Fight Aging!

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

Cellular senescence, an essentially irreversible arrest of cell proliferation, can be triggered when cells experience a potential risk for malignant transformation due to the activation of oncogenes and/or DNA damage. While eliminating aged or damaged cells by inducing senescence is an effective barrier to tumorigenesis, the accumulation of senescent cells (SCs) over time compromises normal tissue function and contributes to aging and the development of age-associated diseases. Often, SCs secrete a broad spectrum of pro-inflammatory cytokines, chemokines, growth factors, and extracellular matrix proteases, a feature collectively termed the senescence-associated secretory phenotype. These factors degrade the local tissue environment and induce inflammation in various tissues and organs if SCs are not effectively cleared by the immune system.

Studies have shown that the genetic clearance of senescent cells extends the lifespan of mice and delays the onset of several age-associated diseases in both progeroid and naturally-aged mice. These findings support the hypothesis that SCs play a causative role in aging and age-associated diseases and, importantly, highlight the tremendous therapeutic potential of pharmacologically targeting SCs. Consistent with these findings, we have shown that ABT-263 (navitoclax), an inhibitor of the antiapoptotic Bcl-2 family proteins, acts as a potent senolytic agent to deplete SCs in vivo and functionally rejuvenates hematopoietic stem cells in both sublethally irradiated and naturally-aged mice. Complementary studies from other labs have confirmed that the Bcl-2 protein family is a promising molecular target for the development of senolytic drugs. These studies further establish the concept that the pharmacological depletion of SCs is a promising, novel approach for treating age-associated diseases. ABT-263 was identified by screening a small library of structurally diverse, rationally-selected small molecules that target pathways predicted to be important for SC survival. By titrating their cytotoxicity against normal human WI-38 fibroblasts and ionizing radiation (IR)-induced senescent WI-38 fibroblasts, this targeted screen also identified the promising senolytic agent piperlongumine (PL); PL is a natural product isolated from a variety of species in the genus Piper. Here, we report the characterization of PL as a potential novel lead for the development of senolytic agents.

Selective depletion of SCs is a potentially novel anti-aging strategy that may prevent cancer and various human diseases associated with aging and rejuvenate the body to live a longer, healthier life. As such, several senolytic agents, including ABT-263, have been identified recently, demonstrating the feasibility of pharmacologically targeting SCs. However, ABT-263 induces thrombocytopenia, and it remains to be determined whether ABT-263 can be used to safely treat age-related diseases, since individuals may require long-term treatment with a senolytic drug. Thus, it is necessary to identify a safer senolytic drug. In the present study, we evaluated PL as a novel senolytic agent. PL induced caspase-mediated apoptosis in SCs and effectively killed SCs induced by IR, replicative exhaustion, or ectopic expression of the oncogene Ras. Unlike ABT-263, the precise mechanism of action by which PL induces SC apoptosis remains unclear. PL modulates the activity of many cell signaling and survival pathways in cancer cells, and a number of studies have investigated the mechanism of action by which PL induces apoptosis in these cells. Data from these studies may be translatable to PL-induced SC apoptosis because SCs and cancer cells share some common pro-survival pathways. In addition, mass spectrometry-based proteomic approaches using probes derived from PL could be used to identify direct molecular targets of PL in SCs. In this regard, novel anti-senescent protein targets and mechanisms of action could be identified, making it possible to develop promising novel classes of senolytic agents. Importantly, PL appears to be safe; the maximum tolerated dose in mice is very high, and it maintains high bioavailability after oral administration. Furthermore, our initial structural modifications to PL demonstrate that we can develop PL analogs with increased potency and selectivity toward SCs, supporting the use of PL as a lead for further drug discovery and development.