Request for Startups in the Rejuvenation Biotechnology Space, 2020 Edition

This is the latest in a series of yearly posts in which I suggest areas of development for biotech startups I'd like to see actively developed as a part of the longevity industry in the near future. Today, this year, is a good time to be starting a company focused on the production of a novel therapeutic approach to intervening in the aging process. There is a great deal of funding for seed stage investment, and many compelling projects lacking champions, yet to be carried forward from academia into preclinical development. Numerous scientific and industry crossover conferences are now held every year, at which it is possible to meet a mix of entrepreneurs, scientists, and investors, all interested in advancing the state of the art. The industry, and its pool of potential funds for later stage investment, are both growing rapidly, driven by the energetic activities of patient advocates such as Aubrey de Grey and activist investors such as Jim Mellon and his allies. The public at large is becoming ever more aware of the potential to change the progression of aging. This will become a very large industry in the years ahead, and rejuvenation will eventually become the largest portion of medicine as a whole. There is tremendous opportunity here, both for returns on investment, and to change the human condition for the better.

A Viable Approach to Medical Tourism for the Era of Rejuvenation Therapies

Rejuvenation therapies, by their nature, have a far greater market size than any existing medical technology intended to treat the clinically ill. Many more people will undergo rejuvenation treatments than presently undergo medical procedures or take medications. This opens the door for radical change and improvement in the poorly organized, scattered, and unhelpful medical tourism industry. A population of potential customers an order of magnitude larger than is the case today is a great opportunity for any company to successfully smooth the road of regulatory arbitrage, allowing people in restrictive regulatory regions to effectively make use of reputable services available in other countries. The first rejuvenation therapies already exist, but discovery, validation, and access are all challenging. There is considerable room for improvement.

Restoration of Hematopoietic Stem Cell Function

Hematopoietic stem cell populations are responsible for producing blood and immune cells, as well as other important cell types, such as endothelial progenitor cells that help to maintain blood vessel integrity. All of this degrades with aging, but the standard approach to bone marrow transplantation, involving chemotherapy to destroy existing stem cells, is too harsh to be used as a basis for any therapy based on replacement of cells. There are potential alternatives, however, a fair number of them. For example, mobilizing stem cells to leave the bone marrow produces enough spare room in stem cell niches to allow a meaningful fraction of transplanted stem cells to engraft, resulting in extension of life and improved function in mice. The function of the immune system is so vital in aging that treatments to restore hematopoiesis are of great importance.

A Low Impact Method of Destroying the Peripheral Immune System

The peripheral immune system becomes cluttered with senescent and dysfunctional cells with advancing age, one of the numerous issues that must be addressed in order to repair an aged immune system. There is plenty of evidence for the selective destruction of specific dysfunctional cells to be beneficial. The entire B cell complement can be cleared to remove dysfunctional and harmful B cells, for example. The lost B cells are quickly replaced with functional B cells even in later life. What is needed is a way to clear out the peripheral immune system in entirety without undue side-effects, a form of therapy that should be useful not just to clear out the problem cells from an aged immune system, but also to effectively treat autoimmune disease. This goal can at present be accomplished via the application of high dose immunosuppressive drugs, but with significant side-effects that make it unsuitable for widespread use in a frail population. Thus something akin to suicide gene therapies or other targeted means of low-impact cell destruction is needed instead.

Build a Physician Network to Bring Low-Cost Senolytics to the Masses

The evidence for dasatinib and quercetin to meaningfully clear senescent cells, one of the causes of degenerative aging, is presently compelling. Soon we will know whether or not fisetin performs well in humans. All of these substances cost little. As yet, only a few groups are trying to build physician networks or services that will deliver these and other actual or potential senolytic treatments to patients. To my eyes this is an important exercise in logistics and exercising the right to off-label use of approved drugs. Functional senolytics have the capacity to greatly improve the state of health for every older person, and it is reasonable to believe, based on the evidence, that at least a few of the portfolio of potentially senolytic low-cost drugs and supplements can achieve this goal right now. Yet they are not being widely used. Tens of millions of patients in the US alone are suffering when their situation could be improved. At the very least, many more people should be made aware that senolytics exist, so as to be able to make a decision based on present evidence as to whether or not to try this form of therapy.

A Competitor for Revel Pharmaceuticals in Glucosepane Cross-link Breaking

Persistent cross-links between extracellular matrix proteins are likely very influential on both late life mortality, due to stiffening of blood vessels and consequent hypertension, and on the loss of elasticity in skin, a sizable component of skin aging. One of those topics is much more important than the other, but, as any survey of the community will tell you, opinions differ on which one it is. The market size for methods of reversing either outcome of aging is very large, and breaking cross-links is a plausible way forward given what is known of their biochemistry. Revel Pharmaceuticals is presently the only startup biotech company working on development of ways to break down the primary form of persistent cross-link in human tissues, those based on glucosepane. Competing with Revel in the discovery of compounds that can break glucosepane cross-links is a very feasible prospect: this part of the field is presently at the same point that senolytics were five to ten years ago, and most likely has a similar trajectory ahead of it.

Interfere with Telomere Lengthing to Defeat All Cancers

The requirement for telomere lengthening is the Achilles' heel of cancer. All cancer cells must abuse at least one of the two available mechanisms of telomere lengthening, telomerase and alternative lengthening of telomeres (ALT), in order to continue unfettered replication. Successfully sabotage this process and any cancer will wither as a result, no matter how advanced it is in its progression. This is truly the best basis for the development of a single, universal cancer therapy, and numerous potential approaches exist at various stages of development. Some have made it to the point of preclinical work, such as the program at Maia Biotechnology, but most have yet to make the leap from academia to industry. There is considerable opportunity here to revolutionize the treatment of cancer.

Break the Link Between DNA Repair and Epigenetic Change

One of the more interesting of recent discoveries in the field of aging research is that DNA double strand break repair causes epigenetic changes characteristic of aging. This opens the door to investigations of the intricate and complex DNA repair mechanism of the cell nucleus, in search of points of intervention that might stop this process of epigenetic change from occurring, or slow it down, or perhaps even reverse it. A sizable literature on DNA repair exists, and this part of our biochemistry is comparatively well mapped. Somewhere in there are the starting points for therapies that might be very influential on the state of degenerative aging - perhaps the basis for reversing epigenetic changes and cellular dysfunction in ways other than the approach of in vivo reprogramming that is growing in popularity.

Restore Lost Mitochondrial Function to a Much Greater Degree than can be Achieved via NAD+ Upregulation

At present NAD+ upregulation is a popular topic, as is the application of mitochondrially targeted antioxidants. Both approaches appear to sufficiently restore the quality control mechanism of mitophagy in old cells to allow some degree of restored mitochondrial function throughout an aged body. How sizable is the effect? In the same ballpark as exercise, judging from the few small human trials conducted to date, focused on the cardiovascular system: blood pressure, blood vessel compliance, vascular smooth muscle function, pulse wave velocity. We might take this as an encouraging sign that if mitochondrial function was actually fully restored, the benefits could be sizable. There are any number of possible approaches that might prove to be much more effective than NAD+ upregulation: tinker directly with gene expression changes that appear to impair mitophagy; epigenetic reprogramming in vivo; delivery of whole mitochondria to tissues; targeted destruction of damaged mitochondrial DNA; and so forth. Any group able to demonstrate significantly better outcomes in animal models than have been obtained from NAD+ upregulation should have no issues in raising funds for commercial development.

Restore a Youthful Human Gut Microbiome

Work on the human gut microbiome and the changes that take place with age has picked up considerably in past years. A number of groups have identified specific metabolites that are produced at lower levels by the aged microbiome, as well as changes in the balance of beneficial and harmful gut microbes that lead to greater chronic inflammation. In animal studies, transplantation of a young microbiome into old animals results in a lasting restoration of the microbiome in those older animals. In human medicine, fecal microbiota transplantation is well developed for use in a number of pathological conditions. It has not yet been applied to aging, but it should, or variants that dispense with the donor and just provide the appropriate mix of microbes directly. Further, it is not unreasonable to build probiotic-like treatments that deliver the right mix of microbes in sufficient volume to achieve the same effect. Given the diverse influences of the gut microbiome and the metabolites it produces, this may be a way to meaningfully reduce chronic inflammation, restore stem cell activity, and generally improve health in older people.

Reverse the Loss of Capillary Density with Age

Capillary density declines throughout the body with advancing age, reducing delivery of oxygen and nutrients, and thereby leading to dysfunction in cells and tissues, particularly in the energy hungry brain and muscles. The underlying causes of this manifestation of aging are not well understood, but the processes of angiogenesis in general, the regulatory mechanisms governing generation of blood vessels, are fairly well explored. There is an opportunity here to take what is known and apply it to this challenge. Approaches that restore lost capillary density may prove to be a useful means of reversing the loss in tissue function that occurs with age, but it requires a successful methodology to be demonstrated in at least animal models in order to understand just how useful. Loss of capillary density is directly implicated in neurodegeneration and heart failure, providing well-understood indications to target for any company working towards this form of repair biotechnology.

Comments

Extracorporeal shockwave therapy has been demonstrated to promote angiogenesis.

Extracorporeal Shock Wave Therapy for Coronary Artery Disease: Relationship of Symptom Amelioration and Ischemia Improvement
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765327/

Interesting but less relevant because it is in a mouse model.
Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474945/

Also
Cellular Signaling Pathways Modulated by Low-intensity Extracorporeal Shock Wave Therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587965/

One advantage of extracorporeal shock wave therapy at lower levels, below that used in lithotripsy, is it can be self-administered.

Posted by: anonymous at February 17th, 2020 5:13 PM

The technology to clear out B cells already exists - car T cell therapy targeting the cd19 receptor.

Cytokines release syndrome cancer be counter med with car T cells that can be expanded in response to a drug to allow a slow increase in dosing, or by having receptors that bind to a specific antibody allowing dosing that way. The cells can then be destroyed using a built in suicide gene. I'm surprised this is not in clinical trials already?

Posted by: Jimofoz at February 17th, 2020 5:19 PM

Car T cells against specific autoantibody producing B cells are already in phase 1 trials:

https://cabalettabio.com/pipeline/

Posted by: Jimofoz at February 17th, 2020 5:22 PM

A bit off topic, but I was surprised to see this editorial on Russia Today opposing classifying aging as a disease considering how supportive Russia has been towards life extension:

https://www.rt.com/op-ed/481011-old-age-who-disease/

Posted by: Corbin at February 17th, 2020 6:39 PM

@Corbin

Didn't one of the Russian ministers say that in theory humans can live up to 200 years?
... Just before raising the retirement age..

Posted by: Cuberat at February 17th, 2020 6:52 PM

regarding telomerase, inhibiting it will also kill stem cells and thus significantly shorten life span and health span. The solution? Use substaces that selectively inhibit it only in cancer cells. But if you can target cancer so selectively, there are more effective cancer killers than telomerase inhibitors. Or use substances that work as strong telomerase inhibitor on cancer cells and telomerase enhancer on healthy cells, like sylibinin or baicalin. As SASP already inhibits telomerase (by TGFBeta) and thus incresses greatly cancer risk, telomerase inhibition as as a cancer cure seems as a failure by design. By the same token combination of even week telomerase enhancers combined with anti SASP cures like senolytics have the potential greater than anyone suspects. Such combination occuring naturally in herbs produced countless number of super centenarians living up to 110-120.

Posted by: SilverSeeker at February 18th, 2020 3:42 AM

"The industry, and its pool of potential funds for later stage investment, are both growing rapidly, driven by the energetic activities of patient advocates such as Aubrey de Grey and activist investors such as Jim Mellon and his allies. "

This is just flat out not true - there are NO funds for later stage investment, specifically targeting aging, in this space

While there has been more seed stage activity, later stage private equity is still quite nascent - of course there are later stage private equity groups that participate in rounds to develop therapeutics for targeted diseases, but if you ask them what they feel about aging as a specific condition, you get a very different answer

Juvenescence, LifeBiosciences, even Calico, are NOT true private equity funds, but holding companies, which is a very different model - they should not be included as perspective pools of later stage capital for young companies starting up

The valley of death in this space is real and growing, which make it still a highly risky area

On a related note:

Jeff Bezos - a few million $$ into Unity

$10 billion into climate change

Get the point yet???

https://www.npr.org/2020/02/17/806720144/jeff-bezos-pledges-10-billion-to-fight-climate-change-planets-biggest-threat

Posted by: don dagle at February 18th, 2020 5:18 AM

@SilverSeeker, do you have any references for this life extension from herbs in supercentenarians?

Posted by: Morpheus at February 18th, 2020 9:49 AM

Jim Mellon only gave a ridiculous amount compared with his fortune, like Thiel or Bezos as don dagle said. But Reason is closer to this field and maybe knows things we don't ...

Posted by: Pierre at February 18th, 2020 9:50 AM

@Pierre

Correct about Mellon - he has been for the most part using "other peoples money" as opposed to making major risk investments himself

Nothing intrinsically wrong with that (VC 101) but he is far from "all in" committed to the space

Posted by: don dagle at February 18th, 2020 10:39 AM

While this isn't (yet) a competitor to Revel Pharmaceuticals, here's a competing idea about how to break crosslinks from Dr. Christian Schafmeister: "We are developing 'therapeutic catalysts' - small, robust, non-immunogentic catalysts that will permeate the tight spaces within tissues and fix things. Our specific targets include reversing the unwanted cross-links that develop in the extracellular matrix with aging."

https://www.undoing-aging.org/news/dr-christian-schafmeister-to-speak-at-undoing-aging-2020

Posted by: Florin at February 19th, 2020 1:02 PM

It would be nice to see some work on mast cells in neurodegenerative diseases and aging in general, but I suppose at this point more basic science research is needed.

Posted by: CD at February 22nd, 2020 10:20 AM

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