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.