Senolytics
Senolytics are drugs that selectively kill senescent cells. The first senolytics were found by identifying the survival pathways that senescent cells use to resist apoptosis and then finding compounds that block those pathways. A senolytic dose removes a fraction of the senescent cell burden, and because senescent cells take weeks to reaccumulate, the drugs can be given intermittently.12
Principle
Senescent cells resist apoptosis and upregulate anti-apoptotic pathways that protect them from their own SASP. This survival dependence is the vulnerability that senolytics exploit: the drug transiently disables those pathways, and senescent cells die while proliferating and quiescent cells survive. The researchers called the schedule “hit-and-run” because the drug acts during a short window and the target cells rebuild slowly. The approach mirrors the INK-ATTAC strategy of removing senescent cells, carried out here with small molecules.2
First-generation drugs
The first senolytics came from a transcriptome analysis of senescent cells. Silencing key nodes of the pro-survival network killed senescent cells while sparing proliferating and quiescent cells, and drugs against the same nodes reproduced the effect. Dasatinib cleared senescent human fat-cell progenitors, quercetin worked better against senescent endothelial cells and mouse mesenchymal stem cells, and the combination cleared senescent mouse fibroblasts. In aged mice, in irradiated mice, and in progeroid Ercc1-deficient mice, the combination reduced the senescent cell burden, improved cardiac function and vascular reactivity, and extended healthspan.1
Effects in animals
A later study transplanted small numbers of senescent cells into young mice. The transplanted cells caused lasting physical dysfunction and spread senescence to host tissues, and a smaller dose reduced survival in old recipients. Intermittent oral dasatinib plus quercetin reduced the senescent cell burden and frailty-related cytokine secretion in human fat tissue explants, alleviated physical dysfunction in the mice, and increased post-treatment survival by 36%, lowering the mortality hazard to 65% of control.3
Clinical status
Kirkland and Tchkonia reviewed the translation in 2020. Preclinical work covered more than 40 conditions, and early human trials showed reductions in senescent cell markers and inflammation along with some improvement in frailty. Trials were underway or starting for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye disease, and complications in transplant and childhood-cancer survivors. The authors placed senolytics inside clinical trials while safety and efficacy data accumulated.2
Limits
Senescent cells are heterogeneous, and the available markers identify overlapping populations, so a drug that clears one subset can leave others. Some senescent cells perform useful roles in wound healing and tumor suppression, which makes lifelong clearance a different proposition from intermittent treatment, and the p16-positive and p21-positive populations respond differently to removal.[citation needed] The clinical evidence rests on small trials, and the field has yet to establish which conditions, doses, and schedules produce durable benefit.
See also
References
Footnotes
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–658. doi:10.1111/acel.12344. ↩↩2
- Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. Journal of Internal Medicine. 2020;288(5):518–536. doi:10.1111/joim.13141. ↩↩2↩3
- Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nature Medicine. 2018;24(8):1246–1256. doi:10.1038/s41591-018-0092-9. ↩