Early onset-caloric restriction alleviates ageing-associated steatohepatitis in male mice via restoring mitochondrial homeostasis

Abstract

Abstract Non-alcoholic fatty liver disease is associated with ageing, and impaired mitochondrial homeostasis is the main cause for hepatic ageing. Caloric restriction (CR) is a promising therapeutic approach to reduce fatty liver. The present study aimed to investigate the effect of early onset CR on decelerating the progression of ageing-related steatohepatitis. The potential mechanisms regarding to mitochondria were further evaluated. Eight-week-old C57BL/6 male mice (n = 21) were randomly divided into three groups, Young-AL (AL, ad libitum), Aged-AL, and Aged-CR (60% intake of AL). Mice were sacrificed at the age of 7 months (Young) or 20 months (Aged). Aged-AL mice displayed the greatest body weight, liver weight and liver relative weight among treatments. Ageing caused a great grade of steatosis, lipid peroxidation, inflammation, and fibrosis in the liver. Mega mitochondria with short, randomly organized crista were noticed in the aged liver. CR ameliorated these negative phenomena in aged liver. Ageing was accompanied with a lower level of hepatic ATP, while CR restored it. Mitochondrial-related protein expressions of respiratory chain complexes (NDUFB8 and SDHB), and fission (DRP1) were suppressed in aged liver. Proteins related to mitochondrial biogenesis (TFAM), and fusion (MFN2) were upregulated in aged liver. CR reversed the expressions of SDHB, TFAM, DRP1, and MFN2 in aged liver. To conclude, early onset CR significantly prevented the negative effect of ageing-associated steatohepatitis, including lipid peroxidation, inflammation, steatosis and fibrosis. Moreover, CR eased ageing-associated energy deficit in liver partially via maintaining mitochondrial homeostasis.