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. 2022 Dec 16;7:391. doi: 10.1038/s41392-022-01251-0

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — Crosstalk between aging and NAFLD in aging-related metabolic disease. Aging is related to impaired insulin sensitivity. Under insulin-resistant conditions, the amount of NEFAs in the circulation that are derived from white adipose tissue lipolysis increases, resulting in fat overload in the liver. Aging-related impairment of autophagy and mitochondrial dysfunction reduce hepatic lipid droplet breakdown and fatty acid β-oxidation, respectively. Moreover, under conditions of aging-related obesity, hepatic DNL increases due to ChREBP pathway activation. These disorders of lipid metabolism result in the pathogenesis of NAFL. Following hepatic lipid metabolic impairment and lipid accumulation, lipotoxicity and ER stress are induced, and mitochondrial function further worsens, leading to oxidative stress, hepatocyte apoptosis, hepatocyte senescence and inflammation and thus promoting the progression of NASH. Senescent hepatocytes secrete proinflammatory cytokines (IL-6, IL-8, TNF-α, and IL-1β) that stimulate resident KCs in the liver. Activated KCs present M1-like proinflammatory activity and secrete cytokines to induce monocyte infiltration into the liver and differentiation into macrophages. Furthermore, impaired resident KCs can induce monocyte differentiation into monocyte-derived KCs to maintain the KC pool in the liver. Both resident KCs and monocyte-derived KCs interact with HSCs and activate HSCs to produce collagen. In addition, dysbiosis of the gut microbiota impairs intestinal permeability; thus, bacteria-derived molecules enter the liver via the portal vein and in turn influence hepatic metabolism and the progression of NAFLD. However, hepatic metabolic impairment and inflammation further worsen insulin resistance and dysbiosis of the gut microbiota. Moreover, hepatic lipid metabolic disorder results in hypercholesterolemia and hypertriglyceridemia, leading to accelerated progression of atherosclerosis. (Fig. 4 includes modified templates from Servier Medical Art (http://www.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License.)