$54,000
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Request for Startups in the Rejuvenation Biotechnology Space, 2018 Edition

A shift in the character of rejuvenation research has taken place over the past couple of years. Greater attention is being given to this work, and the most advanced lines have made - or will soon make - the leap from non-profit laboratory and philanthropic funding to for-profit startup company and venture funding. A growing community of angel investors and a fair few venture funds are now interested in supporting startup companies whose founders implement approaches to rejuvenation that follow the SENS model of repairing fundamental damage. A brief selection includes Kizoo Technology Ventures, Methuselah Fund, the Longevity Fund, Mann Bioinvest, and Apollo Ventures. Others will join them in the next year or two - it is a growing area of interest.

The point to be made here is that there is more than enough funding waiting in the wings to power any credible rejuvenation-focused company through its first few years. It is in fact much, much easier at this point to raise that funding than it is to obtain philanthropic funding for early stage research in the laboratory. The message for those with technologies that can make the leap is to go ahead and do it. Don't wait around; reach out to the venture community and take a look at the present state of play. Many different and interesting approaches to the treating of aging as a medical condition are on the verge of viability for commercial development, and what follows is a list of those I'd like to see emerge sooner rather than later, in no particular order of priority. If you are working on something that looks a lot like any of the following, then please do reach out; there are many in our community who would like to hear from you.

Better Approaches to Assessing the Outcome of Senolytic Treatments

Senolytic therapies that destroy senescent cells are going to be a very big deal in medicine. But how to determine whether or not they are working, and how well they work? One can measure all the usual metrics of disease, but that is a poor second best to understanding the actual load of senescent cells, and therefore the degree of impact. Currently all of the useful ways to count senescent cells involve tissue samples, and since wounding creates senescent cells there is some question as to the viability of biopsy-based approaches. We need some better: approaches that will lead to non-invasive or minimally invasive tests that quantify cellular senescence. A couple of years from now there will be a dozen companies putting forward various senolytic treatments, but next to no-one appears to be thinking about viable commercial assays for senescence. In such an important space, there is currently a single startup and perhaps one or two research groups with interesting ideas. This needs to change.

Make Medical Tourism Work for Enhancement Therapies

If any of the first generation senolytic drug candidates prove useful in humans, that will result in a tremendous market opportunity for medical tourism. The same is true when, in the next few years, CRISPR-based approaches to gene therapy become capable of reliable transfection of a large fraction of target cells. There are four or five gene targets, such as myostatin and follistatin, that make for very interesting enhancement therapies. There are many, many more healthy people who might want to undergo rejuvenation or enhancement therapies than there are patients seeking treatments for specific medical conditions. A number of groups related to the longevity science community have been gnawing away slowly at various aspects of the challenge of making medical tourism work, such as BioViva, Ascendance Biomedical, and Libertas Biomedical, and all have found it harder than one might suppose it to be. Somewhere in here there is a recipe that works, a way to make overseas clinical trials and treatments transparent, cost-effective, safe, and attractive, building a growth market that works in synergy with the advent of practical rejuvenation therapies and enhancement technologies.

Rejuvenating the Immune System

The immune system touches on so very many processes and aspects of aging that turning back its age-related dysfunction will be enormously influential on health in later life. There are potentially viable approaches for each of the various parts of this puzzle, and most of them are within striking distance of commercial development. Selective destruction of errant immune cells, or even the entire immune system, if it can be done without the present working approach of high dose, damaging immunosuppressants. Periodic infusion of patient-specific immune cells in bulk. Addressing the failing activity of the bone marrow stem cell populations responsible for creating immune cells. Restoring activity to the thymus, where T cells mature, to increase the supply of new T cells. Immune dysfunction is a sizable component of age-related frailty, and any of these items should move the needle.

Glucosepane Cross-Link Breaking and Supporting Technologies

At some point in the near future, the Spiegel Lab staff will uncover enzymes to break glucosepane cross-links, and then no doubt roll that effort into a startup company. There are probably numerous other approaches that will work, however, such as suitable small molecule drugs. As cross-link breaking will reverse blood vessel stiffening and skin aging, it will be an enormous market with plenty of room for competition. Drug screens are not massively expensive, though getting set up to work with glucosepane is still a specialty concern; there is a real opportunity here for any group that can adapt to the developing infrastructure for glucosepane research and make some progress. Further, this field has the same challenge in measurement of outcomes as senolytics: while companies will start by forging ahead with therapies, how do we tell how greatly a specific individual is affected by glucosepane cross-linking without cutting chunks out of them for analysis? Non-invasive or minimally invasive means of assessment will be important, and very much in demand as the first therapies roll out.

Better, Faster, Cheaper Amyloid Clearance

Current immunotherapy approaches to the amyloid-β of Alzheimer's disease are characterized by their enormous expense, both in development and implementation. Unless the cost is crushed down quite radically, and unless the pace of progress towards something that actually works speeds up to the same degree, this will be a poor platform for the future clearance of the other twenty or so types of amyloid that build up in aged tissues. We need to do better than this. More thinking outside the box is needed, such as the cerebrospinal fluid drainage focus of Leucadia Therapeutics or the catabodies of Covalent Bioscience, both approaches that could be far more economically viable if successful. More similarly inventive biotechnologies are called for.

Clearing Out as Yet Untouched Forms of Lysosomal Garbage

Companies such as human.bio and Ichor Therapeutics are working on some of the first implementations of biotechnologies to break down specific problem forms of metabolic waste, those that clog up the lysosomal recycling mechanisms, or otherwise cause cells to become dysfunctional. This is a small start on a sizable challenge: there are a great many problem compounds, and thus a great many opportunities to make meaningful inroads in removing these contributing causes of age-related disease. The Ichor Therapeutics model of picking one compound strongly tied to a specific disease is a strategy that can probably sustain a dozen companies for a variety of targets given the current state of knowledge.

Components of an Ecosystem for Targeted Blockade of Telomere Lengthening

Defeating all cancer with one single form of therapy, based on blockade of telomere lengthening, is a very plausible solution to the problem of too many types of cancer, too few researchers, and the current mainstream focus on overly specific forms of cancer treatment. If we want to see meaningful progress to an end to cancer in our lifetimes, the existing research and development model must change. The scientific path forward to this class of universal cancer therapy is well defined: selectively block the effects of (a) telomerase and (b) the alternative lengthening of telomeres (ALT) mechanisms, and couple that with a targeted delivery mechanism. It is unlikely at this stage that any one company could move directly to the full unified approach as a product, but a solution for even part of the overall problem, the portion of the final ecosystem, should be valuable in and of itself. That is likely to start with one of the demonstrated means of sabotaging telomerase activity, but we shall see.

Bringing Cell Therapies into the Rejuvenation Space

Today the overwhelming majority of cell therapies used in clinics do not produce rejuvenation. They achieve temporary benefits in patients largely through reductions in inflammation, accompanied by modest increases in regeneration and tissue maintenance that would not otherwise have taken place. The transplanted cells die quickly, and achieve these results through signaling in the period of time that they remain alive. The next generation of more sophisticated cell therapies is still waiting in the wings, approaches that can actually replace lost or damaged cell populations for the long term, with transplanted cells that survive and integrate into tissues, in order to restore function to specific organs and biological systems. Further, there are a range of other less immediately obvious possibilities that may also prove useful, such as induction of pluripotency in vivo, the aforementioned infusion of patient-matched immune cells, and accelerated cell replacement strategies. All in all, stem cell based regenerative medicine is a field that has reached a comfortable point, a box, and now needs to break out of it to reach the next level.

Reliable, High-Coverage Gene Therapy Platforms

The big stumbling block for moving the most promising genetic edits direct to human access via medical tourism is the reliability and cell coverage of the delivery methods when used in adult individuals. They are not consistent enough, and they are not delivering the payload into a large enough fraction of cells - and particularly stem cells, needed to make any change truly permanent for the recipient. Success here would be transformative for medicine and human enhancement technologies, and it appears that the research community is on the verge of solving this challenge in a number of different ways. Any one of these methods, carried forward to the clinic, should be enough to unlock an explosive growth in the size and capabilities of the gene therapy marketplace.

Comments

"Currently all of the useful ways to count senescent cells involve tissue samples, and since wounding creates senescent cells there is some question as to the viability of biopsy-based approaches. We need some better: approaches that will lead to non-invasive or minimally invasive tests that quantify cellular senescence."

I wonder if senolytic drugs will be regarded as performance enhancing drugs? I assume they will be, and as several companies are already about to start putting such drugs through clinical trials, it wont be long before aging sportsmen get hold of them in order to try to prolong their careers. Thus anti-doping authorities will have to design an effective test, as well as define 'normal ranges' for selected ages.

When Googling senolytics and peds/doping, I get no relevant results. Could it be possible that the likes of WADA are blissfully unaware of the senolytic tsunami that is about to hit the sporting world (and society)? There are already people in the longevity community self-experimenting, I would imagine the first professional sportsmen wont be far behind.

So..perhaps we should petition WADA, the USADA and alert them to the need to come up with an accurate test?

Posted by: alt-transhumanism at December 26th, 2017 4:28 PM

I don't think they will be regarded as doping, for the same reason surgery is not regarded as doping. At much, they will put their users to the same level than when they were younger/healthier, or at the same level than their younger/healthier competitors. They will not create superhumans nor make training unnecessary.

Posted by: Antonio at December 26th, 2017 4:53 PM

Senolytic drug use is probably already detected by standard sports drug tests.
It should have an effect on growth hormones.

Posted by: Anonymoose at December 26th, 2017 5:17 PM

@Antonio - well maybe that would be the fair policy but I'm pretty sceptical that sports will allow athletes to use a powerful drug that allows them to perform better, even if it only benefits older athletes, at least not without plenty of debate. It would certainly be a first as far as I know.

Just like the FDA, the USADA does not recognize aging as a disease and that means that athletes cannot attempt to fix it through drugs.

TRT is banned in all sports now I think. Up until recently athletes fighting in the UFC were allowed 'therapeutic usage exemptions' if they had lower than average testosterone - in other words, pretty much every competitor over 30 was going to their doctors to get the sick note to allow them to restore their testosterone back to their 21 year old levels. The result? The UFC began getting dominated by guys in their late 30's such as Vitor Belfort, who had 20 years of top level experience, and in some sense the vigour of his 20 year old athletic peak and was viciously knocking out guys a decade or more younger.

If senolytic drugs suddenly mean that guys in their late 30s (and perhaps even older) begin dominating sports, then there is sure to be a big debate about their use.

Posted by: alt-transhumanism at December 27th, 2017 2:55 AM

@alt-transhumanism I'm sorry to say but you're suggesting an unrealistic picture of senolytic drugs. Shall we now reduce the aging process to senescent cells just because they can soon be ablated with still unknown precision and effectiveness? Even if they were perfectly working you'd still not restore function to level of your young competitors or your own peak in younger years as you're still hampered by several kinds of other damage. It will probably restore function and vigor to a certain degree but not anywhere near how you describe it.

Posted by: K. at December 27th, 2017 5:19 AM

Enough with the negativity! The first commenter came up with an original idea about how we could make WADA / USADA work for us. So yes, give it a try! Point out to WADA / USADA that there may already be professional athletes who use senolytics to improve their performance. And since there are many possible methods for removing senescent cells, the only reliable way of detecting this type of "doping" is to come up with an accurate test to measure the levels of senescent cells.

The same trick could then be used in future too regarding other rejuvenation treatments. For example, tell WADA / USADA that they should really start looking into measuring glucosepane levels because there may be some athletes gaining unfair advantage by rejuvenating their blood vessels (by removing glucosepane cross-links).

Posted by: Not a Negative Nancy at December 27th, 2017 9:26 AM

As I said, the tests currently in use which detect IGF-1 in athletes are probably sufficient to detect senolytics use. So there won't be a need to develop new assays.

Secondly even if the sports commissions decided they need to develop and assay for senolytic use there is no guarantee they would design one which detects senescent cells.

Posted by: Anonymoose at December 27th, 2017 3:26 PM

@Reason, as far as I know they discovered many useful enzymes and plan to found a company within several months. From AMA:

Q: Is there anything new you are able to say about the breaking of crosslinks in the extra cellular matrix? The announcement that they were able to artificially create the main culprit in the lab was great new but was a while ago. Has there been any success on finding a way to break that stuff that you are able to share with us?

de Grey: Absolutely. Short stor, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

Posted by: Ariel at December 27th, 2017 4:33 PM

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