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MASLD does not affect fertility and senolytics fail to prevent MASLD progression in male mice
Jessica D Hense1, Driele N Garcia1, Bianka M Zanini1
1Nutrition College, Universidade Federal de Pelotas, Rua Gomes Carneiro, 1 Sala 228, Pelotas, RS, CEP 9601-610, Brazil.
Abstract:
Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.
Insights
Senolytic drugs did not reduce liver damage or inflammation in mice with metabolic dysfunction-associated steatotic liver disease (MASLD). Fertility in male mice also remained unaffected by MASLD or senolytic treatments.
Area of Science:
- Hepatology
- Cellular senescence
- Metabolic diseases
Background:
- Cellular senescence contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis.
- The efficacy of senolytic drugs in mitigating MASLD-induced liver damage and their impact on male fertility are not well-established.
Purpose of the Study:
- To investigate the protective effects of senolytic drugs against liver damage and male reproductive dysfunction in a mouse model of MASLD.
- To determine if senolytics can reverse established liver damage, senescence, and inflammation in MASLD.
Main Methods:
- Male mice were fed a choline-deficient western diet (WD) to induce MASLD.
- Mice received senolytic treatments (dasatinib + quercetin or fisetin) or vehicle control.
- Liver damage, cellular senescence, inflammation, sperm quality, and fertility were assessed.
Main Results:
- Choline-deficient WD induced MASLD characteristics, including liver damage, fibrosis, triglyceride accumulation, and increased senescence and inflammation.
- Senolytic treatments did not significantly reduce liver damage, senescence, or systemic inflammation.
- MASLD and senolytic treatments did not alter sperm quality or fertility in male mice.
Conclusions:
- Senolytic drugs demonstrated limited efficacy in ameliorating established liver damage, senescence, and inflammation in a mouse model of MASLD.
- MASLD and senolytic interventions did not impact male fertility in the studied mice.
- Liver damage and senescence in MASLD may not be reversible with current senolytic therapies.
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