Project description:Leanness is associated with increased lifespan and is linked to favorable metabolic conditions promoting life extension. We show here that deficiency of the lipid synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which reduces body fat in mice, promotes longevity. Female DGAT1-deficient mice were protected from age-related increases in body fat, non-adipose tissue triglycerides, and markers of inflammation in white adipose tissue. These metabolic changes were accompanied by an increased mean and maximal lifespan of ~25% and ~10%, respectively. The gene expression profile of DGAT1-deficient mice was not highly correlated with calorie restriction of sex and age matched wild-type littermates. Our findings indicate that loss of DGAT1-mediated lipid synthesis results in leanness, protects against age-related metabolic consequences, and thus extends longevity. Liver gene expression profiles between short-term calorie restricted wild-type (WTCR) and Dgat1 deficient (KO) middle-aged (15-16 mo) female mice were compared to determine if calorie restriction and Dgat1 deficiency rely on common regulatory pathways for the promotion of longevity. Both CR and KO were compared to middle-aged wild-type female littermates fed a standard chow diet ad libitum (WTAL).
Project description:Leanness is associated with increased lifespan and is linked to favorable metabolic conditions promoting life extension. We show here that deficiency of the lipid synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which reduces body fat in mice, promotes longevity. Female DGAT1-deficient mice were protected from age-related increases in body fat, non-adipose tissue triglycerides, and markers of inflammation in white adipose tissue. These metabolic changes were accompanied by an increased mean and maximal lifespan of ~25% and ~10%, respectively. The gene expression profile of DGAT1-deficient mice was not highly correlated with calorie restriction of sex and age matched wild-type littermates. Our findings indicate that loss of DGAT1-mediated lipid synthesis results in leanness, protects against age-related metabolic consequences, and thus extends longevity.
Project description:Age influence the severity and progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), yet their specific contributions to liver injury and molecular alterations remain unclear. This study investigates how aging influences MASLD progression in a murine model, focusing on histological, biochemical, and transcriptomic differences. Young (2-month-old) and middle-aged (10-month-old) C57BL/6N male and female mice were fed chow (CD) or a high-fat diet (HFD) for 20 weeks. Metabolic and biochemical parameters were assessed, and liver tissue analyzed by histology and RNA sequencing. Differentially expressed genes were identified with Limma and GO enrichment. Translational relevance was evaluated using the unbiased ranking MASLD Human Proximity Score (MHPS). Middle-aged males developed insulin resistance and more severe hepatic injury than young males after HFD. NAFLD Activity Score confirmed more advanced disease in middle-aged mice, with extensive lipid accumulation, hepatocellular hypertrophy, inflammation and fibrosis. Females showed milder hepatic damage. Diet was the main determinant of transcriptomic changes in males, with young HFD mice activating tissue remodeling pathways and middle-aged mice showing inflammatory activation and reduced energy metabolism. In females, transcriptomic responses were attenuated, with metabolic and stress-related changes restricted largely to young HFD animals. MHPS ranked the middle-aged male model highest in translational similarity to human MASLD.These findings highlight that age is a primary determinant of hepatic responses to dietary stress, with sex-specific modulation. The middle-aged male model closely mirrors human MASLD, providing a more relevant preclinical platform to improve patient stratification and therapeutic discovery.
Project description:The effect of a short-term calorie restricted diet was evaluated in six strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age Tissues were collected from mice at 22 weeks of age; there were 96 microarrays used in total: for each of the 6 strains of mice, there were 8 control-fed mice and 8 calorie restricted mice (one individual mouse per microarray)
Project description:The effect of a short-term calorie restricted diet was evaluated in six strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:The effect of a short-term calorie restricted diet was evaluated in heart in seven strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:The effect of a short-term calorie restricted diet was evaluated in cerebral cortex in seven strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:The effect of a short-term calorie restricted diet was evaluated in gastrocnemius muscle (GASTROC) in seven strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:The effect of a short-term calorie restricted diet was evaluated in epididymal white adipose tissue (WAT) in seven strains of mice The dietary intervention was initiated at 8 weeks of age and continued until 22 weeks of age
Project description:In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1Δhep) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1Δhep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1Δhep mice during fasting, highlighting the increased recruitment of macrophages to the liver.
