Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders
Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managin...
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Elsevier
2025-01-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824001960 |
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| author | Tábatha de Oliveira Silva Guilherme Lunardon Caroline A. Lino Amanda de Almeida Silva Shiju Zhang Maria Cláudia Costa Irigoyen Yao Wei Lu John D. Mably Maria Luiza M. Barreto-Chaves Da-Zhi Wang Gabriela P. Diniz |
| author_facet | Tábatha de Oliveira Silva Guilherme Lunardon Caroline A. Lino Amanda de Almeida Silva Shiju Zhang Maria Cláudia Costa Irigoyen Yao Wei Lu John D. Mably Maria Luiza M. Barreto-Chaves Da-Zhi Wang Gabriela P. Diniz |
| author_sort | Tábatha de Oliveira Silva |
| collection | DOAJ |
| description | Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined. Objective: We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters. Methods and Results: We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice. Conclusions: Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders. |
| format | Article |
| id | doaj-art-d498681e12994eee98dc1c59881f0ffa |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-d498681e12994eee98dc1c59881f0ffa2025-01-09T06:13:52ZengElsevierMolecular Metabolism2212-87782025-01-0191102065Senescent cell depletion alleviates obesity-related metabolic and cardiac disordersTábatha de Oliveira Silva0Guilherme Lunardon1Caroline A. Lino2Amanda de Almeida Silva3Shiju Zhang4Maria Cláudia Costa Irigoyen5Yao Wei Lu6John D. Mably7Maria Luiza M. Barreto-Chaves8Da-Zhi Wang9Gabriela P. Diniz10Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil; Center for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, USADepartment of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, BrazilDepartment of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, BrazilHypertension Unit, Heart Institute (InCor), School of Medicine, University of Sao Paulo, Sao Paulo, SP, BrazilCenter for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, USAHypertension Unit, Heart Institute (InCor), School of Medicine, University of Sao Paulo, Sao Paulo, SP, BrazilVascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, and Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USACenter for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, USADepartment of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, BrazilCenter for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, USADepartment of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil; Center for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, USA; Corresponding author. Center for Regenerative Medicine, University of South Florida Health Heart Institute, University of South Florida, 560 Channelside Dr., MDD 715, Tampa, FL 33602, USA.Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined. Objective: We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters. Methods and Results: We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice. Conclusions: Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders.http://www.sciencedirect.com/science/article/pii/S2212877824001960ObesityCellular senescencebrown adipose tissueMetabolic dysfunctionCardiac dysfunction |
| spellingShingle | Tábatha de Oliveira Silva Guilherme Lunardon Caroline A. Lino Amanda de Almeida Silva Shiju Zhang Maria Cláudia Costa Irigoyen Yao Wei Lu John D. Mably Maria Luiza M. Barreto-Chaves Da-Zhi Wang Gabriela P. Diniz Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders Molecular Metabolism Obesity Cellular senescence brown adipose tissue Metabolic dysfunction Cardiac dysfunction |
| title | Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders |
| title_full | Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders |
| title_fullStr | Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders |
| title_full_unstemmed | Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders |
| title_short | Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders |
| title_sort | senescent cell depletion alleviates obesity related metabolic and cardiac disorders |
| topic | Obesity Cellular senescence brown adipose tissue Metabolic dysfunction Cardiac dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824001960 |
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