Combining Senolytic Pathways Has Synergistic Effects

Some drugs with no senolytic effects increase the power of senolytics.



A team of researchers have explained in Aging how multiple compounds that target the BCL-2 protein family are considerably more effective against senescent cells than each compound by itself [1].

The limitations of existing senolytics

The researchers begin their paper with a familiar discussion of senescent cells and their dangers, citing a 2019 paper outlining their effects on a panoply of age-related diseases [2]. The paper then discusses methods of eliminating these cells, focusing on the BCL-2 family of proteins, which prevent senescent cells from eliminating themselves: they are anti-apoptotic. ABT-737 and its more orally bioavailable cousin, ABT-263 (navitoclax), target some, but not all, of these proteins [3] by mimicking proteins that promote apoptosis..

However, navitoclax diminishes the number of blood platelets (thrombocytopenia), making it dangerous to use at high doses [4]. It also does not target the full BCL-2 family of proteins, most notably MCL-1. Therefore, the researchers sought to determine if navitoclax could be made more effective when taken in combination with an MCL-1 inhibitor.

Many doses, many tests

To begin their experiment, the researchers used homoharringtonine (HHT), a non-specific MCL-1 inhibitor, in conjunction with navitoclax and ABT-737 on a wide variety of senescent cells. These included multiple quiescent and proliferating cells along with cells that were driven senescent through chemicals, radiation, and cancer-related gene expression.

HHT is a cellular killer (a cytotoxin). Worse, it preferentially kills proliferating, rather than senescent, cells. However, moderate doses of HHT in conjunction with navitoclax had a synergistic effect, significantly increasing the ability of navitoclax to preferentially kill senescent, rather than proliferating, cells.

With these results in hand, the researchers moved on to a less dangerous MCL-1 inhibitor: MIK665. This is a drug that has been studied as a potential cancer treatment [5] but, on its own, is not effective as a senolytic. However, when testing it in conjunction with the BCL-2 inhibitors, the researchers were able to find doses that significantly increased the ability of navitoclax to preferentially remove senescent cells, regardless of whether that senescence was induced by radiation or drugs.

The team then examined three other inhibitors: ABT-199 (venetoclax), which only targets BCL-2 itself, A1331852, which targets BCL-XL, and S63845, another inhibitor of MCL-1. Similar results were found here as well: each of the first two compounds was found to work in synergy with the third, providing much more senolytic power than either has by itself.

Further analysis confirmed the researchers’ results, showing that cells that are resistant to BCL-2 inhibitors exhibit increased amounts of MCL-1. The researchers note that senescent cells are naturally heterogenous in this way, showing that it is necessary to defeat all of the potential methods of self-preservation in order to completely remove a population of senescent cells.


This is a cellular in vitro study that was not conducted in an animal model; therefore, it has yet to be seen whether or not its findings will be found to hold true in mice, let alone people. However, these findings are particularly promising, and such experiments are certainly worth conducting. It may be that such a combination, or even a more detailed combination with a broader range of targets, will succeed where previous senolytic therapies have failed.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

Developing a Treatment for Arthritis from Stem Cell Signals

Resarchers publishing in Aging have found that extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (MSCs) reduce...

Creating a Noise Clock to Measure Biological Age

Publishing in Aging, the Conboy research lab has outlined the problems with existing machine learning-based clocks and created a new...

EARD2023: Using NFTs to Support Video Gaming for Good

In this talk, Lifespan.io President Keith Comito describes use cases for "Proof of Philanthropy" (PoP) dynamic NFTs - a new...

Senolytics as a Potential Back Pain Treatment

In a recent paper, researchers from McGill University in Canada have investigated how a combination of two senolytics, RG-7112 and...


[1] Rysanek, D., Vasicova, P., Kolla, J. N., Sedlak, D., Andera, L., Bartek, J., & Hodny, Z. Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells. Aging, 14(undefined).

[2] Myrianthopoulos, V., Evangelou, K., Vasileiou, P. V., Cooks, T., Vassilakopoulos, T. P., Pangalis, G. A., … & Gorgoulis, V. G. (2019). Senescence and senotherapeutics: a new field in cancer therapy. Pharmacology & therapeutics, 193, 31-49.

[3] Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., … & Elmore, S. W. (2008). ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer research, 68(9), 3421-3428.

[4] Knight, T., Luedtke, D., Edwards, H., Taub, J. W., & Ge, Y. (2019). A delicate balance–The BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics. Biochemical pharmacology, 162, 250-261.

[5] Wei, A. H., Roberts, A. W., Spencer, A., Rosenberg, A. S., Siegel, D., Walter, R. B., … & Stein, A. (2020). Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood reviews, 44, 100672.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called β€œreal life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
No Comments
Write a comment:


Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.