Request for Startups in the Rejuvenation Biotechnology Space, 2019 Edition

I am a little late with the 2019 list of projects in rejuvenation biotechnology that I'd like to see startups tackling sometime soon. In my defense, this year I have a startup of my own to keep up with, and the first part of 2019 was a wall to wall series of conferences alternating between the US and Europe. It continues to be the case that this is a new industry of near endless potential, yet little of that potential is under active development. This is the state of affairs despite the arrival of hundreds of millions of dollars in venture funds managed by the like of Juvenescence, Life Biosciences, and so on. The research community remains packed full of low-hanging fruit, potential approaches to rejuvenation that are barely even hidden; anyone with a modest knowledge of the field knows where they are. Anyone without that modest knowledge can find out easily enough - just send an email to Aubrey de Grey and the rest of the SENS Research Foundation crowd and ask for introductions. There has never been a better time to start a company focused on one or more aspects of rejuvenation biotechnology.

No More New Senolytics for a Little While

I know that many of you out there have the Best Idea Ever when it comes to ways to destroy senescent cells - but I think it best for everyone to sit back and let the existing set of senolytic therapies work their way closer to the clinic first. New senolytic companies are now competing with a dozen different approaches that are several years further along in their process of development. It is true that the world is a very large place, containing a great many old people who would benefit from senolytics, and there is plenty of room for a dozen competing ways to remove senescent cells as a part of a large medical ecosystem of rejuvenation. That said, there is the very real threat that failures on the part of any of the leading companies in this space will throw a pall over the funding environment. Start a senolytics company now, and you are at the mercy of Unity Biotechnology's trial results. This isn't fair, and Unity's programs are no reflection on the other, largely better approaches to clearance of senescent cells, but this is the way the world works. If Unity stumbles, investors will become nervous.

Deliver Existing Low Cost Senolytics to the Aged Masses

The most noteworthy point in all of the past five years of senolytic development is that the first compounds used as proof of principle in animal and human studies are actually pretty good at their job. They are also cheap and easily available. The dasatinib and quercetin combination, fisetin, and piperlongumine all have quite compelling animal data to support their senolytic effects, and all are very cheap. Why then are tens of millions of people in the US alone still suffering from arthritis and other inflammatory age-related conditions that have senescent cell accumulation as a significant cause? Why is it that no-one has yet stepped up to start a logistics company to improve all these lives considerably with one dose of senolytics that would cost something like $50-100 to manufacture and deliver at scale, and could be sold for twice that? This is a rare confluence of profit and public service.

Tailored Biological Age Assessment

Epigenetic clocks to assess biological age rather than chronological age are great in the abstract - except that no-one knows exactly what they measure, and thus they are useless at the present time for assessing the outcome of specific approaches to rejuvenation, such as senolytics. The technology is now far enough along that it is in principle possible to build a company based on supplying suitably tailored biological age assessment approaches that can be used to assess the results of a senolytic therapy, or other meaningful approach to aging. It is my belief that measures of biological age must be developed hand in hand with the therapies as they emerge, and only then can they be made useful. This is work that is presently not being accomplished in the for-profit marketplace, and thus here is opportunity.

A Competitor for Revel Pharmaceuticals in Glucosepane Cross-link Breaking

Revel Pharmaceuticals is the only company working on glucosepane cross-link breaking, emerging from the only lab that is working in a significant way on glucosepane cross-link breaking. These cross-links are a significant cause of loss of skin elasticity and loss of blood vessel elasticity. A success here will be as big as senolytics. I've spoken to more than one researcher who is either interested in this area, or has worked on this area, and would take funding to move ahead with their approach to the problem. So where are the competitors for Revel? This will be the next big thing in true rejuvenation therapies, I predict.

A Platform for Bacterial Enzyme Discovery to Break Down Metabolic Waste Targets

While I'm issuing predictions, here is another: the process of screening bacterial species from soil and seawater samples to find useful enzymes will prove to be far more cost effective than the present, or even machine-learning-enhanced, small molecule drug development process when it comes to establishing ways to break down harmful molecular waste in the human body. This is particularly true given the major advances in culturing bacterial species achieved in the past few years. So far as I know, no-one has started a company specifically to develop this approach as a platform for the many, many potential rejuvenation therapies that could result. There are a score of amyloids, numerous oxidized lipids, and countless components of lipofuscin to deal with just as a starting point. Companies such as LysoClear and Revel Pharmaceuticals found their lead compounds via mining the bacterial world, but have not made their process into a platform; the next generation of companies in this space should.

Make a Start on Interdiction of Telomere Lengthening as a Universal Cancer Therapy

Work in the laboratory to block lengthening of telomeres by telomerase is quite advanced - either close or ready to make the leap to a startup company. Someone should get out there, license one of these approaches, and get started on the process of bringing it to the clinic. The truly effective cancer therapies of the near future, those that will supplant immunotherapy because they are cheaper, more general, and more effective, will be based on suppression of telomere lengthening. All cancers must lengthen their telomeres, no cancer can avoid doing so, and if it is blocked, the cancer will wither. Any cancer, no matter what type, could be defeated by this single form of therapy, once implemented.

The Three Pillars of Immune System Rejuvenation

There are three vital initial components to the rejuvenation of the immune system, and this is a sufficiently important goal that there should be far more than the small number of companies presently working in this space. Firstly, the aged thymus must be regenerated in size and function; more competitors and more competing approaches than those of Repair Biotechnologies, Intervene Immune, and Lygenesis would be welcome. Secondly, a way to clear out and replace the damaged and malfunctioning cells of the aged peripheral immune system that does not involve the harsh, high-risk approaches of hematopoietic stem cell transplant and high dose chemotherapy. A kinder, more gentle targeted cell killing strategy that can be used in older, frail individuals is needed. Thirdly, the industry needs a way to introduce a new, functional, youthful hematopoietic stem cell population that, again, is kinder and more gentle than present transplant procedures, and can thus be used with older patients. Success in any one of these three will produce sizable gains, enough to help usher in the other two.

A Cell Therapy Platform to Reliably Deliver and Engraft New Stem Cell Populations

Stem cell decline is a major feature of aging. Existing stem cell therapies do little to nothing to address this issue. Aged stem cell populations must be supplemented or replaced with new, youthful stem cells. The surrounding niche and signaling must be adjusted to prevent the new cells from lapsing into inactivity. Platforms are needed that allow these goals to be achieved for arbitrary stem cell populations, or even just a majority of the most important stem cell populations. This is a path to delivering major gains in late life health and function.

An 80/20 Solution for Robust Gene Therapy

The community needs a gene therapy platform that works most of the time and for most tissues with minimal alteration, provides a high degree of cell coverage, and a high degree of configurable targeting by cell or tissue type. Perhaps this can be built atop the leading viral vector type, AAV, or perhaps it will emerge from some of the programmable gene therapy approaches, such as that of Oisin Biotechnologies. Regardless, it is very much needed. There is so much that could accomplished right now, today, it if wasn't necessary to build every new gene therapy completely from scratch, with years of work going into ways to obtain sufficient cell coverage, and to bypass the biggest obstacles, such as the patient's immune system. In the future, gene therapy will largely replace small molecule drugs for most uses - but that requires a great increase in the efficiency of development. The first 80/20 platforms that are good enough for most uses will drive the creation of an enormous amount of value.

Fix the Problems with Medical Tourism

Enhancement therapies, such as rejuvenation therapies, will be used by a hundred times as many people as presently undergo medical procedures. There are far more individuals who want to be enhanced than who have a medical condition and are at the point of needing treatment in the present system. The nature of the medical tourism industry will change dramatically given the much larger population of potential customers that will exist in a world of many novel enhancement therapies. There is an enormous opportunity here to solve the scattered, fraud-ridden nature of the existing marketplace, and to realize the full potential of regulatory arbitrage in responsibly bringing new therapies into trials and the clinic. Many companies present opt to take therapies into their first human trials in Australia because the cost is half or less of running through the standard process in the US or Europe. There is no reason why, in other jurisdictions, the cost couldn't be a tenth of that in the US and Europe, and a therapy deployed to the clinic entirely via medical tourism. That sort of competition is the only way to reduce the weight of the ball and chain of regulatory waste that holds back progress.

Methods of Outright Mitochondrial Repair

Loss of mitochondrial function occupies a central position in the declines of aging, implicated as a contributing cause of many age-related conditions. While mitochondrially targeted antioxidants that make the situation incrementally better are a going concern, with several products in the marketplace, much better approaches will be needed to deal with the issue of mitochondrial damage and decline with age. An implementation of the MitoSENS strategy of allotopic expression as a backup source of vital mitochondrial proteins, carried out for at least most mitochondrial genes, for example. Barring that, delivery of replacement mitochondria into tissues, perhaps engineered to be resistant to the signaling and damage that causes a general malaise in mitochondrial function and quality control. Or ways to robustly and completely restore the normal, youthful processes of mitophagy and mitochondrial fission in old tissues. This is a big problem and ambitious solutions are needed.

Comments

Two more ideas:
- Build a platform for developing new enzymes in the lab through evolution (to break down metabolic waste)
https://www.youtube.com/watch?v=05r-FLGtsEQ
- Create a cheap (as in <100$ material, sold for $500) senescent cell counting microscope using two smartphone cameras and sophisticated software.

Posted by: Matthias F at February 25th, 2019 1:20 PM

@Reason
Do you believe those topics are ready for commercialization ?
>A Competitor for Revel Pharmaceuticals in Glucosepane Cross-link Breaking
We need a proof of concept scientific work, and preferably, in-vivo. It sill doesn't guarantee that it could safely work in humans but would be ready for more commercial R&D.

>A Platform for Bacterial Enzyme Discovery to Break Down Metabolic Waste Targets
A lot of companies try to pitch platforms so much that it has become a marketing tool with questionable real-life applications. I would say if there is one single instance that works without the platform, , the platform methodology could be "harvested" from the working process.

>Start on Interdiction of Telomere Lengthening as a Universal Cancer Therapy
Is there a proof of concept that works in-vivo ?

ok. I will stop here because I already sound too negative...

Posted by: cuberat at February 25th, 2019 4:46 PM

We need a venture capital fund dedicated to anti aging start ups.

Posted by: Peter Christiansen at February 25th, 2019 4:55 PM

@Peter Christiansen: There are several.

Posted by: Reason at February 25th, 2019 5:13 PM

@Reason, I wish to add a platform for creating medical nanorobots, even simplest form. This is a shame that we have no even one contemporary computer program for simulate MN. We have enough technology for working in that area. We have enough computer power. We only lack initial framework. Which will play the same role like CRISPR in bioengineering.

Posted by: Ariel at February 25th, 2019 5:21 PM

@cuberat: Yes, ready to move to development in companies, which isn't quite the same as commercialization. Lack of in vivo proof isn't much of an obstacle for for-profit programs that will likely have gene therapy implementations, at least not in the present market.

Posted by: Reason at February 25th, 2019 5:23 PM

Another area that is just getting started is the 'circulating youth factors' in the blood of young animals. First to narrow down what the factor(s) are and then to up-regulate them.

I have been commenting on anti-aging blogs from 2000, and basically until a year or two ago we were speculating on pharmaceutical anti-aging companies that might exist at some point in the future.

Now several anti-aging startup companies have raised over $100 million, and are up to 'dozens' of employees. Next stop is companies that have raised over $1 billion, and get up to the 'hundreds' of full time employees.

Posted by: aa3 at February 25th, 2019 5:45 PM

In one of the links in the article you mentioned the DRACO antiviral. Any news there? I cannot believe this lead is not pursued - getting rid of viruses the same way we largely defeated bacteria with antibiotics would have enormous health benefits.

Posted by: Jamie_NYC at February 25th, 2019 8:44 PM

If you watched the movie of Spielberg "Back to the Future", then probably remember the rejuvenating skin. Something like this I dream to create. I also want to create an inhalation powder for treating pulmonary emphysema.
For this purpose, I want to use conditional cell reprogramming technology.
So far, this technology has been successfully tested only for in vitro experiments. However, there are prerequisites to use this technology in vivo. See my review, which focuses on the rationale for this approach based on available developments in this direction. For literature sources see: https://files.portalus.ru/files/1550000742.doc
The text is in Russian, but you can understand the essence by looking at the presented literature. All the necessary substances (Roxithromycin, Fasudil or Y-27632, Pirfenidone, LiCl, nicotinic acid and/or mixodil, recombinant human tropoelastin or gelatin - for the manufacture of adhesive polymerizable film or inhalation powder) have already passed clinical trials - it is only necessary to combine them in order to obtain synergy in vivo, and not in vitro as it is now in experiments.
The only substance not been approved in the clinic is Δ133p53α, a natural p53 isoform.
I am looking for those who will be able to realize my plans.
For contact, add to my group on facebook: Rejuvenation Science News (RSN)- https://www.facebook.com/groups/Rejuvsci/

Posted by: Dmitry Dzhagarov at February 26th, 2019 1:45 AM

An 80/20 Solution for Robust Gene Therapy.

Oisin's fusogenix lipid nanoparticles fuse with all cell membranes, but as I understand it the suicide capase is only activated in senescent cells wth a particular promoter present.

I don't know if you could just use different promoters to target different gene therapies to different cells?

Maybe targeting of specific cells based on cell surface proteins could be enabled by putting a protein or aptamer cap on the fusogenix proteins on the surface of Oisin's particles. An antibody to the cell surface protein of interest could be conjurgated to some form of enzyme that removes the caps on the fusogenix proteins, so that the nanoparticles only fuse wth the desired cells?

As a layman I don't really know how feasible any of that is?

Posted by: Jim at February 26th, 2019 1:47 AM

@Peter Christiansen; @Reason

No - there are actually no true venture capital funds focused on aging at all

Juvenescence and Life Biosciences are not venture capital funds in the traditional sense nor are they structured as such per the LP/GP model - they are acting more like holding companies which is a much different risk management proposition

Laura Deming's Longevity Fund is a drop in the bucket, at best considered a seed fund, and can do nothing more than "follow" other VC investors, throwing in a few $$ here and there into deals, but have no real impact on company direction

And the new Longevity Vision Fund seems to be not much more than a pr campaign from In-Silico - they are even are stealing SoftBank "Vision Fund" name

The field needs more real investors

Posted by: BioInvest99 at February 26th, 2019 5:28 AM

A start-up who is entering a drug on clinical phase 1 in 2020-2022 won't reach the market before the 2030s. Investors need fast return on investments. How can you tell someone to give millions/billions now but will win them back in 2035 at best ? I wonder if it is feasible to "create" an artificial "country" only for medical tourism, with almost no regulations so that people can get therapies once they cleared phase 1 toxicity.

Posted by: Jonathan Weaver at February 26th, 2019 6:08 AM

@Jonathan Weaver
Investors would be perfectly ok with 30 years Time to return the investment if it wasn't that risky. After all, the typical mortgage bonds have Merry over 25 years. That's why we need the first successful proof of concept in vivo with a good chance of working in humans.

For now rejuvenation research is akin looking for diamonds in a random plot. A single diamond can make you rich. But you have a very pour information on what your chances are. And yet you have the ongoing expenses to run the research.

When the first "gem" is "found" (near prospects of commercialization) it will attract attention and investors. There might be even a gold rush. Ultimately a gold rush scenario would waste funds compared to a steady investment but is still much better than nothing

Posted by: Cuberat at February 26th, 2019 8:06 AM

How is Revel Pharmaceuticles using synthetic glucose pane to find enzymes that break it?

Posted by: Jim at February 26th, 2019 8:44 AM

@Jim: Revel is quiet on their methods, but the approach is basically the same for any medical bioremediation discovery program. Create an environment in which the only food is the compound you want destroyed, dump in a mixed set of bacteria, and see what thrives. Then narrow it down from there.

Posted by: Reason at February 26th, 2019 10:33 AM

@ Dmitry, there is evidence that ROCK inhibition can work in vivo, as statins have been shown to have 'pleiotropic effects' such as anti-inflammation and telomere lengthening.

Posted by: Mark at February 26th, 2019 11:59 AM

Please don't forget Methuselah Foundation/Methuselah Fund. We are founding investors/incubators of the following companies thanks to our donors and investors:

Organovo (public)
Matchgrid (acquired)
Oisin (senolytics)
OncoSenX (cancer indications using Oisin tech)
Leucadia (Alzheimers)
Volumetric (microvascularization via carbohydrate glass bio inks and hi res stereolithographic printer (revenue stage))
Turn Bio ( makes old cells young again - really)
Viscient (human 3d tissues rather than mouse testing to more quickly/accurately deliver clinical interventions)
Repair Athero (large artery rejuvenation ie aorta etc) (Hi Reason!)

We believe each of these companies will make significant contributions to our mission success - sooner rather than later.

Posted by: david. gobel at February 26th, 2019 12:27 PM

@ David Gobel : What is the minimum amount to invest in the mFund ?
I'd love to invest but I'm certainly not a high net worth individual.

Posted by: Spede at February 26th, 2019 1:45 PM

@ David - I second Spede's question.

Posted by: Mark at February 27th, 2019 3:34 AM

"the industry needs a way to introduce a new, functional, youthful hematopoietic stem cell population that, again, is kinder and more gentle than present transplant procedures, and can thus be used with older patients. Success in any one of these three will produce sizable gains, enough to help usher in the other two "

We have pretty well got that via stem cell therapy for graft versus host disease-GVHD. Now in late stage 111. Accepted that the clearance of the existing immune system needs to be less traumatic. No reason why the stem cell graft should not be partial.

Posted by: JLH at February 27th, 2019 4:01 AM

Hi Spede and Mark! The Mfund had a $2,000,000 goal, and that was already achieved - so it is closed. I do recommend that you might contact Sergio@methuselahfund.com who manages our Mfund, and placements directly in our portfolio companies.

We are considering options for doing a follow on fund, but haven't yet decided our go forward vehicle design.

Posted by: David Gobel at February 27th, 2019 8:32 AM

@BioInvest99
Also don't forget Kizoo Technology Ventures.

@Jamie_NYC
It's a shame, but the DRACO guys aren't responding anymore since ~2017 and their website also isn't updated since then:
https://riderinstitute.org/blogs/news

Posted by: Nicolai at February 27th, 2019 3:04 PM

@Reason
A Platform for Bacterial Enzyme Discovery to Break Down Metabolic Waste Targets

Often ignored are antibodies targeting Bacterial Enzyme building up in the serum. The enzyme Asparaginase from bacteria Escherichia coli is the best example. A chemotherapy drug in the treatment of acute lymphoblastic leukemia as part of a multi-agent chemotherapeutic regimen used as early as 1974. Hypersensitivity is the result of antibodies produced against the enzyme. For patients who develop hypersensitivity to E. coli-derived formulations of L-asparaginase, the use of PEGylated or Asparaginase from bacteria Erwinia chrysanthemi (renamed Dickeya dadantii) is recommended. https://www.drugbank.ca/drugs/DB00023

For useful enzymes that break down harmful molecular waste in the human body, an alternative is shielding the enzyme from antibodies through encapsulation in red blood cells - for example Erytech Pharma for L-Asparaginase targeting multiple cancers and Rubius Therapeutics for Phenylketonuria (PKU) - PKU results in decreased metabolism of the amino acid phenylalanine and therefore the buildup of dietary phenylalanine to potentially toxic levels. Untreated, PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. Hence Break Down Metabolic Waste Targets.

Bacterial Enzyme = Antibodies in Serum of the patient = lost of therapeutic activity, with mild to severe side effects

Posted by: Denis Demarais at March 7th, 2019 7:43 AM

What we need is a fightaging.org venture capital fund.

Posted by: Tj Green at March 22nd, 2019 10:38 AM

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