Today's open access research paper outlines the discovery of yet another new candidate drug for the selective destruction of senescent cells. This is an increasingly popular research topic nowadays. Senescent cells perform a variety of functions, but on the whole they are bad news. Cells become senescent in response to stresses or reaching the Hayflick limit to replication. They cease further division and start to generate a potent mix of signals, the senescence-associated secretory phenotype or SASP, that can provoke inflammation, disarray the surrounding extracellular matrix structures, and change behavior of nearby cells for the worse. Then they destroy themselves, or are destroyed by the immune system - for the most part at least. This is helpful in wound healing, and in small doses helps to reduce cancer incidence by removing those cells most at risk of becoming cancerous. Unfortunately a growing number of these cells linger without being destroyed, more with every passing year, and their presence eventually causes significant dysfunction. That in turn produces age-related disease, frailty, and eventually death. Senescent cells are not the only root cause of aging, but they provide a significant contribution to the downward spiral of health and wellbeing, and even only their own would eventually produce death by aging.

The beneficial aspects of senescent cells seem to require only a transient presence, so the most direct approach to the problem presented by these cells is to destroy them every so often. Build a targeted therapy capable of sweeping senenscent cells from tissues, and make it efficient enough to keep the count of such cells low. That is the way to prevent senescent cells form contributing to age-related disease. Working in mice, researchers have produced results such as functional rejuvenation in aged lungs and extended life span through the targeted destruction of senescent cells. Since perhaps only a few percent of the cells in old tissue are senescent, this targeted destruction can be accomplished with few side-effects beyond those generated by off-target effects of the medication itself. There are a range of potential ways to destroy senescent cells while leaving other cells intact: the last twenty years of work on the basis for targeted cell destruction in the cancer research community has produced many useful tools. These include the programmable gene therapy approach adopted by Oisin Biotechnologies, immunotherapies of the sort under development by SIWA Therapeutics, and apoptosis inducing senolytic drugs of the sort championed by UNITY Biotechnology. This last category has a particularly close tie to the cancer research community, and in fact the senolytic drugs we know the most about, such navitoclax, also known as ABT-263, are well-categorized precisely because they have been trialed as cancer therapies in past years.

Senescent cells are in a sense primed for apoptosis, a process of programmed cell death. They need less of a nudge to finish that process than normal cells, and so a large number of the varied drugs that can induce apoptosis to some degree might have a future as plausible senolytic therapies. Cancer research groups have libraries of such compounds, many of which might turn out to be far more useful as senolytics than they ever were as cancer treatments. So we should expect to see a growing number of such drug candidates in the years ahead as various research groups and companies shake their archives to see what falls out. So far the first set of drugs, including navitoclax, are largely based on inhibition of bcl-2 family proteins, and have a range of unpleasant side effects. They are in effect chemotherapeutics, but it is likely that their use as senolytics will require lower doses than were used in cancer trials, but that remains to be established, however. The possible side-effects of repurposed chemotherapy drugs are one good reason to favor an approach like that taken by Oisin Biotechnologies, which is a treatment that has next to no side-effects, or at the very least to put more effort into finding drug candidates with alternative mechanisms and far fewer side-effects, as is the case in the research here.

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents