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Reviewing Juvenescence: Investing in the Age of Longevity

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Posted 27 September 2017 - 06:00 PM

Jim Mellon and Al Chalabi's new book Juvenescence: Investing in the Age of Longevity is, I think, an important milestone, and the Juvenescence team were kind enough to send me a review copy a few days ago, prior to today's launch. Why important? It is the first time that a group of financially influential individuals have come out and, at length and in detail, outlined why exactly they support the cause of rejuvenation research and why they think it has a good chance of success in the near future. Of course people such as Peter Thiel and Michael Greve have declared much the same degree of support in the past, and their material contributions have helped the SENS approach to rejuvenation research reach its present state of progress, but their public outlines have so far appeared in summary form, rather than producing a book-length treatment of the topic. In fairness, producing a book is a major investment in time, always a scarce resource for people managing large amounts of wealth - I have certainly been putting off that exercise for at least a decade so far, and I am about as far removed from having the workload of a billionaire as any of the rest of the audience here.

The importance isn't that Juvenescence is a book, per se, but rather that it is a comprehensive outsider's consideration of the prospects, delivered by the principals of an investment group who intend to make a mark in the clinical translation of therapies to turn back aging. Fields need outsider views, they need the process by which outsiders become enthusiastic, join in, and bring their own package of biases, optimism, and new ideas. Without this there is only stagnation, which is exactly what had happened to aging research prior to the turn of the century. That stagnation is why the field required people like Aubrey de Grey and organizations such as the Methuselah Foundation and SENS Research Foundation to advocate for better ways forward, to take the knowledge that existed about the causes of aging and actually apply it, rather than sitting around pretending that aging was intractable. Now we have arrived at a stage in which larger amounts of outside investment and startup companies are required to take progress from the laboratory to the clinic, and that makes the contributions of vocal investment figures such as Jim Mellon very welcome. The market for working rejuvenation therapies will be enormous, a huge tidal wave of change and financial growth:

Jim Mellon's investment philosophy, which has led him to be recognised as one of the most successful investors of his generation, is underpinned by his ability to identify so-called "money-fountains" - market trends which will lead to step changes and the resulting investment opportunities. "This is the biggest money fountain idea that Al and I have ever seen. The longevity business has quickly moved from wacky land to serious science, and within just a couple of decades we expect average human life expectancy in the developed world to rise to around 110."

In this book, you will learn about one of the hottest new areas of research, one that is being unravelled for the first time ever: how to treat ageing as if it were a disease. We are so excited about these developments that we have started a new company named after this book. Juvenescence has a mission to find diagnostic and therapeutic agents in order to treat ageing as well as associated diseases. We are hopeful that this business will be the most profitable of our companies to date and will provide at least part of the "solution" to ageing, should one ever be found.

Very few disagree with Ashley Montagu, the long-lived 20th century anthropologist, who said that "the idea is to die young as late as possible." Achieving Montagu's goal is the central aspiration of our book. Today, we are finally at a tipping point where what was once pure science fiction is transitioning into scientific reality. Just as with aviation a century ago, anti-ageing science is about to take flight. The incremental addition of 30 years or so to average lifespans over the next two or three decades will represent the single greatest investment opportunity in recorded history.

Delving beneath this high level overview, what are the more nuanced views of Mellon's team at Juvenescence? They believe the processes of aging should be officially classified as a disease, because that will expand and speed progress towards working therapies for aging. They support the view of aging as damage accumulation and thus the SENS approaches of damage repair, such as senolytic therapies to clear senescent cells, but not necessarily as the only or the most effective way forward. They have a mix of views on the utility of genetic information, on investigations of the detailed operation of metabolism, on adjusting metabolism to modestly slow aging through drug candidates such as rapamycin, and on a range of other items that I suspect will largely turn out to be distractions of limited utility, in the near term at least. They think that the current forest of competing scientific views of aging will converge to one true understanding fairly soon. They are agnostic on the degree to which healthy human life span can be extended in the decades ahead once past the point of ensuring that nearly everyone reaches 110 years of age: they acknowledge the possibilities of de Grey's acturial escape velocity and Kurzweil's "bridge to a bridge" taxonomy of life-extending therapies and the likely time of their arrival. That incremental progress should lead to large gains over time, the point being that an extra 20 to 30 years of life will allow new and better therapies to arrive and produce even greater gains. Mention is given to the prospect of radical life extension and indefinite life spans outlined by transhumanists and other futurists, but the Juvenescence team don't put their support behind such ideas. Adding a few decades of additional health and life, however? That is, correctly I think, declared to be very plausible, and a goal to work towards, with the first therapies enabling the start of this improvement nearly in clinics now.

After the initial blurb, Juvenescence provides an overview of the molecular biochemistry of aging, targeted at laypeople, a tour of the current state of the science, and particularly of the current differences of opinion and theory, such as programmed theories versus aging as damage accumulation. All of this is presented in such a way as to reinforce the main point that aging can now be considered a treatable medical condition. This is a tough set of summaries to write for an unfamiliar audience, as one has to provide enough of the details to explain why it is that the current state of the science is meaningfully different from that of a generation past, that now is the time, that now is different from all of the times past when someone stood up to (falsely) claim a way to influence the aging process. But providing any of the details is like pulling on a piece of thread - soon you need more details to justify what was said about the former details. Biochemistry is enormously complex, and the fine distinctions matter at every level. It is a real challenge to find the stopping point that avoids all of the pitfalls: failing to justify the claims; burying the reader; omitting items in a way that will lead to later confusion. One of the strengths of Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime was that it didn't try to cut the thread, and just went all the way to outlining in detail the relevant biochemical mechanisms. Here, for a different audience, that isn't possible. The authors do a good job, but I suspect that the initial promise of a vast future market for longevity science is very much required for the intended readership to work through the first few dozen pages covering the important details of aging, piece by piece.

Obviously, the target audience for Juvenescence is not us. Well, maybe those of us who intend to start companies in the next decade or so, as a reminder that Juvenescence, the business development company, would like to invest. The target audience is investors and analysts who are currently unfamiliar with longevity science, everyone involved in the decision chain that leads to capital flowing into an industry. Early participation in a new market is great way to become wealthy, provided that the new market does in fact take off rapidly enough. I don't think there is any doubt that longevity assurance therapies will become an industry greater than every present area of medical science - every human over the age of 40 is a customer at some price point. The open question is just when and how fast it will take off. Groups like the SENS Research Foundation have been working on that at the interface between the academic and business worlds. Juvenescence is intended to work on this at the interface between the finance and business worlds, to accelerate the process. Nothing magically just happens without effort in this world of ours: it takes work to ensure that technologies are handed off between researchers and developers, and also to ensure that venture funding is available.

This is a very modular book: the chapters stand alone; the overall thesis is built upon, repeated, and reinforced in each section; small few-page self-contained sections contain overviews of specific important topics, such as inflammaging, basics of genetics and gene expression, DNA damage, and so forth. It is intended to be picked up and read in small bursts by busy people. After the tour of the science of aging come chapters exploring the current spectrum of work on specific age-related diseases and interventions into processes of aging: the details of specific approaches in development, from parabiosis to calorie restriction mimetics to senolytics to stem cell therapies and most of what is in between, including a number of other SENS proposals; the animal models used in the laboratory and how they relate to the activities of a few companies in the space; showcases of specific groups that the Juvenescence team currently supports or intends to support, such as In Silico Medicine, the SENS Research Foundation, and the Buck Institute for Research on Aging. Investment topics are considered in a similar capsule format: lists of companies in the space that are likely investment targets of one sort or another; likely societal changes and benefits brought by extended longevity; benchmarks for how to think about how this area of medical technology will likely shape the next few decades.

Noted opinion leaders in the field of aging research are given their own sections - again, recall that this is a book targeted at investors, who will want to know who to talk to in order to validate the Juvenescence thesis - ranging from David Sinclair and Nir Barzilai, who have worked on approaches I think are not all that useful, to Aubrey de Grey and Laura Deming, who put repair of molecular damage and radical life extension front and center. There are also a few choice quotes on just how difficult it is to get anything out of the California Life Company where Cynthia Kenyon is now working; Jim Mellon and company are the latest folk to come to the conclusion that all the secrecy there is hiding nothing of relevance to the field.

Getting information on what Cynthia Kenyon, or Calico, is up to is a bit like getting the KGB to reveal its secrets in the old Soviet days. For mere authors such as us, there is no way that we could get past the gatekeepers of a company whose motto was until recently "Don't be Evil". It has now been changed to "Do the right thing" but might have better been changed to "Say Nothing". Scientists generally have been disappointed with Calico's progress. Nir Barzilai has been quoted as saying: "The truth is, we don't know what they're doing, but whatever it is doesn't really seem to be attacking the problem."

In reading all of this, I did discover items that I wasn't aware of; that David Sinclair's Life Biosciences is presently involved in developing a senolytic therapy and intends to target fibrosis at the outset, for example. The book is an interesting mix of support for the SENS rejuvenation biotechnology vision on the one hand, and on the other interest in metabolic tinkering of the sort that probably won't produce significant results. It also echoes many of the themes assembed by Kurzweil and Grossman in Fantastic Voyage, their specific view of better maintaining health with today's methods in order to remain healthy for long enough to take advantage of the first (and then incrementally improving) longevity enhancement therapies - there is a possibly too lengthy section on basic good health practices after the fashion of Kurzweil's Bridge One. It remains to be seen how the Juvenescence team will follow up on their evaluation of the field with investments beyond the first few made to date. Clearly we stand at a point of transition, and not just growth in this field, but in the first proof of principle rejuvenation therapies. What will happen once senolytics are proven far more effective than any other presently near-term approach of metabolic adjustment in humans? Will those other approaches wither away, or will that take a lot longer to occur? It will be interesting to watch how the investment community and markets react to this sort of discovery. Without a concrete underlying assemblage of theory, such as SENS, to explain why some things work and some things don't, investors will be throwing darts. The challenge is that for an outsider, how does one tell the difference between the likely prospects of damage repair approaches such as those of SENS, and the likely prospects of, say, metformin or rapamycin or other metabolic adjustment approaches?

Juvenesence is a valuable survey of the field as it stands today; I think it worth reading even if you are familiar with the past few years of progress. It isn't clear from the contents as to whether or not Jim Mellon and the others at Juvenescence have yet digested and built upon this survey to the point of forming their own robust understanding of the expectation value of different classes of approach to aging. For me, that took years and reading a lot of papers. But do they and other well-heeled investment groups need to achieve that goal right this instant? They could, for example, instead take a ten year longer view of the situation, make generally sensible bets in a variety of approaches, and let the market and the realities of development sort out the answer. So long as a reasonable fraction of their bets are backing the implementation of SENS and SENS-like repair biotechnologies, the job will get done, and lives will be extended. In the process of this, investors will in the fullness of time develop their own understandings as to why certain things work, and will hopefully come to the conclusion that it is as simple as identifying the root cause, original damage in human biochemistry, and then repairing it. The approaches that work will win out in the end, given enough funding for the field to progress at an optimal pace.

View the full article at FightAging
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