Senolytic treatments selectively destroy senescent cells, and several different approaches have been shown to produce some degree of rejuvenation in mice: reversal of measures of aging; reversal of the progression of specific age-related conditions; extension of life span. Most of these initial senolytics are repurposed pharmaceuticals drawn from cancer research databases, with the exceptions being the engineered peptide FOXO4-DRI, the suicide gene therapy developed by Oisin Biotechnologies, and SIWA Therapeutics' immunotherapy. Where animal study data has been published, the results produced by these varied senolytics are remarkably similar: up to 50% clearance of senescent cells from old tissues in mice, varying widely from tissue to tissue.
One of the repurposed pharmaceuticals is dasatinib, a drug already approved by the FDA for cancer treatment, with a sizable amount of human data by which we can judge side-effects and safety. Dasatinib is a generic drug that is mass produced by numerous manufacturers worldwide, whether with or without approval from the US government, and as a consequence it costs very little. This presents an interesting challenge for those companies attempting to produce senolytic therapies, as new treatments must run through clinical trials at enormous expense. In addition to proving new drug candidates or other classes of treatment, these trials will also provide supporting evidence that will allow physicians to prescribe off-label use of dasatinib at a tiny fraction of the cost that must be charged for new therapies in order to recoup development expenditure.
The principals of senolytic development companies will thus find themselves needing to produce treatments that can clear senescent cells far more effectively than the dasatinib and quercetin combination therapy. Even given the choice between a $100 drug that can clear 50% of senescent cells versus a $20,000 drug that can clear 80% of senescent cells, a company might struggle to obtain the desired level of sales over the long term. Though in fact the situation is more complex than this overly simplistic example, given the variability of results tissue by tissue, and there will be room for senolytics that turn out to be better for the heart, or lungs, or specific other organ than the competitors. But still, you see the challenge. This is particularly problematic for small molecule development, in which it is very expensive, uncertain, and time-consuming to attempt to improve specific aspects of an existing family of drugs. It is by no means certain that small molecule developers such as Unity Biotechnology will be able to produce drugs that are better enough to justify the price premium over dasatinib.
Dasatinib provides a certain degree of sink or swim encouragement to do better, but this pales before the state of affairs that will result should piperlongumine turn out to be senolytic to much the same level in mammals. Which may well be the case, given recent data, but nothing is yet proven in certainty. If piperlongumine is in fact approximately as good at removing senescent cells as the dasatinib and quercetin combination, then this discovery will unleash the dietary supplement industry and in short order allow them to become the major players in the senolytic marketplace, rather than merely a gaggle of hopeful onlookers. Piperlongumine is a plant extract, a natural product that is regulated in a completely different way from small molecule drugs and other medical biotechnologies. It costs far less in time and funding to bring a new natural product to the marketplace, and the resulting supplements are as a result far cheaper than medicine. Given effectiveness for piperlongumine, established dietary product concerns will be selling low-cost senolytics to much of the world well prior to the point at which the first expensive senolytic therapies emerge from the FDA regulatory process.
One could argue that this particular vision is unlikely to come to pass on the basis that the other potentially senolytic categories of natural product are not in fact capable of killing enough senescent cells to be worthy of the name. The flavonoid quercetin, for example, doesn't do much on its own. Certainly not enough to be an alternative to a real senolytic, no matter how cheap it might be. Is this a valid argument to direct at piperlongumine? Maybe so, maybe not. We shall see when the data arrives. Anyone with a few hundred thousand dollars to invest could run the necessary mouse studies to prove or disprove the senolytic capacity of piperlongumine, and that is not a large number in comparison to what it requires to build a new supplement manufacturing and distribution business. Given this, one might wonder whether or not anyone in the industry is already working on this project.
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