Now that clearing senescent cells as a therapy for aging finally has meaningful support in the research community, there is far more funding available to turn the wheels of the standard drug discovery and evaluation process. Researchers are in search of senolytic drugs, those that can kill senescent cells without harming normal cells. The process starts at first with an evaluation of the performance of each molecule in the standard compound libraries in cell cultures, in search of molecules that preferentially kill senescent cells. This can be automated to a fair degree, especially when the desired result is as black and white as destroying one distinctive class of cell. It is very similar to the sort of cancer drug screening that the research community has a great deal of experience in carrying out. At scale, this might cost a few dollars per molecule screened these days. In fact, the existing candidates for senolytic drugs have largely emerged from the cancer drug candidate databases, and were tested for their effects on cancer for some years without noticing their strong effects on senescent cells - it wasn't in the list of items to evaluate at the time.

Given the starting point of a few promising compounds, preferably already tried in animals and humans, and thus with decent pharmacology data, researchers then branch out to examine other chemically similar compounds. It is usually the case that a better version with greater primary effects and lesser side-effects can be established one way or another. The level of work to achieve that end varies greatly, however, ranging from finding another well-characterized small molecule drug candidate in the archives to the researchers having to carry out all of the work to model and synthesize a novel molecule and prove it to be effective. It is usually the case that researchers and developers are far more willing to push ahead with a suboptimal compound that is already fairly well tested than to work with a less well explored but potentially better compound. Nonetheless, in theory the competition in the system weeds out worse drugs in favor of better drugs, though that process may never seem as efficient in practice or as fast as we'd like it to be. Personally, I'd like to see more funding going towards the sort of programmable gene therapy pioneered by Oisin Biotechnologies, a better approach than mining cancer chemotherapy drugs in search of those with side-effects that are minimal enough for patients to accept.

Then it is on to animal studies, starting companies, and human trials, the standard process for moving forward with the development of new medicine. Many candidates will turn out to be not so useful in human medicine, others will pass all the way through. Insofar as senolytic drug discovery goes, all of the groundwork has already taken place for a number of cancer drug candidates that can promote apoptosis in senescent cells, such as navitoclax and dasatinib, some of which are being carried forward into clinical trials by UNITY Biotechnology. In animal studies, these appear to remove on the order of 10-50% of senescent cells in a single course of treatment, varying widely by tissue type. The research community isn't resting on its laurels, however, and is turning up new candidates on a fairly regular basis at the moment, such as piperlongumine. The paper below offers another few candidates for consideration, though I would say that they are less interesting in and of themselves at this stage, but rather as an indication that we should expect the list of potential drugs to expand quite rapidly in the next few years, and hopefully the quality of the best candidates along with it.

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463