ABT-737 is Another New Senolytic Drug Candidate, Working via BCL-W, BCL-XL, and Induced Apoptosis

Our friends at fightaging have posted about another new Senolytic ABT-737 which we have talked about before here but this is a more detailed article covering the potential of this second generation BCL inhibitor and its potential for clearing senescent "death resistant" cells more efficiently than previous candidates. Needless to say MMTP is keen to test ABT-737 and we will be adding this drug to our combination testing in our subsequent testing rounds. Anyway the article by Reason from fightaging is below and gives a good account of the progress being made in the field of senolytics;

Senolytic therapies are those that cause senescent cells to die while causing minimal side-effects. Developing methods to selectively destroy senescent cells has been on the SENS rejuvenation research agenda for going on fifteen years, based on strong evidence from many fields, but only recently have factions within the broader research community started to pick up on this approach to treating one of the causes of aging. Over the past two years a tipping point of sorts was reached and passed, and now a number of drug candidates are emerging from research groups, and the startup Oisin Biotechnologies has a more selective gene therapy approach to achieve the same aim. The open access paper I'll point out today describes one of these candidates, along with animal data that shows it destroying between a quarter and a half of senescent cells in a few tissues. This is on a par with the performance of some of the other candidates that have produced improved measures of health in mice.

Why destroy senescent cells? Because they help to make us old. Cells become senescent in response to reaching theHayflick limit to the number of divisions, or when suffering damage, especially DNA damage likely to produce cancerous mutations, or a toxic local environment that seems likely to produce that sort of damage. Senescent cells cease to replicate and most self-destruct via apoptosis, or are targeted by immune cells for destruction. Some linger however, secreting a problematic mix of signals that induce inflammation and remodeling of tissue structures, while also encouraging neighboring cells to become senescent. As the years pass ever greater numbers of these cells cause ever greater disarray, contributing meaningfully to the development and progression of all common age-related diseases, and ultimately the tissue and organ failures that cause death. If all senescent cells were periodically removed, however, never permitted to assemble in large numbers, then this part of the aging process would be eliminated, the span of healthy life extended, and age-related disease pushed off that much further into the future. This has been demonstrated in a life span study in mice, in which continuous senescent cell removal via genetic engineering produced a 25% extension of median life span.

How to destroy senescent cells? In past years, I predicted that targeted therapies like those under development in the cancer research community would be used, combining a smart detector of cell chemistry that delivers a not-so-smart kill mechanism, but only to specific cells. At present immunotherapies are the best of these, but there are also selective viral therapies, and others involving nanoparticles. As it turned out, however, all of the more advanced techniques for destroying senescent cells are not targeted at all, and focus on inducing apoptosis, a path to destruction that these cells are already primed to take in comparison to a normal cell. A gentle nudge to the right cellular pathways, such as by increasing or reducing the levels of proteins relevant to apoptosis, will be ignored by near all cells other than those in a senescent state. There, however, it can be enough to tip them over the edge in large numbers. So a senolytic therapy can be delivered generally without targeting. Interestingly, inducing apoptosis is a long-standing line of work in the cancer research community, so there are already stables of drug candidates to explore for use in destruction of senescent cells. If recent deals are any indication, we'll probably see a lot of cross-pollination between these fields in the next few years. Aside from that, a lot of the recent work on senolytic drugs has focused on bcl-2 inhibitors capable of reducing levels of bcl-2bcl-xl, and bcl-w, all of which act in various ways to suppress apoptosis. This latest published research is along these lines:

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL