Today, we present an interview with Reason, the editor of Fight Aging! and co-founder of Repair Biotechnologies. We asked him about the state of rejuvenative therapies, some of which may be available in the near future.
Fight Aging! was the first blog that tackled the science of aging in a serious fashion. Many people still treat it as the go-to site for high-quality information and opinion on the rapidly growing field of biogerontology.
Reason (he goes by only his first name), the brain behind the Fight Aging! blog, has been involved in one way or another with anti-aging science for almost two decades as a writer, researcher, and investor. His new company, Repair Biotechnologies, is focused mainly on halting thymic atrophy and atherosclerosis, which causes about 20 percent of all human deaths
The anti-aging field has been experiencing rapid growth in recent years. LEAF has put together a regularly updated “rejuvenation roadmap” that tracks the progress of key longevity therapies. We are now at a point that a number of therapies are entering human clinical trials – the step before commercial availability if the trials yield positive results. Four of the therapies tracked are in phase 2 clinical trials, and three others are in phase 1.
I met Reason at the RAADFest 2018 event in San Diego. Reason may seem an unlikely person to be at such a science-lite event, but many people are starting to see its merit as a venue for generating enthusiasm for pro-longevity ways of thinking and for people to compare notes in a serious way. Reason had this to say about this year’s event:
I spent an interesting few days last week attending RAADfest and came away somewhat optimistic that this strange collision of subcultures may herald an acceleration in the adoption of solid science and working therapies on the part of the anti-aging marketplace, accompanied by a driving out of the ineffective nonsense and fraud of past decades. This sea change is very much a work in process, and there is plenty of that nonsense still to be found. Yet the advent of senolytic therapies to clear senescent cells has clearly invigorated certain groups, who have now turned a sizable amount of their advocacy and attention to the adoption of this first legitimate rejuvenation therapy, an implementation of the SENS model of damage repair.
I interviewed Reason by email in late 2018. Our focus was on near-term promising therapies as well as the therapies on which Repair Biotechnologies is focused.
What are the most promising near-term therapies that may actually turn back the clock on biological aging?
Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie-restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.
The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we’re unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.
Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.
I’m not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging – they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.
What led to your interest in longevity science and then writing a well-known blog about it?
I woke up one day quite certain that I didn’t want to die. The rest followed naturally from that point; the reading about the topic; the realization that not enough was being done in a sensible way; the discovery of transhumanist thought on radical life extension; the discovery of Aubrey de Grey’s thoughts on the matter. Once I came to the point of doing something, it is arguably the case that a better decision would have been to switch careers to the life sciences rather than continue as I was and put spare time into writing and patient advocacy. Still, someone has to do the writing and patient advocacy. It is a tapestry, and all the threads are needed.
How seriously should we take Wyvern Pharmaceuticals’ announcement that it will be beginning whole-body skin rejuvenation clinical trials next year and expect to have commercially available therapies on this in the next few years?
There are a few groups who have demonstrated whole skin tissue engineering. There is also the interesting work on delivering pluripotency factors into the skin or even systemically in mice, producing enhanced tissue function – another example of pushing damaged systems to work harder, and getting what looks like a benefit from the process.
Against that backdrop, whether or not something is rejuvenation is a different question. Is it repairing the forms of damage known to cause aging, or is it only forcing greater regeneration without repair? Wyvern is a gene therapy company, and it hasn’t yet discussed in public what exactly it is doing with the skin, but of the single gene targets for doing something interesting in the skin, the most plausible tend to revolve around increased elastin deposition. The principals will no doubt get around to telling us what they are doing when they are ready.
Your new company, Repair Biotechnologies, is focused on bringing gene therapies to market, similar to Wyvern. Your focus, for now, is on thymic atrophy (impacting our immune system in a serious way) and cholesterol transport (impacting atherosclerosis and cardiovascular health). Why have you chosen these two areas to focus on? What is your timeline for reaching clinical trials?
The immune system is a powerful lever. If it can be restored to greater function, then it will set forth and help to fix a number of issues, with cancer risk and senescent cell burden being two of the more important – it isn’t just about preventing older people from succumbing to infection. Thus, in the present environment of all too few entrepreneurs and companies tackling aging in a serious way, it makes sense to pick goals that have broader effects.
Atherosclerosis accounts for nearly a fifth of all deaths, and the progressive exploration of what can be done with cholesterol transport to reverse the condition, achieved through development and trials, is proceeding painfully slowly despite a large number of companies in the field. It is a field that needs more aggressive assistance and new groups trying new things, and, again, the benefit to humanity in the event of success is large.
What is your company’s “special sauce” in terms of providing to the market that isn’t already being provided by other groups?
Our connections within the rejuvenation research community, allowing us to pick up research that is ready but below the radar of the venture community, near two decades of time spent in analysis of the field as it evolved on a day to day basis, and a strong focus on damage repair as a guiding principle. All too many of the groups whose principals are earnestly interested in doing something to ameliorate the effects of aging do not focus on repair as a strategy. They attempt to make adjustments to the operation of metabolism in the disease state or interfere with mechanisms that are far downstream of root causes and thus have a small effect on disease. As a consequence, they have a much lower chance of producing a therapy at the end of the day that has a large enough and reliable enough benefit to be worth the investment or to have good odds of passing large trials. Only repairing of the root causes of aging offers good odds of providing benefits across most or all of the patient population.
Are you planning clinical trials in the near future for these therapies?
“Near future” is a slippery term in life science development. As soon as is feasible, yes, we’d like to get clinical trials going for our projects. That said, it is a long road from the initial proving studies to that point; it will certainly be a couple of years, even if everything goes exactly according to plan, and it is usually more. We would hope that the usual roadblocks that have surfaced in the past, largely meaning lack of venture funding for this field, are no longer a problem in the present environment, which would just leave us to buckle down and get the work done efficiently and well.
Does telomerase therapy, like those being researched by Bill Andrews and Sierra Sciences and Michael Fossel’s Telocyte, have real potential to roll back the clock by lengthening telomeres and restoring healthy genetic expression? Is it accurate to view telomerase therapy as one variety of many different kinds of gene therapy?
I’m not optimistic about telomerase therapies. I think the bounds of the possible here are similar to those of early stem cell therapies: some modest gain. These therapies work by putting stem cells back to work, increasing cell division. However, that is in the context of an aged biochemistry that is riddled with molecular damage, and these treatments repair little of that damage. The DNA damage is still there. The senescent cells are still there. The molecular waste of amyloid and lipofuscin is still there.
That it actually reduces cancer risk in mice is because the immune system is being forced back to work as well, most likely. We cannot extrapolate that outcome to humans, however, as telomere dynamics in mice are very different from those in our species, as is the nature of age-related molecular waste in the brain and elsewhere. The balance of damage, cancer risk, and greater regeneration works out positively for mice. It could very well increase cancer risk or produce other issues for us.
It seems likely that brave volunteers will determine whether or not this is the case, and for a much older individual, as was true of early stem cell therapies, the risk/reward calculation can make sense.
Fossel, a long-time proponent of telomerase therapy, is of the view that lengthening telomeres will turn back the clock on most or all of the issues you mention by restoring normal cell function and allowing cells to clean up all of the intra-and extra-cellular issues you describe. He states in a recent LEAF interview: “The change in gene expression that occurs has ubiquitous effects throughout the cell, but among them, it turns down the rate of DNA repair, it turns down mitochondrial function, it turns down lipid turnover, it turns down beta-amyloid turnover between cells, it turns down the rate of turnover in elastin, collagen, and hundreds of other critical molecules. Those things are what’s going on as cells become senescent.” Will we just have to wait for clinical trials to see the actual outcome of these planned telomerase therapies? Or do you think we know enough to be pretty sure already of the outcomes?
We wait for the trials. I think that it isn’t unreasonable to expect all sorts of useful and beneficial things to happen as a result of increased work on the part of stem cells and somatic cells in old tissues, and that part of it will look very similar in mice and people. The question marks revolve around the side effects resulting from increased cell activity in a heavily damaged environment, wherein numerous forms of that damage cannot be adequately repaired by our cellular biochemistry no matter how active it is; therefore, we should have an appropriate degree of concern regarding cancer risk, immune system overactivation risk, that sort of thing. The only practical way to find out what the risk looks like is to run human trials. There will, I am sure, be no shortage of volunteers.
You’ve mentioned that you see breaking extracellular crosslinks as one of the most promising areas for near-term breakthroughs. Why is this so important? What are the most promising therapies for breaking extracellular crosslinks, which is what the SENS program calls GlycoSENS?
This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems – which do absolutely nothing to eliminate the root cause, the biochemical damage of aging – can still produce large reductions in mortality risk.
All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients.
Glucosepane is hard to work with, so very few groups have done anything meaningful – the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel’s team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.
What is your preferred umbrella theory for aging? Do you agree with the notion that we are in various ways programmed by evolution to age and die?
For me, the old-school view of aging as a side-effect of relentless evolutionary optimization of reproductive success in earlier life works just fine. Systems have evolved that (a) function exceptionally well out of the gate but (b) have limited capacity to run indefinitely. This is because running indefinitely would require resources to be directed to maintenance rather than reproductive success, and mutational drift in that direction will be promptly out-competed. Selection pressure in later life exists (see the grandmother hypothesis), but it clearly isn’t enough to select for anything that will devote resources to greater life-long repair rather than reproductive success while young.
What’s your best projection for when therapies that truly turn back the clock, biologically, will become available? And what’s your thinking on the likely costs of such therapies?
They are already here. The solid proof that senolytics work in humans will arrive later this year and over the course of 2019. The cheapest senolytic with good results in mice, fisetin, is a plant extract supplement that costs something like $25 for a dose that you might take once every year or so. Others such as chemotherapeutic small molecules and peptides are in the $100 to $3000 range for a dose, and they are also available to anyone who cares to set forth to obtain them. The next generation of significantly better senolytics will arrive in the clinic in five to ten years and will be much more expensive, as they involve more sophisticated biotechnologies.
It will be some years before the next few repair-based rejuvenation therapies rise to the same level of availability as senolytics, however. All of the candidates are earlier in the development process and some are more complex approaches, requiring gene therapy or similar methodologies. So, five years, at the most optimistic.
Quercetin has received a lot more attention, but it seems that fisetin may be showing more promising results in the latest research. Do you expect fisetin to work better than quercetin as a senolytic (with dasatinib) in humans?
We can’t say anything yet about the combination of fisetin and dasatinib – no one has data for that. It seems reasonable to expect it to work better than the quercetin and dasatinib combination based on the mouse evidence to date for quercetin (no meaningful effect) and fisetin (about as effective as any of the other top-tier senolytics) on their own, but any combination remains to be verified. One caution is that fisetin is used by humans and has been for some time. While the senolytic dose is half a bottle of fisetin supplement pills taken at once, as it is currently packaged, making that an unlikely choice for a casual consumer in the past, it still seems a little strange that there were no anecdotal reports if it is indeed effective in humans as well as in mice.
What are your preferred sources for the best information on anti-aging science and therapies?
The Lifespan Extension Advocacy Foundation is a doing a good job, as are a couple of other volunteer advocacy efforts. However, browsing the feeds of publicity materials and published papers every few days is still required to notice a fair proportion of the items of interest that arrive on a regular basis. You might look at EurekAlert!, Science Daily, and PubMed, for example. The industry isn’t large enough yet to have dedicated sole-focus coverage provided by journalists and professional organizations, but I’m eagerly awaiting that transition.
We would like to thank Reason for taking the time to speak with us and share his insights.