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January 18, 2012

Interview with Aubrey De Grey on Progress in Therapies for Rejuvenation and Their Delivery

HPlus Magazine- Adam Ford conducted a fascinating video interview with biogerontologist Aubrey de Grey.

* SENS - there are seven deadly things (known damage caused by aging processes)


Aging Damage                SENS Solution
Cell loss, tissue atrophy   Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations
(only cancer matters)      Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria         Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells       Targeted ablation (ApoptoSENS)
Tissue stiffening           AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates    Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates    Novel lysosomal hydrolases (LysoSENS)

We’re doing them all at the same time. I’m interested in making sure that none of these things are left behind. We prioritize certain things over others is simply if they are not being prioritized by the rest of the world.



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There are just a few areas within SENS that we are de-prioritizing because they are being funded quite well elsewhere. One of them is the Elimination of Amyloids, that the garbage outside cells, that occurs in Alzheimer’s disease. And even there, it’s only sort of that one subset of that one deadly thing that we are not working on.

At the moment, our Research Center in Mountain View, we are working on LysoSENS, as you said, but we are also working on MitoSENS, the elimination of mitochondrial mutations in aging, and ways to make those mitochondrial mutations harmless essentially by putting copies of the mitochondrial genome into the nuclear genome. And in projects that we are funding in university labs around the country, we are doing a number of other things relating to other aspects of SENS. So yes, we are interested in focusing on all of these things in parallel.

We are working on something very similar, the accumulation of a similar type of garbage outside cells that occurs predominantly in the heart. It just turns out that even though Alzheimer’s work is well-funded and well respected and everything, nevertheless during the same sort of approach for other types of Amyloids, other types of extracellular garbage, it is not being particularly enthusiastically pursued by other people, so we are doing our bit.

Similarly, in the case of lost cells where cells die and they are not automatically replaced by other cells or by the division of other cells – That is what stem cells are for. Stem cell Therapy is very real- People are working in lots of areas in that field, so of course we are not trying to duplicate that effort. But even there, we are doing one of two things. For example, we’re interested in a particular type of cell loss which is the shrinkage of an organ called the Thymus, which is responsible for the creation of certain types of immune cells.

It turns out that restoration of the Thymus to its useful size is something that not many people work on. The approaches that have been tried have not been very successful. We are looking at some more ambitious but we think more promising approach is that have not been looked out by other people. And for all the other areas of SENS essentially we are doing everything.

LYSOSENS progress

The introduction of non-human genes or enzymes into our cells, that will improve the ability of the LysoSENS to breakdown substances that currently it can’t breakdown that’s why it accumulates slowly but inexorably in various cell types and of course certainly the most important disease of old age.

No Need for Monitoring

The good thing about the various types of accumulating damage that contribute to aging, is that they are mainly caused by very intrinsic and non-negotiable, shall we say, aspects of metabolism like breathing, for example. The result of that, the rate at which various different types of damage accumulate in the body is not all that different from one person to another. I mean there will be some difference always, but not more than, let’s say, a factor of two between any pair of people.

So that means actually that the motivation for monitoring people to see how much damage they’ve got of any particular type is a good deal lower than it is for most diseases. Ultimately if you don’t have that information then all that means is that you may end up having to administer certain therapies twice as often as necessary, and there’s really not much harm in that.

It may actually end up being easier in many cases, in most cases, not to bother with the monitoring and just to assume the worst case scenario for everybody.

Tissue Engineering

Tissue Engineering is all about creating organs that have never been in another individual and putting them in after having been created in the laboratory. So the actual Transplantation process is exactly the same as it is when the organ would come from another individual. But, first of all, the risk of infection will be very greatly minimized because the organ can be created in the lab in a sterile environment. Secondly, the immunity problem can be completely eliminated by creating the organ using cells that come from the individual that you are helping, that you’re going to be eventually giving the organ to.

Now, for those reasons, Tissue Engineering has been a very big goal bio medical technology for a long time now, at least for twenty to thirty years. But progress in actually making it work has been patchy, pretty slow – and the number one reason for that has been ‘Vascularization’. In other words, the requirement to actually create this organ with a blood supply that goes sufficiently thoroughly throughout the organ so that every cell in the organ is very close to a blood vessel, same as it happens in the natural body. People have tried the most extraordinary number of very creative approaches to making that happen but none of them have really panned out. What has really changed over the past few years is the development of a new approach to doing all of this. We involves taking the organ from another individual, as per a regular transplantation, but rather than putting as it currently exists into the patients, what one does is, first of all, one gets rid of all the cells that belong to the organ. So that sounds crazy – but what it involves basically getting rid of the cells but not getting rid of the vasculature. Because the vasculature is defined by protein called the Extracellular Matrix which are not removed by this process. So the vasculature is still there. And then what you do is you take cells from the prospective patient and you basically just infuse them into this denuded vasculature, so that they can take up residence in the place of the cells that you got rid of.

That means you end up with an organ that is *not* going to be rejected because the Extracellular Matrix itself is the only part that’s foreign and it is not very immunogenic. And yet, the vasculature is really there because it comes from a regular organ that’s ingested in another individual. Perhaps not even the organ of a human, maybe a pig or something like that. And so this is a very exciting area and people are working on it hand over fist across the world in many different organizations and in many different laboratories!

Cell Therapies

The removal of the existing (bad cells) ones is a separate issue. In general, removal of cells which are getting in the way, that they are not functioning anymore but they’re not dying, is something that’s in principle a good deal easier than replacement of cells because one can do a lot of different tricks. For example, one can actually immunize against these things. Typically cells that are not behaving look different – they have different protein on their cell surface and that can be used as a signature to get rid of these cells. I’m not saying it’s easy but that’s the sort of approach that can be taken.

The replacement of cells, well, that depends. It turns out that in research in stem cells, we’ve discovered an awful lot over the years about how different cells arise from other types of cells. In other words, basically the Phylogenetic Tree, the lineage of how the original embryonic zygote, the first cell of the body, divides and differentiates into a whole bunch of different other cells.

We’ve also discovered ways to take cells that have already been differentiated into a specific cell type and to de-differentiate them back into a more primitive form. So what this all adds up to is that we’re pretty close now to being able to create any cell type that we like, again, without the rejection problem, without the problem of the DNA being different, and therefore the immune system getting active when you put the cells into the body.

So that means that we have the potential to be able to replace any cell that we like into the body by introducing cells surgically that are precursors of the cells that we don’t have enough of anymore. And then the cells will differentiate to replace the cells that have gone missing. That’s what Stem Cell Therapy is all about. And yes, it sounds pretty technical and in many cases we’re a long way to making it work. But in some cases we’re not very far away. There are already clinical trials out there for a number of different problems caused by loss of cells including problems related to aging! So Parkinson’s disease is probably the best example of that.

Gene Therapy

We’ve got to distinguish between a number of different approaches to Gene Therapy. So the classical concept with Somatic Gene Therapy is just as you described – one introduces these genes into the body typically packaged viruses and the viral DNA has the capacity to invade the cells and get into the nucleus of the cell. And by doing so, integrate into the chromosomes of which the cargo, the DNA that we engineered, that we want to introduce, then behave as transcribed and translated and so on just in the same way that our natural genes are. But there are, as you say, number of variations on that theme.

One of them is often called Ex Vivo Gene Therapy. It essentially means extracting cells from the body doing the genetic manipulation outside the body and then bringing the modified cell back. That has a lot of advantages when you can do it because, well the biggest advantage of all is safety, we can make sure that the cells we put back are modified in the appropriate way, the way that we intended to and not in any other way. We can do that simply by doing the modification and then by testing the cells in a variety of different ways to make sure that the genetic composition is as we intended.

However there are plenty of cases where that approach – Ev Vivo Gene Therapy simply isn’t available especially the cases where the cells that we want to fix up are cells that are long-lived and are not dividing and that we don’t want to kill, we just want to alter them while in the body – so we do Somatic Gene Therapy itself some of the time. The safety concerns that I just alluded to are quite severe. There have certainly been cases where people have suffered quite badly from the unintended side effects from Somatic Gene Therapy.

So one big thing that we’d like to be able to do that would alleviate most of those potential risks is to put the DNA not into some random place of the genome which what happens typically when you use viruses in this way, but instead to put the DNA into a specific place, a place that has been pre-chosen to be harmless – so nothing would be disrupted. And some very important progress has been made over the past decade especially in doing exactly that. My concept is called Gene Targeting and there’s a number of ways to go about it. The way that currently looks the most promising involves something called Zinc-Finger Nucleases and it would take me a little while to explain what those are.

Crude Therapies Initially that become more convenient

I think that we are likely to see over the years a substantial evolution of the delivery modalities for these therapies in general. I think when they first arrive, and of course we still don’t know when that’s going to be, I think we have a 50-50 chance of getting that within the next 20 or 25 years, it could be sooner or later. But, anyway, when they do arrive, like any new experimental first generation therapy and it’s perhaps quite risky. So I expect what’s going to happen is people will go in the hospital for maybe a couple of months even, and will get these therapies with regular monitoring going on to make sure that the therapies are not doing any harm, and such like.

Well, as time goes on as the therapies will get more proven and more convenient and cheaper and so on, I wouldn’t be at all surprised to see that they will become *outpatients* as everything is done by injection and to a certain extent, one might be able to go as far as oral administration, as you suggest. We just can’t tell when and to what extent that’s going to happen.

Money - Funding is the one bottleneck to SENS

There’s really only one bottleneck which is money at the moment. No, I’m serious. We have at the moment a very good, very sophisticated and detailed idea about what SENS needs to be done, needs to be developed, in order to actually bring SENS to reality. We also have an equal essential ingredient. We have the right scientists, all the real world leaders in all of the various areas that are relevant to the SENS. They are very enthusiastic about the applying their expertise to the problems of aging and to the application of regenerative medicine to diseases and disabilities of old age.

This is essentially what SENS is. So that’s what’s in place. What is not in place is the resources to allow those people to actually get on and do that experiment. So that’s why I spend humongous amount of my time going around the world, getting additional funding to be allocated to this work.

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Making the case for Preventative Geriatrics

Basically everyone, however wealthy you are, you can do something. So if you’re a journalist, you can interview me. If you are a conference organizer, you can get me or one of my colleagues to come speak. You know, getting the word out is an enormous part of this. What anyone can do, whoever they are, is advocacy. You can always talk to your family, your friends, your colleagues.

You can get them to understand that this is both feasible and desirable and to be realistic about this to understand that ultimately this is no different than any other type of medicine except for the fact that it doesn’t nearly exist. It is no different than any type of medical research.

I use the phrase “Preventive Geriatrics” a lot, In other words, to emphasize that what we’re talking about here is simply preventative medicine for the diseases and disabilities of old age and all of us already know that we don’t want to get. So it’s perfectly legitimate, perfectly regular, normal medical research and it just needs to be thought about in that way. The more the word gets out, the more public enthusiasm there is for this, the more public policy will respond to that public enthusiasm and the more public money will be available and it won’t be reliant any longer on the largesse of private individuals.

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