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Liver, ageing and disease

Nature Reviews Gastroenterology & Hepatology volume 22, pages 680–695 (2025)Cite this article

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Abstract

As the global population ages, research on the biology of ageing and its role in chronic disease is expanding, alongside a growing clinical focus on the unique needs of older adults. In the past, the liver was not thought to undergo substantial age-related changes, nor was there thought to be any liver disease characteristic of older adults. Current studies challenge this perspective, revealing that ageing substantially influences liver pathophysiology at the organ level and within each of the liver cell types. These observations have implications for understanding the pathogenesis of liver diseases common in older adults, including hepatocellular carcinoma, hypoxic hepatitis and metabolic dysfunction-associated steatotic liver disease. Previously, managing older patients with liver disease mostly addressed age-related changes in drug metabolism and liver function tests. However, current clinical practice increasingly emphasizes age-specific issues such as frailty, sarcopenia, multimorbidity and polypharmacy. Given the liver’s pivotal role in systemic metabolism, immunity and detoxification, ageing of the liver can contribute to systemic diseases. In the future, interventions that target ageing biology might offer new treatment options for liver diseases. Here, we review those age-related changes in the liver that have substantial biological and clinical consequences for older adults.

Key points

  • The liver undergoes ageing processes that are comparable to those of other organs and tissues, contributing to impaired liver function and increased susceptibility to liver diseases in older adults.

  • Age-related changes in hepatocytes and non-parenchymal liver cells drive fibrosis, inflammation, steatosis, metabolic dysfunction, reduced detoxification and impaired regenerative capacity.

  • Elevated serum liver enzyme levels are often a result of comorbidities, whereas low serum alanine transaminase levels are associated with older age, frailty and increased mortality.

  • Liver diseases prevalent in older adults, including hepatocellular carcinoma and metabolic dysfunction-associated steatotic liver disease, share pathogenic mechanisms with the biological processes of ageing.

  • Liver ageing is associated with cardiometabolic syndromes, including dyslipidaemia, insulin resistance and vascular disease, and with neurodegenerative conditions such as dementia.

  • The liver is a key target for longevity-extending interventions, including pharmacological and nutritional strategies to modulate ageing processes that might mitigate liver diseases.

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Fig. 1: Structural changes in the ageing liver.
Fig. 2: Epidemiology of the effects of ageing on liver diseases.

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Data availability

Epidemiological data referred to in Fig. 2 and information on their source are available in Supplementary Tables 1–4.

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Acknowledgements

The authors acknowledge funding by the Australian National and Health Medical Research Council (Investigator Grant no. 2025511 (to D.G.L.C.) and Programme Grant no. 1149976 (to S.J.S. and D.G.L.C.)) and the MRFF Targeted Translation Research Accelerator Program (to N.J.H., V.C.C. and D.G.L.C.).

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Authors and Affiliations

  1. ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia

    David G. Le Couteur, Meng C. Ngu, Nicholas J. Hunt, Amanda E. Brandon & Victoria C. Cogger

  2. Concord Hospital, Sydney, New South Wales, Australia

    David G. Le Couteur, Meng C. Ngu, Nicholas J. Hunt, Amanda E. Brandon & Victoria C. Cogger

  3. Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia

    David G. Le Couteur, Amanda E. Brandon & Stephen J. Simpson

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All authors researched data for the article. All authors contributed substantially to discussion of the content. D.G.L.C. and V.C.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to David G. Le Couteur.

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Competing interests

D.G.L.C. has received consultancy fees via the Reimbursement Advisory Expert Panel (REAP) for independent pre-submission advice to pharmaceutical companies on regulatory and funding applications to government. D.G.L.C., N.J.H. and V.C.C. are founder members and N.J.H. is the CEO of a start-up company (Endo Axiom) with Sydney University, Sydney Local Health District and Proto Axiom, which hold patents on nanomedicines for the treatment and prevention of diabetes mellitus. The other authors declare no competing interests.

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Le Couteur, D.G., Ngu, M.C., Hunt, N.J. et al. Liver, ageing and disease. Nat Rev Gastroenterol Hepatol 22, 680–695 (2025). https://doi.org/10.1038/s41575-025-01099-z

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