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Biomolecules
Volume 15
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10.3390/biom15121727
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Aging Promotes Spontaneous Liver Injury: Insights from Metabolic, Inflammatory, and Fibrotic Pathways in C57BL/6 Mice

by
Poonam Sagar
1,2,†,
Sathish Kumar Perumal
1,2,†,
Ramachandran Rajamanickam
1,2,
Ramesh Bellamkonda
1,3,
Sundararajan Mahalingam
1,3,
Natalia A. Osna
4,
Karuna Rasineni
1,3,* and
Kusum K. Kharbanda
1,2,3,*
1
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
2
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
3
Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
4
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2025, 15(12), 1727; https://doi.org/10.3390/biom15121727
Submission received: 4 November 2025 / Revised: 26 November 2025 / Accepted: 3 December 2025 / Published: 11 December 2025
(This article belongs to the Section Molecular Medicine)
Review Reports Versions Notes

Abstract

Aging is a critical factor influencing susceptibility to hepatic injury. In this study, the spontaneous development of liver injury with advancing age and potential sex-related differences in these processes are examined. This study focuses on key mechanisms such as fatty acid metabolism, immune response, and cellular stress in male and female C57BL/6 mice. Aged male and female mice (20 to 22 months old) exhibited higher body weight and an altered metabolic profile and fatty acid metabolism compared to their younger counterparts (8 to 10 weeks old). In addition, increased oxidative stress, cellular senescence, expression of inflammatory markers, and cytokines/chemokines levels were also observed in aged male and female mice compared to younger mice. Furthermore, the aged mice exhibited increased indices of hepatic fibrosis, evident from the upregulation of smooth muscle actin-α, collagen, and transforming growth factor-β. In conclusion, aging promotes spontaneous liver injury by increasing indices of oxidative stress, steatosis, inflammation, and fibrosis. These results highlight the impact of chronological age on the liver that can increase its susceptibility to secondary hepatic stressors such as alcohol, high-calorie diet, or hepatotropic infections. Understanding how metabolic and inflammatory pathways change with aging in males and females is essential for elucidating the mechanisms that drive chronic liver disease progression. These insights are particularly important for developing targeted, sex-specific prevention and therapeutic strategies for the aging population.
Keywords: aging; liver injury; Steatosis; hepatic fibrosis; inflammation; metabolic dysfunction aging; liver injury; Steatosis; hepatic fibrosis; inflammation; metabolic dysfunction

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MDPI and ACS Style

Sagar, P.; Perumal, S.K.; Rajamanickam, R.; Bellamkonda, R.; Mahalingam, S.; Osna, N.A.; Rasineni, K.; Kharbanda, K.K. Aging Promotes Spontaneous Liver Injury: Insights from Metabolic, Inflammatory, and Fibrotic Pathways in C57BL/6 Mice. Biomolecules 2025, 15, 1727. https://doi.org/10.3390/biom15121727

AMA Style

Sagar P, Perumal SK, Rajamanickam R, Bellamkonda R, Mahalingam S, Osna NA, Rasineni K, Kharbanda KK. Aging Promotes Spontaneous Liver Injury: Insights from Metabolic, Inflammatory, and Fibrotic Pathways in C57BL/6 Mice. Biomolecules. 2025; 15(12):1727. https://doi.org/10.3390/biom15121727

Chicago/Turabian Style

Sagar, Poonam, Sathish Kumar Perumal, Ramachandran Rajamanickam, Ramesh Bellamkonda, Sundararajan Mahalingam, Natalia A. Osna, Karuna Rasineni, and Kusum K. Kharbanda. 2025. "Aging Promotes Spontaneous Liver Injury: Insights from Metabolic, Inflammatory, and Fibrotic Pathways in C57BL/6 Mice" Biomolecules 15, no. 12: 1727. https://doi.org/10.3390/biom15121727

APA Style

Sagar, P., Perumal, S. K., Rajamanickam, R., Bellamkonda, R., Mahalingam, S., Osna, N. A., Rasineni, K., & Kharbanda, K. K. (2025). Aging Promotes Spontaneous Liver Injury: Insights from Metabolic, Inflammatory, and Fibrotic Pathways in C57BL/6 Mice. Biomolecules, 15(12), 1727. https://doi.org/10.3390/biom15121727

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