Undoing Aging: An Interview with Aubrey de Grey

The Undoing Aging conference in Berlin is presently underway, a gathering of everyone who is anyone in the rejuvenation research community. It is hosted jointly by the SENS Research Foundation and the Forever Healthy Foundation, and is a unification of the varied themes of the past fifteen years of SENS conferences: the science of aging and its treatment from the earlier SENS conference series mixed with the industry, startup, and commercial development focus of the Rejuvenation Biotechnology series of recent years.

The first rejuvenation therapies to be implemented and shown to work, those based on clearance of senescent cells, are presently entering human trials and being carried forward to the clinic by startups. The next set of rejuvenation therapies, targeted at different mechanisms of aging such as cross-links and mitochondrial damage, are still in the laboratory, working their way towards completion. This is a time of transition, the birth of a new field of applied biotechnology, one that will grow to subsume most of the present medical community and provide services and products to every adult human being.

To commemorate the occasion, the Life Extension Advocacy Foundation volunteers have published a three-part interview with Aubrey de Grey of the SENS Research Foundation, the person who did the most to start this ball rolling back at the turn of the century. Later joined by a range of allies within and outside the scientific community, and then by a community of advocates and supporters, a bootstrapping process of growth towards the industry needed to bring an end to aging has been underway since. These are fairly lengthy interviews, and I'm not quoting more than a fraction of the whole here - you'll certainly find further interesting comments if you read the whole thing.

Undoing Aging With Aubrey de Grey Part One

Why did you choose Berlin and not California or elsewhere in the USA for the event?

Basically, because the suggestion came from our main German donor, Michael Greve, who is also the conference's main sponsor. Hard to argue with that!

Is SRF planning to make Undoing Aging into a recurring event, much like the Rejuvenation Biotechnology conferences in America?

We'll certainly be continuing to do both more science-centered events like Undoing Aging and the SENS Conferences, as well as more rejuvenation biotechnology industry-oriented events like the Rejuvenation Biotechnology series, but we haven't yet decided on the sequence and orientation of future meetings. We certainly want to maintain a strong conference presence in California, but it may be best to do that with smaller, more frequent events, such as the one we did with the California Life Sciences Association.

Recently, SRF has received significant donations amounting to over 7 million dollars. What priorities does SRF plan to address with this money?

First and foremost, we will be gearing up our existing programs in mitochondrial gene replacement, scaling up glucosepane research, rejuvenation biotechnology against cytosolic aggregates, and so on. We will also be initiating new ones; those are still being discussed with potential extramural collaborators, but you can expect some announcements later this year. They will all be within the same seven-strand framework that has defined SENS since the beginning. And after having sometimes in the past allocated nearly all of our available research budget at the beginning of the fiscal year and thereby limiting our ability to take advantage of new opportunities that arose later in the year, we will be maintaining a research reserve fund so that we are always poised to get good work funded year-round.

For anyone reading this who is thinking about doing the same as our recent donors, I will just say that we are a very long way from running out of productive ways to invest more money.

Undoing Aging With Aubrey de Grey Part Two

Regarding the use of senolytics, are you concerned about their potential to remove highly specialized cells like cardiomyocytes, which do not divide or do so very slowly?

Cells that don't divide (like cardiomyocytes and neurons) are far less likely to become senescent in the first place than cell types that divide; many of the main drivers of senescence are related to cell division. In the specific case of cardiomyocytes, there's already significant evidence in rodents that senolytics improve cardiac function overall. However, there is some reason for concern here, which is why we're already working to develop the next generation of senescent cell ablation therapies. The selectivity of senolytic drugs for senescent cells comes from the fact that they target the activity or expression of genes involved in cell survival, on which senescent cells are much more reliant than healthy cells under normal, unstressed conditions. But during times in which the cell is under stress, normal cells also rely on those same pathways to carry them through and give them time to recover. Future therapies can target truly senescent cells more selectively, and SENS Research Foundation is helping to advance those next-generation senescent cell therapies, even as UNITY Biotechnology prepares for human testing, through our investment in Oisín Biotechnologies.

Senolytic drugs gave mice increased healthy lifespan in experiments. Given that every living organism produces senescent cells the same way, could this mean that it may translate to humans?

Interventions that lead to gains in median lifespan only in laboratory mice, with no corresponding effect on a robust maximum lifespan (tenth-decile survivorship), still need to be heavily discounted when speculating on effects in humans. Interventions that only affect median lifespan primarily affect deaths in the first half of the lifespan - and here there is a critical difference between mice in a lab and modern humans, for whom medicine has already eliminated many causes of such early deaths, from vaccines (which also impact late-life mortality by reducing lifelong inflammatory burden), to surgery, to antibiotics, to drugs that more obviously affect middle-aged people.

The force of this reasoning is somewhat attenuated in the case of interventions like senescent cell clearance, which actually repair aging damage, than with interventions affecting environmental or metabolic risk factors driving "premature" disease (obesity, inflammation, cardiovascular risk factors, environmental toxins, etc). Still, you have to assume that the effect on lifespan of any single damage-repair intervention in isolation will be modest, based on the principle of the "weakest link in the chain": all the links are weakening over time, and shoring up only one of them still leaves the rest of the links damaged and ready to shear, whereupon the whole chain is broken. To move the needle on lifespan in modern humans, we have to push back on all of the cellular and molecular damage of aging, not just one form.

Regarding the breakdown of extracellular aggregates, what will you do if the first wave of treatments using antibodies is unable to repair the whole system?

Certainly, it's guaranteed that no first-generation SENS therapy will be able to repair every single contributor to any given category of aging damage - and it doesn't have to. All we have to do to reach "longevity escape velocity" is to remove or repair the specific forms of cellular and molecular aging damage within each category that meaningfully restrict our lives to the extremes of current lifespans. During the extra decades of healthy life that we'll then enjoy, scientists can then work to identify the constraints that limit life- and healthspan to those newly-expanded horizons. Accordingly, all SENS therapies will need to be iteratively improved; we will want safer and more effective ways to repair the damage targeted by earlier iterations of rejuvenation biotechnologies and also to repair additional specific targets within each category. It's only once those first therapies are developed and in use that we'll know what their specific limitations will be

Have you reviewed you position that nuclear mutations matter only in cancer in light of recent research results suggesting that certain ominous mutations in hematopoietic stem cells increase the risk of developing not only blood cancers (50 fold) but dying of all causes by 40%?

The research on this "clonal hematopoiesis" phenomenon is certainly provocative but doesn't ultimately change our view on this question. Remember first that it has never been our position that nuclear mutations matter only in causing cancer; at a minimum, they also matter in causing apoptosis ("cellular suicide," which denudes the body of functional cells with age, most importantly stem cells) and cellular senescence (ditto, plus the baleful effects of the senescence-associated secretory phenotype). And then remember that SENS is fundamentally an engineering approach to aging, focused on practical solutions rather than acquiring a full understanding of mechanistic details. Our position has been, therefore, that all the effects of nuclear mutations that meaningfully constrain current human lifespan/healthspan can be obviated by removing, repairing, or obviating the effects of mutations that are relevant to our health over the course of currently-normal lifespans: clearing senescent cells, replacing cells lost to apoptosis and senescence and other causes, and making the body impervious to cancer.

In clonal hematopoiesis, blood stem cells with one of a small number of mutations gain a selective advantage over blood stem cells with other genotypes, which allows them to "take over" the stem cell compartment. This isn't exactly what an oncologist would call "cancer," but it is a clear case of "too many cells" caused by nuclear mutations proliferating at the expense of their neighbors, which fits the operational criteria for the oncoSENS category. And the periodic purging of all native bone marrow stem cells and their wholesale replacement with fresh, mutation-free, cancer-proof ones - which would immediately eliminate clonal hematopoiesis - is already planned to be the very first clinical phase of the whole body interdiction of lengthening of telomeres (WILT) plan to pre-emptively shut down cancer.

Undoing Aging With Aubrey de Grey Part Three

Has your position on the relevance of telomere attrition changed since you first devised SENS, especially in the light of the recent results with fibrosis and your involvement with AgeX Therapeutics?

No. Let's start with the big picture. Neither I nor anyone sensible has ever suggested that telomere attrition has no functional effects in aging: telomere attrition causes cells to become senescent and runs down the proliferative capacity of stem cells, amongst other things. Nor have I suggested that there wouldn't be some short-term health benefits to activating telomerase or telomerase gene therapy in aging animals or animal models of age-related disease. The issue is rather that those short-term benefits come with the longer-term (and sometimes not so long-term) risk of increased rates of cancer.

So, why don't we see a plague of excess cancers in animal studies that show the benefits of telomerase-based treatments? Depending on the study, it's one or more of several reasons. The most common one is that such studies are usually too short-term. A related issue is that many of these studies involving animal models of age-related disease are actually done in quite young animals that have been damaged in some way that simulates aspects of an age-related disease. Because such animals are still quite young, they haven't yet lived long enough to have accumulated a high burden of the kinds of mutations that predispose cells to become cancerous. A third reason why many animal studies of telomerase treatments don't result in high reported rates of cancer is that the animals may actually be deficient in telomerase to begin with, such that telomerase gene therapies actually just restore the normal activity of telomerase in the animals.

The solution to problems caused by age-related attrition of telomeres is not to juice up telomerase to lengthen them again in often-damaged stem cells, but to take telomerase out of the picture, purge those defective stem cells, and replenish stem cell pools periodically with cancer-proofed, pristine replacement cells that are unable to replicate out of control.

You have been engineering glucosepane-eating bacteria that use enzymes effectively 'gifted' to them. Have the enzymes you identified demonstrated specificity to glucosepane?

We can say that Dr. David Spiegel's SRF-funded lab at Yale has identified some candidates, but we can't go into the details at this time. Still, expect some news on the commercialization front in the glucosepane space in coming months.

Given the state of immunotherapy, and taking into account the rate of progress in the field, how confident are you that OncoSENS may be unnecessary?

The recent progress in cancer immunotherapy has certainly made me much more optimistic than I was five years ago that new cancer therapies might hold off cancer for more than a very small number of years - but not that it might make whole body interdiction of lengthening of telomeres (WILT) redundant. If we had all the other components of a comprehensive panel of rejuvenation biotechnologies assembled and deployed, ongoing progress with these therapies might well give us a slightly longer runway along the path to "longevity escape velocity" than I had expected at the time. But only slightly; within an all-too-short few additional years, I expect that without WILT, the surging rocket of "longevity escape velocity" will still run headlong into a wall of cancer until we have a way to definitively defeat its evolutionary engine of selection and replication. At present, WILT is the sole foreseeable approach to doing that.

Which rejuvenation treatments can we reasonably expect to reach the clinic first?

If you don't count stem cell therapies (some of which are in clinical use, but not as rejuvenation biotechnology), it's a race between ablating senescent cells with senolytics (with UNITY Biotechnology expected to perform their first-in-human trials early next year) and one of the many immunotherapies targeting the intracellular or extracellular aggregates that drive the neurodegenerative diseases of aging.

Comments

"Still, expect some news on the commercialization front in the glucosepane space in coming months."

this is the line which is most exciting to me I give this 3 years.

Posted by: Salman at March 17th, 2018 12:15 AM

I'm so happy to find Aubrey de Grey talking about the vitreous. I first noticed very bad vitreous floaters at age 10, and have been dealing with them for all of life. Now, at 61, they remain very bothersome a lot of the time.

For what it's worth, I have one pathogenic variant of the SERPINA1 gene, associated with autosomal recessive alpha-1 anti-trypsin deficiency (the Z allele). And one pathogenic variant in the ABCA4 gene, associated with autosomal recessive Stargardt disease.

I wish we could get to the bottom of what causes really bad vitreous floaters, and engineer a treatment.

Posted by: NY2LA at March 17th, 2018 3:20 AM

I wonder if there will be an explosion in research around glucosepane like that around senescent cells once an antibody to detect it in vivo, and a rudimentary means of removing it (enzyme, catabolic antibody) are available?

Posted by: Jim at March 17th, 2018 12:26 PM

@Jim: From now one I have started to click on your name every time you write to get to your blog so it gets more clicks and you get more for your ads.

Posted by: Norse at March 17th, 2018 1:06 PM

Yeah, I've known about those two methods of "treating" floaters for years. Not interested.

Laser vitreolysis is not new. Someone was doing it in the 1980s.

Posted by: NY2LA at March 17th, 2018 4:13 PM

@norse - there are no ads on it so don't bother.

Posted by: Jim at March 17th, 2018 6:54 PM

Hi, just a 2 cent,

It is indeed great that there are developments and that we will see glucosepane breakers soon enough. The 7 M donations is truly great and happened at the right time when funds getting low. On AdG response to telomerase question, WILT is great but that changes nothing on telomere shrinking problem, periodic pristine stem cell replacement does not halt telomere shrinkage and only keeps tissues healthy, not younger. It is not reversal of aging . The epigenome of old tissues is still aged, WILT, stem cell replacement or not. AdG spoke of LEV, but it's unfeasable with partial periodic damage repair and anyone over 40 years old has less than 0.0000....1 chance of being able to reach LEV, LEV requires damage levels akin to a teenager body. Epigenetics are better than WILT and could allow, if done in tandem with damage repair, to reach LEV; but only for someone below 40 years old.

Just a 2 cent.

Posted by: CANanonymity at March 17th, 2018 8:12 PM

Cananonymity

Your whole post seems kind of arbitrary and completely speculative. Why 40? Why not 30 or 50? I mean no one really knows...

Posted by: Coor at March 17th, 2018 8:34 PM

Hi Coor ! Thanks for that and asking. Just a 2 cent.

It really is speculative, just my 2 cent opinion.

From many studies, the downhill slope starts from 30 to 60 years old, which makes an avg of 45.
While some studies put that as 30 to 50, thus an avg of 40.

The fourth to mid-forth decade is mostly when the slope is just about to start. Staying fourth decade and pushing back slope to later decades means younger biological age and post poning of diseases onset of later decades.
Some people, especially women, have up to 15-20 years of biological aging delay; thus, in their fourth decade they still have the near equivalent of late teenager body (due to stronger neotenous features in women because of exposure to estrogen that activate brain estrogenic receptors, in doing so activate telomerase).

LEV requires pristine very low damage levels because the downhill aging slope end up winning over mortality rate curve in the 8th to 12th decade.

Just my 2 c.

Posted by: CANanonymity at March 17th, 2018 9:29 PM

But again. This is all speculative. This isn't something that has happened. No one knows what lev requires or doesn't. Saying what it requires is disingenuous at best. No one knows. We'll see I suppose.

Posted by: Coor at March 17th, 2018 9:38 PM

It's true, it's speculation.

Certain animals don't reach LEV but tell us a lot about it because they live up to 523 years (quahog bivalve clams, Greenland sharks). They all share a pattern slope stabilization (forever plateauing) in early mid-life (human equivalent of 30-40 years old).
The only way to thwart the stochastic downhill slope damage cumul, is damage repair, end replicative solving, telomere shrinkage abrogation, lysosomal lipofuscin removal, mitochondrial DNA lesion, deletion repair, chromosome laxing, progerin, lamine, histone loss, protein aggregation, redox thiol milieu and epigenome transcription drifting and demethylation reversal.

That's a hefty load of limits that need solving otherwise LEV is very hard to think will be a reality. The only other way would be Total Replacement of body with young fetal organs, but that's enough, the ECM and cellular must be put back like that of a 20 year old.

Just my 2 cent.

Posted by: CANanonymity at March 17th, 2018 10:27 PM

I agree with coor. And I believe that 75 is probably the cut off.

Posted by: Scott at March 18th, 2018 5:01 AM

I'm in agreement with Scott and Coor. Currently LEV is not possible so all speculation is quite pointless. But as Aubrey keeps reiterating it's all about 'surviving' towards each next step along the process towards that goal.

Posted by: Steven B at March 18th, 2018 6:40 AM

@steven B totally agree there

Posted by: scott emptage at March 18th, 2018 8:58 AM

I agree that 75 is the limit. Since I am already 77, I will be shooting for 120 instead.

Posted by: Biotechy at March 18th, 2018 12:04 PM

@Biotechy,limit for what? While you are alive you can rely on the any future therapy. All you need is to be alive when they arrive. First of all, you cannot live to 120 without rejuvenation and if you reach 120, you will already reach LEV. Don't you think that whithin next 43 years we solve 99% of ageing problem? So in 120 you will be either dead (long before) or young and vigour. Unfortunatelly, some of commentators are constantly write a hysteric flow of speach with meaningless and often wrong numbers.

Look at that phrase -- 'only keeps tissues healthy, not younger. It is not reversal of aging'. Hovewer, this is a nonsense, because yonger is by defenition healthy! There is no 'healthy ageing' so if you are healthy, you are younger. This is an age reversal!

Posted by: Ariel at March 18th, 2018 12:51 PM

@Biotechy, I love your attitude and I certainly hope you will be around to take advantage of the rejuv treatments soon to be available.

I am quite optimistic when Audrey said,

If you don't count stem cell therapies (some of which are in clinical use, but not as rejuvenation biotechnology), it's a race between ablating senescent cells with senolytics (with UNITY Biotechnology expected to perform their first-in-human trials early next year) and one of the many immunotherapies targeting the intracellular or extracellular aggregates that drive the neurodegenerative diseases of aging.

So, it sounds like there will be at least 2 of the 7 causes of ageing that may be available within a fairly short time, 5-10 years? I assume that concurrently, they (SENS and others) are working on the other causes too.

Posted by: Robert at March 18th, 2018 1:04 PM

Glad you enjoyed the interviews, it was a community effort and we were really pleased to give the folks back home not at the show something to get their teeth into while we were away at the event.

We are processing the pile of interviews and information from the conference next week so expect to hear more on that front soon.

In summary, the event was superb, lots of really promising results, new techniques, and data. There was also plenty of opportunities to network, make contacts, and develop strategies with those working on the frontlines. LEAF also worked with journalists and a TV station, more on that later when we are all home and rested from four punishing days of activity.

Posted by: Steve Hill at March 18th, 2018 1:08 PM

Thanks Steve, Nicolà and the rest of the LEAF team for providing us with this juicy interview with Aubrey. I'm looking forward to reading the upcoming materials you're working on.

Glad to know you had productive media contacts, too !

Posted by: Spede at March 18th, 2018 1:23 PM

@Steve Hill, thank you very much for your long full of info interview! They are even better than mine! ;-)

Posted by: Ariel at March 18th, 2018 1:26 PM

Thanks Scott Emptage. I also agree with Ariel; age limits are arbitrary right now. If someone wants to guess 75 as the upper limit let them, but there are 75-yr-olds out there who can barely walk up the stairs without stopping to catch their breath... At the other end of the spectrum Clint Eastwood turns 88 in May but he's still working as hard as ever. And (my speculation) probably jogs up stairs!

Posted by: Steven B at March 18th, 2018 2:22 PM

@steven B your right, it's like Aubrey said that it all depends on who you are, plus not everyone of the same age is the same biological age. Also look at William shatner, he was in Ray kurzweils documentary and said he wants to live as long as he can. He is 87 but looks 65

Posted by: Scott at March 18th, 2018 2:38 PM

Shatner's another great example Scott. Mick Jagger, Paul McCartney, Brian May - three rock stars off the top of my head who are all touring the world this yr, all stayed slim/fit and all were born in the 1940's. I know money helps but a lot of it is mental attitude and a lust for life (to quote a veteran American rock star!). Biotechy may not be famous but I love his attitude.

Posted by: Steven B at March 18th, 2018 3:15 PM

My dad is 73 and looks 65 too. Drives better than most his age and dosent need glasses

Posted by: Scott at March 18th, 2018 3:21 PM

Come to think of it, Chuck Norris 78, who works out on machines all the time, doesn't look over 65 yet either.

Posted by: Biotechy at March 18th, 2018 4:14 PM

@Ariel

Hi Ariel, I understand what you mean, it's technically true that there is no such thing as healthy aging, such as how see in elderly people whom all show some damage - in that sense, yes. Yet, some much more aged centenarians show parameters that are closer to younger adult in his/her 60s. Thus, much older yet can have better health than Younger sick elders whom may die earlier and not reach a 100. I.e. there is semantical (def ambiguity) and biological (mechanisms) that end up making Aging and Health, dependent but independent also/dissociate them. Health is a threshold that can be partially uncoupled from aging because they are distinct yet entwined. Aging is the supplanting 1st element, health is 2nd driving threshold element. Not the inverse, health cannot twarth aging process. They are distinct and aging is the independent/dissociate intrinsic element. This was demonstrated on cellular level, thhat would end up manifestins as health compromising.
Cells became prematurely senescent (Spontaneous Senescence/DDR (DNA Damage Response) DNA oxidative stressed-induced senescence) in early passages, but while the cells senesced prematurely; they showed no aging (by S. Horvath clock).. Thus, it showed there is more nuance between aging, Damage cumul and health. That they can be diassociated (permeable conditional loose coupling thus uncoupled in specific cases where health is disengaged from aging. Because aging supercedes health. It's why the permissive disengagement of health from the aging process.

Just my 2c.

Posted by: CANanonymity at March 18th, 2018 6:34 PM

Found this on reddit i thought this shoulld be paste here

As we age, our bone structure changes quite a lot. To what extent would age reversal mitigate this? If a 90yr old developed a hunched back, but then took therapies to revert to a younger age, would their skeletal structure correct? Would those of us that are older, made young again look strange? Like an old person's physique and skeletal structure but in a new skin?

Posted by: salman at March 19th, 2018 4:22 AM

@salman

Hi salman ! Just a 2 cent.
In the short term, it would mostly be as you said, an elder body that shows skeletal
problems inside a rejuvenated skin, which may look strange, i have seen this in elders whom have younger skin for their age but display skeletal problems such as arthritis, osteoporosis, spinal disc lumbary squash weakening, BMD (Bone Mineral Density) loss, sarcopenia, frailty, hip or femur fracture, immune weakening from less bone marrow immune cell production because of bone demineralization. Thus, in short term there would be no reversal of skeletal posture but over long term a skeletal posture can be somewhat reshaped. As long as there would bone remineralization, bone celll osteoclast, bone growth.. If that bone sees no growth or reshaping (via retinoic acid pathway that controls skeletal morphogenesis), it is unlikely that the elder would see reversal of skeleton. A very hunched back could somewhat improve much later after the therapies, bone growth is slowmo, but there would be a need of concerted effort of posture working, skeletal muscle exercise working for posture requires enough muscle/tendon/ECM cartilage attached to skeletal bone, all of this together would partially improve hunched curving posture. Sitting straight up posture on your chair, as exercise, helps . Likewise, standing up and stretching up/holding upwards posture, just like in the military marches, spine, straight up. It's of course much harder to keep in elder age.

Just a 2 cent.

Posted by: CANanonymity at March 19th, 2018 10:27 AM

Salman, also keep in mind, that nanotechnology can alleviate any deformiteis.

Posted by: Robert at March 19th, 2018 12:44 PM

Completely agree, bones and ECM are live tissues or part of live tissues so when we rejuvenate the whole metabolism their slow turnover will make them young again. Of course, in any critical case we will be able to make a surgery to improve things! Anyway this is not a first order problem!

Posted by: Ariel at March 19th, 2018 1:43 PM

I agree with many of the commenters here that it is very much a matter of staying as healthy and you can and hanging on in there if you are getting on in years. These therapies are starting to arrive now. The earlier you want them the more speculative and incomplete they will be, but they are no longer the stuff of science fiction.

It is true what CANanonymity says that age reversal is more challenging the more damage has been done, but at this point I'm not sure there is a definite cut off - other than something like advanced Alzheimer's when the brain has been damaged to such an extent the information of mind, for want of a better description, is lost.

On the backup plan Antonio mentioned, I've never considered it before, but given the recent advances it no longer looks like such a bad idea.

Posted by: Mark at March 20th, 2018 5:06 AM

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