Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin
Open accessAbstract
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. METHODS: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. RESULTS: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. CONCLUSIONS: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.
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Dasatinib and quercetin decreased the burden of senescent cells and reduced hepatic steatosis in one study, but failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.
“Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study, 21 it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.22”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [22]
Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease; its efficacy seems to be controversial.
“Given that use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial.”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [22]
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Reduced fertility induced by MASLD in female mice is improved by senolytic treatment
Hense, J. D., Isola, J. V. V., Garcia, D. N., Zanini, B. M., Prosczek, J. B., Osorio, C. A. P., de Brito, C., Mondal, S. A., Rice, H. C., VAUCHER, R. A., et al. (2026) · Biology of Reproduction · doi:10.1093/biolre/ioag060 · Cited by 5 · see citing works
The role of cellular senescence in metabolic dysfunction-associated steatotic liver disease
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Downregulation of Aging-Associated Gene SUCLG1 Marks the Aggressiveness of Liver Disease
Tsoneva, D. K., Napoli, A., Teneva, M., Mazza, T., & Vinciguerra, M. (2025) · Cancers · doi:10.3390/cancers17030339 · Cited by 3 · see citing works
Gerosuppressive and Senolytic Nutrients
Nehlin, J. O. (2021) · Healthy ageing and longevity · doi:10.1007/978-3-030-83017-5_22 · Cited by 3 · see citing works
Sea urchin bioactive compounds: emerging interventions for age-related diseases
Escobar-Doncel, B., Papakosta, A., Storm‐Mathisen, J., & Fang, E. F. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102979 · Cited by 2 · see citing works
Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease
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Targeting anxiety and senescence with senolytics
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Potential approaches for intervening aging
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DRUGS WITH SENOLYTIC ACTIVITY: PROSPECTS AND POSSIBLE LIMITATIONS
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Drugs with Senolytic Activity: Prospects and Possible Limitations
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DNA damage and histone variants
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Senotherapy as a Novel Therapeutic Method in Cancer Treatment: With a Focus on Head and Neck Cancer
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Tirzepatide reduces diet-induced senescence and NETosis-mediated liver fibrosis in micePreprint
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Rôle de FAT10 dans la sénescence des hépatocytes et le développement de la NASH
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Espinoza-Pérez, C., Osorio, J. M., Vélez, R., Bustos, J. O., Machuca, V., Rivas, S., Sánchez‐Ferrer, C. F., Peiró, C., Vivar, R., & Dı́az-Araya, G. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1877172
- Authors
- Raffaele, M., Kovacovicova, K., Frohlich, J., Lo Re, O., Giallongo, S., Oben, J. A., Faldyna, M., Leva, L., Giannone, A. G., Cabibi, D., & Vinciguerra, M.
- Affiliations
- International Clinical Research Center, St. Anne's University Hospital Brno (CZ)
- Masaryk University (CZ)
- University College London (GB)
- Veterinary Research Institute (CZ)
- University of Palermo (IT)
- Medical University of Varna (BG)
- Corresponding author
- Raffaele, Marco
- Vinciguerra, Manlio
- ORCID
- Venue
- Cell Communication and Signaling
- Published
- 2021-04-08
- Volume
- 19
- Issue
- 1
- Pages
- 44-44
- ISSN
- 1478-811X (ISSN-L)
- PMC
- PMC8034117
- OpenAlex
- W3144190080
- Cited by
- 60
- References
- 39
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 10 · 2023: 16 · 2022: 9 · 2021: 7
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Communication and Signaling (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- Funders
- European Social Fund (CZ.02.1.01/0.0/0.0/15_003/0000492)
- Ministerstvo Zdravotnictví Ceské Republiky (NV18-03-00058)
- Ministerstvo Zemědělství (RO0518)
- Horizon 2020 Framework Programme (856871)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- senolytics, dasatinib, quercetin, non-alcoholic fatty liver disease, hepatocellular carcinoma, cellular senescence, aging, obesity, diethylnitrosamine, high-fat diet, liver fibrosis, liver inflammation, drug-induced liver injury
- MeSH terms
- Dasatinib, Senotherapeutics, Aging, Animals, Diethylnitrosamine, Disease Models, Animal, Gene Expression Regulation, Liver Diseases, Male, Mice, Inbred C57BL, Obesity, Quercetin, Disease Progression, Mice, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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