Senolytics: Navitoclax

ABT-263 aka Navitoclax is confirmed as a Senolytic by a second research group

I reported previously about the ABT-263 drug aka Navitoclax and the promising results hereNow another collaborating research group, previously involved in identifying dasatinib and quercetin as a senolytic drug combination has published results from testing the same drug candidate ABT-263. Navitoclax is an experimental orally active anti-cancer drug that also acts as a senolytic agent that targets Bcl-2 and related proteins. These proteins regulate apoptosis, or programmed cell death. Senescent cells should in theory enter apoptosis or are detected by the immune system and are destroyed by them failing that, however, as we age the immune system becomes increasingly poor at removing senescent cells and their numbers build up. By targeting Bcl-2 the therapy can push senescent cells already close to apopotosis over the edge causing them to die making this a viable approach to clearing senescent cells from the body. 

"Senescent cells contribute to age-related diseases. Much like cancer cells, senescent cells are resistant to poptosis, potentially protecting them from their own pro-inflammatory secretions, reactivemetabolites, and activated DNA damage response. They are instead eliminated by the immune system. We therefore hypothesized that senescent cells depend upon anti-apoptotic defenses similarly to cancer cells. Indeed, our analysis of the transcriptome of senescent human preadipocytes identified pro-survival pathway up-regulation."

"Here, we tested if the Bcl-2 family inhibitors, navitoclax and TW-37, are senolytic. Like the combination of dasatinib and quercetin, navitoclax is senolytic in some, but not all types of senescent cells: it reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, TW-37 had little senolytic activity. Navitoclax targets Bcl-2, Bcl-xl, and Bcl-w, while TW-37 targets Bcl-2, Bcl-xl, and Mcl-1. The combination of Bcl-2, Bcl-xl, and Bcl-w siRNA's was senolytic in HUVECs and IMR90 cells, while combining Bcl-2, Bcl-xl, and Mcl-1 siRNA's was not. Susceptibility to navitoclax correlated with patterns of Bcl-2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to navitoclax. Thus, navitoclax is senolytic and acts in a potentially predictable cell type-restricted manner."

The researchers conclusion is very encouraging indeed for this new class of drugs and the methods and efficacy will no doubt improve in the near future. The removal of senescent cells has long been proposed as a method to treat aging dysfunction by SENS Research and indeed is part of their ApotoSENS strategy and one of the seven forms of damage/dysfunction aging causes. The researchers here conclude with some very positive words:

"Senolytics could be valuable in treating disorders related to senescent cell accumulation, e.g.,atherosclerosis, chronic obstructive lung disease, idiopathic pulmonary fibrosis, osteoarthritis, diabetes,kidney dysfunction, dementias, and neurodegenerative diseases. It appears that the senolytics described so far are limited in the senescent cell types they can target, underscoring the value of testing each cell type involved in particular diseases of interest as part of the senolytic drug development process. We speculate that it may be possible to base selection of senolytic drugs for a particular disease indication on the molecular profiles of the types of senescent cells that underlie that disease. Furthermore, combination treatments for certain indications involving multiple senescent cell types may be optimal in some cases. Overall, our findings support the feasibility of using our hypothesis-driven, bioinformatics-based strategy to develop more, perhaps better senolytic agents. Furthermore, it appears feasible to develop senolytic agents that target senescent cells of a particular type, in a particular tissue, or for a particular indication."

The MMTP is interested in applying such inteventions to lifespan studies and also combinations with other interventions eg, stem cell replacement or rejuvenation to see if powerful synergies can be discovered.