Metabolism: clinical and experimental · 2025
Exercise mitigates liver senescence but does not outmatch dietary restriction in obesity-related MASLD.
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Katsarou Angeliki, Papadopoulos Grigorios, Moustakas Ioannis I, Papadopetraki Argyro, Moustogiannis Athanasios, Legaki Aigli-Ioanna, Giannousi Eirini, Agrogiannis George, Pantelis Pavlos, Veroutis Dimitris, Evangelou Konstantinos, Kotsinas Athanassios, Gorgoulis Vassilis G, Philippou Anastassios, Koutsilieris Michael, Chatzigeorgiou Antonios
Аннотация
BACKGROUND: The present study aims at deciphering the individual or combined benefits of aerobic exercise and dietary restriction on liver senescence, a state characterized by cell cycle arrest and simultaneous resistance to apoptosis, which is considered an established hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: C57BL6 mice were subjected to a normal diet (ND) for 20 weeks or a high-fat diet (HFD) supplemented with 5 % High-fructose Corn Syrup (HFCS) for 12 weeks, followed by eight-week interventions, including dietary restriction (DR), aerobic exercise (EX), a combination of both (DREX) or continuation of a HFD-HFCS diet without intervention. Biomarkers of senescence were analyzed in terms of their liver mRNA expression levels, while GL13 and p21WAF1/CIP1 immunohistochemical stainings were conducted to examine the levels of senescence-associated lipofuscin and p21WAF1/CIP1 respectively, to finally investigate their relationship with the grade of hepatic steatosis and fibrosis observed in the studied mice.
RESULTS: DR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis and fibrosis, to a greater extent than the respective amelioration driven by aerobic exercise only in HFDEX animals. A statistically significant increase of mRNA expression was detected for cyclin-dependent kinase p21WAF1/CIP1 in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. Immunohistochemical stainings for GL13 and p21WAF1/CIP1, as well as for p16INK4A confirmed the aforementioned alterations of p21WAF1/CIP1 at the tissular level while also revealed a p16INK4A elevation in HFD livers which was reversed only upon DR/DREX.
CONCLUSION: Liver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.
METHODS: C57BL6 mice were subjected to a normal diet (ND) for 20 weeks or a high-fat diet (HFD) supplemented with 5 % High-fructose Corn Syrup (HFCS) for 12 weeks, followed by eight-week interventions, including dietary restriction (DR), aerobic exercise (EX), a combination of both (DREX) or continuation of a HFD-HFCS diet without intervention. Biomarkers of senescence were analyzed in terms of their liver mRNA expression levels, while GL13 and p21WAF1/CIP1 immunohistochemical stainings were conducted to examine the levels of senescence-associated lipofuscin and p21WAF1/CIP1 respectively, to finally investigate their relationship with the grade of hepatic steatosis and fibrosis observed in the studied mice.
RESULTS: DR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis and fibrosis, to a greater extent than the respective amelioration driven by aerobic exercise only in HFDEX animals. A statistically significant increase of mRNA expression was detected for cyclin-dependent kinase p21WAF1/CIP1 in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. Immunohistochemical stainings for GL13 and p21WAF1/CIP1, as well as for p16INK4A confirmed the aforementioned alterations of p21WAF1/CIP1 at the tissular level while also revealed a p16INK4A elevation in HFD livers which was reversed only upon DR/DREX.
CONCLUSION: Liver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.