{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T15:16:53Z","timestamp":1771341413572,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Animal Free Research UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Repurposing previously approved drugs may fast track the route to the clinic for potential senotherapeutics and improves the inefficiency of the clinical drug development pipeline. We performed a repurposing screen of 240 clinically approved molecules in human primary dermal fibroblasts for their effects on CDKN2A expression. Molecules demonstrating effects on CDKN2A expression underwent secondary screening for senescence-associated beta galactosidase (SAB) activity, based on effect size, direction, and\/or molecule identity. Selected molecules then underwent a more detailed assessment of senescence phenotypes including proliferation, apoptosis, DNA damage, senescence-associated secretory phenotype (SASP) expression, and regulators of alternative splicing. A selection of the molecules demonstrating effects on senescence were then used in a new bioinformatic structure\u2013function screen to identify common structural motifs. In total, 90 molecules displayed altered CDKN2A expression at one or other dose, of which 15 also displayed effects on SAB positivity in primary human dermal fibroblasts. Of these, 3 were associated with increased SAB activity, and 11 with reduced activity. The female synthetic sex hormones\u2014diethylstilboestrol, ethynyl estradiol and levonorgestrel\u2014were all associated with a reduction in aspects of the senescence phenotype in male cells, with no effects visible in female cells. Finally, we identified that the 30 compounds that decreased CDKN2A activity the most had a common substructure linked to this function. Our results suggest that several drugs licensed for other indications may warrant exploration as future senotherapies, but that different donors and potentially different sexes may respond differently to senotherapeutic compounds. This underlines the importance of considering donor-related characteristics when designing drug screening platforms.<\/jats:p>","DOI":"10.3390\/cells13060517","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T12:02:39Z","timestamp":1710504159000},"page":"517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Repurposing Drugs for Senotherapeutic Effect: Potential Senomorphic Effects of Female Synthetic Hormones"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4069-3959","authenticated-orcid":false,"given":"Laura R.","family":"Bramwell","sequence":"first","affiliation":[{"name":"RNA-Mediated Mechanisms of Disease Group, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter EX2 5DW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Frankum","sequence":"additional","affiliation":[{"name":"RNA-Mediated Mechanisms of Disease Group, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter EX2 5DW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-8061","authenticated-orcid":false,"given":"Lorna W.","family":"Harries","sequence":"additional","affiliation":[{"name":"RNA-Mediated Mechanisms of Disease Group, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter EX2 5DW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1007\/s11033-016-4065-0","article-title":"The Cell Fate: Senescence or Quiescence","volume":"43","author":"Terzi","year":"2016","journal-title":"Mol. Biol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mad.2014.03.004","article-title":"The Hallmarks of Fibroblast Ageing","volume":"138","author":"Tigges","year":"2014","journal-title":"Mech. Ageing Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cell.2013.10.019","article-title":"Programmed Cell Senescence during Mammalian Embryonic Development","volume":"155","author":"Maraver","year":"2013","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.cell.2013.10.041","article-title":"Senescence Is a Developmental Mechanism That Contributes to Embryonic Growth and Patterning","volume":"155","author":"Storer","year":"2013","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The Serial Cultivation of Human Diploid Cell Strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp. Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/S1357-2725(02)00034-1","article-title":"From the Hayflick Mosaic to the Mosaics of Ageing. Role of Stress-Induced Premature Senescence in Human Ageing","volume":"34","author":"Toussaint","year":"2002","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0092-8674(00)81902-9","article-title":"Oncogenic Ras Provokes Premature Cell Senescence Associated with Accumulation of P53 and P16 INK4a","volume":"88","author":"Serrano","year":"1997","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nrd.2018.44","article-title":"Senotherapeutics for Healthy Ageing","volume":"17","author":"Niedernhofer","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21S","DOI":"10.1097\/PRS.0000000000008782","article-title":"Senotherapeutic Drugs: A New Avenue for Skincare?","volume":"148","author":"Lee","year":"2021","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1111\/jgs.14969","article-title":"The Clinical Potential of Senolytic Drugs","volume":"65","author":"Kirkland","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature10600","article-title":"Clearance of P16 Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders","volume":"479","author":"Baker","year":"2011","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nature16932","article-title":"Naturally Occurring P16Ink4a-Positive Cells Shorten Healthy Lifespan","volume":"530","author":"Baker","year":"2016","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/s12933-023-01955-9","article-title":"The Tyrosine Kinase Inhibitor Dasatinib Reduces Cardiac Steatosis and Fibrosis in Obese, Type 2 Diabetic Mice","volume":"22","author":"Gu","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"572","DOI":"10.18632\/aging.203835","article-title":"Combination of Dasatinib and Quercetin Improves Cognitive Abilities in Aged Male Wistar Rats, Alleviates Inflammation and Changes Hippocampal Synaptic Plasticity and Histone H3 Methylation Profile","volume":"14","author":"Krzystyniak","year":"2022","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e13528","DOI":"10.1111\/acel.13528","article-title":"Deletion of SA \u0392-Gal+ Cells Using Senolytics Improves Muscle Regeneration in Old Mice","volume":"21","author":"Dungan","year":"2022","journal-title":"Aging Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ebiom.2019.08.069","article-title":"Senolytics Decrease Senescent Cells in Humans: Preliminary Report from a Clinical Trial of Dasatinib plus Quercetin in Individuals with Diabetic Kidney Disease","volume":"47","author":"Hickson","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ebiom.2018.12.052","article-title":"Senolytics in Idiopathic Pulmonary Fibrosis: Results from a First-in-Human, Open-Label, Pilot Study","volume":"40","author":"Justice","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1038\/s41591-023-02543-w","article-title":"Senolytic Therapy in Mild Alzheimer\u2019s Disease: A Phase 1 Feasibility Trial","volume":"29","author":"Gonzales","year":"2023","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.18632\/aging.101500","article-title":"Mitochondria-Targeted Hydrogen Sulfide Attenuates Endothelial Senescence by Selective Induction of Splicing Factors HNRNPD and SRSF2","volume":"10","author":"Latorre","year":"2018","journal-title":"Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/nbt.2786","article-title":"Clinical Development Success Rates for Investigational Drugs","volume":"32","author":"Hay","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1096\/fj.201801154R","article-title":"FOXO1 and ETV6 Genes May Represent Novel Regulators of Splicing Factor Expression in Cellular Senescence","volume":"33","author":"Latorre","year":"2019","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Latorre, E., Birar, V.C., Sheerin, A.N., Jeynes, J.C.C., Hooper, A., Dawe, H.R., Melzer, D., Cox, L.S., Faragher, R.G.A., and Ostler, E.L. (2017). Small Molecule Modulation of Splicing Factor Expression Is Associated with Rescue from Cellular Senescence. BMC Cell Biol., 18.","DOI":"10.1186\/s12860-017-0147-7"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Barra, V., Chiavetta, R.F., Titoli, S., Provenzano, I.M., Carollo, P.S., and Di Leonardo, A. (2022). Specific Irreversible Cell-Cycle Arrest and Depletion of Cancer Cells Obtained by Combining Curcumin and the Flavonoids Quercetin and Fisetin. Genes, 13.","DOI":"10.3390\/genes13071125"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11103-012-9885-2","article-title":"MiRDeepFinder: A MiRNA Analysis Tool for Deep Sequencing of Plant Small RNAs","volume":"80","author":"Xie","year":"2012","journal-title":"Plant Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/nar\/29.9.e45","article-title":"A New Mathematical Model for Relative Quantification in Real-Time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.molcel.2012.05.036","article-title":"Short Structured RNAs with Low GC Content Are Selectively Lost during Extraction from a Small Number of Cells","volume":"46","author":"Kim","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1093\/bioinformatics\/btn307","article-title":"ChemmineR: A Compound Mining Framework for R","volume":"24","author":"Cao","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1093\/nar\/gkr320","article-title":"ChemMine Tools: An Online Service for Analyzing and Clustering Small Molecules","volume":"39","author":"Backman","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1093\/bioinformatics\/btt475","article-title":"FmcsR: Mismatch Tolerant Maximum Common Substructure Searching in R","volume":"29","author":"Wang","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_31","unstructured":"(2024, January 25). RStudio Team RStudio: Integrated Development Environment for R 2020.RStudio: Integrated Development for R. RStudio, PBC, Boston, MA, USA. Available online: http:\/\/www.rstudio.com\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.mad.2013.05.006","article-title":"Changes in Splicing Factor Expression Are Associated with Advancing Age in Man","volume":"134","author":"Holly","year":"2013","journal-title":"Mech. Ageing Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1474-9726.2008.00414.x","article-title":"Nordihydroguaiaretic Acid and Aspirin Increase Lifespan of Genetically Heterogeneous Male Mice","volume":"7","author":"Strong","year":"2008","journal-title":"Aging Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1001\/archpsyc.61.12.1235","article-title":"Metyrapone as Additive Treatment in Major Depression: A Double-Blind and Placebo-Controlled Trial","volume":"61","author":"Jahn","year":"2004","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Holczer, M., M\u00e1rton, M., Kurucz, A., B\u00e1nhegyi, G., and Kapuy, O. (2015). A Comprehensive Systems Biological Study of Autophagy-Apoptosis Crosstalk during Endoplasmic Reticulum Stress. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/319589"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1073\/pnas.022631999","article-title":"Life Extension in Drosophila by Feeding a Drug","volume":"99","author":"Kang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s10522-022-09974-x","article-title":"Exploring the Fuzzy Border between Senolytics and Senomorphics with Chemoinformatics and Systems Pharmacology","volume":"23","author":"Gutierrez","year":"2022","journal-title":"Biogerontology"},{"key":"ref_38","unstructured":"FSRH (2020). FSRH Clinical Guideline: Combined Hormonal Contraception, FSRH."},{"key":"ref_39","unstructured":"(2024, January 25). Joint Formulary Committee Diethylstilbestrol. British National Formulary. Available online: https:\/\/bnf.nice.org.uk\/drugs\/diethylstilbestrol\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jnr.23827","article-title":"Sex and the Development of Alzheimer\u2019s Disease","volume":"95","author":"Pike","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00125-019-05040-3","article-title":"Sex Differences in Metabolic Regulation and Diabetes Susceptibility","volume":"63","author":"Tramunt","year":"2020","journal-title":"Diabetologia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00021.2015","article-title":"Mechanistic Pathways of Sex Differences in Cardiovascular Disease","volume":"97","author":"Kararigas","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_43","first-page":"198","article-title":"The Influence of Sex and Gender on Immunity, Infection and Vaccination","volume":"52","author":"Ruggierii","year":"2016","journal-title":"Ann. Ist. Super. Sanita"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/S0891-5849(02)01356-4","article-title":"Mitochondria from Females Exhibit Higher Antioxidant Gene Expression and Lower Oxidative Damage than Males","volume":"34","author":"Sastre","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"H538","DOI":"10.1152\/ajpheart.00244.2022","article-title":"Proteogenomics Reveals Sex-Biased Aging Genes and Coordinated Splicing in Cardiac Aging","volume":"323","author":"Han","year":"2022","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e63425","DOI":"10.7554\/eLife.63425","article-title":"Sex Differences in Biological Aging with a Focus on Human Studies","volume":"10","year":"2021","journal-title":"eLife"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Rubin, J.B., Lagas, J.S., Broestl, L., Sponagel, J., Rockwell, N., Rhee, G., Rosen, S.F., Chen, S., Klein, R.S., and Imoukhuede, P. (2020). Sex Differences in Cancer Mechanisms. Biol. Sex Differ., 11.","DOI":"10.1186\/s13293-020-00291-x"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.neurobiolaging.2022.08.014","article-title":"Evidence of Sex Differences in Cellular Senescence","volume":"120","author":"Ng","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e13094","DOI":"10.1111\/acel.13094","article-title":"Tissue Specificity of Senescent Cell Accumulation during Physiologic and Accelerated Aging of Mice","volume":"19","author":"Yousefzadeh","year":"2020","journal-title":"Aging Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"903","DOI":"10.18632\/aging.100099","article-title":"Drosophila Melanogaster P53 Has Developmental Stage-specific and Sex-specific Effects on Adult Life Span Indicative of Sexual Antagonistic Pleiotropy","volume":"1","author":"Waskar","year":"2009","journal-title":"Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"21066","DOI":"10.18632\/aging.203519","article-title":"Sex-Specific Differences in DNA Double-Strand Break Repair of Cycling Human Lymphocytes during Aging","volume":"13","author":"Friedl","year":"2021","journal-title":"Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1016\/j.freeradbiomed.2008.08.031","article-title":"Age, Sex, and Race Influence Single-Strand Break Repair Capacity in a Human Population NIH Public Access","volume":"45","author":"Trzeciak","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2174\/1874609807666140321150751","article-title":"Germline Genetics of the P53 Pathway Affect Longevity in a Gender Specific Manner","volume":"7","author":"Mmel","year":"2014","journal-title":"Curr. Aging Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/13548506.2014.936884","article-title":"Predictors of the Gender Gap in Life Expectancy across 54 Nations","volume":"20","author":"Rochelle","year":"2015","journal-title":"Psychol. Health Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"47","DOI":"10.5551\/jat.47993","article-title":"Estrogen-Sirt1 Axis Plays a Pivotal Role in Protecting Arteries against Menopause-Induced Senescence and Atherosclerosis","volume":"27","author":"Sasaki","year":"2020","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JME-20-0196","article-title":"Aging, Senescence and Mitochondria: The PGC-1\/ERR Axis","volume":"66","author":"Vernier","year":"2021","journal-title":"J. Mol. Endocrinol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.4161\/cc.24550","article-title":"Progesterone Receptors Induce FOXO1-Dependent Senescence in Ovarian Cancer Cells","volume":"12","author":"Diep","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e13328","DOI":"10.1111\/acel.13328","article-title":"17-a-Estradiol Late in Life Extends Lifespan in Aging UM-HET3 Male Mice; Nicotinamide Riboside and Three Other Drugs Do Not Affect Lifespan in Either Sex","volume":"20","author":"Harrison","year":"2021","journal-title":"Aging Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.maturitas.2017.06.026","article-title":"The Role of Estrogen in Cutaneous Ageing and Repair","volume":"103","author":"Wilkinson","year":"2017","journal-title":"Maturitas"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nrm2234","article-title":"Endocrine Regulation of Ageing","volume":"8","author":"Russell","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S2213-8587(18)30026-3","article-title":"The Physiology of Endocrine Systems with Ageing","volume":"6","author":"Kaufman","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6089","DOI":"10.18632\/aging.103008","article-title":"Estradiol-Induced Senescence of Hypothalamic Astrocytes Contributes to Aging-Related Reproductive Function Declines in Female Mice","volume":"12","author":"Dai","year":"2020","journal-title":"Aging"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e12786","DOI":"10.1111\/acel.12786","article-title":"Male Lifespan Extension with 17-\u03b1 Estradiol Is Linked to a Sex-Specific Metabolomic Response Modulated by Gonadal Hormones in Mice","volume":"17","author":"Garratt","year":"2018","journal-title":"Aging Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"12283","DOI":"10.1038\/s41598-020-69112-w","article-title":"17\u03b2-Estradiol Supplementation Changes Gut Microbiota Diversity in Intact and Colorectal Cancer-Induced ICR Male Mice","volume":"10","author":"Song","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1007\/s11357-023-00843-0","article-title":"Sexual Dimorphic Metabolic and Cognitive Responses of C57BL\/6 Mice to Fisetin or Dasatinib and Quercetin Cocktail Oral Treatment","volume":"45","author":"Fang","year":"2023","journal-title":"GeroScience"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Saemann, L., Naujoks, P., Hartrumpf, L., Pohl, S., Simm, A., and Szab\u00f3, G. (2023). Sex-Specific Protection of Endothelial Function after Vascular Ischemia\/Reperfusion Injury by the Senomorphic Agent Ruxolitinib. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411727"},{"key":"ref_67","unstructured":"(2024, January 25). National Institute on Aging Intervention Testing Program: Supported Interventions, Available online: https:\/\/www.nia.nih.gov\/research\/dab\/in-terventions-testing-program-itp\/supported-interventions."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1093\/ppar\/prad026","article-title":"Sex Differences in Mouse Longevity and Responses to Geroprotective Drugs: Implications for Human Intervention","volume":"33","author":"Jiang","year":"2023","journal-title":"Public Policy Aging Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2165\/00003088-200948030-00001","article-title":"Sex Differences in Pharmacokinetics and Pharmacodynamics","volume":"48","author":"Soldin","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref_70","unstructured":"Wizemann, T.M., and Pardue, M.-L. (2001). Committee on Understanding the Biology of Sex and Gender, Exploring the Biological Contributions to Human Health: Does Sex Matter? Sex Begins in the Womb."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1080\/13685530400004199","article-title":"Progesterone: The Forgotten Hormone in Men?","volume":"7","author":"Oettel","year":"2004","journal-title":"Aging Male"},{"key":"ref_72","first-page":"153","article-title":"The Endocrine System: An Overview","volume":"22","author":"Bartke","year":"1998","journal-title":"Alcohol Health Res. World"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Fuentes, N., and Silveyra, P. (2019). Estrogen Receptor Signaling Mechanisms. Adv. Protein Chem. Struct. Biol., 116.","DOI":"10.1016\/bs.apcsb.2019.01.001"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"708","DOI":"10.3389\/fendo.2019.00708","article-title":"Non-Canonical Estrogen Signaling in Endocrine Resistance","volume":"10","author":"Ranganathan","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Thomas, P. (2022). Membrane Progesterone Receptors (MPRs, PAQRs): Review of Structural and Signaling Characteristics. Cells, 11.","DOI":"10.3390\/cells11111785"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cell.2015.06.023","article-title":"The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity","volume":"162","author":"Slack","year":"2015","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/6\/517\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:14:17Z","timestamp":1760105657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/6\/517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,15]]},"references-count":76,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cells13060517"],"URL":"https:\/\/doi.org\/10.3390\/cells13060517","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,15]]}}}