Senolytic compounds are those capable of selectively destroying senescent cells. They are useful because the buildup of senescent cells over time is one of the root causes of aging. A number of mechanisms have been discovered by which senescent cells can be provoked into self-destruction, such as bcl-2 inhibition or interference in FOXO4-p53 interactions. These examples are fairly well understood. Other mechanisms are known but less well understood; they require more work in order to proceed on the production of improved senolytic compounds.
In some cases, however, the primary mechanism of action of a compound found to be senolytic through experimental screening isn't yet known. The open access paper noted here is an example of how to move forward in this situation: the researchers report on their efforts to characterize the mechanism underlying the ability of piperlongumine to selectively destroy senescent cells. This line of work has been ongoing for a few years now; it takes time. Given sufficiently knowledge of the mechanism, however, it is usually possible to find or develop more effective candidate drugs in this family. Piperlongumine isn't perfect, and can be improved upon.
Cellular senescence occurs when irreversible cell cycle arrest is triggered by telomere shortening or exposure to stress. Senescent cells (SCs) accumulate if they cannot be removed rapidly by the immune system due to immune dysfunction and/or a sustained, overwhelming increase in SC production. This occurs during aging or under certain pathological conditions. Under these circumstances, SCs can be detrimental and play a causal role in aging, age-related diseases, and chemotherapy- and radiotherapy-induced side effects, in part through the expression of the senescence-associated secretory phenotype.
This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age-related diseases and disorders in both progeroid and naturally aged mice. Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti-aging strategy and a new treatment for chemotherapy- and radiotherapy-induced side effects.
However, a major challenge facing the discovery and development of effective senolytic agents is to identify and validate more senolytic targets. Since the first senolytic was published, twelve molecular targets have been identified. These findings led to the discovery of a few senolytic agents, but the clinical application of these senolytic agents for age-related diseases and cytotoxic cancer therapy-induced side effects may be limited by agent toxicity and manufacturing challenges.
Piperlongumine (PL) is one of a few natural products identified to have the ability to selectively kill SCs. Compared to other known senolytic agents, PL has the advantage of low toxicity, an excellent PK/PD profile, and oral bioavailability. However, its molecular targets and mechanisms of action are unknown. To facilitate the development of PL and its analogues as senolytic drug candidates, it is critical to identify PL molecular targets, which can form a molecular basis for the rational design of new PL analogues.
Herein, we report the identification and validation of oxidation resistance 1 (OXR1) as a molecular target of PL in SCs. OXR1 is a cellular oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes and modulates the cell cycle and apoptosis. We found that OXR1 was upregulated in SCs induced by ionizing radiation or extensive replication. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. Knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide (H2O2). These findings suggest that OXR1 is a potential senolytic target that can be exploited for the development of selective senolytic agents with improved potency and selectivity. In addition, these findings also provide new insight into the mechanism by which SCs are highly resistant to oxidative stress.