Sexual dimorphism in liver cell cycle and senescence signalling pathways in young and old rats.

Key points In rats RNA-Seq analysis showed sexual dimorphism in gene expression across the life-course between 110 and 650 days of life. Fourteen times more liver transcriptome and six times more pathway changes were observed in males compared with females. We observed significant changes in several signaling pathways during ageing. In this study, we focussed our bioinformatic analysis to changes in genes and protein product related to cell cycle and cellular senescence pathways. Males showed decreased protein product and expression of the key genes CDK2, CDK4 responsible for cell cycle progression while females increased protein product and expression of p21 and p15 key genes responsible for cell cycle arrest. We conclude that normative rat hepatic ageing involves changes in cellular pathways that control the cell cycle arrest but through changes in different genes in males and females. These findings identify mechanisms that underlie the well-established sexual dimorphism in ageing. Abstract At the molecular level, cellular ageing involves changes in multiple gene pathways. Cellular senescence is both an important initiator and a consequence of natural ageing. Senescence results in changes in multiple cellular mechanisms that result in a natural decrease in cell cycle activity. Liver senescence changes impair hepatic function. Given the well-established sexual dimorphism in ageing, we hypothesized that the natural hepatic ageing process is driven by sex-dependent gene mechanisms. We studied our well-characterized normal, chow-fed rat ageing model, lifespan ∼850 days, in which we have reported ageing of metabolism, reproduction and endocrine function. We performed liver RNA-seq on males and females at 110 and 650 days (d) to determine changes in the cell cycle and cellular senescence signaling pathways. We found that natural liver ageing shows sexual dimorphism in these pathways. RNA-seq revealed more male (3967) than female (283) differentially expressed genes (DEG) between 110d and 650d. Cell cycle pathway signaling changes in males showed decreased protein and expression of key genes (CDK2, CDK4, Cycd and PCNA) and increased p57 at 650d vs. 110d. In females, protein and gene expression of cell growth regulators, e.g. p15 and p21, that inhibit cell cycle G1 progression were increased. The cell senescence pathway also showed sexual dimorphism. Igfbp3, mTOR and p62 gene and protein decreased in males while Tgfb3 increased in females. Understanding the involvement of cell cycling and cellular senescence pathways in natural ageing will advance evaluation of mechanisms associated with altered ageing and frailty trajectories. This article is protected by copyright. All rights reserved.