First evidence that senolytics are effective at decreasing senescent cells in humans

The increasing life expectancy of the world population has become an economic and global public health problem. Increased life expectancy tracks with a higher incidence of multiple chronic conditions, despite unprecedented advances in prevention, diagnostics, and treatment. Ageing is the greatest risk factor for many life-threatening disorders, including cardiovascular disease, neurodegeneration and cancer. Ageing in all tissues is associated with increased cellular senescence(definition), a stress-response process whereby damaged cells exit the cell cycle permanently and produce a pro-inflammatory senescence-associated secretory phenotype (SASP). Moreover, senescent cells accumulate in multiple chronic diseases across the age range, like Obesity and Chronic Kidney Disease (CKD). Long-term persistence of senescent cells and their SASP disrupt tissue structure and function having deleterious paracrine and systemic effects causing fibrosis, inflammation, and a possible carcinogenic response. Remarkably, even a relatively low abundance of senescent cells (10–15% in aged primates) [[1]Herbig U. Ferreira M. Condel L. Carey D. Sedivy J.M. Cellular senescence in aging primates.Science. 2006; 311: 1257https://doi.org/10.1126/science.1122446Crossref PubMed Scopus (739) Google Scholar] is sufficient to cause tissue dysfunction [[2]Xu M. Pirtskhalava T. Farr J.N. Weigand B.M. Palmer A.K. Weivoda M.M. et al.Senolytics(definition) improve physical function and increase lifespan in old age.Nat Med. 2018; 24: 1246-1256https://doi.org/10.1038/s41591-018-0092-9Crossref PubMed Scopus (538) Google Scholar]. Prof. James Kirkland and his team at Mayo Clinic have pioneered a new class of agents which eliminate senescent cells named ‘senolytics’ - from the words “senescence” and “lytic” – destroying. Through exploiting senescent cells’ dependence on specific pro-survival pathways, senolytics transiently disable the pro-survival networks that defend senescent cells against their own apoptotic environment without affecting proliferating or quiescent, differentiated cells [[3]Kirkland J.L. Tchkonia T. Zhu Y. Niedernhofer L.J. Robbins P.D. The clinical potential of senolytic drugs.J Am Geriatr Soc. 2017; 65: 2297-2301https://doi.org/10.1111/jgs.14969Crossref PubMed Scopus (228) Google Scholar,[4]Kirkland J.L. Tchkonia T. Cellular senescence: a translational perspective.EBioMedicine. 2017; 21: 21-28https://doi.org/10.1016/j.ebiom.2017.04.013Summary Full Text Full Text PDF PubMed Scopus (329) Google Scholar]. Senolytics thus far tested include dasatinib (D, a FDA-approved tyrosine kinase inhibitor), quercetin (Q, a flavonoid present in many fruits and vegetables), navitoclax, A1331852 and A1155463 (Bcl-2 pro-survival family inhibitors) and fistein (F, a flavonoid) [[3]Kirkland J.L. Tchkonia T. Zhu Y. Niedernhofer L.J. Robbins P.D. The clinical potential of senolytic drugs.J Am Geriatr Soc. 2017; 65: 2297-2301https://doi.org/10.1111/jgs.14969Crossref PubMed Scopus (228) Google Scholar]. Pre-clinical studies conducted in mice have shown senolytics eliminate senescent cells resulting in delaying, preventing or alleviating multiple age- and senescence-related conditions, including frailty, cataracts, age-related osteoporosis, age-related muscle loss, radiation-induced damage, cardiac dysfunction, vascular dysfunction and calcification, pulmonary fibrosis, hepatic steatosis, metabolic syndrome, diabetes and dementia [3Kirkland J.L. Tchkonia T. Zhu Y. Niedernhofer L.J. Robbins P.D. The clinical potential of senolytic drugs.J Am Geriatr Soc. 2017; 65: 2297-2301https://doi.org/10.1111/jgs.14969Crossref PubMed Scopus (228) Google Scholar, 4Kirkland J.L. Tchkonia T. Cellular senescence: a translational perspective.EBioMedicine. 2017; 21: 21-28https://doi.org/10.1016/j.ebiom.2017.04.013Summary Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 5Tchkonia T. Kirkland J.L. Aging, cell senescence, and chronic disease: emerging therapeutic strategies.JAMA. 2018; 320: 1319-1320https://doi.org/10.1001/jama.2018.12440Crossref PubMed Scopus (86) Google Scholar]. Overall, in mice, administration of senolytic agents and elimination of senescent cells have shown to improve physical function and extend health span and lifespan [[2]Xu M. Pirtskhalava T. Farr J.N. Weigand B.M. Palmer A.K. Weivoda M.M. et al.Senolytics improve physical function and increase lifespan in old age.Nat Med. 2018; 24: 1246-1256https://doi.org/10.1038/s41591-018-0092-9Crossref PubMed Scopus (538) Google Scholar,[6]Yousefzadeh M.J. Zhu Y. McGowan S.J. Angelini L. Fuhrmann-Stroissnigg H. Xu M. et al.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine. 2018; 36: 18-28https://doi.org/10.1016/j.ebiom.2018.09.015Summary Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. The results of the first-in-human, single-arm, open-label clinical trial of senolytics were published early this year in this Journal [[7]Justice J.N. Nambiar A.M. Tchkonia T. LeBrasseur N.K. Pascual R. Hashmi S.K. et al.Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study.EBioMedicine. 2019; 40: 554-563https://doi.org/10.1016/j.ebiom.2018.12.052Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar]. Subjects with idiopathic pulmonary fibrosis, a cellular senescence-driven fatal disease, showed significantly improved walking endurance, gait speed, chair rise test performance, and scores in the Short Physical Performance Battery 5 days after 9 doses of D + Q over 3 weeks [[7]Justice J.N. Nambiar A.M. Tchkonia T. LeBrasseur N.K. Pascual R. Hashmi S.K. et al.Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study.EBioMedicine. 2019; 40: 554-563https://doi.org/10.1016/j.ebiom.2018.12.052Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar]. Published recently in EBioMedicine, Kirkland and colleagues, demonstrate for the first time that a short (3 day) course of senolytics D +