Month: July 2017

Considering Juvenescence

As noted this morning, Juvenescence is the new venture fund slash business development company created by investor Jim Mellon and allies as a part of his interest in the development of real, working anti-aging medicine. No-one is getting any younger, and that includes people with the resources to do something about this state of affairs, should they finally wake up to the ongoing revolution in biotechnology and put their shoulders to the wheel. This is the latest instance of a well-heeled group setting forth in earnest to achieve something in aging research and related biotechnology relevant to treating aging as a medical condition. Is it the most promising to date? Perhaps.

Past examples have included Larry Ellison’s initiative, Paul Glenn’s support of research, Peter Thiel’s support of SENS, and Google’s California Life Company, among others. In many cases, the rhetoric at the outset gave some hope that these large investments would be more visionary than a funding of the same old dead-end work on pharmaceutical alteration of metabolism to slightly slow aging that has characterized the mainstream for the past fifteen years. But in only one case was there in fact material support for the better, visionary alternative, rejuvenation research of the sort exemplified by the SENS programs, the only plausible way to greatly extend lives and turn back aging in our lifetimes. If there is caution and a wait and see attitude related to Juvenescence and the rhetoric from its founders, it is because Lucy has snatched away the ball one too many times these past years. Still, this is promising rhetoric, I have to admit that much. It comes from a fellow who has raised talking up his position to something of an art form, so I’m sure we’ll be hearing more of it:

Mellon on the Markets: New “highs” for early investors

On the subject of Juvenescence, I am off to San Francisco with my old best friend Anthony Baillieu to meet my new best friend Aubrey de Grey (Google him!) and my dear colleague Greg Bailey. We are all spending the day at the Buck Institute of Aging – not to be rejuvenated ourselves, but to understand more of the amazing science that is coming out of this institution.

One of the key senolytic drugs in development, being trialled by Unity Biotechnology, first emerged at the Buck. In a nutshell, senolytics are among the first of several compounds that will add significantly to human lifespan in the next ten or twenty years. While more fully described in the new book, these are drugs that clear so-called senescent cells from tissues. Senescent cells become more prevalent as we age, and are cells that are neither dead nor healthy, but which exist in a limbo like state. They contribute significantly to inflammatory disease and their removal, at least in part, is demonstrably life extending in animal models.

We are also visiting another company involved in senolytics, and will be looking to make an investment in it for our venture, Juvenescence Limited, which is jointly owned by Greg, Dec Doogan (formerly head of drug development at Pfizer, the world’s biggest drug company) and myself. We have collectively recently invested a largish sum in a venture called Insilico Medicine, which uses deep neuronal networks (aka AI) to enhance medical discoveries, and we have capitalised a joint venture with Insilico called Juvenescence AI which will look to discover five new chemical entities a year for several years, using AI. These are exciting times in the field of longevity, and believe me, staying healthy today will allow you to cross a bridge to ultra-long life in the not too distant future.

Alex Zhavoronkov at Insilico Medicine will, I’m sure, forgive me when I say that I haven’t been following the Juvenescence work all that closely because the early focus appeared to be fairly standard aging-related drug discovery in areas that I think have little potential. He knows my views on these matters. Should the staff at Insilico Medicine set their sights on senolytics and small molecule glucosepane breakers, I will be the first to laud their efforts, as that is a portion of the SENS rejuvenation research agenda wherein standard issue drug discovery processes, rational drug design, and improvements thereof can shine. But building more marginal geroprotectors that target mTOR or regulators of mitochondrial function or autophagy or other line items associated with the scores of ways to modestly slow aging in mice? Not so promising. We’re twenty years in to that sort of work, and what do we have to show for it? More knowledge of the operation of metabolism, yes, but also a distinct absence of ways to add healthy years to life that are any more effectively than eating less and exercising more.

I think that the evidence to date gives us all good reason to think that there is a low ceiling to the utility of such mainstream work in terms of years of life gained at the end of the day, and that the ceiling isn’t going to rise with the input of far greater amounts of funding. It is a fundamental aspect of these mechanisms. Aging is damage, and if research doesn’t aim to directly repair or remove that damage, than it will always be of low utility. Try keeping any damaged machine running without actually repairing it. Further, stand back for a moment and take an earnest look at calorie restriction mimetic development versus senolytic development. Fifteen years of the former has given us nothing to compare to the reliability and breadth of effects on aging and age-related diseases in animal studies resulting from a mere five years of earnest development in senolytics. This is because calorie restriction mimetics do not repair any form of damage that causes aging, whereas senolytic therapies to clear senescent cells do. It is that simple.

To return to Juvenescence, their clear interest in senolytics, and all of the obvious incentives to be involved in senolytics now that the commercial side of the field has been validated by large investments in Unity Biotechnologies, makes me more cautiously optimistic for this initiative than I was when Calico launched. Even if the Juvenescence principals do no more than vocally and materially bolster the senolytics industry, that will still be a great good. Will they do more than that for the development of SENS biotechnologies? We shall have to wait and see.


Using Nanoparticles to Vitrify and Rapidly Thaw Fish Embryos

Not so long ago, researchers demonstrated that infusing tissues with nanoparticles could allow for safe and rapid thawing following low-temperature vitrification, avoiding damage that can occur due to ice crystal formation during a slower warming process. In the research noted here, a different scientific group is working on the nanoparticle approach as a way to cryopreserve fish embryos. They have achieved a proof of principle demonstration, but clearly have a way to go in terms of the quality of the result – it isn’t yet as good as the earlier work on tissue sections. Taken as a whole the nanoparticle approach has the potential to help expand the use of vitrification for tissue storage, something that could greatly improve the logistics of organ donation, tissue engineering, and many areas of research by allowing indefinite storage of large sections of tissue. Greater use and development of tissue vitrification should in turn also help to advance the state of the art in human cryopreservation, the most important backup plan for those who will not survive to benefit from the rejuvenation therapies of decades to come, and a field in need of far greater investment and attention.

Zebrafish embryos have for the first time been frozen, thawed, and brought back to life. Researchers have been working on cryopreservation of zebrafish embryos for decades. It’s never been done before. Over the past 60 years, scientists have had success preserving the sex cells and embryos of humans, cattle, mice, and many other animals. Trying to freeze and thaw fish embryos, however, has been more difficult because of their size and structure. The embryos are relatively large, bigger than a human egg. Fish embryos also have different compartments that freeze and thaw at different speeds. That can lead to the development of ice particles, which can damage the embryo.

Building on work by other scientists, researchers tweaked an existing cryopreservation method by injecting gold nanoparticles into zebrafish embryos, along with a cryoprotectant. The team froze the embryos in about one second using liquid nitrogen, then, after a few minutes, warmed them using a laser. The gold nanoparticles, which were distributed evenly throughout the embryos, absorbed the laser light and turned it into heat. The laser, which shown on the embryos for a millisecond, warmed developing fish so rapidly that they may have avoided being damaged by ice formation or other untoward effects of the quick-chill and thaw technique.

In the trials, only about 10 percent of the embryos survived to 24 hours. At this point, survivors started squirming and wiggling as their hearts, eyes, and nervous systems developed, proving their viability, yet none survived to day five, the final time point the team used. The advance is important for the field of genetics. Zebrafish have become an important model organism for studying the genetics of vertebrates and humans. Being able to preserve the different genetic lines of zebrafish generated in these studies means researchers wouldn’t need to maintain live populations or run the risk losing irreplaceable research lines. It is also the most cost-effective method for this kind of research. The team is continuing to work on the technique to improve the viability of the embryos. Tweaks to the laser, gold nanoparticles, and even the cryoprotectant could make the method more suitable for embryos with a diameter of a millimeter or smaller. That would mean there would be one way of cryopreservation for all organisms with embryos of that size.



A Few More Details on Juvenescence

Jim Mellon is making a high profile investment in the development of therapeutics to treat aging, and this article offers a few more details on the company founded to carry this forward, Juvenescence. It is good to see new funding and vigor joining the field, but by the sound of it most of the proposed work is not actually all that interesting. It will be more of the standard drug development to try to slightly slow the aging process: consider the present panoply of work on calorie restriction mimetics, enhancement of autophagy, exercise mimetics, and so forth. Billions have been spent in this area in the past two decades with essentially nothing of practical use to show for it, because this approach to treating aging cannot possibly either produce significant rejuvenation or add decades to life spans. It fails to directly address the root causes of aging, does nothing more than tweak the operation of metabolism to slightly slow the consequences, and after twenty years of this work, the results still cannot even perform near as well as either actual calorie restriction or exercise.

Aside from the promise of investment in senolytic development, this initiative appears to be largely the Longevity Dividend approach so far; pour vast investment into perhaps adding a couple of years of life by 2030 or 2040. It is underwhelming, especially in comparison to the animal studies arising out of even just a few years of serious work on the alternative, which is to repair the forms of damage that cause aging. If Juvenescence focuses on senolytic drugs to clear senescent cells, it will be useful – the more the merrier in that part of the field. This is one of the few places where SENS rejuvenation research overlaps significantly with long-standing drug discovery practices, and not coincidentally it is also where results on aging and age-related disease in animal studies these past few years are both reliable and exciting in their magnitude – more has been achieved here in a few years than in the past two decades of work on calorie restriction, and at far less cost. Beyond these overlaps with SENS, all of the other usual suspects in the drug discovery agenda for slowing aging will, I predict, continue to produce little to no meaningful outcome no matter how much is invested in their development.

When British billionaire Jim Mellon wants to map out an investment strategy, he likes to write a book first. Out of that process came his most recent work – Juvenescence: Investing in the Age of Longevity. Now he and some close associates with some of the best connections in biotech are using the book as inspiration to launch a new company – also named Juvenescence – with plans to make a big splash in anti-aging research. “We are at an inflection point for the treatment of aging,” says Greg Bailey, who likes to highlight some of the new cellular pathways that are pointing to new therapies that can counter the effects of aging. “I think this is going to be the biggest deal I’ve ever done. It will need repetitive financing. Five to $600 million was raised for Medivation. As we hit inflection points, we will need to raise a dramatic amount of money.”

Bailey, the CEO of Juvenescence, was one of the early backers of Medivation, where he was a board director for 7 years – before Pfizer stepped in to buy the biotech for $14 billion. The primary game plan at Juvenescence is to come up with various operations engaged in developing new anti-aging drugs. Juvenescence AI is a joint venture they’ve just set up with Alex Zhavoronkov, who runs Insilico Medicine. Mellon met Zhavoronkov while he was researching his book, and believes that the tech the scientist developed can illuminate new programs with a better chance of success. “They are going to take up to 5 molecules from us every year for development,” says Zhavoronkov, an enthusiastic advocate of AI in drug research who’s also been working on some alliances with big pharma players. The group has invested about $7 million in the technology so far getting the joint venture set up. More will follow.

Aside from the cellular pathways that have attracted their attention, the biotech will look to effect change in the mitochondria, the cell’s powerhouse, as well as clean up senescent cells that accumulate as the body grows older. And Bailey expects he’ll be working some Biohaven-like deals to develop an advanced pipeline at a rapid pace. The principals chipped in the seed millions for the company and invested in the joint venture with Zhavoronkov. Bailey says you can expect to see $20 million to $50 million more from a friends-and-family raise before the end of the year. And it’s expected to grow from there.