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Plasticity of life-long calorie restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age

ABSTRACT: Calorie 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 life-long, 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, 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 1578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the life-long 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE102593 | GEO | 2018/01/24

REPOSITORIES: GEO

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Project description:Mice and diets. One-month-old male mice of the long-lived B6C3F1 strain were purchased from Harlan (Indianapolis, IN) and maintained as described after weaning (15). Mice were housed in groups of 4 per cage and fed a non-purified diet, PMI Nutrition International Product #5001 (Purina Mills, Richmond, IN). At 5 months of age, the mice were individually housed, and randomly assigned to one of two groups, control (CON) or long-term CR (LTCR). CON mice were fed 93 kcal per week of a defined control diet (AIN-93M, Diet No. F05312, BIO-SERV). LTCR mice were fed 52.2 kcal per week of a defined CR diet (AIN-93M 40% Restricted, Diet No. F05314, BIO-SERV). The LTCR mice consumed approximately 40% fewer calories than mice in the CON mice. The CR diet was enriched so that the CR mice consumed approximately the same amount of protein, vitamins, and minerals per gram body weight as the control mice. Experimental design. At 20 months of age, cohorts of mice in the CON group were randomly assigned to one of 7 experimental groups (Fig. 1). A CON group continued to be fed 93 kcal per week of control diet for 8 weeks. A CR8 group was fed 77 kcal per week of CR diet for 2 weeks, followed by 52.2 kcal per week of CR diet for 6 weeks. The remaining dietary groups were fed the control diets containing, respectively, metformin (MET; Sigma, St. Louis, MO), glipizide (GLIP; Sigma), GLIP plus MET (GM), rosiglitazone (ROS; Avandia, SmithKline Beecham) or soy isoflavone extract (SOY; NOVASOY 400, Life Extension Foundation) for 8 weeks at the dosages indicated in Table 1. The drugs were mixed with powdered control diet and cold-pressed into one gram pellets (BIO-SERV Inc.). At 0900, all mice were fed 2/7 of the weekly allotment of food on Monday and Wednesday and 3/7 on Friday. The mice had free access to acidified tap water. They were fasted for 48 hours and killed by cervical dislocation at 22 months of age. No signs of pathology were detected in the animals used for the studies reported (n=4 per group). Organs were removed rapidly, flash frozen, and stored in liquid nitrogen. The weights of the mice were monitored bi-weekly. Mouse weights are given in Table 1. Measurement of specific mRNA levels. Liver total RNA was isolated as described from livers of pathology-free mice in each group (n=4 per group) (13). mRNA levels were measured using Affymetrix mouse U74Av2 arrays according to standard Affymetrix protocols (Affymetrix). Probe set expression measurement and normalization. After hybridization and scanning, raw image files were converted to probe set data (*.CEL files) using Microarray Suite (MAS 5.0). Probe set data from all 32 arrays were simultaneously analyzed with the Robust multichip Average (RMA) method to generate normalized expression measures for each probe set (Fig. 2; Ref. 24) The data were further filtered to exclude probe data sets that were “Absent” across all 32 arrays according to the MAS 5.0 detection algorithm (1,47). Keywords = CR mimetics Keywords = microarray profiling Keywords = drug discovery Keywords = gene-expression biomarkers Keywords: other

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Plasticity of life-long calorie restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age

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