Senolytics
DESenolytika
Reviewed by Maurice Lichtenberg
Senolytics are compounds that selectively induce cell death in senescent cells by exploiting context-specific survival vulnerabilities, including BCL-2 family proteins and PI3K/AKT signalling; specific compounds such as the FOXO4-DRI peptide additionally target the FOXO4-p53 interaction. The vulnerabilities targeted are heterogeneous and compound-specific. Studied candidates include the dasatinib plus quercetin combination, fisetin and navitoclax. In animal models, intermittent senolytic dosing improves physical function and extends healthspan, but human evidence is still limited to early-phase trials and clinical use outside studies is not established.
Sources
- Zhu Y, Tchkonia T, Pirtskhalava T, et al.. (2015). The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. *Aging Cell*doi:10.1111/acel.12344
- Hickson LJ, Langhi Prata LG, Bobart SA, et al.. (2019). Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. *EBioMedicine*doi:10.1016/j.ebiom.2019.08.069
- Chang J, Wang Y, Shao L, et al.. (2016). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. *Nature Medicine*doi:10.1038/nm.4010
- Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, et al.. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. *Cell*doi:10.1016/j.cell.2017.02.031