Abstract
SummaryCalorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver‐specific responses caused by a diet switch to a medium‐fat (MF) diet in 24‐month‐old lifelong, CR‐exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine‐week‐old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitum MF feeding (CR‐MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long‐term exposure to the CR regimen, mice in the CR‐MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR‐improved survival was observed in the diet switch group. The liver transcriptomic profile of CR‐MF mice largely shifted to a profile similar to the MF‐fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR‐MF‐exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies.
Highlights
Aging has been described as an important risk factor for most chronic diseases, largely due to the impaired capacity to maintain homeostasis and resilience against environmental stress or damage at old age
Other fatty acid uptake/transporter genes were explored (Fig. S6 for genes without significant alteration), and we found that the expression levels of caveolin 1 (Cav1) (Figure 5b; confirmed by qPCR analysis in Fig. S4) and fatty acid binding protein 4 (Fabp4) (Figure 5b) were elevated in the Calorie restriction (CR)-MF diet group, implying that, while the cluster of differentiation 36 (Cd36) expression was repressed, there were alternatives for fatty acid uptake
We show that a number of CRrelated features were maintained in the CR-MF group: (i) the prevention of hepatic fibrosis and injury, (ii) the improved survival, and (iii) the expression levels of a subset of CR-related genes that were not altered by 4-month exposure to the MF diet
Summary
Aging has been described as an important risk factor for most chronic diseases, largely due to the impaired capacity to maintain homeostasis and resilience against environmental stress or damage at old age. For the liver, aging has been associated with an increasing risk to develop nonalcoholic fatty disease (NAFLD) (Argo, Northup, Al-Osaimi, & Caldwell, 2009; Frith, Day, Henderson, Burt, & Newton, 2009). NAFLD covers a spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Aging has been linked to NAFLD development through a number of commonly shared molecular mechanisms associated with both the NAFLD/NASH development and hallmarks of aging, for example, reactive oxygen species formation, DNA damage, and hepatocyte senescence (Lopez-Otın, Blasco, Partridge, Serrano, & Kroemer, 2013).
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