Senotherapy: scientific advances and clinical potential of senolytic therapies
DOI:
https://doi.org/10.15343/0104-7809.202650e18732025IKeywords:
Cellular Senescence, Senolytics, Aging, Therapeutics, Precision MedicineAbstract
Senotherapy represents an emerging therapeutic approach to combat deleterious senescent cells, whose pro-inflammatory accumulation contributes to various aging-associated pathologies. This study aimed to analyze and systematize recent scientific advances in senotherapy, with emphasis on senolytic therapies, their innovations, and clinical potential. An integrative literature review was conducted covering the period from January 2019 to June 2025, carried out across four databases: SciELO, PubMed, ScienceDirect, and Web of Science, following PRISMA 2020 guidelines for the identification, screening, eligibility, and inclusion stages. Fifteen articles were selected from a total of 113 identified publications, with a predominance of preclinical evidence (13 of the 15 studies were restricted to in vitro or in vivo designs) and only two compounds referenced in preliminary clinical trials. The results evidence a rapidly expanding field, with a peak of scientific productivity in 2024, revealing that senolytic therapies predominantly target the modulation of anti-apoptotic pathways – such as the Bcl-2 protein family and the PI3K/AKT/mTOR pathway. Agents such as the dasatinib and quercetin combination, fisetin, and navitoclax demonstrated preclinical efficacy in models of neurodegenerative diseases, metabolic disorders, musculoskeletal and cardiovascular conditions, and in stem cell preservation. However, significant challenges persist, including on-target toxicity (e.g., navitoclax-induced thrombocytopenia), contextual heterogeneity of response across tissues and age groups, and the absence of fully validated non-invasive biomarkers in all analyzed studies for quantifying the senescent burden and monitoring therapeutic efficacy. It is concluded that senotherapy represents a promising frontier, but its clinical consolidation requires articulated advances in safety, specificity, patient stratification, and standardization, in order to translate preclinical potential into effective applications in aging medicine.
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Senoterapia: avanços científicos e potencial clínico das terapias senolíticas
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Englund DA, et al. Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia. JCI Insight [Internet]. 2024 [acessado em 10 jun. 2025];9(2):e169512. Disponível em: https://doi.org/10.1172/jci.insight.169512
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Xu M, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med [Internet]. 2018 [acessado em 30 set. 2025];24(8):1246-56. Disponível em: https://doi.org/10.1038/s41591-018-0092-9
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Whittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs [Internet]. 2005 [acessado em 05 mai. 2025];52(5):546-53. Disponível em: https://doi.org/10.1111/j.1365-2648.2005.03621.x
Souza MT, Silva MD, Carvalho R. Revisão integrativa: o que é e como fazer. Einstein (Sao Paulo) [Internet]. 2010 [acessado em 05 mai. 2025];8(1):102 6. Disponível em: https://doi.org/10.1590/S1679-45082010RW1134
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Queiroz AN, Corrêa MV, Souza WS, Silva JR. Avaliação do cuidado farmacêutico na atenção primária à saúde: uma revisão integrativa da literatura. Braz J Health Rev [Internet]. 2024 [acessado em 05 mai. 2025];7(9):e75733. Disponível em: https://doi.org/10.34119/bjhrv7n9-352
Roever L, et al. Compreendendo o GRADE: PICO e qualidade dos estudos. Rev Soc Bras Clin Med. 2021;19(1):54-61.
Santos CM, Pimenta CA, Nobre MR. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem [Internet]. 2007 [acessado em 05 mai. 2025];15(3):508-11. Disponível em: https://doi.org/10.1590/s0104-11692007000300023
Nazaré AO, Mota LCT, Albuquerque PGS, Silva JR, Queiroz NA. O impacto da impressão 3D no desenvolvimento de medicamentos. Rev Eletronica Acervo Saude [Internet]. 2024 [acessado em 05 mai. 2025];24(12):e19051. Disponível em: https://doi.org/10.25248/reas.e19051.2024
Zhang P, et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci [Internet]. 2019 [acessado em 30 set. 2025];22(5):719-28. Disponível em: https://doi.org/10.1038/s41593-019-0372-9
Aguayo-Mazzucato C, et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab [Internet]. 2019 [acessado em 30 set. 2025];30(1):129-42.e4. Disponível em: https://doi.org/10.1016/j.cmet.2019.05.006
Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab [Internet]. 2019 [acessado em 30 set. 2025];29(5):1045-60.e10. Disponível em: https://doi.org/10.1016/j.cmet.2019.01.021
Kamada K, Kurio N, Mouri Y, Kudo Y. Combination treatment with hyaluronic acid synthesis and Bcl-2 inhibitors induces senolytic elimination of oral squamous cell carcinoma cells in vitro. J Oral Maxillofac Surg Med Pathol [Internet]. 2024 [acessado em 30 set. 2025];37(2):289-96. Disponível em: https://doi.org/10.1016/j.ajoms.2024.09.003
Mullen M, et al. Fisetin attenuates cellular senescence accumulation during culture expansion of human adipose-derived stem cells. Stem Cells [Internet]. 2023 [acessado em 30 set. 2025];41(7):698-710. Disponível em: https://doi.org/10.1093/stmcls/sxad036
Aguado J, et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging [Internet]. 2023 [acessado em 30 set. 2025];3(12):1561-75. Disponível em: https://doi.org/10.1038/s43587-023-00519-6
Fan Z, et al. Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence. Exp Gerontol [Internet]. 2024 [acessado em 30 set. 2025];186:112359. Disponível em: https://doi.org/10.1016/j.exger.2024.112359
Chin AF, et al. Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis. Aging Cell [Internet]. 2023 [acessado em 30 set. 2025];22(11):e13979. Disponível em: https://doi.org/10.1111/acel.13979
Escriche-Navarro B, Garrido E, Sancenón F, García-Fernández A, Martínez-Máñez R. A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells. Acta Biomater [Internet]. 2024 [acessado em 30 set. 2025];176:405-16. Disponível em: https://doi. org/10.1016/j.actbio.2024.01.002
Moaddel R, et al. Identification of gingerenone A as a novel senolytic compound. PLoS One [Internet]. 2022 [acessado em 30 set. 2025];17(3):e0266135. Disponível em: https://doi.org/10.1371/journal.pone.0266135
Sangfuang N, et al. Effects of senotherapeutics on gut microbiome dysbiosis and intestinal inflammation in Crohn’s disease: a pilot study. Transl Res [Internet]. 2025 [acessado em 30 set. 2025];278:36-47. Disponível em: https://doi.org/10.1016/j.trsl.2025.02.004
Yao M, et al. Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model. Neurobiol Dis [Internet]. 2024 [acessado em 30 set. 2025];202:106711. Disponível em: https://doi.org/10.1016/j.nbd.2024.106711
Gil TH, et al. Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis. Aging (Albany NY) [Internet]. 2022 [acessado em 30 set. 2025];14(15):6006-27. Disponível em: https://doi.org/10.18632/aging.204204
Scalise M, et al. Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids. Mech Ageing Dev [Internet]. 2024 [acessado em 30 set. 2025];223:112007. Disponível em: https://doi.org/10.1016/j.mad.2024.112007
Arora S, et al. Invariant natural killer T cells coordinate removal of senescent cells. Med [Internet]. 2021 [acessado em 30 set. 2025];2(8):938-50.e8. Disponível em: https://doi.org/10.1016/j.medj.2021.04.014
Lelarge V, et al. Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment. NPJ Aging [Internet]. 2024 [acessado em 03 jun. 2025];10(1):12-20. Disponível em: https://doi.org/10.1038/s41514-024-00138-4
Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med [Internet]. 2022 [acessado em 06 jun. 2025];28(8):1556-68. Disponível em: https://doi.org/10.1038/s41591-022-01923-y
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol [Internet]. 2018 [acessado em 03 jun. 2025];28(6):436 53. Disponível em: https://doi.org/10.1016/j.tcb.2018.02.001
Prasanna PG, et al. Therapy-induced senescence: opportunities to improve anticancer therapy. J Natl Cancer Inst [Internet]. 2021 [acessado em 10 jun. 2025];113(10):1285-98. Disponível em: https://doi.org/10.1093/jnci/djab064
Sapieha P, Mallette FA. Cellular senescence in postmitotic cells: beyond growth arrest. Trends Cell Biol [Internet]. 2018 [acessado em 03 mai. 2025];28(8):595-607. Disponível em: https://doi.org/10.1016/j.tcb.2018.03.003
Englund DA, et al. Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia. JCI Insight [Internet]. 2024 [acessado em 10 jun. 2025];9(2):e169512. Disponível em: https://doi.org/10.1172/jci.insight.169512
Hall SA, Lesniewski LA. Targeting vascular senescence in cardiovascular disease with aging. J Cardiovasc Aging [Internet]. 2024 [acessado em 10 jun. 2025];4:16. Disponível em: https://doi.org/10.20517/jca.2023.45
Childs BG, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov [Internet]. 2017 [acessado em 03 jun. 2025];16(10):718 35. Disponível em: https://doi.org/10.1038/nrd.2017.116
Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med [Internet]. 2020 [acessado em 03 jun. 2025];288(5):518-36. Disponível em: https://doi.org/10.1111/joim.13141
Justice JN, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine [Internet]. 2019 [acessado em 10 jun. 2025];40:554-63. Disponível em: https://doi.org/10.1016/j.ebiom.2018.12.052
Hickson LJ, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine [Internet]. 2019 [acessado em 30 set. 2025];47:446-56. Disponível em: https://doi.org/10.1016/j.ebiom.2019.08.069
Jin P, Duan X, Li L, Zhou P, Zou C, Xie K. Cellular senescence in cancer: molecular mechanisms and therapeutic targets. MedComm (2020) [Internet]. 2024 [acessado em 30 set. 2025];5(5):e542. Disponível em: https://doi.org/10.1002/mco2.542
Xu M, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med [Internet]. 2018 [acessado em 30 set. 2025];24(8):1246-56. Disponível em: https://doi.org/10.1038/s41591-018-0092-9
García-Fleitas J, García-Fernández A, Martí-Centelles V, Sancenón F, Bernardos A, Martínez-Máñez R. Chemical strategies for the detection and elimination of senescent cells. Acc Chem Res [Internet]. 2024 [acessado em 30 set. 2025];57(9):1238-53. Disponível em: https://doi.org/10.1021/acs. accounts.3c00794
Whittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs [Internet]. 2005 [acessado em 05 mai. 2025];52(5):546-53. Disponível em: https://doi.org/10.1111/j.1365-2648.2005.03621.x
Souza MT, Silva MD, Carvalho R. Revisão integrativa: o que é e como fazer. Einstein (Sao Paulo) [Internet]. 2010 [acessado em 05 mai. 2025];8(1):102 6. Disponível em: https://doi.org/10.1590/S1679-45082010RW1134
Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 [acessado em 05 mai. 2025];372:n71. Disponível em: https://doi.org/10.1136/bmj.n71
Queiroz AN, Corrêa MV, Souza WS, Silva JR. Avaliação do cuidado farmacêutico na atenção primária à saúde: uma revisão integrativa da literatura. Braz J Health Rev [Internet]. 2024 [acessado em 05 mai. 2025];7(9):e75733. Disponível em: https://doi.org/10.34119/bjhrv7n9-352
Roever L, et al. Compreendendo o GRADE: PICO e qualidade dos estudos. Rev Soc Bras Clin Med. 2021;19(1):54-61.
Santos CM, Pimenta CA, Nobre MR. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem [Internet]. 2007 [acessado em 05 mai. 2025];15(3):508-11. Disponível em: https://doi.org/10.1590/s0104-11692007000300023
Nazaré AO, Mota LCT, Albuquerque PGS, Silva JR, Queiroz NA. O impacto da impressão 3D no desenvolvimento de medicamentos. Rev Eletronica Acervo Saude [Internet]. 2024 [acessado em 05 mai. 2025];24(12):e19051. Disponível em: https://doi.org/10.25248/reas.e19051.2024
Zhang P, et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci [Internet]. 2019 [acessado em 30 set. 2025];22(5):719-28. Disponível em: https://doi.org/10.1038/s41593-019-0372-9
Aguayo-Mazzucato C, et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab [Internet]. 2019 [acessado em 30 set. 2025];30(1):129-42.e4. Disponível em: https://doi.org/10.1016/j.cmet.2019.05.006
Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab [Internet]. 2019 [acessado em 30 set. 2025];29(5):1045-60.e10. Disponível em: https://doi.org/10.1016/j.cmet.2019.01.021
Kamada K, Kurio N, Mouri Y, Kudo Y. Combination treatment with hyaluronic acid synthesis and Bcl-2 inhibitors induces senolytic elimination of oral squamous cell carcinoma cells in vitro. J Oral Maxillofac Surg Med Pathol [Internet]. 2024 [acessado em 30 set. 2025];37(2):289-96. Disponível em: https://doi.org/10.1016/j.ajoms.2024.09.003
Mullen M, et al. Fisetin attenuates cellular senescence accumulation during culture expansion of human adipose-derived stem cells. Stem Cells [Internet]. 2023 [acessado em 30 set. 2025];41(7):698-710. Disponível em: https://doi.org/10.1093/stmcls/sxad036
Aguado J, et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging [Internet]. 2023 [acessado em 30 set. 2025];3(12):1561-75. Disponível em: https://doi.org/10.1038/s43587-023-00519-6
Fan Z, et al. Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence. Exp Gerontol [Internet]. 2024 [acessado em 30 set. 2025];186:112359. Disponível em: https://doi.org/10.1016/j.exger.2024.112359
Chin AF, et al. Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis. Aging Cell [Internet]. 2023 [acessado em 30 set. 2025];22(11):e13979. Disponível em: https://doi.org/10.1111/acel.13979
Escriche-Navarro B, Garrido E, Sancenón F, García-Fernández A, Martínez-Máñez R. A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells. Acta Biomater [Internet]. 2024 [acessado em 30 set. 2025];176:405-16. Disponível em: https://doi. org/10.1016/j.actbio.2024.01.002
Moaddel R, et al. Identification of gingerenone A as a novel senolytic compound. PLoS One [Internet]. 2022 [acessado em 30 set. 2025];17(3):e0266135. Disponível em: https://doi.org/10.1371/journal.pone.0266135
Sangfuang N, et al. Effects of senotherapeutics on gut microbiome dysbiosis and intestinal inflammation in Crohn’s disease: a pilot study. Transl Res [Internet]. 2025 [acessado em 30 set. 2025];278:36-47. Disponível em: https://doi.org/10.1016/j.trsl.2025.02.004
Yao M, et al. Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model. Neurobiol Dis [Internet]. 2024 [acessado em 30 set. 2025];202:106711. Disponível em: https://doi.org/10.1016/j.nbd.2024.106711
Gil TH, et al. Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis. Aging (Albany NY) [Internet]. 2022 [acessado em 30 set. 2025];14(15):6006-27. Disponível em: https://doi.org/10.18632/aging.204204
Scalise M, et al. Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids. Mech Ageing Dev [Internet]. 2024 [acessado em 30 set. 2025];223:112007. Disponível em: https://doi.org/10.1016/j.mad.2024.112007
Arora S, et al. Invariant natural killer T cells coordinate removal of senescent cells. Med [Internet]. 2021 [acessado em 30 set. 2025];2(8):938-50.e8. Disponível em: https://doi.org/10.1016/j.medj.2021.04.014
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2026-07-14
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Miranda, A. A., Leal, A. C. M., Fontes, A. W. G., Barros, E. A., da Silva, J. R., & Queiroz, A. N. (2026). Senotherapy: scientific advances and clinical potential of senolytic therapies. O Mundo Da Saúde, 50. https://doi.org/10.15343/0104-7809.202650e18732025I
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