Combining BCL-2 Family Inhibitors May Yield More Effective Senolytic Therapies

Senolytic therapies are those that can selectively destroy senescent cells. Clearance of the lingering senescent cells in old tissues has been shown to produce a sizable degree of rejuvenation in animal models, extension of healthy life span, reduction in chronic inflammation, and reversal of aspects of various age-related conditions, some more so than others. The various small molecule senolytic drugs work by stressing senescent cells, or by inhibiting the mechanisms by which senescent cells resist the fate of self-destruction via apoptosis. Senescent cells are primed to enter apoptosis, and only a few lynchpin proteins and their interactions prevent this from happening.

It is suspected that there are sufficient differences between subtypes of senescent cell to make combination senolytic therapies much better than the use of single drugs. Targeting multiple points of intervention in the anti-apoptosis machinery of senescent cells should in principle kill a larger fraction of such cells than targeting any one specific part of these mechanisms. The research community is largely quite reluctant to investigate combination therapies, however, and the industry of medical development is even more so. The incentives placed on research and development by the intersection of regulators, investors, and intellectual property law make it difficult for initiatives intending to use combination therapies to even get off the ground. At present the largest such efforts are funded by philanthropy, and small in comparison to the scope of work that might be usefully undertaken.

Still, a few projects do take place, usually with little funding and a modest scope. Today's open access paper is one such example, in which the authors report on in vitro experiments combining different senolytic compounds that inhibit various members of the BCL-2 family, involved in protecting senescent cells from apoptosis. The researchers convincingly note the existence of senescent cells resistant to the BCL-2 family inhibitor navitoclax due to high expression levels of a BCL-2 family protein that navitoclax does not interact with; these cells can be killed by a different BCL-2 family inhibitor that does interact with that problem protein. We should expect to find that this sort of biochemistry is prevalent in the senolytic space, a good argument for, sooner rather than later, combining senolytic therapies for greater benefit to patients.

Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

Cellular senescence, a complex cellular response to stress characterized by a halt of cell cycle progression, is one factor contributing to aging and age-associated diseases. It is believed that selective elimination of senescent cells can lead to rejuvenation of the aged organism and increase the healthspan, and as a result, clearance of senescent cells can serve as a therapeutic approach to combat many negative aspects of aging. The age-dependent accumulation of senescent cells is caused by age-related attenuated efficiency of the immune system and their higher resistance both to extrinsic and intrinsic pro-apoptotic stimuli, including oxidative stress. While the mechanisms driving senescence are well studied, understanding the mechanisms endowing these cells with increased survival capacity is limited.

The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This protein family, in addition to multidomain pro-apoptotic proteins Bax, Bak, and Bok and BH3-only proteins, also includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1, and A1, and is intensively studied as a target for pharmacological intervention in cancer. Researchers have evaluated the contribution of individual members of the BCL-2 family and their combinations to the viability of senescent cells. They found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis and their combined inhibition induces the death of senescent cells. This mechanism is believed to be a basis for senolytic effects of BCL-2 inhibitors such as ABT-737 or ABT-263 (Navitoclax).

ABT-737 and ABT-263 both display a high affinity for BCL-2, BCL-XL, and BCL-W, but not A1, or MCL-1. In this study, we aimed to search for synergistic selective senolytic effects. We found that combining selective MCL-1 inhibitors with non-MCL1 BCL-2 inhibitors results in marked synergistic effects with higher sensitivity of senescent compared to proliferating cells. These findings indicate that a combination of drugs targeting different BCL-2 family members can benefit for senolytic therapies.


This is a really interesting paper, and I have to say I learned a good amount from it. Reports like this lead me to believe that we can do substantially better than D+Q with what's known now, it just takes a really long time to run any kind of testing on it.

I do hope someone (who knows more than I do) puts together a 'plausible' senolytic protocol based on stuff like this. IMO there's value in "probably helpful" protocols that minimize risk or side effects.

Since hope is not a strategy, I suppose I should hit the books and work on something like this myself.

Posted by: Dennis Towne at August 19th, 2022 2:03 PM
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