For some years now, I've offered a yearly set of suggested projects for new startups in the rejuvenation biotechnology space. Or, alternatively, it might be viewed as a series of lengthy complaints about the slow pace of process towards human rejuvenation, given the many opportunities that exist. That slow pace is particularly galling in the case of the lowest-hanging fruit, a range of therapies that have been practical to carry out for at least a few years now, and yet have still not been meaningfully assessed for their ability to produce at least some degree of rejuvenation in aged humans. Given that the level of funding available to for-profit and non-profit ventures in the treatment of aging has increased dramatically in the last year, it is coming time to be much more aggressive about setting up and running clinical trials.
No More Reprogramming Startups for a Few Years
An enormous amount of funding is now devoted to the topic of in vivo reprogramming of cells. Altos Labs and NewLimit alone represent more than three billion dollars of interest. All of the important questions that stand open on the topic of cellular reprogramming as a potential path to rejuvenation are likely to be answered in the decade ahead. If you have an interest in starting a venture to advance the state of the art, pick another promising area that needs support and funding to make progress.
Elements of an Alternative Clinical Trial Ecosystem
In the last few years, scores of low cost clinical trials for age-related diseases could have run for the existing senolytic treatment of dasatinib and quercetin alone. Those trials have not been undertaken largely because there is not enough profit in this to interest large players in the industry. It takes so much funding to achieve regulatory approval that many therapies are simply not economically viable. Then we have Khavinson peptides for thymic regrowth, gut microbiome rejuvenation via a few different methods, and other comparatively straightforward approaches likely to improve health in late life, and which are also lacking the low cost clinical trials needed to produce convincing demonstrations of efficacy. This, again, is largely because it is seen as challenging to make enough profit from these interventions to justify the cost of regulatory approval.
Yet the component parts of a separate, parallel ecosystem of simple proof-of-efficacy trials and treatment via medical tourism that can successfully operate at a fraction of the cost of the formal regulatory system in the US and Europe all exist today: clinics; funding organizations; alternative credible regulatory systems in smaller countries; many people interested in seeing progress. Such an alternative could carry forward these and other potentially useful therapies, those that are suppressed by the economics of regulation in the US and Europe. It has yet to be stitched together into a functional whole, and to do so would be a worthwhile achievement
Rejuvenating the Gut Microbiome
Rejuvenation of the gut microbiome produces large enough effects on life span in short-lived species to suggest that it is interesting to pursue in humans, given how little the various demonstrated approaches cost, and how ready they are to proceed immediately to the clinic. Fecal microbiota transplantation and flagellin immunization are not complex technologies, but we do lack initial clinical trials to show robust benefits in older people. These trials would not be costly to run in a hundred people or so, considered in the grand scheme of things, and success in reducing age-related inflammation and improving other measures of health would enable a variety of business models.
Prove the Merits of the Khavinson Peptides
Various forms of the Khavinson peptides have been used in Russia for quite some time. Some are shown to regrow the atrophied thymus in aged animal models, thereby improving immune function. Some have caught the eye of the small community of self-experimenters that uses peptides in the hope of obtaining health benefits. The published Russian data on reduction of mortality in aged human patients is interesting, though lacking sufficient assays to support thymic regrowth or immune restoration. It is nonetheless perhaps enough to think that where there is smoke there is fire. One could start a clinical company given good results in human trials in the US or Europe, and it would not be excessively expensive to run a trial with a few hundred participants.
Deliver Proven Senolytics to the Masses
It has been several years since the combination of dasatinib and quercetin was shown to reduce senescent cells in humans in much the same way as it does in mice. The animal data continues to roll in, showing impressive reversal of age-related pathology in models of many conditions. Yet the research community is conducting very few clinical trials, and those under way are slow to publish. Dasatinib and quercetin are cheap and can be used legally off-label. There is nothing standing in the way of the formation of a physician network and clinical businesses that provide senolytics to patients. Running small, low cost, rapid trials to prove efficacy and confirm the known safety profile in humans would pave the way to bringing the first senolytic drugs to many of the older people who could benefit.
A Validated Consensus Clock for Biological Age
Clocks to assess biological age are proliferating rapidly. None can yet usefully be applied to the only task that really matters, which is assessing how well a candidate rejuvenation therapy works in practice. This is because no-one understands how specific underlying mechanisms of aging produce specific epigenetic, transcriptomic, or proteomic changes. Without that connection, the only way to validate a clock for a specific class of therapy is to run calibrating life span studies. Without that calibration, the data produced by a clock is of little value, because it is unknown as to whether the clock accurately integrates the contribution of the mechanism of aging targeted by the rejuvenation therapy under evaluation. This is a problem that is blocking the entire industry; rapid assessment of rejuvenation therapies is desperately needed in order to optimize progress.
Restoring Youthful Elastin Structures
Elastin structure is complex and degrades with age, leading to tissue stiffness. Elastin is largely only laid down in skin and other elastic tissues during the developmental period of life. To restore this structure it will most likely be necessary to enlist cells to undertake the task in the same way as they did during early life. This may be quite the challenge, requiring reprogramming, manipulation of regulatory pathways, and greater knowledge of the biochemistry of elastin deposition. But it is very important. Loss of elasticity in skin is just the visible sign of far worse consequences inside the body.
More Cross-Link Breaking, and More Variety in Approaches to Cross-Link Breaking
The only near term path to finding out just how important cross-linking is in vascular aging, and other aspects of aging in which the structural properties of tissue change with time, is to develop and test a therapy that breaks persistent cross-links. This is not a well populated area of development: there is Revel Pharmaceuticals targeting glucosepane cross-links, the Novartis program targeting a specific form of cross-link that occurs only in the lens of the eye, and that is about it. There is plenty of room for competition, particularly in the type of approach taken to break down this unwanted, harmful molecular waste.