GSE160153
Liver sexual dimorphism in key signaling pathways across the rat life course
Introduction: At the molecular level, cellular aging involves changes in multiple gene pathways, which can produce many aging phenotypes. In the liver, senescence changes lead to impaired hepatic function. We hypothesized that the natural hepatic aging process is driven by sex-dependent mechanisms. Purpose: We studied our well-established model of aging in which we have previously determined aging of metabolism, reproduction and endocrine systems. We performed liver transcriptomics (RNA-seq) on male and female rats at 110 and 650 days (d) fed with normal rat chow to determine changes key signaling pathways related to senescence processes. Methods: To identify the functional F1 liver changes due to natural aging processes, we evaluated the differentially expressed genes (DEGs) between 650d and 110d in males and females, with separate pairwise comparisons due to the marked differences. Genes were filtered based on ?1.4 fold change (FC) and nominal P value <0.05 (Student?s t-test). Results: We found that the natural liver aging process shows sex-differences. RNA-seq revealed more male (3,967) than female (283) differentially expressed genes (DEG) and pathways over the 110d to 650d period studied. Cell cycle pathway signaling in males was accompanied by decreased protein and gene expression of key genes (CDK2, CDK4, Cycd and PCNA) and an increase of p57 at 650d vs. 110d. In females, protein and gene expression of cell growth regulators such as p15 and p21, that inhibit cell cycle G1 progression were increased. Moreover, additionally the cell senescence pathway showed sexual dimorphism in liver gene regulation. Conclusions: Our results demonstrate how the natural aging process affects the liver transcriptome signature in a sex-dependent manner, specifically in cell cycle and cell senescence pathways, pathways that contribute in a major fashion to the development of aging-induced liver diseases. Understanding cellular senescence pathways involved in the natural aging process will aid evaluation of mechanisms associated with altered aging and frailty trajectories. Overall design: Liver transcriptomic profiles from 110d and 650d male and female Wistar rats were analyzed by RNA-seq. 24 samples, 6 animals per group: 1) 110 d MALE n=6, 2) 650d MALE,n=6; 3) 110d FEMALE, n=6 and 4) 650d FEMALE n=6