A Review of Clinical Trials of Senolytics

A team of researchers, including Dr. James Kirkland of Mayo Clinic, has published a review of the ongoing efforts of researchers to clear senescent cells through senolytics.

Why we Age: Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
Read More

A growing push for senolytics

We have recently published a discussion on the various roles of senescent cells within the body, some of which are helpful but many of which are harmful, especially in people who are significantly affected by aging. Today’s review highlights the potential therapeutic benefits of directly removing these cells through senolytics. While senomorphics (drugs that alter senescent cells to lose their senescent qualities) are mentioned, they are not currently being explored as thoroughly.

Acknowledging the landmark 2013 paper The Hallmarks of Aging, the researchers promote a Unitary Theory of Fundamental Aging Processes. With a great deal of supporting evidence, this theory holds that the Hallmarks of Aging are largely bi-directional; hallmarks that are thought of as “downstream” can significantly influence the “upstream” hallmarks. This review singles out cellular senescence as being able to affect all eight of the other hallmarks, and it explains the effects of the SASP.

The reviewers also promote the Translational Geroscience Network (TGN), which is comprised of 8 institutions, including Mayo Clinic. One of its stated aims is to conduct new assays for fundamental markers of aging and disease, including senescent cells. It intends to navigate the obstacles involved in creating clinical trials of interventions that target the basic mechanisms of aging.

Drug discovery and preclinical trials

This review discusses the history and current state of senolytic drug discovery. It includes the well-known combination of dasatinib and quercetin (D+Q), the flavonoid fisetin, and navitoclax; however, navitoclax has off-target effects that include platelet deficiency and neutropenia, a serious immune disorder. Efforts are being made to reduce these effects [1], and high-throughput screening is being used to identify more targeted and potent senolytics [2].

The reviewers also showcase the preclinical research involved in these drugs. The researchers cite multiple mouse studies showing the effectiveness of D+Q against metabolic disorders, heart problems, frailty, pulmonary fibrosis, and other age-related issues. Fisetin may be effective against neurodegenerative disorders [3], although more thorough research needs to be done in this regard.

Human trials

The reviewers list several ongoing human trials involved in senolytics. These include a recently completed Phase 1 trial of D+Q against Alzheimer’s disease with results that have yet to be published, a D+Q trial against kidney disease, fisetin trials against frailty and inflammation, fisetin trials against osteoarthritis, and a fisetin trial that specifically targets COVID-19. Additionally, both D+Q and fisetin are being tested for their effects on skeletal health in people.

Future trials will include fisetin against COVID-19, further trials of senolytics as therapies for Alzheimer’s disease, and a trial showing the effectiveness of senolytics in adult survivors of childhood cancer.

Conclusion

The reviewers conclude by saying that senomorphics, along with multiple aging therapeutics in combination therapies, require further exploration. They caution that while some combinations may have synergistic effects, others may have reduced efficacy instead, and they champion the need for collaborative efforts, such as the TGN, in discovering and developing effective combination approaches.

Literature

[1] He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., … & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1-14.

[2] Munoz-Espin, D., Rovira, M., Galiana, I., Gimenez, C., Lozano-Torres, B., Paez-Ribes, M., … & Serrano, M. A versatile drug delivery system targeting senescent cells. EMBO Mol Med. 2018; 10 (9).

[3] Maher, P. (2020). Preventing and treating neurological disorders with the flavonol fisetin. Brain Plasticity, 6(2), 155-166.