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Review
. 2022 Jul 11;13(4):1239-1251.
doi: 10.14336/AD.2022.0318.

Non-alcoholic Fatty Liver Disease and Liver Fibrosis during Aging

Yuan Li  1 , Nia T Adeniji  1 , Weiguo Fan  1 , Koshi Kunimoto  1 , Natalie J Török  1
Affiliations
Review

Non-alcoholic Fatty Liver Disease and Liver Fibrosis during Aging

Yuan Li et al. Aging Dis. .

Abstract

Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease-related mortality. The prevalence of NAFLD/NASH is expected to increase given the epidemics of obesity and type 2 diabetes mellitus. Older patients are disproportionally affected by NASH and related complications such as progressive fibrosis, cirrhosis and hepatocellular carcinoma; however, they are often ineligible for liver transplantation due to their frailty and comorbidities, and effective medical treatments are still lacking. In this review we focused on pathways that are key to the aging process in the liver and perpetuate NAFLD/NASH, leading to fibrosis. In addition, we highlighted recent findings and cross-talks of normal and/or senescent liver cells, dysregulated nutrient sensing, proteostasis and mitochondrial dysfunction in the framework of changing metabolic milieu. Better understanding these pathways during preclinical and clinical studies will be essential to design novel and specific therapeutic strategies to treat NASH in the elderly.

Keywords: NAFLD; aging; fibrosis; liver; senescence.

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Conflict of interest statement

Conflicts of interest The authors have declared that no conflict of interest exists.

Figures

Figure 1.
Figure 1.
Schematic summary of aging-related events predisposing to fibrogenic injury in NASH. Aging-mediated changes in several adaptive pathways exacerbate NASH with enhanced necroinflammation, fibrogenic processes, and reduced fibrolysis. These include cellular senescence, that has distinct, cell type-dependent effects, dysregulated nutrient-sensing pathways (e.g., mTOR, AMPK, GCN2, SIRTs), loss of proteostasis, impaired autophagy, and mitochondrial dysfunction. These either alone or in combination can drive the activation of stellate cells and progression of fibrosis. AMPK, AMP-activated protein kinase; GCN2, general control nonderepressible 2; mTOR, mammalian target of rapamycin; SIRT, Sirtuin; HSC, hepatic stellate cell; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cell; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NOX, NADPH oxidase; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.
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