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Undoing Aging With Aubrey de Grey Part Three

Welcome to part three and the final part of our SENS Undoing Aging 2018 interview; we have a few more scientific questions today for Aubrey and his team as well as questions about future developments and taking new therapies to market.

Dr. de Grey, 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?

Aubrey: 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 (or even their human equivalents). Indeed, there was plenty of animal data to support this long before the recent results with a mouse model of idiopathic pulmonary fibrosis (IPF)[1].

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 — something that has been in multiple animal studies (also here, here, here and here) as well as in human epidemiology.

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 four reasons. The most common one is that such studies are usually too short-term: a few weeks or months, which is long enough for the benefits of mobilizing stem cells to help repair some particular problem in an aged or disease-model mouse, but not long enough for a precancerous lesion to erupt into mature clinical cancer. This was true in the IPF study you reference, which lasted just eight weeks [1].

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, so it’s much less likely that telomerase will enable precancerous cells to develop into full-blown cancers. This, again, was true in the IPF study, which involved animals that were little furry teenagers, only 8-10 weeks old [1]. By contrast, the average age of onset of human IPF is 67, and nearly all human IPF patients are over the age of 50. (We’ll get into how they made these adolescent mice develop something resembling IPF a little further along).

At the ages when IPF and other age-related pathology that might otherwise benefit from telomerase treatments emerge in humans, the human body has already acquired multiple cancer-disposing lesions, and most people harbor precancerous cells in their breasts, prostate, and elsewhere. Indeed, autopsy studies show that 30-45% of men who die of other causes in their fifties have actual prostate cancers in their bodies, not just precancerous lesions; their disease just hadn’t yet become aggressive enough to kill them before something else did [2].

Extended over the decades of current human middle age and into the early period of lifespans extended by the first rejuvenation biotechnologies, telomerase activation can be strongly expected to give precancerous and indolent cancerous cells that might otherwise have run out of replicative steam the extra rounds of proliferation needed to gain the mutations that will turn them malignant and ravage the body. Again, this is what we actually see in longer-term studies in aging mice administered extra telomerase and in humans with more permissive telomerase variants.

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. This again was a feature of the mouse IPF study: these were mice with their normal telomerase genes completely knocked out, which were then bred for two additional generations to progressively wear down the residual telomeres in their stem cells (and then had DNA-damaging bleomycin applied down their tracheas to their lungs to boot!) [1]. In fact, their original publication reporting that this generated a working model of IPF was even entitled “Mice with pulmonary fibrosis driven by telomere dysfunction”! [3]

When you start off by taking the normal telomerase gene away from a mouse, it’s not exactly surprising that putting that same telomerase gene back in the same mouse ameliorates its short-telomere-driven pathology. The same was true of another study in telomerase-deficient mice that was widely and mistakenly reported in the popular press as showing the “rejuvenating” effects of telomerase therapy [4].

Finally, a significant number of studies where telomerase treatments are shown to have benefits and aren’t reported to have high rates of cancer are done in animals that are made cancer-resistant by other means, such as by giving them extra copies of cancer-resistance genes [5] or by imposing CR on them [6].

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.

Could someone from SENS explain why phiC31 integrases are still important in the age of CRISPR? Looking at the Calos Labs webpage, it is not clear that there is any real advantage to using phage integrases.

Aubrey: Let’s start with what the CRISPR/Cas9 system is good for before explaining why it won’t be much help for rejuvenation biotechnology. CRISPR/Cas9 is an amazing tool for making relatively modest edits in existing genes in isolated cells. This makes it great for things where we can take a few of a patient’s cells out of his or her body, correct a mutation or make similar minor changes, and then reintroduce them. So, for instance, it’s incredibly powerful for genetic diseases involving blood cells, because we can take out some of a patient’s bone marrow stem cells, make the minor edits required to correct the genetic defect, and then wipe out the patient’s original, defective bone marrow using chemotherapy and repopulate it with modified stem cells, which will then replace the entire blood cell system.

It can also be used to create mutant animal models, by making minor edits in embryos (which are, again, single cells or only a few of them) and then growing out a mature organism, every one of whose cells contains the modified gene. And as the technology matures, and with better delivery systems, it could also be used to correct other relatively minor mutations that cause very early-onset versions of diseases of aging, like the ApoEε4 allele (which greatly speeds the onset and course of Alzheimer’s disease) or the BRCA1 and BRCA2 mutations that put one at higher risk for breast, ovarian and possibly prostate cancer.

But in order to deliver rejuvenation biotechnologies, we need to do something quite different: deliver large, entirely new genes across tissues still in the body. For such purposes, CRISPR/Cas9 is really not much help. (For some of the technical details on why, see here — skip down to “As to the CRISPR/Cas9 system”). Reserchers are working to improve on all of CRISPR/Cas9’s limitations, but it’s not at all clear that it will ever be able to go as far as needed for most rejuvenation biotechnologies. Calos’ webpage doesn’t highlight the key contrast the way we do because, as it stands, it’s a bit of a moot question; we can’t use the phiC31 integrase clinically because we don’t have the needed “landing pads” for the integrase in our cells. And that’s exactly what the second stage of the Maximally-Modifiable Mouse project is for: to eventually engineer those “landing pads” into all of our cells, at which point we’d be able to use the integrase for safe, reliable delivery of arbitrarily-large new genes across adult tissues.

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

Aubrey: 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.

Dr. de Grey, can you make any estimates as to the name and/or date of creation of the company spun out to market glucosepane breakers?

Aubrey: First, to break this down a bit: spinoff companies don’t actually market therapeutics; they don’t have the size or the resources (legal, clinical, or financial) to run the large-scale phase III clinical trials required to gain licensure from the FDA and similar regulators around the world and then mass-manufacture a therapy for global distribution, this latter being especially challenging for biologicals like antibodies and cell therapies (which is the form that most rejuvenation biotechnologies will take, as opposed to conventional small-molecule drugs). So, we wouldn’t be literally spinning out a company to market glucosepane breakers. The spinoff will take research that has identified a strong candidate glucosepane-breaker and demonstrated its efficacy in initial proof-of-concept research and do some further R&D (perhaps taking it as far as initial phase I trials) until they are ready to begin courting the large pharma/biotech players who bring their much larger resources and wider expertise to bear in late-stage clinical development and marketing.

As mentioned in response to another question, Dr. David Spiegel’s SRF-funded research has identified some early-stage candidates, but none that are solid enough for a spin off company just yet; that said, do expect some news on the commercialization front in the glucosepane space in coming months.

A question for Dr. O’Connor about MitoSENS: We recently heard that your team was close to four of the thirteen genes. Can you tell us how you are progressing with the mitochondrial gene transfers?

Oki: We are working on several other genes. Nothing solid enough to announce yet, but I think we’ll have some new things to announce at Undoing Aging 2018.

Dr. O’Connor, has anyone else than SRF tried to replicate the results of your 2016 paper on allotopic expression or tried to do the same with other mitochondrial genes?

Oki: I’ve passed our materials on to several researchers who have requested them, and we also made our plasmids publically available through Addgene. So, it looks like there is some interest in repeating our work, but I haven’t heard about any results yet.

RMR, or robust mouse rejuvenation, is intended to be a SENS implementation that is complete enough to double the remaining life expectancy of an elderly mouse, as demonstrated and then replicated in rigorous laboratory studies. Given the current state of research and funding and the current rate of progress, what is the expected timeframe for RMR?

Aubrey: This is difficult to say, and, as you say, is always heavily dependent on funding levels. So far, insufficient funding has held us back to going less than half as fast as I had predicted was possible with full funding. Granted adequate funding going forward, a reasonable if still-speculative estimate would be seven years.

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? Even if not soon, do you think it’s possible that cancer could ever be completely defeated without implementing OncoSENS, i.e. without deleting the telomerase and ALT genes?

Aubrey: 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 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.

What single item or reagent used in research (exempting wages) costs the most across research projects?

Aubrey: Probably Fetal Bovine Serum. It’s necessary for all cell culture projects, and you can’t skimp on the price since cells are so sensitive — and no one has figured out how to make it well without requiring the expensive initial animal involvement.

SRF showed that it is possible to degrade oxidized cholesterol using external enzymes from bacterial sources. Has there been any other progress in this direction? In other words, how is LysoSENS research progressing against this particular kind of intracellular aggregate?

Aubrey: We licensed out the original research to which you refer several years ago, and we don’t have much visibility into what the company in question is up to. I can also say that we’re aware of a very promising LysoSENS project working at the problem from a quite different and novel angle, but can’t make any announcements at this time.

Which rejuvenation treatments can we reasonably expect to reach the clinic first? Assuming ideal conditions, when could the more easily implementable among them be expected to be tested and approved for human use?

Aubrey: 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.

When a branch of the basic research done at SENS goes far enough that it becomes commercially interesting and could spawn a new therapy, is it conceivable to convert SENS to a for-profit organization and seek investments? Why do you choose to start new companies instead of taking the Elon Musk approach of using discoveries for profit and financing basic research with the money? Would it be possible to only involve investors who understand this vision?

Aubrey: The Foundation itself won’t become a for-profit organization, though we have, in the past, spun out individual projects as startups or sold them to investors once they were ripe enough to be carried forward on that basis, and we will continue to do so in the future. Examples include licensing our funded LysoSENS project on 7-ketocholesterol to Human Rejuvenation Technologies, Inc. and licensing our LysoSENS project on A2E to Ichor Therapeutics.

We also provided seed capital to senescent cell ablation startup Oisín Biotechnologies, and work that we have supported was also the basis of the MitoSENS technology behind Gensight Biologics; the AmyloSENS technology targeting senile cardiac amyloidosis that is part of Covalent Bioscience’s portfolio; and Revel LLC, which is in the process of commercializing products emerging from Dr. David Spiegel’s SRF-funded research on glucosepane at Yale. Once these therapies are turned into therapies that are on the market and earning revenues, we will earn royalties and similar monies which we’ll roll into other important areas of SENS research.

However, the Foundation itself will not become a for-profit venture, because doing so would interfere with our ability to pursue our mission: to catalyze the development of a comprehensive platform of rejuvenation biotechnologies. While we’re always looking for opportunities for true blind spots in rejuvenation biotechnologies that can be quickly nudged into proofs-of-concept ready to be spun out into startups with just a little more support, it’s also critical that we invest in planks of the SENS platform that are in much earlier stages of development. And it’s essentially impossible to run a sustainable for-profit enterprise doing such early-stage research. Investors don’t have the patience for the long lead times and uncertainty that yawns between putting down the money and an IPO or full-on commercialization.

Even the true giants of the legacy pharmaceutical industry — who were once able to support significant amounts of relatively early-stage work in-house because of their enormous budgets and soaring profitability — have been in rapid retreat from that model for decades now, shutting down in-house research campuses in favor of buying up startups. On the other end, Elon Musk’s admirable and disruptive ventures — SpaceX, Tesla, and SolarCity — are doing mission-driven work in commercializing and innovating technologies that were already on the market, the early-stage work having already been done (and continues to be done) in university labs, the National Laboratories, and Advanced Research Projects-Energy (ARPA-E).

The best places for early-stage work to be done has always been university labs or not-for-profit research facilities supported by major government health institutes like the NIH, or by philanthropy, where the funding can be allocated and lines of research pursued based on merit and long-term considerations free from investor pressures.

Additionally, a critical part of our work in getting us to a future beyond degenerative aging is our efforts to nurture an entire rejuvenation biotechnology ecosystem, not just the direct sponsorship of research projects aimed at developing individual therapies. This is why we place young students into opportunities for rejuvenation research as part of their academic training through SRF Education; why we bring together academic researchers working in disparate strands of rejuvenation research who labor in ignorance of each others’ work at the Strategies for Engineered Negligible Senescence conferences (and the upcoming Undoing Aging conference); and why we bring some of those same researchers together with investors and the existing biotech industry at the more industry-oriented Rejuvenation Biotechnology conference series. Such work simply can’t be justified to venture capitalists looking for the next IPO payout.

Similarly, companies already close to SENS, such as Unity, could apply the strategy of funding more basic research using profits. Are any of these companies planning to do this?

Aubrey: Note that in this case, UNITY Biotechnology is supporting additional work on the intellectual property that they have themselves licensed from Campisi’s and others’ labs, and on small molecules that they have acquired and identified independently of any of the investigators whose IP they have licensed; they are not disbursing funds that can be reallocated into other kinds of research, which (again) is key to the ongoing progress of SRF. That’s a model to which we’re certainly open, and we will negotiate on a case-by-case basis as opportunities arise.

Once a significant part of the science work behind rejuvenation has been done and spun off to other companies, does SRF plan to fade out, or is there any plan to work with policy-makers and institutions to ensure rapid and widespread access to rejuvenation treatments?

Aubrey: The latter! However, the moment to make the shift from development to distribution and access is likely somewhat later in the process than when you suggest; depending on how the industry evolves, it would more likely be either when it is clear that the “damage-repair” heuristic of SENS has become accepted as the dominant paradigm for tackling diseases of aging or when the individual components of a comprehensive panel of rejuvenation biotechnologies have all been licensed and are being used to treat people who do not yet have obvious age-related pathology. At that point, the research needed to carry us forward will be self-sustaining, and the pressing issue of the day will be making sure that therapies become widely and justly available as rapidly as possible.

We would like to thank Dr. Aubrey de Grey and the SENS Research Foundation team for taking the time to answer all these questions, and we look forward to catching up with you again in the near future. You can find part one and part two of this interview by following the linked text.

Literature

[1] Povedano, J. M., Martinez, P., Serrano, R., Tejera, Á., Gómez-López, G., Bobadilla, M., … & Blasco, M. A. (2018). Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres. eLife, 7, e31299.

[2] Martin, R. M. (2007). Commentary: Prostate cancer is omnipresent, but should we screen for it?. International journal of epidemiology, 36(2), 278-281.

[3] Povedano, J. M., Martinez, P., Flores, J. M., Mulero, F., & Blasco, M. A. (2015). Mice with pulmonary fibrosis driven by telomere dysfunction. Cell reports, 12(2), 286-299.

[4] Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., … & Horner, J. W. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469(7328), 102.

[5] Tomás-Loba, A., Flores, I., Fernández-Marcos, P. J., Cayuela, M. L., Maraver, A., Tejera, A., … & Viña, J. (2008). Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell, 135(4), 609-622.

[6] Vera, E., de Jesus, B. B., Foronda, M., Flores, J. M., & Blasco, M. A. (2013). Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity. PLoS One, 8(1), e53760.

Undoing Aging With Aubrey de Grey Part Two

Welcome to part two of our three-part Undoing Aging 2018 interview of Dr. Aubrey de Grey and his team at SENS Research Foundation. Today, we have some of the scientific questions that the community had about SENS; there are some very detailed responses, and we hope you enjoy them.

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? Could taking senolytics without the ability to replace these specialized lost cells be risky unless combined with replacement therapies?

Aubrey: This is not a major concern, for a few reasons. First, when cells turn senescent, they cease carrying out their specialized function (as a cardiomyocyte, or neuron, or what have you), so no such function is lost by ablating them. Second, 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. And third, in the specific case of cardiomyocytes, there’s already significant evidence in rodents that it improves cardiac function overall [1] as well as wider cardiovascular health [2-3].

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. Thus, although the net effect of these drugs is undeniably positive, their mechanism of action will necessarily entail occasionally killing off healthy cells that are experiencing a moment of vulnerability when the drug is administered and that they could otherwise have survived. Again, such cells could include difficult-to-replace cells like heart muscle cells and neurons.

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 prepares for human testing through our investment in Oisín Biotechnologies. We’ll have more to say on this in an upcoming blog post.

But. certainly, no single rejuvenation biotechnology will work as well on its own as it will as part of a comprehensive panel of such biotechnologies, and matching senescent cell ablation with cell replacement therapies is one of the most straightforward examples.

Senolytic drugs gave mice about 35% 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?

Aubrey: First, let’s be clear on just what senescent cell ablation has been shown to do. In the study of which you’re thinking [4], senescent cell ablation didn’t extend lifespans by 35%; it increased median lifespan by 24-27% under most conditions, with no effect on maximum lifespan. It only increased median lifespan by 35% in a subset of animals where the controls were exceptionally short-lived compared to all the other animals in the study. (In fact, all the animals in the study were at least a bit shorter-lived than healthy mice normally are, probably due to some combination of the stress of twice-weekly injections and possibly some effect of the transgenes, though the latter is probably minor — but the 35% figure is clearly not robust and certainly shouldn’t be extrapolated to normal, otherwise-healthy aging humans).

Now, confining ourselves to that 24-27% median lifespan figure: 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.

Are senescent cells fewer in number or less destructive in humans than in other animals because we are more advanced organisms than they are?

Aubrey: Evolutionary biologists would quibble with the notion that humans are “more advanced” organisms than mice (or even than roundworms), but we’re certainly longer-lived organisms than they are — and of necessity, this entails that the rate of accumulation of all the cellular and molecular damage of aging — including senescent cells — is slower in us than in them.

Some proteins can facilitate DNA repair. However, what can SENS do to prevent cells from collecting DNA damage in addition to the proteins that already exist in our body? Also, what approaches are being taken to correct benign mutations?

Aubrey: Because the levels or activity of some of the proteins that repair DNA are downregulated by the downstream metabolic effects of aging damage (such as inflammation and oxidative stress), or are known to be downregulated with age for unknown reasons, removing the underlying damage driving these age-related declines (such as by ablating senescent cells and rendering mitochondrial mutations harmless)  will “take the brakes off” these proteins and restore their ability to repair DNA to the youthful norm, just as rejuvenation biotechnology will reset other downstream derangements of the aging metabolism.

By “benign mutations,” I take it that you mean mutations that don’t cause cancer. Regardless, there is no foreseeable technology (meaning, a technology that can be described in detail and is technically feasible to implement within the next 2-3 decades) that will be able to correct existing mutations. Instead, the focus must be on 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. That will buy us time during which scientists can develop future generations of rejuvenation biotechnology to repair DNA mutations directly.

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?

Aubrey: 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; what the relative prioritization and, in most cases, even the identities of the next-most important targets will be (our project on Target Prioritization of Adventitious Tissue Crosslinking is tackling a notable exception); and how exactly to design improved or new therapies in each category.

In old age, the vitreous body—an acellular component of the eye—liquifies. The resulting change in viscosity may cause a post-vitreous detachment that can be dangerous for the retina. Where does the relevant age-related damage fit within the SENS categorization? What regenerative interventions might be applied to reverse it?

Aubrey: As with all age-related degeneration, post-vitreous detachment (PVD) can only ultimately flow from stable changes in the cellular and molecular structures responsible for normal, youthful vitreous function. However, the structural basis for PVD is unfortunately still poorly understood. Up until recently, it’s been difficult to study the organ at all, let alone its aging, because of the inherent difficulty of visualizing a tissue that is, by design, invisible and because many of the techniques that have historically been used to study it have required the use of reagents that precipitate the jelly-like material out of the vitreous humor [5]. And even today, with better tools available, there is precious little research in this area.

But let’s focus on what we do know. The vitreous is composed of a network of collagen fibres that are coated by non-covalently bound structural molecules (glycoproteins and chondroitin sulfate) that allow the collagen fibers to slide past one another without sticking to each other and also to interact with the gel phase of the vitreous (primarily comprised of a glycoprotein called hyaluronan). In youth, most of the hyaluronan remains in a gel phase, but over the lifespan, a rising amount of it is degraded into a liquid phase. This degenerative process is already apparent in four-year-old children, and liquid-phase vitreous occupies about 20% of the total vitreous volume by the time one is in one’s late teens; this process accelerates after age 40, to the point where more than half the vitreous has been degraded into a liquid in octogenarians. Along with the shift from gel phase to liquid phase, there is a reduction in the volume of gel vitreous, without a change in total collagen until the extremes of current lifetimes [5].

As the gel shrinks, it begins to separate from the retina, with the gap filled by the accumulated liquid vitreous. If this process of separation happens too quickly in a given area, or if the vitreous gel and the retina remain adherent despite the contraction of the vitreous, then the retina or a retinal blood vessel can tear, leading to symptoms like “flashes” and “floaters.”

As of yet, we don’t know what’s driving these processes. The most suspicious change in the structure of the vitreous with age is the “lateral aggregation” of the collagen fibrils — in other words, the bunching-together of adjacent collagen fibrils. The two prime suspects for this aggregation are age-related loss of the coating proteins that keep the collagen fibrils from naturally sticking to their neighbors, and AGE or other crosslinks forming between the fibrils.

Abnormal AGE crosslinks certainly do occur in the collagen in the vitreous of diabetics, which likely contributes to diabetic retinopathy, an important complication in diabetes that leads to blindness [5]. To the extent that those are involved in PVD in aging nondiabetics, AGE-breakers could be brought to bear to liberate the bound collagen fibrils, allowing them to support gel-phase vitreous hyaluronan again.

Alternatively, the aggregation may result from an age-related loss of the coating proteins that keep the fibrils from sticking together [6]. There are several protein-degrading enzymes in the vitreous that could, in principle, do this if their expression rises with age, and aggregation and liquefaction can be triggered in the lab by injecting any of several common physiologic enzymes into the vitreous. Conversely, peptides have been designed that shield the coating proteins from some of these enzymes; these peptides have protective effects against degradation of bovine vitreous treated with some suspect enzymes, but not others [7].

Along with trypsin, matrix metalloproteinases (MMPs) are among the enzymes most strongly suspected of involvement in an age-related rise in such “stripping” of vitreous collagen [6]. While the link has not been directly made, several lines of circumstantial evidence suggest that a rise in MMP levels with age could be driven by the accumulation of senescent cells in the eye. Senescent cells do accumulate in the retina and other ocular tissues with age, and MMPs are a component of the toxic soup that senescent cells secrete — the so-called senescence-associated secretory phenotype or SASP. And while they didn’t look specifically at MMPs, one study did find increased levels of other components of the SASP in the vitreous of patients suffering from proliferative diabetic retinopathy [8]. If senescent cells are indeed driving an age-related rise in collagen-stripping MMPs, then ablating those cells would put a stop to it, potentially preventing or reversing PVD.

Another possible contributor to PVD is damage to hyaluronan molecules by free radicals, which warp the three-dimensional structure of hyaluronan in model systems. Lifelong exposure to free radicals from metabolic processes and/or ultraviolet light could cause structural changes that either cause gel-phase hyaluronan to dissociate from collagen fibrils or damage hyaluronan decorating adjacent collagen fibrils so that they no longer slide past each other but instead aggregate, leading to liquefaction and PVD [5]. Rendering mitochondrial mutations harmless would eliminate the main driver of the age-related rise in oxidative stress.

Again, none of this is certain; experts don’t know for sure what’s driving the damage underlying PVD, and we’ll need to understand that in order to know what rejuvenation biotechnologies will prevent and treat it. But as with all diseases and disorders of aging, structural changes are driving it, and structural remediation will be the key to ending it; looking at the existing lineup of suspects, it appears that all can be addressed with therapies that contribute to planks of the existing SENS platform.

Increased anabolic signalling, which signals an abundance of nutrients, appears to accelerate aging, while decreased anabolic signalling is shown to extend lifespan. Does this suggest that excessive caloric intake accelerates aging and that a reduced intake may slow it down? If so, may practices such as bodybuilding, which require significant food intake, lead to accelerated aging?

Aubrey: Anabolic signalling is one important driver of the cellular and molecular damage that accumulates over a lifetime, leading ultimately to age-related pathology. This is even true of the normative physiological level of anabolism that supports processes like normal growth and development; wound healing and other regenerative responses; and maintenance of a lean adult body plan. And many interventions that decrease anabolic signalling below this physiologic level meaningfully slow aging in rodents and other relatively short-lived animals; reducing energy intake (i.e., calorie restriction (CR)) and mutations in insulin-like growth factor-1 (IGF-1) pathway are well-known examples.

However, even in rodents, it’s not clear that increasing anabolic signalling above the normative physiological level hastens aging relative to the base case. Obesity, of course, is bad for your health, whether you’re a (wo)man or a mouse — but it’s not clear that the reason it’s harmful is just a matter of “more of the same” anabolic stimuli that contribute to aging in the base case, rather than primarily a distinct pathophysiological process. And the ill-health of obesity is clearly not the simple inverse of the slow-aging phenomenon of low-anabolic states like CR. Further complicating matters, it’s important to bear in mind that there is significant debate as to whether the age-retarding effects of low-anabolic states like CR meaningfully impact aging in humans or other long-lived species [9-10].

Of course, bodybuilders are both lean and have high energy intake. This is also true of endurance athletes, and it’s clear in both rodents and humans that endurance exercise is healthy and does not appear to either accelerate or decelerate aging. The data are significantly more sparse as regards the specific effects of bodybuilding. It’s a difficult kind of activity to model in rodents, and it’s also more difficult to study in the long term in free-living humans than endurance exercises like running: fewer people bodybuild, they are less likely to carry on with it past middle age, there is greater variation in training routines, and the data are confounded by the prevalent abuse of anabolic steroids and other drugs, even among amateurs.

Whatever its effects on “aging itself,” there’s certainly compelling evidence that modest levels of strength training are good for your long-term health, associated with similar or lower risk of mortality as compared with endurance exercise [11], although elite bodybuilders may lose some of its benefits [12-14]. A sensible approach would be to pursue strength training without seeking to push the limits of your genetic potential through very high energy and protein intake or the use of anabolic steroids or IGF-1; this will improve your insulin sensitivity and reduce your risk of osteoporosis and premature frailty, with less risk of injury or truly harmful levels of anabolic signaling.

Has SENS/Aubrey reviewed their 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%), particularly cardiovascular diseases, including atherosclerosis and stroke?

Aubrey: 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 SASP). 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. [15] This isn’t exactly what an oncologist would call “cancer,” but it is a clear case of “cells too many” 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 WILT plan to pre-emptively shut down cancer.

Even before we begin implementing WILT, there are rejuvenation biotechnologies in the SENS platform that can minimize the harms that these aberrant cells are suspected of causing. In reported studies, the cause of the excess non-cancer mortality associated with clonal hematopoiesis has been death from cardiovascular disease and stroke [16-18]. In an accompanying animal study, the investigators showed that this could be accounted for by changes in the macrophages derived from bone marrow-bearing clonal hematopoiesis mutations; these macrophages express higher levels of inflammatory mediators that contribute to atherosclerosis than macrophages derived from normal bone marrow [9]. Work by independent researchers also finds that the gene whose loss is modelled in that study is essential to the differentiation of macrophages [19], which could be an additional mechanism.

Of course, atherosclerosis and stroke can be prevented by lysoSENS rejuvenation biotechnology: clearing the macrophage/foam cell lysosome of cholesterol waste products, ablating senescent arterial macrophages and smooth muscle cells, [2, 3] and to a lesser extent, reversing large artery stiffness. So, again, we have ways to deal with the harms that clonal hematopoiesis causes, despite having no medium-term prospects for reversing the underlying mutations.

Finally, it should also be emphasized that this phenomenon should not be extrapolated to other aging tissues. Clonal hematopoiesis is enabled by the very high genetic diversity of the blood stem cell compartment and its high rate of replication as compared to other tissues (even other stem cell compartments) — and even with those enabling characteristics, only about 10%–20% of people develop it by the time they are in their 70s [16]. No other non-cancerous cell types have this inherent potential for mutation-driven clonal expansion.

And while anecdotal, we should also note the case of a female supercentenarian whose exceptional longevity (by current, unremediated aging standards) was still possible despite having nearly all of her blood stem cell compartment dominated by two such clonal lines [19].

That concludes part two of our Undoing Aging 2018 interview; we’ll publish the third and final part tomorrow here on our blog. If you missed part one you can find it here.

Literature

[1] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. [2] Roos, Carolyn M., Bin Zhang, Allyson K. Palmer, Mikolaj B. Ogrodnik, Tamar Pirtskhalava, Nassir M. Thalji, Michael Hagler et al. “Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.” Aging Cell 15, no. 5 (2016): 973-977. [3] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & Van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477. [4] Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & Khazaie, K. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184. [5] Sebag, J. (1992). Anatomy and pathology of the vitreo-retinal interface. Eye, 6(6), 541. [6] Bishop, P. N., Holmes, D. F., Kadler, K. E., McLeod, D., & Bos, K. J. (2004). Age-related changes on the surface of vitreous collagen fibrils. Investigative ophthalmology & visual science, 45(4), 1041-1046. [7] Zhang, Q., Filas, B. A., Roth, R., Heuser, J., Ma, N., Sharma, S., … & Shui, Y. B. (2014). Preservation of the structure of enzymatically-degraded bovine vitreous using synthetic proteoglycan mimics. Investigative ophthalmology & visual science, 55(12), 8153-8162. [8] Oubaha, M., Miloudi, K., Dejda, A., Guber, V., Mawambo, G., Germain, M. A., … & Mallette, F. A. (2016). Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Science translational medicine, 8(362), 362ra144-362ra144. [9] de Grey, A. D. (2005). The unfortunate influence of the weather on the rate of ageing: why human caloric restriction or its emulation may only extend life expectancy by 2–3 years. Gerontology, 51(2), 73-82. [10] Rae, M. J. (2006). You don’t need a weatherman: famines, evolution, and intervention into aging. Age, 28(1), 93-109. [11] Stamatakis, E., Lee, I. M., Bennie, J., Freeston, J., Hamer, M., O’Donovan, G., … & Mavros, Y. (2017). Does strength promoting exercise confer unique health benefits? A pooled analysis of eleven population cohorts with all-cause, cancer, and cardiovascular mortality endpoints. American journal of epidemiology. [12] Clarke, P. M., Walter, S. J., Hayen, A., Mallon, W. J., Heijmans, J., & Studdert, D. M. (2015). Survival of the fittest: retrospective cohort study of the longevity of Olympic medallists in the modern era. Br J Sports Med, 49(13), 898-902. [13] Teramoto, M., & Bungum, T. J. (2010). Mortality and longevity of elite athletes. Journal of Science and Medicine in Sport, 13(4), 410-416. [14] Sarna, S. E. P. P. O., Sahi, T., Koskenvuo, M. A. R. K. K. U., & Kaprio, J. A. A. K. K. O. (1993). Increased life expectancy of world class male athletes. Medicine and science in sports and exercise, 25(2), 237-244. [15] Jan, M., Ebert, B. L., & Jaiswal, S. (2017, January). Clonal hematopoiesis. In Seminars in hematology (Vol. 54, No. 1, pp. 43-50). [16] Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., … & Baber, U. (2017). Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New England Journal of Medicine, 377(2), 111-121. [17] Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., … & Higgins, J. M. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine, 371(26), 2488-2498. [18] Kallin, E. M., Rodríguez-Ubreva, J., Christensen, J., Cimmino, L., Aifantis, I., Helin, K., … & Graf, T. (2012). Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells. Molecular cell, 48(2), 266-276. [19] Holstege, H., Pfeiffer, W., Sie, D., Hulsman, M., Nicholas, T. J., Lee, C. C., … & Meijers-Heijboer, H. (2014). Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome research, 24(5), 733-742.

Undoing Aging With Aubrey de Grey Part One

As the Undoing Aging 2018 Conference approaches, excitement and interest about the event are growing among both aging scientists and rejuvenation enthusiasts alike. If you’re a regular on our blog, neither Undoing Aging 2018’s main organizer, SENS Research Foundation, nor the main sponsor, Michael Greve’s Forever Healthy Foundation, need much of an introduction, but for the benefit of any newcomers, here’s a brief summary of all you need to know before diving into the questions that we’ve asked the SRF team on behalf of the members of the growing rejuvenation community.

SENS Research Foundation

SENS Research Foundation is a medical research charity based in California and the UK. A spin-off of the Methuselah Foundation, SRF is the engine room of research on biotechnologies against aging. Co-founded by Dr. Aubrey de Grey, the first proponent of the so-called “maintenance approach” to aging, the foundation has, over the years, funded and conducted cutting-edge research on the known root causes of aging, producing solid evidence that rejuvenation biotechnologies that can undo the damage of aging may be achievable within a few decades, given sufficient effort and funding.

Forever Healthy Foundation and the Undoing Aging 2018 Conference

Effort is not a problem; while initially controversial, the maintenance approach is now endorsed and pursued by some of the most eminent names of gerontology, not to mention the start-up companies that have spun off SRF itself or conduct SENS-related research. However, funding is still an issue, and this is where the Forever Healthy Foundation has stepped in.

The Forever Healthy Foundation’s stated goal is to be part of the first generation to cure aging. In order to achieve this ambitious goal, the foundation is actively investing significant sums into research and advocacy. The Undoing Aging 2018 Conference, to be held in Berlin on March 15-17, 2018, is part of the foundation’s outreach efforts. The event, open to everyone, will feature leading scientists from all over the world, and it is meant to offer a first-hand understanding of the current state of research in the emerging field of rejuvenation medicine.

The Undoing Aging 2018 SENS Interview Part One

We have been working with the life extension community on the Lifespan Discord server and collecting the best questions about research progress and developments in the field. Dr. Aubrey de Grey and other SRF team members kindly took the time to answer these questions for us. This is the first of our three-part Undoing Aging 2018 interview, which we will publish over three days in support of the Undoing Aging 2018 conference.

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

Aubrey: 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!

Will the Undoing Aging conference 2018 be live-streamed and later have videos uploaded so that people can watch the conference at their convenience?

Aubrey: It won’t be live-streamed, but many of the presentations will be available for viewing on our website afterwards.

Can you explain what the motivation was for this show and, in particular, the change from the invite-only format to being open to the wider community?

Aubrey: It’s not really a change – more of a reversion to past practice. The RB conference last year was relatively small, and we wanted it to be available mostly to investors and opinion-formers, but we have in no way lost sight of the role of educated laypeople.

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

Aubrey: We’ll certainly be continuing to do both more science-centred 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.

With the Undoing Aging show this year, will there be an RB2018, or is this new show format replacing it?

Aubrey: We are still working on that question. 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?

Aubrey: 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.

What is the current status of the SENS Project 21?

Aubrey: Project 21 was created in order to give greater focus and exposure to our efforts to attract major donations from high-net-worth individuals. It is necessarily an initiative whose success is hard to measure for a while, since, by definition, such donations are very sporadic. However, with the receipt of so much in cryptocurrency over the past few months, nearly all of it in the form of four 7-digit donations, I think it’s fair to say that Project 21 is flourishing. We certainly hope that such donations will accelerate!

Is SRF trying to reach out to other celebrities than those already involved in the “Reimagine Aging” campaign? Are there any celebrities in particular whose endorsement may significantly help spread more awareness?

Aubrey: The Reimagine Aging celebrity campaign was a few years ago; we have not been focused on recruiting celebrities in recent years. We always welcome new people who can carry our message to a wide audience. As to individual celebrities, each person advocates for rejuvenation research and the vision of a future free of age-related debility and disease in their own way, bringing different personal symbolism or personal stories to their advocacy, and will thereby be compelling to different audiences.

How important do you think the work of organizations such as LEAF/lifespan.io are in respect to their activities in advocacy and fundraising? Does our presence make your job easier?

Aubrey: Oh, it’s massive. Thank you so much for existing! I have always felt (and said) that the single biggest thing that this mission needs on the outreach side is diversity: that I can do what I can, but ultimately there are large audiences out there who just aren’t receptive to my way of saying things but who may be much more receptive to other voices saying materially the same thing. Also, we mustn’t forget the simple manpower aspect – like anyone else, I have only 24 hours in my day.

During our advocacy, we often find that people use terms like ‘immortality’ and ‘living forever’ to describe the work we are involved in. What influence do you think such words have on the credibility of the field and also on advocacy efforts?

Aubrey: I’ve been on the record for some time as saying that such terminology is not helpful. Most people who support biomedical intervention in aging who speak in such terms are using it in a stipulative sense to mean what they call “biological immortality” — by which they mean no manner of “immortality” at all, but rather a medical solution to end age-related debility and death. If that’s what they mean, they should just say so! To call this “immortality” (including “biological immortality”) simply confuses the discussion and makes people think that you’re saying things that you don’t mean. It reduces your credibility while also raising concerns that don’t apply to eliminating one very widespread and particularly terrible cause of death.

Policymakers are typically conservative towards disruptive biotechnologies, such as genetic engineering. How do you expect they will react once the first rejuvenation treatments are proven to work? Do you expect a lot of obstructionism, heavy regulations, and perhaps even attempts to ban these treatments, or do you think that politicians will understand the importance of rejuvenation without much need for lobbying from advocates?

Aubrey: Actually, I don’t expect significant amounts of either reaction. We’ve clearly seen already that the vast majority of people (whether bioethicists, or policymakers, or the person on the street) who express reservations about hypothetical therapies that would greatly extend life expectancy will nonetheless still express their support for therapies that would prevent or reverse individual, specific diseases of aging. But remember, rejuvenation biotechnology will not come in the form of a single, permanent ‘cure’ for aging like we have for many infectious diseases. Instead, there will be multiple rejuvenation biotechnologies, each targeting a different kind of cellular or molecular aging damage.

Because various specific diseases of aging are driven primarily by small subsets of such damage, individual rejuvenation biotechnologies will therefore initially appear as treatment and prophylaxis against those specific diseases, with relatively minor effects on life expectancy when considered in isolation. I am supremely confident that the support for each such therapy will be very strong and the opposition confined to a very small number of ever-more isolated ideological holdouts.

Additionally, remember that truly dramatic effects on life expectancy will — of mathematical necessity — not begin to manifest for decades after an entire panel of such therapies is widely available and in use as a comprehensive regimen. It is implausible that any strong constituency will arise in the intervening decades to insist that individual patients be denied any one of these therapies — let alone all of them — because of feared consequences for life expectancy and related social consequences decades into the future.

That concludes part one of our Undoing Aging 2018 interview; check out parts two and three, which we will publish here on our blog over the next two days.