266 replies to this topic

[Danail Bulgaria]

 

I don't know how the young cells recover their mitochndria. If the mitochondria can multiply, then their mechanism of constant repairment may be the sam as the cells - old mitochondria get destroyed, new mitochnondria get formed?

 

 

Old mitochondria get destroyed, known als mitophagy. The creation of new mitochondria requires a division of existing mitochondria and the mtDNA is passed on to the new mitochondria.

 

Of course mitochondrial dysfunction contributes to the aging phenotype, but basically, the damage accumulation is due to a shutdown of repair.

 

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair!  Rejuvenation research should first focus on reactivation of endogenous repair.

 

 

Well. xEva named her topic "Aging as progressive failure of existing repair mechanisms" so, I suppose, that she will like your idea about the shut down of the mitochondrial repair shut down, and yup, would claim, that this shut down appears later in life. 

 

Alright, if our genes contain the blueprint of the complete repair, how would we make them repair our mitochondria (or cells). How do you imagine it? 

[sthira]

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair! Rejuvenation research should first focus on reactivation of endogenous repair.

Yay! Exactly. Too bad that's really hard, or else we'd all be happy, healthy & immortally youthful by now.

[corb]

 

I don't know how the young cells recover their mitochndria. If the mitochondria can multiply, then their mechanism of constant repairment may be the sam as the cells - old mitochondria get destroyed, new mitochnondria get formed?

 

 

Old mitochondria get destroyed, known als mitophagy. The creation of new mitochondria requires a division of existing mitochondria and the mtDNA is passed on to the new mitochondria.

 

Of course mitochondrial dysfunction contributes to the aging phenotype, but basically, the damage accumulation is due to a shutdown of repair.

 

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair!  Rejuvenation research should first focus on reactivation of endogenous repair.

 

 

The early embryo and zygote handle damage with an aggressive program of cell death. They don't bother with repair and autophagy at all.

And they don't change the mtDNA they inherit in any way - doesn't matter if it's mutated or not, if it leads to a disease or disorder you inherit it and that's that. Inherited mitochondrial diseases are very widespread, no better proof than that.

 

It's easy to kill cells without restraint if the whole organism is a clump of cells without a formed nervous system. Sure this program could be activated. But it would feel like constant chemotherapy to a live person.
And if you do it to someone in an advanced age I'm almost positive he'd die faster, not the other way around.

[niner]

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair!  Rejuvenation research should first focus on reactivation of endogenous repair.

 

No, they don't.  Our genes contain blueprints for repair of mitochondria that are broken in typical ways, but not all ways.  Mitochondria can get into states where they are broken but don't trigger mitophagy.  That's the problem.  They clonally expand and eventually take over.

 

We should bear in mind that there is no "one cause" of aging.  Aging has multiple causes.

[HighDesertWizard]

We should bear in mind that there is no "one cause" of aging. Aging has multiple causes.

Now this conversation is cooking with gas... Instead of arguing, and because this thread is about repair, how about we talk about the various categories of repair that can actually be done and the practical means for doing it.

Edited by HighDesertWizard, 05 February 2015 - 03:41 PM.

[addx]

Well, someone ticked my previous post of ketogenic diets as offtopic, but I'll reiterate again

http://www.anti-agin...death-pathways/
 

Glucose depletion and ketogenic diet – Mitochondrial heteroplasmy refers to the cellular phenotype where there exists a population of normal mitochondria (wild type) and mutated mitochondria (mtDNA mutations). This scenario occurs in several inherited disorders, but also occurs with aging. In in vitro studies of artificially created cybrid cells (cells with mitochondrial heteroplasmy), a glucose-depleted, ketongenic cell media promoted an increase in wild type mitochondria and decreased the proportion of mutant mitochondria. A ketogenic diet is one that features keytone bodies as energy sources rather than glucose and involves metabolism in the cytoplasm instead of in mitochondria. Glucose inhibitors such as 2-deoxyglucose which prevent glycolysis and are “calorie restriction mimetics” have also been shown to select for health mitochondria and to get rid of damaged mitochondria. This effectively was a “dietary induction of selective mutant mitophagy,” which is what one would expect based on what has been discussed previously in this blog.

Btw. the link I gave seems quite informative.

In this blog, I will discuss the following key concepts of the mitochondrial responses to stress:
1.Mitochondrial signaling pathways
2.The role of the Mitochondrial Heat Shock Proteins
3.TRAP-1 and the mitochondrial permeability transition pore (MPTP)
4.The 3 Key fast acting ROS-driven responses to cellular stress
5.Mitochondrial unfolded protein response (UPRmt)
6.Mitochondrial specific autophagy (mitophagy)
7.Programmed cell death (Apoptosis)
8.Unprogrammed cell death (Necrosis)

So is worth checking out.

Edited by addx, 05 February 2015 - 03:42 PM.

[LeeYa]

 

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair! Rejuvenation research should first focus on reactivation of endogenous repair.

Yay! Exactly. Too bad that's really hard, or else we'd all be happy, healthy & immortally youthful by now.

 

 

I don't think that this task is really that hard.

 

@niner:

 

the expansion of the mitochondrial gene pool is a consequence of disrupted communication between mitochondria and the cell nucleus. This is not seen in the germline.

 

However, it might be nessesary to implement minor corrections from time to time.

[Kalliste]

 

I don't know how the young cells recover their mitochndria. If the mitochondria can multiply, then their mechanism of constant repairment may be the sam as the cells - old mitochondria get destroyed, new mitochnondria get formed?

 

 

Old mitochondria get destroyed, known als mitophagy. The creation of new mitochondria requires a division of existing mitochondria and the mtDNA is passed on to the new mitochondria.

 

Of course mitochondrial dysfunction contributes to the aging phenotype, but basically, the damage accumulation is due to a shutdown of repair.

 

I don't care wether this shutdown process takes place shortly after birth or later on, as suggested by xEva. What matters is that our genes contain blueprints of complete repair!  Rejuvenation research should first focus on reactivation of endogenous repair.

 

 

Even when everything goes to plan, the cellular repair program is so stupid that it sometimes actually considers malfunctioning mitochondria to be superior to normal mitochondria. It then kills every functioning mitochondria and leaves the damaged ones to take over the entire cell turning it into a free radical spraying monstrosity. Our biology has not yet figured out how to export the last of the 13 mtDNA sequences to the nDNA, maybe because these segments code for proteins that can not be moved across the mitochondrial membrane, or maybe for some other weird reason.

 

That is one problem we need repair to fix and I seriously wonder if it will be solved by some built in latent repair mechanism.

[LeeYa]

@Cosmicalstorm

 

I am aware of the SENS strategies, but lack of inclusion of mtDNA into the nucleus isn't the reason why we age.

 

We do not age because biology is imperfect. We age because it makes sense from an evolutional viewpoint. We are designed to age.

[Kalliste]

So you are saying that malfunctioning mitochondria play no part in aging? I expect you can back that up with more than your personal opinion.

 

http://www.ncbi.nlm....pubmed/25232829

http://www.ncbi.nlm....pubmed/17460184

[LeeYa]

@Cosmicalstorm

 

I fully agree with you that malfunctional mitochondria play a major part in the aging process.

 

That is a well researched mechanism. But it is not what's going to happen in the germline.

 

 

@niner:

 

the expansion of the mitochondrial gene pool is a consequence of disrupted communication between mitochondria and the cell nucleus. This is not seen in the germline.

 

 

 

Edited by LeeYa, 05 February 2015 - 07:28 PM.

[LeeYa]

To maintain mitochondrial function, a thight control is nessesary and consequently, a nuclear-mitochondrial communication must also be maintained. Partial restauration of communication signals results in partial reversal of the aging phenotype:

 

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

http://www.ncbi.nlm....les/PMC4076149/

[LeeYa]

Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function

 

http://www.hindawi.c...014/238463/abs/

 

 

Only recently, attention has been drawn on mitochondrial protein alterations and on the fate of intra-mitochondrial protein quality control in these processes. Nevertheless, specific proteins involved in energy production and/or redox regulation have been already shown to represent sensitive targets for age- and/or oxidative stress-induced modifications. The mitochondria are housing chaperones, repair and proteolytic enzymes that all participate to intra-mitochondrial protein quality control, the function of which has been found to be affected with age. Modulation of the expression of several mitochondrial chaperones (e.g. Hsp22) and proteases such as Lon and Clp has demonstrated their implication in longevity and protection against oxidative protein modifications.

 

http://www.sciencedi...568163714001457

 

 

 Triggering mitochondrial biogenesis has beneficial effects in aged cells and organisms. However, if other quality control pathways do not balance mitochondrial proliferation, the consequences of aberrant mitochondrial accumulation, increased oxygen consumption, and ROS generation eventually result in oxidative stress and cell death

http://www.sciencedi...531556514000333

 

Age-dependend mitochondrial dysfunction is a typical example of the shut down of repair.

Edited by LeeYa, 05 February 2015 - 09:19 PM.

[corb]

NAD+

 

I just like to point out something before you embarrass yourself even further.

Aubrey de Grey has been publishing papers on NAD/NADH since the mid 90s.

He's written a couple hundred pages on the topic so it would make sense for him to know a bit about it.

 

Really not the best thing to use as a counterpoint to a proposed SENS therapy. Carry on if you wish.

[LeeYa]

 

 

Well. xEva named her topic "Aging as progressive failure of existing repair mechanisms" so, I suppose, that she will like your idea about the shut down of the mitochondrial repair shut down, and yup, would claim, that this shut down appears later in life. 

 

Alright, if our genes contain the blueprint of the complete repair, how would we make them repair our mitochondria (or cells). How do you imagine it? 

 

 

Indeed, this theory leads to different conclusions in comparison to the wear-and-tear/damage thinking.

 

For example, according to the damage theory, antioxidants should extend lifespan from toddler to the elderly. In contrast , according to the "progressive failure" theory, you should avoid strong antioxidants when you are young because they mess up with your working repair systems, but go for it when you are old.

 

Applying the progressive failure theory to the SENS approach, we have a limited set of genes involved in repair. This kind of gene expression is diminished during aging/development and should be reactivated, for example.

[niner]

I am aware of the SENS strategies, but lack of inclusion of mtDNA into the nucleus isn't the reason why we age.

 

We do not age because biology is imperfect. We age because it makes sense from an evolutional viewpoint. We are designed to age.

 

There is no "the" reason.  There are many.  Mitochondrial DNA damage is one of them.

 

As for the second line, my response, sentence by sentence, is:  Wrong. Wrong. We are not designed.

 

Biological imperfection is certainly A reason for aging, and very likely a big part of it.  It's probably not the whole story, but might be.

 

The Programmed Aging Pied Pipers have spun a bunch of stories in an attempt to show that aging makes evolutionary sense, but they are out of the biological mainstream, ill informed, and frankly I think they just get it totally wrong. 

 

We aren't "designed", but you probably didn't mean that.  We evolved to spread our genes effectively.  Aging is a side effect of being highly adapted to do that. 

[Kevnzworld]

I think the conflicting opinions regarding if and how we are designed is a confusion over meaning and definition, not the validity of natural selection.
We are genetically predisposed to age in a relatively linear fashion. After all, with few exceptions, we all reach puberty at approximately the same time. We go into meno/ andropause in our latter forties, early fifties. Most of us that enter our eighth decade won't exit it.
It's fairly easy to visibly age people within a five year window, with also few exceptions. Yes some look better or worse for their age mostly attributable to lifestyle factors.
If " special " diets ( CR ) or periodic fasts altered the aging dynamic in any meaningful way, that would be evident. Human history is replete with populations and sects that practice CR, though they don't call it that.
Periodic fasting was part of life for native Americans , and devout Muslims fast annually during Ramadan. We don't see them living beyond 100yo
We now know many of the factors in the aging process and by using supplements/ hormones/lifestyle alterations we can mitigate some of the processes in the hopes of achieving modest life extension. If by no other means than by allowing ourselves to live out our full genetically programmed life. Squaring the curve so to speak

Edited by Kevnzworld, 05 February 2015 - 11:59 PM.

[niner]

We now know many of the factors in the aging process and by using supplements/ hormones/lifestyle alterations we can mitigate some of the processes in the hopes of achieving modest life extension. If by no other means than by allowing ourselves to live out our full genetically programmed life. Squaring the curve so to speak

 

I agree with your post (well-stated, btw), but I'd like to comment on the term "genetically programmed life".  Our lifespan is encoded in our genes, so it's "programmed" in that way, but the "Programmed Aging" camp thinks that we have evolved a death program, as though the default state of biology was to live forever, and we needed help dying.  Needless to say, I find that ludicrous. 

[corb]

 

Considerable evidence now indicates that both inflammation and oxidative stress contribute to the development of various neuropathologies including Alzheimer’s and Parkinson’s disease [14], [16], [23]. While age is the major risk factor for the development of most neurodegenerative disorders it has yet to be confirmed if oxidative stress and inflammation increase during normal brain aging in humans. To our knowledge this is the first study to show that both oxidative damage and inflammation increase after the age of 45 in the central nervous system (CNS) of relatively healthy humans. In this study we report that the CSF of participants aged over 45 years contained statistically higher amounts of the oxidative damage marker F2-isoprostane and the inflammatory cytokine IL-6. Those aged over 45 years also tended to have increased CSF levels of the DNA damage marker 8-OHdG. These data are consistent with previous results from both our laboratory and others showing that DNA and lipid oxidation increase with age in multiple organs, including the brain in animals [11], [12], [24], [43]. While limited research has been conducted within the CNS of living humans, an age related accumulation in markers of both oxidative damage (8-OHdG) and inflammation (IL-6) has been previously reported in postmortem brain tissue [9], [44].

It is well established, that oxidative DNA damage activates the NAD-dependent DNA repair enzyme, PARP, which is involved in base excision repair [45]. Utilizing unexposed human skin, our laboratory has previously shown that that PARP activity increases with age and correlates with NAD⁺ depletion [46]. In the present study we investigated whether levels of CSF NAD(H) were also associated with age and report for the first time that [NAD(H)] does decline with age in the CNS of healthy humans. As expected an inverse trend between CSF [NAD(H)] and markers of central DNA (8-OHdG) and lipid (F2-isoprostanes) oxidative damage was also observed. In addition, as would be predicted, after controlling for age, increased CSF total antioxidant capacity was significantly correlated with higher CSF levels of NAD(H).

 

http://journals.plos...al.pone.0085335

 

 

Oxidative damage depletes the NAD reserve (which is sparse to begin with). No proof of program here.
 

And antagonistic pleiotropy strikes again:

 

 

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld^S prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld^S protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.Cell Death and Differentiation advance online publication, 17 October 2014; doi:10.1038/cdd.2014.164.

 

http://www.ncbi.nlm....pubmed/25323584

 

NMN is what they used in the popular experiment with the mice. Good thing it's too expensive, the last thing life extension research needs is some crazy "biohacker" to get a bump on the head and become a vegetable after pumping himself full of a popular life extension supplement.

[LeeYa]

@corb

do you think, ROS aren't regulated?

 

In germline you will find a pretty good redox balance. This balance is under epigentic control.

The initial spark of the development program leads to epigenetic changes. The epigenetic changes finally are directed to senescence - with all consequences, for example altered metabolism.

Endogenous ROS production increases with aging, because there is a setpoint shift. Have you heared from the EROS therory of aging?

 

As emphasized by DeGrey, the need to supply NAD(+) for glucose oxidation and maintain redox balance with impaired mitochondrial NADH oxidoreductase requires the upregulation of other oxidoreductases. In contrast to the 2% inefficiency of mitochondrial reduction of oxygen to the oxyradical, these other oxidoreductases enable glycolytic energy production with a deleterious 100% efficiency in generating oxyradicals. To avoid this catastrophic cycle, lactate dehydrogenase is upregulated at the expense of lactic acid acidosis. This metabolic shift is epigenetically enforced, as is insulin resistance to reduce mitochondrial turnover. The low mitochondrial capacity for efficient production of energy reinforces a downward spiral of more sedentary behavior leading to accelerated aging, increased organ failure with stress, impaired immune and vascular functions and brain aging. Several steps in the pathway are amenable to reversal for exit from the vicious cycle of EORS.

 

 

Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories.

http://www.ncbi.nlm....pubmed/19945522

 

Most, if not all breakdown of endogenous repair is simply a consequence of epigenetic drift.

 

 

@kevnzworld

 

Interventions such as fasting or CR clearly are not able to fully reactivate endogenous repair, I agree.

However, CR is not squaring the curve, actually. CR induces a modest shift to the right.

 

@niner
 

 

We aren't "designed", but you probably didn't mean that.  We evolved to spread our genes effectively.  Aging is a side effect of being highly adapted to do that.

 

Yes, aging is a consequence of evolution.

According to MItteldorf, aging would be a evolved mechanism to counterbalance drastic fluctuations in population size. However, he thinks that there must be suicide-like mechanisms involved, but evidence of this is sparse.

In this regard,  quasiprogrammed aging as proposed by M. Blagosklonny might be a more accurate model.

 

 

[Danail Bulgaria]

Aging is not a consequence of evolution, people. It is the opposite. The evolution is trying to support our life longer.

 

Everything arround us is constantly damaging us - some times very little, some times very much. Even when the wind is blowing, it is fileing away skin cells from us. If we eat, we wear and thear our digestive system macroscopically, and our cell structures biochemically. If we don't eat, we will certainly die. Everything, that we do, and everything, that we don't do is causing us some sort of damage.

 

It is more logically the threat from dying from aging, or the fact of wearing and thearing our structures to be causing an evolutionary preasure. It is much more logical the evolution to try to make changes, that to keep our structures for a longer period, e.g. the evolution is trying to defeat the aging, and to make us live longer, not shorter.

[LeeYa]

@ seivtcho

 

I guess, you try to avoid further damage of your body like jogging?

 

Your skin ages from the wind instead of failure of UV damage-repair?

 

And no, evolution doesn't take care for the individual after reproduction. Full protection is given for the germline only.

Edited by LeeYa, 06 February 2015 - 08:05 PM.

[Danail Bulgaria]

What I was trying to say, is, that these things like the wind damage of our skin are things, that the evolution has managed tio find a way to cope with.

 

E.g. the evolution does not want us aged, or with damaged bodies, or death. The opposite - it wants us with absolutely damage proof bodies. Simply it can't do it. And the idea, that aging is resulted as an evolution need is wrong.

[xEva]

Well, someone ticked my previous post of ketogenic diets as offtopic, but I'll reiterate again
 

Glucose depletion and ketogenic diet

 
I clicked it off topic. The origin of ketogenic lies in fasting. This diet was designed to mimic some of the processes that go on during a fast. But there are a lot of things that go on during a fast, all in concert, which may or may not go on during the diet. For example, no matter how high a level of ketones, if insulin happens to be above a rather low threshold (for whatever reason) autophagy in its many forms, including mitophagy, which is the workhorse of all repairs, is blocked. There are many threads here to discuss ketogenic diets. This is not one of them.

 

Periodic fasting was part of life for native Americans , and devout Muslims fast annually during Ramadan. We don't see them living beyond 100yo

Actually, in nature periodic fasting is the norm, due to, first, unreliable food supply and, second, most migrating animals fast during their migrations (birds, whales) -or- as part of their natural lives (reproduction + seasonal hibernation). So, modern humans would do well if they reintroduce fasting in their lives, especially if they want to get in touch with their innate repair mechanisms. In the course of evolution nature learned to rely on these periods of abstinence to activate the most effective repairs.

It is true though that fasting won't make one live forever. Interestingly, it was noted long ago that rejuvenating effects of a fast diminish with age -- in the sense that they do not last quite as long as in younger people, i.e. they still occur but become transient with age. Why? This points at some factor(s) that promptly make the organism revert to its old self upon refeeding. The speed with which it occurs with age is not consistent with mere 'accumulation of damage'. Rather, it is consistent with cells quickly reverting to the senescent phenotype due to some signaling factors.

If this is so, then supplying the right signals may be all that is required to make an organism keep the repairs and maintain them at a youthful level.

[niner]

It is true though that fasting won't make one live forever. Interestingly, it was noted long ago that rejuvenating effects of a fast diminish with age -- in the sense that they do not last quite as long as in younger people, i.e. they still occur but become transient with age. Why? This points at some factor(s) that promptly make the organism revert to its old self upon refeeding. The speed with which it occurs with age is not consistent with mere 'accumulation of damage'. Rather, it is consistent with cells quickly reverting to the senescent phenotype due to some signaling factors.

If this is so, then supplying the right signals may be all that is required to make an organism keep the repairs and maintain them at a youthful level.

 

It's also entirely consistent with cells reverting to the senescent phenotype due to accumulated damage, which increases with age.    If this is so, then fixing the damage may be all that is required to make an organism keep the repairs and maintain them at a youthful level.

 

Too bad it's so hard to tell what's the chicken and what's the egg.  We do know that damage increases, because we have measured it as a function of age.  We also know that paracrine signaling factors change with age.   We are not 100% sure which is cause and which is effect, but all evidence I'm aware of favors damage as cause rather than effect.

[xEva]

It is true though that fasting won't make one live forever. Interestingly, it was noted long ago that rejuvenating effects of a fast diminish with age -- in the sense that they do not last quite as long as in younger people, i.e. they still occur but become transient with age. Why? This points at some factor(s) that promptly make the organism revert to its old self upon refeeding. The speed with which it occurs with age is not consistent with mere 'accumulation of damage'. Rather, it is consistent with cells quickly reverting to the senescent phenotype due to some signaling factors.

If this is so, then supplying the right signals may be all that is required to make an organism keep the repairs and maintain them at a youthful level.

 
It's also entirely consistent with cells reverting to the senescent phenotype due to accumulated damage, which increases with age.    If this is so, then fixing the damage may be all that is required to make an organism keep the repairs and maintain them at a youthful level.
 
Too bad it's so hard to tell what's the chicken and what's the egg.  We do know that damage increases, because we have measured it as a function of age.  We also know that paracrine signaling factors change with age.   We are not 100% sure which is cause and which is effect, but all evidence I'm aware of favors damage as cause rather than effect.

You must have misunderstood this part: "The speed with which it occurs with age is not consistent with mere 'accumulation of damage'." i.e. it can happen within a couple of days and then the change is astonishing. No 'damage' can accumulate that fast. This implies that repairs a la SENS that may be developed in the future will suffer the same fate. They won't last -- unless and until those mysterious paracrine factors are identified and supplied.

And again you misrepresent the facts: i.e. "damage increases, because we have measured it as a function of age" -- in people over 25.
 

So, accept it at last. There are repair mechanisms, named regeneration capacity, and it declines with age.

 
You're misunderstanding the argument completely.
Everyone in the thread knows it happens. What we're arguing about is WHY it happens.

 
... most of the argument in this thread has been about the repair of glycation damage to non-injured tissues.

lol the point of this thread that children and young adults do not accumulate damage. No convincing data was posted to the contrary. One can say that, after reaching adulthood, humans enjoy 'negligible senescence' -- for a while, on par with animals with negligible senescence, whose main distinction is that they appear to do it indefinitely, despite being subject to the same metabolic insults as the rest of us. It is quite clear that the main distinction has to lie in unfailing efficiency of their repairs.


And I hope I was not the only one who fully enjoyed the irony of the following posts informing me of what sort of studies I have to run in order "to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25".
 

You can try to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25, but then they start accumulating linearly. That is your hypothesis, right?

All you have to do is get appropriate collagen samples from people under 25:

You said that you couldn't prove a negative, and I'm telling you how to do it. It's not an unprovable negative, it's a matter of seeing how much AGE crosslinking is there as a function of chronological age in the young. All you have to do is repeat the tendon measurements posted above, with more data in the young range. It will probably be necessary for you to acquire a grant in order to fund this experiment, but it's not impossible.

With this you essentially agreed that there is no studies showing AGE crosslinking "as a function of chronological age in the young". It's ironic that I am the one here having to prove the obvious, while you, SENS and de Grey are not held by the same high standards.

But I'm glad this discussion spurred some of you guys to reconsider this long past retirement idea. Why, you even began to speculate that damage may be "masked" in children and young adults "giving the false impression that it is not accumulating". False impression? What exactly makes this old idea right?

Edited by xEva, 06 February 2015 - 10:05 PM.

[niner]

 

 

It is true though that fasting won't make one live forever. Interestingly, it was noted long ago that rejuvenating effects of a fast diminish with age -- in the sense that they do not last quite as long as in younger people, i.e. they still occur but become transient with age. Why? This points at some factor(s) that promptly make the organism revert to its old self upon refeeding. The speed with which it occurs with age is not consistent with mere 'accumulation of damage'. Rather, it is consistent with cells quickly reverting to the senescent phenotype due to some signaling factors.

If this is so, then supplying the right signals may be all that is required to make an organism keep the repairs and maintain them at a youthful level.

 
It's also entirely consistent with cells reverting to the senescent phenotype due to accumulated damage, which increases with age.    If this is so, then fixing the damage may be all that is required to make an organism keep the repairs and maintain them at a youthful level.
 
Too bad it's so hard to tell what's the chicken and what's the egg.  We do know that damage increases, because we have measured it as a function of age.  We also know that paracrine signaling factors change with age.   We are not 100% sure which is cause and which is effect, but all evidence I'm aware of favors damage as cause rather than effect.

You must have misunderstood this part: "The speed with which it occurs with age is not consistent with mere 'accumulation of damage'." i.e. it can happen within a couple of days and then the change is astonishing. No 'damage' can accumulate that fast. This implies that repairs a la SENS that may be developed in the future will suffer the same fate. They won't last -- unless and until those mysterious paracrine factors are identified and supplied.

And again you misrepresent the facts: i.e. "damage increases, because we have measured it as a function of age" -- in people over 25.

Oh BS. Don't accuse me of "misrepresenting facts". There have been two studies posted with subjects as young as ten! You just don't accept published data if it doesn't agree with your erroneous hypothesis.

Regarding the "rejuvenation" from fasting that doesn't last in older people, that's because the "rejuvenation" didn't eliminate the damage, or at least not enough of it. The damage that was still present caused the elderly fasters to rapidly deteriorate. You haven't said exactly what this rejuvenation consists of, so we can really only speculate about it, but I can assure you that fasting will not make elderly skin youthful again.
 

 

 

 

So, accept it at last. There are repair mechanisms, named regeneration capacity, and it declines with age.

 
You're misunderstanding the argument completely.
Everyone in the thread knows it happens. What we're arguing about is WHY it happens.

 
... most of the argument in this thread has been about the repair of glycation damage to non-injured tissues.

lol the point of this thread that children and young adults do not accumulate damage. No convincing data was posted to the contrary. One can say that, after reaching adulthood, humans enjoy 'negligible senescence' -- for a while, on par with animals with negligible senescence, whose main distinction is that they appear to do it indefinitely, despite being subject to the same metabolic insults as the rest of us. It is quite clear that the main distinction has to lie in unfailing efficiency of their repairs.

It was only unconvincing to you, because you refuse to be convinced. You have posted NO data supporting your contention that people under 25 have a unicorn-like ability to eliminate crosslinks in the ECM, an ability that is then lost.
 

And I hope I was not the only one who fully enjoyed the irony of the following posts informing me of what sort of studies I have to run in order "to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25".
 

You can try to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25, but then they start accumulating linearly. That is your hypothesis, right?

All you have to do is get appropriate collagen samples from people under 25:

You said that you couldn't prove a negative, and I'm telling you how to do it. It's not an unprovable negative, it's a matter of seeing how much AGE crosslinking is there as a function of chronological age in the young. All you have to do is repeat the tendon measurements posted above, with more data in the young range. It will probably be necessary for you to acquire a grant in order to fund this experiment, but it's not impossible.

With this you essentially agreed that there is no studies showing AGE crosslinking "as a function of chronological age in the young". It's ironic that I am the one here having to prove the obvious, while you, SENS and de Grey are not held by the same high standards.

What? I didn't say that no data exists. You don't accept the data I've showed you; I'm not going to waste my time looking for more. What I did do in the above paragraph was demonstrate that you were wrong about the impossibility of "proving a negative". Taking a measurement isn't "proving a negative" any more than a gas gauge on "E" is proving a negative. It's just getting a measurement. If the percentage of crosslinks in tissue that shows linear crosslink accumulation in adults is flat over the 15-25 age range, then that would be a very interesting measurement. Based on existing data, I don't expect you to find it, but give it a shot.

There's no irony at all here. People who make claims that are at variance with known science are expected to provide evidence for those claims, at least if you want people to pay any attention to them. You can't just claim it's "obvious", as though everyone else is a moron for not getting it.

[HighDesertWizard]

Too bad it's so hard to tell what's the chicken and what's the egg. We do know that damage increases, because we have measured it as a function of age. We also know that paracrine signaling factors change with age. We are not 100% sure which is cause and which is effect, but all evidence I'm aware of favors damage as cause rather than effect.

I think you're right, niner, that Katcher and Mitteldorf make an extreme argument from some of the rejuvenation study evidence they cite. Still, damage was repaired, to some degree, as an effect from a change of circulation system context.

I asked up thread for an Explanation of those study effects from a Damage Theory point of view. No one, yet, has offered up such an explanation...

Can you provide one now?

[Kevnzworld]

As one ages, NOTHING works as well as it did when one was younger....no matter what the organism is, repair mechanisms included.
If intermittent fasting changed this dynamic in any meaningful way, we would know it. As I wrote earlier, Muslims that fast annually during Ramadan do not live longer than non fasters.
We can mitigate damage, influence gene expression and/ or attempt to reset the clock by replacing declining hormones.
Perhaps augmenting NAD with substances like NR will buy us more time and also promote cellular health.
Maybe C60 will prove to be the ultimate mitochondrial antioxidant....
Since there isn't anything currently that can eliminate or break AGE's , substances that reduce the accumulation and formation of AGE's will have to suffice. ( carnosine , benfotiamine , b6 pyridoxamine , vit c, etc )
Maybe by employing an all of the above approach we will increase our probability of living long enough for some of SENS approaches to come to fruition....and if not , long enough to enjoy life for an additional decade or so...

[niner]

 

Too bad it's so hard to tell what's the chicken and what's the egg. We do know that damage increases, because we have measured it as a function of age. We also know that paracrine signaling factors change with age. We are not 100% sure which is cause and which is effect, but all evidence I'm aware of favors damage as cause rather than effect.

I think you're right, niner, that Katcher and Mitteldorf make an extreme argument from some of the rejuvenation study evidence they cite. Still, damage was repaired, to some degree, as an effect from a change of circulation system context.

I asked up thread for an Explanation of those study effects from a Damage Theory point of view. No one, yet, has offered up such an explanation...

Can you provide one now?

 

I'm not sure exactly which rejuvenation study you're referring to; the parabiosis work?  At any rate, I think they are probably confusing "some things working better" with actual elimination of the most problematic damage, which I don't think is happening.  If paracrine signals that decline with age are brought back up via some form of external supplementation, that hasn't fixed damage, it's just changed the level of some signalling molecules.  The real question is why do those compounds decrease over time?  What drives that?  I can imagine such a thing happening either due to damage or to "programming".  If signals are dropping due to programming, then even if you fixed all the damage, you'd either have to figure out how to reverse the programming or defeat it via supplementation.   If you manage to successfully supplement the various paracrine signals in young blood, you won't get "young".  You will still have to figure out how to repair the damage, or you will be a trashed-out old dude with young blood...