The costs and benefits of senotherapeutics for human health

Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp Cell Res, 25, 585, 10.1016/0014-4827(61)90192-6 Gorgoulis, 2019, Cellular senescence: defining a path forward, Cell, 179, 813, 10.1016/j.cell.2019.10.005 Coryell, 2021, Mechanisms and therapeutic implications of cellular senescence in osteoarthritis, Nat Rev Rheumatol, 17, 47, 10.1038/s41584-020-00533-7 Campisi, 2013, Aging, cellular senescence, and cancer, Annu Rev Physiol, 75, 685, 10.1146/annurev-physiol-030212-183653 Franceschi, 2014, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases, J Gerontol A Biol Sci Med Sci, 69, S4, 10.1093/gerona/glu057 Baker, 2016, Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan, Nature, 530, 184, 10.1038/nature16932 Kirkland, 2017, The clinical potential of senolytic drugs, J Am Geriatr Soc, 65, 2297, 10.1111/jgs.14969 Dolgin, 2020, Send in the senolytics, Nat Biotechnol, 38, 1371, 10.1038/s41587-020-00750-1 Paez-Ribes, 2019, Targeting senescent cells in translational medicine, EMBO Mol Med, 11, 10.15252/emmm.201810234 Kirkland, 2020, Senolytic drugs: from discovery to translation, J Intern Med, 288, 518, 10.1111/joim.13141 Schafer, 2020, The senescence-associated secretome as an indicator of age and medical risk, JCI Insight, 5, 10.1172/jci.insight.133668 Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med, 24, 1246, 10.1038/s41591-018-0092-9 Yousefzadeh, 2018, Fisetin is a senotherapeutic that extends health and lifespan, EBioMedicine, 36, 18, 10.1016/j.ebiom.2018.09.015 Iske, 2020, Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation, Nat Commun, 11, 10.1038/s41467-020-18039-x Camell, 2021, Senolytics reduce coronavirus-related mortality in old mice, Science, 373, 10.1126/science.abe4832 Prasanna, 2021, Therapy-induced senescence: opportunities to improve anticancer therapy, J Natl Cancer Inst, 113, 1285, 10.1093/jnci/djab064 Baar, 2017, Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging, Cell, 169, 132, 10.1016/j.cell.2017.02.031 Mylonas, 2021, Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair, Sci Transl Med, 13, 10.1126/scitranslmed.abb0203 Xu, 2015, Targeting senescent cells enhances adipogenesis and metabolic function in old age, eLife, 4, 10.7554/eLife.12997 Palmer, 2019, Targeting senescent cells alleviates obesity-induced metabolic dysfunction, Aging Cell, 18, 10.1111/acel.12950 Ogrodnik, 2017, Cellular senescence drives age-dependent hepatic steatosis, Nat Commun, 8, 10.1038/ncomms15691 Raffaele, 2021, Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin, Cell Commun Signal, 19, 44, 10.1186/s12964-021-00731-0 Walaszczyk, 2019, Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction, Aging Cell, 18, 10.1111/acel.12945 Dookun, 2020, Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery, Aging Cell, 19, 10.1111/acel.13249 Roos, 2016, Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice, Aging Cell, 15, 973, 10.1111/acel.12458 Childs, 2016, Senescent intimal foam cells are deleterious at all stages of atherosclerosis, Science, 354, 472, 10.1126/science.aaf6659 Anderson, 2019, Length-independent telomere damage drives post-mitotic cardiomyocyte senescence, EMBO J, 38, 10.15252/embj.2018100492 Zhu, 2015, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell, 14, 644, 10.1111/acel.12344 Sugihara, 2020, Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy, Sci Rep, 10, 10.1038/s41598-020-73315-6 Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat Med, 22, 78, 10.1038/nm.4010 Farr, 2017, Targeting cellular senescence prevents age-related bone loss in mice, Nat Med, 23, 1072, 10.1038/nm.4385 Kim, 2020, Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence, JCI Insight, 5, 10.1172/jci.insight.138815 Schoenwaelder, 2011, Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets, Blood, 118, 1663, 10.1182/blood-2011-04-347849 He, 2020, Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity, Nat Commun, 11 Sharma, 2020, The senolytic drug navitoclax (ABT-263) causes trabecular bone loss and impaired osteoprogenitor function in aged mice, Front Cell Dev Biol, 8, 354, 10.3389/fcell.2020.00354 van der Feen, 2020, Cellular senescence impairs the reversibility of pulmonary arterial hypertension, Sci Transl Med, 12, 10.1126/scitranslmed.aaw4974 Schafer, 2017, Cellular senescence mediates fibrotic pulmonary disease, Nat Commun, 8, 10.1038/ncomms14532 Triana-Martínez, 2019, Identification and characterization of cardiac glycosides as senolytic compounds, Nat Commun, 10, 10.1038/s41467-019-12888-x Bussian, 2018, Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature, 562, 578, 10.1038/s41586-018-0543-y Zhang, 2019, Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci, 22, 719, 10.1038/s41593-019-0372-9 Rocha, 2020, Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension, Aging Cell, 19, 10.1111/acel.13089 Azazmeh, 2020, Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation, Nat Commun, 11, 10.1038/s41467-020-16475-3 Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat Commun, 7, 10.1038/ncomms11190 Zaragosi, 2010, Activin a plays a critical role in proliferation and differentiation of human adipose progenitors, Diabetes, 59, 2513, 10.2337/db10-0013 Rouault, 2021, Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity, Diabetologia, 64, 240, 10.1007/s00125-020-05307-0 Hickson, 2020, Corrigendum to ‘Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456, EBioMedicine, 52, 10.1016/j.ebiom.2019.12.004 Yazdanyar, 2009, The burden of cardiovascular disease in the elderly: morbidity, mortality, and costs, Clin Geriatr Med, 25, 563, 10.1016/j.cger.2009.07.007 North, 2012, The intersection between aging and cardiovascular disease, Circ Res, 110, 1097, 10.1161/CIRCRESAHA.111.246876 Getz, 2012, Animal models of atherosclerosis, Arterioscler Thromb Vasc Biol, 32, 1104, 10.1161/ATVBAHA.111.237693 Sousa-Victor, 2014, Geriatric muscle stem cells switch reversible quiescence into senescence, Nature, 506, 316, 10.1038/nature13013 Vinciguerra, 2010, Regulation of muscle atrophy in aging and disease, Adv Exp Med Biol, 694, 211, 10.1007/978-1-4419-7002-2_15 Vinciguerra, 2019, Sarcopenia and Parkinson's Disease, 25 Chen, 2021, Is exercise a senolytic medicine? A systematic review, Aging Cell, 20, 10.1111/acel.13294 Laberge, 2015, MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation, Nat Cell Biol, 17, 1049, 10.1038/ncb3195 Watanabe, 2017, Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases, Cancer Sci, 108, 563, 10.1111/cas.13184 Demaria, 2015, Cell Autonomous and non-autonomous effects of senescent cells in the skin, J Invest Dermatol, 135, 1722, 10.1038/jid.2015.108 Demaria, 2014, An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA, Dev Cell, 31, 722, 10.1016/j.devcel.2014.11.012 Velarde, 2015, Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells, Proc Natl Acad Sci USA, 112, 10407, 10.1073/pnas.1505675112 Lämmermann, 2018, Blocking negative effects of senescence in human skin fibroblasts with a plant extract, NPJ Aging Mech Dis, 4, 4, 10.1038/s41514-018-0023-5 Martyanov, 2019, Senescence signature in skin biopsies from systemic sclerosis patients treated with senolytic therapy: potential predictor of clinical response?, Arthritis Rheumatol, 71, 1766, 10.1002/art.40934 Martyanov, 2017, Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease, PLoS One, 12, 10.1371/journal.pone.0187580 Domaszewska-Szostek, 2021, Flavonoids in skin senescence prevention and treatment, Int J Mol Sci, 22, 10.3390/ijms22136814 Georgakopoulou, 2021, The bright and dark side of skin senescence. Could skin rejuvenation anti-senescence interventions become a “bright” new strategy for the prevention of age-related skin pathologies?, Mech Ageing Dev, 193, 10.1016/j.mad.2020.111409 Ho, 2021, Faces of cellular senescence in skin aging, Mech Ageing Dev, 198, 10.1016/j.mad.2021.111525 Camandola, 2017, Brain metabolism in health, aging, and neurodegeneration, EMBO J, 36, 1474, 10.15252/embj.201695810 Hou, 2019, Ageing as a risk factor for neurodegenerative disease, Nat Rev Neurol, 15, 565, 10.1038/s41582-019-0244-7 Chow, 2015, Genomic integrity and the ageing brain, Nat Rev Neurosci, 16, 672, 10.1038/nrn4020 Yin, 2016, Energy metabolism and inflammation in brain aging and Alzheimer's disease, Free Radic Biol Med, 100, 108, 10.1016/j.freeradbiomed.2016.04.200 Tan, 2014, Are there roles for brain cell senescence in aging and neurodegenerative disorders?, Biogerontology, 15, 643, 10.1007/s10522-014-9532-1 Ogrodnik, 2021, Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice, Aging Cell, 20, 10.1111/acel.13296 Chinta, 2018, Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson's disease, Cell Rep, 22, 930, 10.1016/j.celrep.2017.12.092 Ogrodnik, 2019, Obesity-induced cellular senescence drives anxiety and impairs neurogenesis, Cell Metab, 29, 1061, 10.1016/j.cmet.2018.12.008 El-Nimri, 2020, Evaluating the neuroprotective impact of senolytic drugs on human vision, Sci Rep, 10, 10.1038/s41598-020-78802-4 Romashkan, 2021, National Institute on Aging workshop: repurposing drugs or dietary supplements for their senolytic or senomorphic effects: considerations for clinical trials, J Gerontol A Biol Sci Med Sci, 76, 1144, 10.1093/gerona/glab028 Cho, 2020, Aging and lung disease, Annu Rev Physiol, 82, 433, 10.1146/annurev-physiol-021119-034610 Childs, 2015, Cellular senescence in aging and age-related disease: from mechanisms to therapy, Nat Med, 21, 1424, 10.1038/nm.4000 Frasca, 2016, Inflammaging decreases adaptive and innate immune responses in mice and humans, Biogerontology, 17, 7, 10.1007/s10522-015-9578-8 Boyd, 2011, Dysregulated inflammation as a risk factor for pneumonia in the elderly, Aging Dis, 2, 487 Meyer, 1996, Immune dysregulation in the aging human lung, Am J Respir Crit Care Med, 153, 1072, 10.1164/ajrccm.153.3.8630547 Meyer, 1996, Immune dysregulation in the aging human lung, Am J Respir Crit Care Med, 153, 1072, 10.1164/ajrccm.153.3.8630547 Kaplanski, 2003, IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation, Trends Immunol, 24, 25, 10.1016/S1471-4906(02)00013-3 Frescas, 2017, Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent, Cell Cycle, 16, 1526, 10.1080/15384101.2017.1339850 Kakkola, 2013, Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice, Cell Death Dis, 4, e742, 10.1038/cddis.2013.267 Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study, EBioMedicine, 40, 554, 10.1016/j.ebiom.2018.12.052 Esposito, 2020, Increased odds of death for patients with interstitial lung disease and covid-19: a case-control study, Am J Respir Crit Care Med, 202, 1710, 10.1164/rccm.202006-2441LE John, 2021, COVID-19 and pulmonary fibrosis: a potential role for lung epithelial cells and fibroblasts, Immunol Rev, 302, 228, 10.1111/imr.12977 Fadista, 2021, Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity, EBioMedicine, 65, 10.1016/j.ebiom.2021.103277 Verdoorn, 2021, Fisetin for COVID-19 in skilled nursing facilities: senolytic trials in the COVID era, J Am Geriatr Soc, 69, 3023, 10.1111/jgs.17416 Rachner, 2011, Osteoporosis: now and the future, Lancet, 377, 1276, 10.1016/S0140-6736(10)62349-5 Infante, 2018, Osteogenesis and aging: lessons from mesenchymal stem cells, Stem Cell Res Ther, 9, 244, 10.1186/s13287-018-0995-x Cummings, 2002, Epidemiology and outcomes of osteoporotic fractures, Lancet, 359, 1761, 10.1016/S0140-6736(02)08657-9 Dorshkind, 1990, Regulation of hemopoiesis by bone marrow stromal cells and their products, Annu Rev Immunol, 8, 111, 10.1146/annurev.iy.08.040190.000551 Morrison, 2014, The bone marrow niche for haematopoietic stem cells, Nature, 505, 327, 10.1038/nature12984 Shao, 2014, Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner, Blood, 123, 3105, 10.1182/blood-2013-07-515619 Le, 2010, Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status, Aging Cell, 9, 398, 10.1111/j.1474-9726.2010.00567.x Li, 2017, FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging, J Clin Invest, 127, 1241, 10.1172/JCI89511 Oh, 2014, Stem cell aging: mechanisms, regulators and therapeutic opportunities, Nat Med, 20, 870, 10.1038/nm.3651 Lee, 2019, Causes and mechanisms of hematopoietic stem cell aging, Int J Mol Sci, 20 Megyesi, 2001, Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure, Kidney Int, 60, 2164, 10.1046/j.1523-1755.2001.00044.x Melk, 2005, Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney, Am J Transplant, 5, 1375, 10.1111/j.1600-6143.2005.00846.x Wolstein, 2010, INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction, Am J Physiol Renal Physiol, 299, F1486, 10.1152/ajprenal.00378.2010 Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine, 47, 446, 10.1016/j.ebiom.2019.08.069 Pignolo, 2020, Reducing senescent cell burden in aging and disease, Trends Mol Med, 26, 630, 10.1016/j.molmed.2020.03.005 Volochnyuk, 2019, Evolution of commercially available compounds for HTS, Drug Discov Today, 24, 390, 10.1016/j.drudis.2018.10.016 Fuhrmann-Stroissnigg, 2017, Identification of HSP90 inhibitors as a novel class of senolytics, Nat Commun, 8, 422, 10.1038/s41467-017-00314-z Wakita, 2020, A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells, Nat Commun, 11, 10.1038/s41467-020-15719-6 Hall, 2017, p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli, Aging (Albany NY), 9, 1867, 10.18632/aging.101268 Raffaele, 2020, Senescence-like phenotype in post-mitotic cells of mice entering middle age, Aging (Albany NY), 12, 13979, 10.18632/aging.103637 Grosse, 2020, Defined p16High senescent cell types are indispensable for mouse healthspan, Cell Metab, 32, 87, 10.1016/j.cmet.2020.05.002 Muñoz-Espín, 2018, A versatile drug delivery system targeting senescent cells, EMBO Mol Med, 10, 10.15252/emmm.201809355