The Latest on Heterochromatin and Aging

Heterochromatin is the name given to the more tightly packed structural arrangement of chromosomal DNA in the cell nucleus. Changes in the way in which chromosomes are arranged within the cell nucleus are far from simple and, like various epigenetic modifications to DNA, have considerable influence over the pace of production of proteins. Circulating amounts of various proteins are the switches and dials of cellular machinery, changing constantly, determining behavior, and participating in countless feedback loops to further alter the production of other proteins. Every aspect of the cell plays a part in this dance, including the changing structural arrangement of nuclear DNA: it is characteristic of evolved complex systems that any given discrete part of the machine might be involved in a score of different important mechanisms.

It has been suspected for some time that heterochromatin has some influence on aging. Indeed, why shouldn't it? There are any number of ways to increase or shorten life span by altering levels of specific proteins in lower animals ranging from flies to mice. Alterations to the packing structure of DNA are likely to have many further effects, including changing levels of proteins known to alter the workings of longevity-associated processes. When researchers found a way to alter the proportion of DNA packed as heterochromatin in flies, they could dial up and dial down lifespan to a modest degree. There is considerable speculation as to why this works, but no definitive proof of the underlying mechanism as of yet. Sadly there is definitely an upper ceiling on the process: too much heterochromatin and the flies die.

Another interesting line of research links modifications to heterochromatin levels and cellular senescence. Increasing numbers of senescent cells with old age is well known to be a cause of degenerative aging, but here again the nature of the link with changing packaging of nuclear DNA is all very speculative. Much more research is needed to answer even the most basic of questions regarding how and why with any authority.

It is the case that researchers have used the so-called accelerated aging conditions of progeria and Werner syndrome, among others, to explore concepts and mechanisms that might be of relevance to normal aging. I say "so-called" because these conditions only have the superficial appearance of rapid aging: their underlying causes are in fact largely unrelated to ordinary aging. More than a decade after the identification of the critical breakage in cellular metabolism that causes progeria, for example, it is still far from clear whether this mechanism plays any meaningful role in human aging. It shows up to a small degree in old individuals, but is this significant over the present human life span? Perhaps not.

Here researchers investigating Werner syndrome make progress in understanding the disease mechanisms, which appear to involve heterochromatin. The publicity teams putting out the release are greatly overstating the relevance of this work to normal aging, however. Hype in research is a real problem, and sadly many groups who should know better are just as bad as the tabloids these days. So for my two cents, the relevance of this work on the causes of Werner syndrome to normal aging is just as speculative as is the case for work on the causes of progeria. It is likely that both conditions are the result of forms of damage that just don't happen to a meaningful level in a normal metabolism. When you are looking at broken biochemistry there is no guarantee that any of its operational characteristics are of use when understanding normal biochemistry, and breaking things to create a shorter life span usually has little relevance for any attempts to lengthen life span. Or at least that is the case until researchers can turn things around and demonstrate longer-lived animals via a reversal of the mechanism they are studying. Pay attention to longevity demonstrations, not demonstrations of shortened life spans.

Scientists discover key driver of human aging

Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s. The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person's DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.

Scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell's nucleus. This points to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, scientists showed that the protein interacts directly with molecular structures known to stabilize heterochromatin - revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.

"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations - like remodeling an old house or car - to prevent, or even reverse, age-related declines and diseases."

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
Comments

I think your post about this research is far from being objective. This web only gives support to SENS, and the rest of investigations have no meaning for you. It's really disappointing for me because I thought this web was serious. I hope you can change that.

Posted by: Fernando at May 2nd, 2015 11:15 AM

I guess that "Reason" is on his right to give his opinion, but I partially agree with Fernando. I can distinguish two main types of posts in this web, those related with the latest research on the field (like this one), which I really like to keep myself updated (I work in this field and find it really useful), and those where a more general discussion about the state of the art of the field takes place but unfortunately, most of the times is about SENS. It would be really nice to read more about the research done in other research centres! It is, at least, as interesting as the research at SENS.
Anyway, keep up the good work!

Posted by: Efret at May 2nd, 2015 12:23 PM

This web (or any web, for the matter) should not give equal support to all aging research or all aging theories. It should apply the same scientific rigour to all. If there are sound reasons to think that a research is less important/useful/practical than other research, it should be treated accordingly. Science is not a democracy.

Posted by: Antonio at May 2nd, 2015 1:28 PM

Reason is right that research done in "accelerated aging" diseases like Werner's or in organisms that have been engineered to be "broken" and then are "fixed" is not necessarily as important to normal aging as research shown to extend lifespan in normal organisms. Still, the fly study Reason links was on normal flies, so perhaps this particular area of research may end up being important. What I'd like to see is Heterochromatin used in normally-aged mammal models; if they enjoy an increase in mean or max lifespan then this could really be something important. (Maybe even another category of damage to add to SENS?)

I wish more scientists would experiment on normally-aged organisms rather than altered organisms. I'm not sure why they don't. Perhaps it's a matter of cost and time; I don't know.

Posted by: kim at May 2nd, 2015 4:18 PM

What if two root causes of aging proposed by SENS research foundation (loss of stem cells and cellular senescence) are actually caused by one true root cause ignored by SENS: nuclear DNA damage? Stabilizing of the heterochromatin might be easier than adding new undamaged stem cells to certain parts of the body (such as any other than bone marrow). Maybe it isn't a permanent solution, but if combined to the easier SENS strategies, it could buy us more time to build one.

Posted by: Rude at May 2nd, 2015 4:33 PM

@Rude - I think the SENS strategy focuses on the chokepoints of damage that accumulates and is unrepaired. You could always look at an earlier point in the metabolism to try and slow the rate of damage accumulation. If Heterochromatin does turn out to be a driver of aging in normal mouse models, it would probably still be easier to remove the resultant SENS areas of damage rather than prevent Heterochromatin dysfunction.

A similar argument is made by the SENS foundation with regard to regular somatic DNA damage over the life of an animal. Particularly as they are hypothesizing that there is a bifurcation rather than a linear relationship between damage in the 7 categories and the disease and dysfunction of aging. An animals body can tolerate damage up to a certain level with no ill effect (probably). Rather than prevent DNA somatic mutations just target and remove the downstream effect - senescent cells, cancer cells etc.

Influencing Heterochromatin still looks like messing with metabolism to slow the rate of damage accumulation rather than removing the damage itself.

Oxidised LDL (low density lippoprotein) is perhaps another example. Are there lifespan/healthspan benefits to reducing the rate of oxidized LDL accumulation in foam cells with Satin drugs or PCSK9 antibodies? Yes there are. But oxidised LDL is still building up, just at a slower rate. The SENS proposed technology of using a bacterial enzyme to break up the oxidised LDL would actually reduce this damage level as opposed to slowing its rate of increase. Unless you prevent Heterochromatin disruption completely as soon as it happens it will still cause some of the 7 categories of damage (if it does this) and this damage will still build up, just at a slower rate as with statin drugs.

If you can deal with Heterochromatin dysfunction by removing the downstream damage, then it is probably advantageous to focus on removing this downstream damage for the reasons oft stated on this blog that slowing damage can only result in a slowing of the rate of aging, it is no use to already aged individuals, and slowing damage is messing with the mirror maze of metabolism.

The real question is if growing Heterochromatin disorder causes aging, how does it do this? For it to be of concern to the SENS hypothesis it would have to be causing aging through some new unidentified channel of damage other than the 7 proposed.

Posted by: Jim at May 2nd, 2015 11:27 PM

@Jim - Thank you for your reply. I do understand how SENS strategies work but I think complete ReplenisSENS is technologically so far away that we need to buy some time by slowing down the damage accumulation first (for example by preventing our cells from downregulating heterochromatin maintenance in the old age like Zhang et al paper pointed out).

"The real question is if growing Heterochromatin disorder causes aging, how does it do this?"

Loss of heterochromatin exposes the nuclear DNA to physical damages which causes cellular senescence and depletion of stem cells. Removing the senescent cells will probably be possible in the near future but replacing the damaged stem cells (except those in bone marrow) will be difficult due to the wide distribution of different kinds of stem cells. Think about the skin and muscles for example.

That's why I think the easiest thing to do now is to check if we could prevent our cells from downregulating the heterochromatin maintenance. I'm positive that it could buy us some time when combined to the easier SENS strategies such as LysoSENS, GlycoSENS and AmyloSENS.

Posted by: Rude at May 3rd, 2015 9:53 AM

RepleniSENS, aka stem cell therapy, is actually one of the easiest of the SENS strands (arguably the very easiest). (Skin stem cell replacement is a key aspect of burns therapy, as well as cosmetic peels.) Disorder of heterochromatin is a phenomenon that a number of gerontologists have been getting interested in recently, and if it is important then its importance almost certainly extends to cell loss, cell senescence and cancer. Because it can almost certainly cause cancer, it is in the same boat as all other epigenetic and genetic damage to nuclear DNA: it probably causes nothing except cancer in a currently normal lifetime. (See my paper on "protagonistic pleiotropy" for the detailed reasoning.) In particular, this study does not tell us that heterochromatin disorganisation matters, because it's a study of accelerated damage. However, if there were some easy way to maintain heterochromatin organisation, it would be a valuable safeguard in case for whatever reason the protagonistic pleiotropy logic doesn't apply here. But I don't envisage such a way.

Posted by: Aubrey de Grey at May 3rd, 2015 6:50 PM

@kim
"I wish more scientists would experiment on normally-aged organisms rather than altered organisms. I'm not sure why they don't. Perhaps it's a matter of cost and time; I don't know."

The lack of experimentation on normally-aged organisms may have to do with a paucity of funding. I would imagine that obtaining a grant to do research on something that is classified as a disease (i.e., 'abnormal aging' of Werner's syndrome) is significantly more likely than working on something like 'normal aging' which is not currently classified as a disease itself.

Posted by: aaron at May 3rd, 2015 8:24 PM

@ Aubrey de Grey -
since this is the "easiest", is it possible that SENS either come up with a real-life implementation of RepleniSENS, or license that technology to a different company? That way at least one of SENS strands can be confirmed and lots of (endless) discussions and arguments will be closed. While we understand that RepleniSENS will not offer the "ultimate" rejuvenation that we are all dreaming of, it will confirm the approach and will help TREMENDOUSLY this field and SENS as well.
That will ease the process of funding as donation based, for sure, is not a good model. While even couple days ago I donated a small sum to SENS, these money from donations are "nothing" and going this way will require couple centuries to reach what SENS tries to do.
So I believe (like many others here) that moving towards a "commercial" model will be the true way of funding SENS work and reach milestones soon. Thanks a lot for your work, and I hope I was a rich billionaire that can afford to fund and put to test the most important SENS theories ... to help bring true rejuvenation in the market soon.

Posted by: Adrian Crisan at May 3rd, 2015 9:13 PM

@Adrian
Aubrey de Grey wrote million times that SENS will not focus on stem cell in near future because many others are already researching them. I agree with this decision. However I do not agree with de Grey's statement that stem cells are easiest. Making them is easy. Using them is not.

If you can afford it you can visit Nygard's clinic in Bahama soon. They transfer your DNA into donor oocyte to grow embryonic stem cells. This is the easy part. The real problem is implanting these cells to do some good for you. Nygard believe it is enough to just inject them to your blood with needles.

This is not enough, as already discussed on this website and elsewhere. Erratic stem cells are good for developing cancer, not for reversing aging. Placing them in the right place one by one is beyond today technology. Right now it is better to grow whole tissues of them in vitro and replace this tissue surgically.

Posted by: Martin at May 3rd, 2015 11:23 PM

Martin: you are quite correct that getting stem cells to the right place is often the hardest part. Actually, even making them is sometimes very hard too, because of the cancer risk you mention and also because of the need to ensure that they differentiate correctly. The main reason why stem cell therapy for Parkinson's disease was only occasionally successful 20 years ago is that in most patients the cells gave rise to the wrong type of neuron.

But all this does not refute my view that RepleniSENS is the easiest! That's a relative statement. Perhaps you are misjudging how hard the others are. I actually think AmyloSENS may end up looking easier within another year or so, as we start to see in vivo results against targets other than Alzheimers amyloid, but the other five are pretty definitely harder than stem cell therapy.

Posted by: Aubrey de Grey at May 4th, 2015 9:12 AM

Where would you fit apoptoSENS as far as ease or order of implementation? I ask because of the recent news about those senolytic drugs. Even though that might be a crude way of doing it, it seems like a potentially positive starting point?

Posted by: Ham at May 4th, 2015 11:59 AM

Atherosclerosis and its clearance is also something that seems to be getting a lot of attention. I have seen a number of groups working on this ranging from Pharma solutions to Gene Therapies to clear the foam cells out. Bioviva were saying a gene therapy they use helps clear foam cells for example, this is apparently the same Follistatin therapy that has been tested on MD children at the Nationwide Children's hospital apparently. Whatever the case AmyloSENS I can see coming soon as so many people are working on this with promising progress from some approaches.

Stem Cell therapies are coming along in leaps and bounds, they recently repaired the damage resulting from spinal injury in a patient and restored mobility. They are getting much better at targeting Stem cells as well as producing them. I would agree with ADG that RepleniSENS is the easiest and it is a well funded area of research too.

Apoptosens again is something that is getting attention recently so we could well see this being taken up by Pharma to produce a Senescent cell small molecule solution.

The FDA red tape is the big problem with all this and the time it takes to get products to market and the cost. I am hoping ATHENA and other on chip organs the NIH is very interested in will speed up development rapidly and allow us to move away from Mice into a Human analogue instead.

I think we will start seeing other groups taking up the SENS approach as time goes by too, ADG has got the ball rolling but I suspect some of SENS may be delivered by others who have taken up the ideas of ADG. I also suspect we may see a combination of SENS repair with Epigenetic therapies combined as a "first pass".

Posted by: Steve H at May 5th, 2015 4:07 AM

Yeah, hated FDA (and EMCDDA too) :-)
But I am ok with "therapy tourism" even for a higher price. Better than nothing.

Posted by: Martin S. at May 5th, 2015 5:06 AM

Sorry, wrong acronym. I meant EMA.

Posted by: Martin S. at May 5th, 2015 5:16 AM

I have no doubt medical tourism will increase as gene therapies and other age repair therapies become available. Fact is people will just not be prepared to wait 10+ years for stuff that could dramatically improve their lifespan and health.

The FDA will either have to adapt to the change in medical paradigm or therapies will just bypass them. Stuff like ATHENA will help speed up the process of drug development but the FDA needs to embrace technology like gene therapy and speed up the process of development.

Posted by: Steve H at May 5th, 2015 7:12 AM

ApoptoSENS is looking relatively easy now. Even if these drugs don't work out, there are quite a few approaches that are looking realistic. The hard part may be to get rid of other types of death-resistant cells, such as anergic T cells, but that's going quite well too.

As for a combination of SENS repair with epigenetic therapies, well, that "epigenetic therapies" exactly? I'm not sure why people are so interested in such an idea when we don't actually have any way to rejuvenate the epigenome.

Posted by: Aubrey de Grey at May 6th, 2015 8:49 AM

AmyloSENS seems to be something a lot of people are working on either directly via SENSRF or as independent projects, this is something I think may happen fairly soon via one group or another as its such a big killer.

ApoptoSENS I have seen in the news very recently with combination of drug and a natural compound combining to remove cells. I know SENS had a scrubber for T-Cells etc... how is that progressing?

Gene therapy is one way to influence the Epigenetic drift and a few groups are working on that currently. I think we may see gene therapies combined with other repair strategies as a crude first pass. Our mutual friend Liz has a number of combination therapies planned which I am sure you are aware of Dr de Grey. Her company appears to follow a roughly SENS repair approach with a few key differences. There are other groups out there working on this kind of thing too.

Posted by: Steve H at May 6th, 2015 10:51 AM

"I'm not sure why people are so interested in such an idea when we don't actually have any way to rejuvenate the epigenome."
I hope we can at least repair stem cell's epigenome in vitro.

Posted by: Martin S. at May 6th, 2015 11:01 AM

1. While I do not know as many as you guys in this field, I just did a quick Google search for "rejuvenate the epigenome", and I got a lot of results ... just highlight the three words and right click. Here are couple of them:

"Epigenome rejuvenation: HP1β mobility as a measure of pluripotent and senescent chromatin ground states"
http://www.nature.com/srep/2014/140425/srep04789/full/srep04789.html

"Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock"

http://www.cell.com/cell/abstract/S0092-8674%2812%2900004-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867412000049%3Fshowall%3Dtrue&cc=y=

So is the discussion about something else? when Aubrey de Grey is mentioning
"we don't actually have any way to rejuvenate the epigenome." is referring to something else?

Don't want to deviate the discussion, but as a simple scientific excursion, human body is a closed finite system, and regardless how many cells and interactions between cells/tissues/organs/etc. we have, any closed finite system is REVERSIBLE. Very true that there is a lot of math/genetics/chemistry/etc. and connected sciences in order to find a solution to reverse the system, no doubt about that, but ANY closed finite system IS reversible.

2. "ApoptoSENS is looking relatively easy now" - that is great news!
Is it possible to crowd fund that and accelerate the work? I bet a lot of people will donate to a specific project like that one, just to see it in the real world. For example, Ichor Therapeutics crowdfunded their C60 project and a lot of people from Longecity donated.

Posted by: Adrian Crisan at May 6th, 2015 7:55 PM

"ApoptoSENS is looking relatively easy now" - that is great news!
Is it possible to crowd fund that and accelerate the work? I bet a lot of people will donate to a specific project like that one, just to see it in the real world. For example, Ichor Therapeutics crowdfunded their C60 project and a lot of people from Longecity donated.

I would very much like to see this therapy fast tracked and agree with Adrian's suggestion. Senlyotics has been in the news very recently and a crowd fund is a great idea for this specific project. Dr De Grey or Michael could such a thing be attempted?

Posted by: Steve H at May 7th, 2015 3:20 AM

@Adrian: The human body is not a closed system at all.

Posted by: Antonio at May 7th, 2015 5:14 AM

I think he meant it's an open system and therefore can be intervened in? A closed system would not allow that but we can change things in our systems making it an open system subject to intervention.

Posted by: Steve H at May 7th, 2015 5:48 AM

Very interesting, Steve. I saw it today on TV.

Posted by: Antonio at May 7th, 2015 9:20 AM

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