Exercise mitigates liver senescence but does not outmatch dietary restriction in obesity-related MASLD

TY - JOUR

T1 - Exercise mitigates liver senescence but does not outmatch dietary restriction in obesity-related MASLD

AU - Katsarou, Angeliki

AU - Papadopoulos, Grigorios

AU - Moustakas, Ioannis I.

AU - Papadopetraki, Argyro

AU - Moustogiannis, Athanasios

AU - Legaki, Aigli Ioanna

AU - Giannousi, Eirini

AU - Agrogiannis, George

AU - Pantelis, Pavlos

AU - Veroutis, Dimitris

AU - Evangelou, Konstantinos

AU - Kotsinas, Athanassios

AU - Gorgoulis, Vassilis G.

AU - Philippou, Anastassios

AU - Koutsilieris, Michael

AU - Chatzigeorgiou, Antonios

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/9

Y1 - 2025/9

N2 - 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.

AB - 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.

KW - Aerobic exercise

KW - Dietary restriction

KW - Liver senescence

KW - Metabolic dysfunction-associated steatotic liver disease

KW - p21

KW - Steatosis

UR - https://www.scopus.com/pages/publications/105007859383

U2 - 10.1016/j.metabol.2025.156325

DO - 10.1016/j.metabol.2025.156325

M3 - Article

C2 - 40505886

AN - SCOPUS:105007859383

SN - 0026-0495

VL - 170

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

M1 - 156325

ER -