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.