

Edited by HighDesertWizard, 03 January 2015 - 04:23 PM.