266 replies to this topic

[Danail Bulgaria]

When browsing for stem cells technologies used on people, I stumbled upon one study, that people from this topic may find it interesting.

 

Here you are a full text in pdf:

 

http://ac.els-cdn.co...b04806ca08f50b5

 

A citing:

 

"Regeneration capacity declines with age, but why
juvenile organisms show enhanced tissue repair
remains unexplained."

 

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

 

The study is about an successful aging changes reversal in mice after activating embryonic gene, named "Lin28a", that normally express only during the embryo development. This means, that a drug can be designed to activate the Lin28a gene and continuously repair the mice first, and maybe us later.

[corb]

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.

[niner]

 

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.

 

That paper is about regeneration of injured tissue.  This certainly happens in humans, and it certainly declines with age.  However, most of the argument in this thread has been about the repair of glycation damage to non-injured tissues.  The way the body does that is by protein turnover, but there are some tissues where the turnover rate is not fast enough to keep up with the rate of non-enzymatic glycation.   Possible ways to deal with this problem are the reduction of blood sugar levels, chemical interference in the Maillard reaction (anti-glycation agents), efforts to increase protein turnover (fasting, CR, autophagy inducers), and the "ultimate fix", a crosslink-breaking therapy, which unfortunately does not exist yet.  SENS is working on it.

[corb]

 

 

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.

 

That paper is about regeneration of injured tissue.  This certainly happens in humans, and it certainly declines with age.  However, most of the argument in this thread has been about the repair of glycation damage to non-injured tissues.  The way the body does that is by protein turnover, but there are some tissues where the turnover rate is not fast enough to keep up with the rate of non-enzymatic glycation.   Possible ways to deal with this problem are the reduction of blood sugar levels, chemical interference in the Maillard reaction (anti-glycation agents), efforts to increase protein turnover (fasting, CR, autophagy inducers), and the "ultimate fix", a crosslink-breaking therapy, which unfortunately does not exist yet.  SENS is working on it.

 

 

Yes I am aware of all of this.

As it was already stated in another thread a couple of days ago aging primarily produces pathologies in tissues with slow or no turn over like the brain and the heart. And that is probably where most of the damage and accumulation happens.
Which is why I am a bit baffled with xEva expecting us to produce longitudinal studies with children.

How often does she think children get their brains and hearts biopsied?

 

And one thing I've wanted to point out, we don't necessarily need to prove accumulation in tissues in children.

We already know AGEs are harmful. We already know abeta is harmful - doesn't matter if it's in soluble form or not.

We already know oxydative and heat stress happen. Once your organs with a slow turn over stop their developmental program they are fair game for damage.

I already posted a paper about tissue senescence. The thymus starts losing functional mass as early as the twelfth year of you life. That's pretty early, most children are just hitting their growth spurt around that time. Functional mass is easier to measure than damage - size is standardized a lot of medical tests results are not.

Edited by corb, 28 January 2015 - 05:17 PM.

[Danail Bulgaria]

 

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.

 

 

Or to be more precise you are arguing if the progressive failure of the repair mechanisms is possible to be the reason for the aging.

 

And this is possible.

[LeeYa]

 

That paper is about regeneration of injured tissue.  This certainly happens in humans, and it certainly declines with age.  However, most of the argument in this thread has been about the repair of glycation damage to non-injured tissues.  The way the body does that is by protein turnover, but there are some tissues where the turnover rate is not fast enough to keep up with the rate of non-enzymatic glycation.   Possible ways to deal with this problem are the reduction of blood sugar levels, chemical interference in the Maillard reaction (anti-glycation agents), efforts to increase protein turnover (fasting, CR, autophagy inducers), and the "ultimate fix", a crosslink-breaking therapy, which unfortunately does not exist yet.  SENS is working on it.

 

 

I agree with you!

 

Reducing blood sugar peaks would be an attractive prevention strategy as well as anti-glycation agents.

CR or Intermittend fasting and autophagy inducers should work as well.

 

But why not increase the basal level of protein turnover? This basal level turnover is reduced with advancing age.

 

But the mechanisms of increased collagen production can be turned on and off, for example as a reaction of exogenous physical damage.

 

 

@Cosmicalstorm

 

I guess time will tell us about that LeeYa. As it is, I do not believe that kind of messing about with metabolism is not likely to produce meaningful results. It will be costly and take a long time and in the end we don't know if it will pay of. That is why people ask for repair-approaches.

 

 

Do you think that "crosslink-breaking therapy" is anything other than messing with metabolism?

 

The term "messing with metabolism" may refer best  to deceleration approaches such as CR and rapamycin.

 

However, if restauration of endogenous repair as proposed by xEVA turns out to be a multidimensional approach rather than a simple "one step method", it will tend to look pretty much like the SENS approaches.

[Danail Bulgaria]

Are the changes of the cells so important, if the cells themselves can be replaced?

 

So if, for example, a cell accumulates a lot of AGES, it can simply die and be replaced with another cell of the same type. The process of cells dying and being replaced with the cells of the same type happens in people, at least in the skin, and in it also happens in many other animals. Some living things can regenerate nearly their entire bodies, from small remaining parts.

 

If you find a way not to slow down and stop the controlled replacement of the cells, you are immortal.

[Kalliste]

If it turns out that there are present reparation systems that can be turned online via genetic engineering I would be celebrating that. But I suspect it won't be that simple in humans. It may well be that such approaches will take decades to mature while developing an enzyme that does the same thing (repair) might take a few years if efforts were made. Lets spend time and effort where it matters the most?
Also, chances are that some forms of AGE will not be broken down by the body no matter what genes are active.

[Danail Bulgaria]

How about if the enzyme happens not to work? Why not developing them both - the gene and the enzyme?

[Kalliste]

Really if I was in charge of biotech funding there would be a Manhattan-project-esque thing going on right now where every aspect would be chased down and tried out in the same hurry that we would get if a massive pandemic was killing 100.000 people every day, as aging does. But we are really not there. A pathetically small group of reserachers are pursuing anti-aging related work, most of which is decades away from producing any meaningful results. The microscopically small group that is doing the important work should pursue the avenues most likely to produce quick results. In this case Enzymes or whatever else could break down AGE's.

 

When we have full hardware/software control over our genome, microbiome, proteome, metabolome and whatever else is necessary to stop AGE's in the first place I will take that too of course.

[Danail Bulgaria]

Full software control over genome is not 100% necessary. A gene can be inserted in the cells via viruses.

[niner]

Gene therapy in humans is FAR from easy.   Besides, we don't know of any genes that are involved in the breaking of the important AGE crosslinks.

[Danail Bulgaria]

Alright, but the study, that I cited talks about direct tissues repair, very simmilar to how I imagine it.

 

http://www.sciencedi...092867413012786

[niner]

Alright, but the study, that I cited talks about direct tissues repair, very simmilar to how I imagine it.

 

http://www.sciencedi...092867413012786

 

That's interesting work, but it's about macroscopic injury repair, as far as I can tell.  It doesn't look like Lin28 has any effect on crosslinks.  It improves OxPhos, which is certainly a good thing (c60oo appears to do this as well), and that is apparently involved in injury repair.

[corb]

 

We show that, by 17 years of age, there is a substantial mtDNA point mutation burden. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

 

http://www.longecity...tions-in-aging/

[xEva]

We show that, by 17 years of age, there is a substantial mtDNA point mutation burden. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

 
http://www.longecity...tions-in-aging/

Did you read the full text in question? Why not? Please STOP posting irrelevant stuff. http://journals.plos...al.pgen.1004620

This study confirmed "No significant increase in low level mtDNA mutation frequency with age" and here is the data plotted:
 

 mtDNAmutation.png   149.65KB   1 downloads

Out of 207 subjects aged 17–78, they had exactly 7 people <25 [17, 18, 21, 21, 23, 23, 24] and 4 people=25. They confirmed a previous study with a smaller cohort ages >50 that found NO correlation of mutation mtDNA mutation frequency with age. And so instead they focused on clonal expansion of mtDNA. Now listen carefully: for this part of the study, they cherry picked 8 people under 26 (out of 11 mentioned above) and compared them to a picked group of 8 people over 70. They came to the idea based on the same data arranged by age group:
 

 mtDNAmutationAgeGroup.png   78.18KB   1 downloads
Note how for this part of the study they took the first
and the last groups and picked 8 subjects out of each

Again: they did not show increase with age in people under 26. They found increase only comparing people under 26 to people over 70. Do you understand this? Do you see now how this is irrelevant to this discussion?

PS______
And by the way, out of 16 they picked (8 under 26 and 8 over 70) 10, or 5 in each group, had the same mutation in both buccal and colonic epithelium, which means that this mutation was present already "prior to the fore and hind guts becoming separate which is thought to occur 1–2 weeks post-conception" or, I may add, was already present in the zygote. Interesting, yet another "repair mechanism" at work:

These data do show that 95% of the heteroplasmic mutations detected in both tissues were non-pathogenic polymorphic variants, thus suggesting that pathogenic mtDNA mutations which occur in the germline or early development are selected against, and these non-pathogenic mtDNA mutations may make little contribution to the ageing phenotype. This demonstrates purifying selection in the human germline.

Edited by xEva, 04 February 2015 - 04:08 AM.

[corb]

I can cherry pick quotes from the text as well.

 

 

Due to the small size of the region of the genome under investigation by the RMC assay, and the relative rarity of clonally expanded mutations across the entire mtDNA molecule, the RMC will not detect most of the clonally expanded mtDNA mutations

 

 

Together the NGS and RMC datasets suggest that mtDNA mutation rate does not change significantly with age, but that clonal expansion of mtDNA mutations occurs over time.

 

Please xEva if a research paper doesn't agree with your ideas at least don't lie about it. Have some self respect at the very least.

 

The papers is quite clear on number of points.

• Increase in number of mitochondria with mutated mtDNA with age
• Mutations happen from the cradle to the grave

 

Due to the time taken for clonal expansion of mtDNA mutations to occur in human cells, we hypothesise that late life de novo mtDNA mutational events make negligible contribution to the ageing phenotype and that early to mid-life mtDNA mutations are likely to be much more important.

 

The conclusion is clear.

 

Oh yeah and as it comes to

 

pathogenic mtDNA mutations which occur in the germline or early development are selected against,

 

 

This confirms that there are no selective pressures acting on mtDNA point mutation occurrence with age and that mtDNA mutations present from early adulthood in the human colon could be pathogenic later in life if they were to clonally expand to high levels over time.

 

[corb]

And another thing I'd like to point out.

mtDNA is almost completely coding unlike nuclear DNA, ANY mutation in the mtDNA is detrimental to metabolism. Even if it's not deadly outright.

This paper is supporting wear and tear quite exquisitely.

You know that's the beauty of a theory of aging based on multiple causes, none of the reasons has to be pathological outright.

It doesn't need big proof. It needs a lot of small proofs.

[niner]

Due to the time taken for clonal expansion of mtDNA mutations to occur in human cells, we hypothesise that late life de novo mtDNA mutational events make negligible contribution to the ageing phenotype and that early to mid-life mtDNA mutations are likely to be much more important.

 

This confirms that there are no selective pressures acting on mtDNA point mutation occurrence with age and that mtDNA mutations present from early adulthood in the human colon could be pathogenic later in life if they were to clonally expand to high levels over time.

 

Thanks for pointing this out, corb.  Two consequences of this come to mind-- The first is that a potent mitochondrial antioxidant started relatively early in life may have an outsized influence on lifespan (e.g. Baati's c60oo rats), while starting the same treatment in late life might be a lot less beneficial.  The second is that a technique that sought out and destroyed damaged mitochondria, or cells that were over-run with them, might well be rejuvenative.

[addx]

Since we're talking mitochondria, I have to mention (again) one of the most important findings I've come across.

Epilepsy can be cured via a ketogenic diet (or CR). Cured meaning the healing effects persist after the diet is stopped.

Here's an overview of the subject:

"The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses"
http://www.ncbi.nlm....les/PMC2898565/

Ketogenic diets reduce glucose processing and force mitochondrial ketone body processing for energy. Ketone processing seems to heal mitochondria and mitochondrial status is obviously monumentally important for cell functioning and more.

Here's a study of this:

"Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation."
http://www.ncbi.nlm....pubmed/17240074


It would be also prudent to remember that CR is ketogenic as well and CR increases life span. Ketogenic state has been linked to various benefits that are very related to anti-ageing.

"Ketones to the Rescue: Fashioning therapies from an adaptation to starvation"
http://www.phschool....the_rescue.html

Veech and others have been suggesting for several years that ketosis could help treat, among other conditions, Alzheimer's and Parkinson's diseases, certain insulin disorders such as type 1 diabetes, and several metabolic disorders caused by rare mutations.

I can personally testify to great effects of ketogenic diets. It leveled me out when I was all over the place. Long story, but it worked like a charm.

[Brett Black]

Could the rapid growth that occurs in children and teenagers interfere with and potentially mask the accumulation of damage? If the bodily growth rate equals or outpaces the rate of accumulating damage, then accumulating damage may thus be "diluted", giving the false impression that it is not accumulating.

[Danail Bulgaria]

Could the rapid growth that occurs in children and teenagers interfere with and potentially mask the accumulation of damage? If the bodily growth rate equals or outpaces the rate of accumulating damage, then accumulating damage may thus be "diluted", giving the false impression that it is not accumulating.

 

I am trying to say that more than once in this topic, but no one is paying me attention. The rapid growth of the tissues interferes really with the damage accumulation in the cells. The damaged cells simply die away, and are being replaced with new undamaged cells. Thus the body repairs itself automatically. If the bodily growth rate equals or outpaces the rate of damage accumulation, then accumulating damage may thus be "diluted", as you say, and further it may even stop existing. We have a lot of information about the repairment of the tissues at the level of new cells generation, and it is much more, than we know about the cell metabolism inside each type of cells.

 

Nevertheless, the people here instead of thinking how to rejuvenate the tissues with new, healthy cells, think how to repair the molecules inside the old and the damaged cells, and they dare to do that, without even knowing the entire metabolism of the cell, and that is simply ridiculous. 

[Kalliste]

What are you proposing seivtcho? That we cancel repair treatments and try to find a way to manipulate the body to begin acting like we were children again?

 

I think that will take a long time, much longer and more difficult than developing repair treatments. And then, when that "Make adult biology act like child biology" trick is achieved, what if it still fails because some forms of tissue damage simply can not be repaired by innate biological mechanisms?

 

Do it the other way around I say, develop repair and halt aging.

Then, when we literally have all the time in the world to figure out the spaghetticomplex genetic interactions we can figure out that trick of yours.

[Danail Bulgaria]

I am saying, that simply it will be easier for us to develope a secure tissues repair and rejuvenation techniques, such as using stem cells and cloning organs for transplantaion, or makiing the body to replace its cells, including the most important ones in every tissue, plus finding a way for relatively harmless and secure replacement the clonned cells, tissues and the organs, e.g. to develope ways to implant them.

 

I am also for each other technology, that would enchance regeneration of the tissues, and replacement of the most specialized tissues.

[Brett Black]

Seivtcho, you might have misunderstood what I meant. I'm not saying that children/teenagers are repairing the damage. I'm saying that simply due to their rapid body growth rate, they may gain a large amount of new, "fresh", undamaged biological mass. This rapid gain of new undamaged mass could offset/mask the accumulated/ing damaged mass they have.

Imagine if someone received a knife stab wound("damage"), and then within a couple of minutes their body rapidly grew ten times in size and mass(akin to children/teens.) The stab wound would not grow, so the stab wound would be ten times smaller in comparison to their new larger size: it would now seem more like a pin prick.

[Danail Bulgaria]

lol ok

 

I misunderstood you.

 

Nevermind, I remain on my position.

 

 

[LeeYa]

Let us assume that mitochondrial mutations contribute to the aging phenotype:

 

 

How could this mutations "diluted" by growth of new cells?

 

Cell division requires distribution of the damaged mitochondria! Furthermore, mutations are passed on even during mitochondria neogenesis.

 

Last but not least, if  endogenous repair in the germline is unable to cope with mitochondrial mutations, the germline ages and the species inevitable faces extinction.

 

 

 

 

[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?

[LeeYa]

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.

 

 

 

 

 

 

[ceridwen]

Even a pin prick in the wrong place can cause fatality