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

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 to determine changes in the cell cycle and cellular senescence signalling 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 between 110 and 650 days. Cell cycle pathway signalling changes in males showed decreased protein and expression of key genes (Cdk2, Cdk4, Cycd and PCNA) and increased expression ofp57 at 650 vs 110 days. In females, protein and gene expression of cell growth regulators, e.g. p15 and p21, which inhibit cell cycle G1 progression, were increased. The cell senescence pathway also showed sexual dimorphism. Igfbp3, mTOR and p62 gene and protein expression decreased in males while those ofTgfb3 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. 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. Significant changes were observed in several signalling pathways during ageing. Bioinformatic analysis were focused on changes in genes and protein products related to cell cycle and cellular senescence pathways. Males showed decreased protein product and expression of the key genes Cdk2 and Cdk4 responsible for cell cycle progression while females increased protein product and expression of p21 and p15, key genes responsible for cell cycle arrest. In conclusion, normative rat hepatic ageing involves changes in cellular pathways that control 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.