LONGECITY

http://www.sandiegou...church-reverse/

 

 

While this is just an article, it sheds some light on what George Church's team is working on reverse aging. Hopefully we'll hear more details, soon from Church's team.

 

 

"A lot of the drugs in development are aimed at effects, those things that are downstream of the cause of age," said Church, 61. "The real cause is probably genetic ... We're trying to get at those causes and reverse those. We're talking about reversing the epigenetic changes that are at the nucleus of every cell.

 

He said that aging should be thought of as a program that might be reversed, noting, "If we could take one of my skin cells and turn it into an embryo-like cell and turn it back into a skin cell it has reset almost all of the developmental indications of age. We have 65 gene therapies that are being test in mice and larger animals. If they go well we will go straight into human trials. That could be as little as two years ..."

 

 

"I don't think it is about stalling or curing, its about reversing. Curing gives you the impression of immortality. Stalling gives you the impression that you'll be 85 forever, which is not great."

 

[OT:

 

I already see certain blogs using their typical titles "interesting comments made by George Church" ... and then go on forever with same words, telling us how wrong Church's approach is, and how rightful others are ... lol ... on the other hand, things are getting very interesting in this field and I like that a lot, because we can start seeing results and not just talks]

 

... and yes, this is another "clown" that thinks "aging is a program that might be reversed" ... for some reason, I like these "clowns" a lot.

 

George Church is a very smart guy, and I can't think of a better person to work on the problem of resetting epigenetics to a youthful profile.  It may well be the case that this is something that will have to be done in addition to SENS therapies.  However, if Church thinks that he will turn an 85 year old person into the equivalent of a 25 year old without addressing things like the crosslinks that make our skin sag or the lysosomal debris that turns our vasculature to crap, he's being naive.  He probably doesn't think that, since he's a smart guy, but he didn't make it clear here.  Church is certainly not a "clown".  It's possible to be both smart and naive.  I'm not calling Church naive, since I really don't know his full stance on aging.  I'll say this:  Anyone who thinks that aging is caused by one thing is naive.  It's a multi-dimensional problem.

Niner, I thought that when we are young, our bodies can take care of crosslinks and look after our vasculature. The example of taking a skin cell, turning it into an embryo like cell and back to skin cell, would that not take care of crosslinks? Would it still have crosslinks? Would a youthful blood supply not cleanup cholesterol and soften arteries? That was always my assumption, fix the source of the problem and the body will fix itself.

When we're young, one way we take care of crosslinks is by diluting them with more new tissue as we grow larger.  That trick doesn't work when we're adults, unless maybe we want to be 12 feet tall.  Intracellular crosslinks wouldn't be a problem, because they can be autophagocized (is that a word?) and turnover is fast.  Outside of the cells, in the extracellular matrix, the crosslinks are a much bigger problem because the ECM turns over so slowly.  Atherosclerosis is pretty tough to reverse.  It might be possible to do it to some extent, but the body doesn't have a way to metabolize the 7-ketocholesterol that the foam cells are loaded with.   If we fix the epigenetics but not these things, then we'll have a body that thinks it's young in some ways, but will have saggy skin and organs, and have sick blood vessels, and have a heart full of transthyretin amyloid that's gumming up the works.

^^^ I want to be twelve feet tall.

sthira, we promise you'll be the first.

I think George Church is an example of the adage "if all you have is a hammer, everything looks like a nail."

 

"We don't know what (age reversal) would mean in terms of human years. Animals have had their life extended by factors of two to 10. That seems too good to be true for humans."

 

No commento.

 

edit: Actually I do have something to say, this reminds me of an article by that mTOR preacher Blagosklonny - his "post aging syndrome" might become an excuse these people use when they search for excuses why their age "reversing" therapies don't actually make you much healthier or live significantly longer. The future of linguistic limbo in the medical field is ever brighter!

Edited by corb, 04 March 2016 - 09:47 AM.

When we're young, one way we take care of crosslinks is by diluting them with more new tissue as we grow larger.  That trick doesn't work when we're adults, unless maybe we want to be 12 feet tall.  Intracellular crosslinks wouldn't be a problem, because they can be autophagocized (is that a word?) and turnover is fast.  Outside of the cells, in the extracellular matrix, the crosslinks are a much bigger problem because the ECM turns over so slowly.  Atherosclerosis is pretty tough to reverse.  It might be possible to do it to some extent, but the body doesn't have a way to metabolize the 7-ketocholesterol that the foam cells are loaded with.   If we fix the epigenetics but not these things, then we'll have a body that thinks it's young in some ways, but will have saggy skin and organs, and have sick blood vessels, and have a heart full of transthyretin amyloid that's gumming up the works.

 

There do seem to be people working on some of these problems and there may well be others working quietly in commercial labs. I'm just hoping that both avenues lead to successs. One without the other is going to be very dissappointing.

" Atherosclerosis is pretty tough to reverse. "

 

... here is an example of therapy for atherosclerosis:

 

http://www.cerenis.c...erapies/cer-001

 

from their page:

 

"

CER-001 is a negatively-charged lipoprotein particle which contains human recombinant apoA-I, the natural HDL protein, and two natural phospholipids: sphingomyelin (Sph) and dipalmitoylphosphatidylglycerol (DPPG).

CER-001 mimicks all the structural and functional biological properties of natural, nascent HDL, also known as pre-beta HDL, and has been shown to perform all steps of the Reverse Lipid Transport pathway (RLT), the only natural pathway responsible for lipid elimination.

Administered CER-001 particles increase transient apoA-I and the number of HDL particles, stimulate the removal of excess cholesterol and other lipids from tissues including the arterial wall and become mature HDL particles, support esterification of the trapped cholesterol through the apoA-I highly stereospecific activation of the LCAT enzyme, are recognized by the liver when transformed in mature HDL, leading to the elimination of the transported lipids and cholesterol through a process called Reverse Lipid Transport (RLT); ultimately the empty particles are recycled.

 

CER-001 has shown strong preclinical and clinical efficacy in mobilizing cholesterol and promoting reverse lipid transport (RLT) leading to rapid atheosclerotic plaque regression."

 

 

[NB: if a research group says that this it's hard or impossible "to do that", doesn't mean other people on this planet will not solve that issue in a different way ... when I have time I'll post more ...]

Thanks alc, that's a pretty cool technology.  Here's a presentation they gave.  The change in plaque volume they achieve is relatively small (less than 1% at the highest dose) but they did show a dose-dependent regression of plaque volume.   There are very few things that I would call "impossible", but I still think this is a hard problem.  That doesn't mean it won't get solved, but it probably won't solve itself.

Niner,

Maybe i missed it, but how long were they treated to reduce the plaque burden ?

 

I think George Church is an example of the adage "if all you have is a hammer, everything looks like a nail."

 

It's more like he/his team have a sledge-hammer ... just that they know how to use it very, very well and address the root problems to reverse aging ... you know what they say (since you like adages): "it's the artist, not the tool" ... there are lots of tools around, just some groups like to use the broom and sweeper to clean up the damage from wear and tear, while others are going after root problems ... that is why George Church's (and couple others) approach is/are like a fifth generation jet fighter versus a third generation (like sens) ... go figure which one will bring more results and it's scalable (both "horizontal" and "vertical") in reverse aging.

Thanks alc, that's a pretty cool technology.  Here's a presentation they gave.  The change in plaque volume they achieve is relatively small (less than 1% at the highest dose) but they did show a dose-dependent regression of plaque volume.   There are very few things that I would call "impossible", but I still think this is a hard problem.  That doesn't mean it won't get solved, but it probably won't solve itself.

 

1% might seem small, but if that can be added (... actually "subtracted" ... lol) over consecutive treatments, it is a very good thing.

And might not be that bad in fact, as we want the treatment to be applied gradually.

 

On a parallel note, here is the work by Regeneron:

 

http://www.regeneron...abolic-diseases

 

look @ Evinacumab

 

They just announced couple days ago about a link of ANGPTL4 inhibition and Risk of Coronary Artery Disease.

 

(of course Trevogrumab is of a high interest as it binds myostatin and leads to increase muscle mass, as well as muscle strength and function - their early studies are in elderly people with sarcopenia)

When we're young, one way we take care of crosslinks is by diluting them with more new tissue as we grow larger.  That trick doesn't work when we're adults, unless maybe we want to be 12 feet tall.  Intracellular crosslinks wouldn't be a problem, because they can be autophagocized (is that a word?) and turnover is fast.  Outside of the cells, in the extracellular matrix, the crosslinks are a much bigger problem because the ECM turns over so slowly.  Atherosclerosis is pretty tough to reverse.  It might be possible to do it to some extent, but the body doesn't have a way to metabolize the 7-ketocholesterol that the foam cells are loaded with.   If we fix the epigenetics but not these things, then we'll have a body that thinks it's young in some ways, but will have saggy skin and organs, and have sick blood vessels, and have a heart full of transthyretin amyloid that's gumming up the works.

 

The fact that negligibly senescent species have no problem with crosslinks and all the other SENS priorities shows either that young cells/organisms can deal with this waste on their own or that these species evolved, in a very short time, perfect repair mechanisms (which is very unlikely).

 

And, of course, it seems such waste begins to accumulate in our cells to a measurable degree only after we reach sexual maturity and begin to age.
 

You might be surprised to learn that improved macrophages help with plaques. I have as yet unpublished data showing msc transplants reduce tau pathology via modulation of macrophages. Atherosclerosis is effectively Alzheimer's of the blood as a study earlier this year showed, the same technique should also reduce Atherosclerosis. In fact I have rat data that shows it does. Our researcher also believes that if microglia and other macrophages are improved this is a way to deal with that issue. More than one way to skin a cat and if George has a way to reset macrophages that is a very good start.

Regards AGE we are working with Yale on breakers. If anyone is a molecular chemist with a lab and wants to join us please contact me directly.

Someone also talked about upregulating ecm turnover, this is another approach and we have a potential lead in this direction. We will test it and measure AGE burden to see if it works.

The take home point is. There are many possible approaches to the same problems, we know what needs fixing so now we must test all approaches to see which works. It does not matter what we believe it only matters what works. Guesswork is useless, logic is better but data is king!

Come and join us and we will get this stuff on the bench and test it. Www.majormouse.org

Especially interested in hearing from people with labs interested in joining the effort.

Some of you might find this about MSCs interesting but there are a number of other papers that confirm and expand upon this.

http://www.nature.co...icles/srep15559

 

 

I think George Church is an example of the adage "if all you have is a hammer, everything looks like a nail."

 

When a very large part of the aging process is nails (genes), yes, a hammer (gene therapy) is the ideal tool. 

When a very large part of the aging process is nails (genes)

 

It isn't.
 

Yes and no. Gene expression is very important in aging but epigenetics seem to be more important. Church has mentioned in the past changing methylation patterns so if he is able to effectively reprogram DNAm this could in theory make drastic changes to cellular function. SENS is one approach to aging but there may be others that work too so I would not be so quick to dismiss Church, he has some very interesting ideas.

I don't think so. I think epigenetics is more a marker of aging than a cause of aging.

Yes and no. Gene expression is very important in aging but epigenetics seem to be more important. Church has mentioned in the past changing methylation patterns so if he is able to effectively reprogram DNAm this could in theory make drastic changes to cellular function. SENS is one approach to aging but there may be others that work too so I would not be so quick to dismiss Church, he has some very interesting ideas.

 

What's the evidence that epigenetics is more than just correlated with aging?  I might have missed it, but it seems like all I've seen so far is that DNA methylation is correlated pretty tightly with biological age, but we don't know if it's cause or effect.  I'm glad that you brought up the fact that this isn't an "either/or" contest between SENS and programming.  It could be aspects of both. 

Rando introduces the topic of Epigentics here and how it focuses gene expression almost like a lens, this primer is worth reading and the supporting evidence cited therein to better understand epigentics. It is an older 2012 paper but the research here is an excellent primer on the subject. 

 

http://www.ncbi.nlm....les/PMC3336960/

 

This second paper again shows a direct link between changes to DNAm, pathology and aging.

 

http://www.ncbi.nlm....les/PMC3482848/

 

Despite these data, the question of whether changes in methylation are downstream effects of aging and pathology or actually one of the causative factors has not been conclusively answered yet. It is evident that a broad range of age-related diseases show aberrant methylation and many potential treatments based on rejuvenating the methylome remain unexplored or undeveloped.

 

 

So in conclusion I would not be so fast to discount DNAm changes and the potential of methylation cellular re-programming, we know cells follow a program (I am NOT talking about programmed aging here!) and we know what program is amenable to being changed, hence I would not be so fast to discount what Church is saying.

SENS and cellular programming are not mutually exclusive anyway as many things SENS is proposing will also reprogram the cells eg, cleaving glucosepane will improve cellular signalling and in theory change gene expression profiles to a younger phenotype. This should not be mistaken with programmed aging which is another kettle of fish entirely and not something I am interested in as I advocate an engineering approach to aging via SENS and other approaches that achieve the same. 

It's difficult to differentiate downstream effects of aging from causative factors in an organism that can repair damage. It becomes difficult to determine whether the organism itself is damaged or it's ability for self repair.

Despite these data, the question of whether changes in methylation are downstream effects of aging and pathology or actually one of the causative factors has not been conclusively answered yet. It is evident that a broad range of age-related diseases show aberrant methylation and many potential treatments based on rejuvenating the methylome remain unexplored or undeveloped.

 

So in conclusion I would not be so fast to discount DNAm changes and the potential of methylation cellular re-programming, we know cells follow a program (I am NOT talking about programmed aging here!) and we know what program is amenable to being changed, hence I would not be so fast to discount what Church is saying.

 

I'm not discounting the reality that DNAm changes over time, and that there exists a potential to alter it in a way that re-programs cells, but nothing I've seen so far looks like evidence for "programmed aging".  As I've mentioned, I think Church is a brilliant guy who is well-placed to develop methodologies here.  I don't think that he's yet provided evidence that "reversing aging" is going to be accomplished through reprogramming of the methylome, but it's certainly worth a try. 

Agreed niner though as I said before reprogramming cells is not programmed aging in the sense of what researchers mean by programmed aging. We need to be careful about this as this is often misunderstood. I believe it is possible to reprogram cells to youthful function but I do not believe aging is programmed per se, much of aging is a stochastic process via accumulated waste