Ageing and inflammation with focus on end-stage renal diseases : genetic and epigenetic factors

Abstract: The presence of ageing-associated disorders at a relatively young age in patients suffering from chronic kidney disease (CKD) has led to the hypothesis that CKD is characterized by accelerated ageing, resulting in a marked discrepancy between chronological and biological age. Factors that accelerate biological ageing, such as inflammation, oxidative stress, and toxins, impact the processes of cellular senescence and/or apoptosis, thereby shortening the life span of cells, and consequently, of the organism as a whole. Numerous studies have linked increased cellular senescence and apoptosis to disorders commonly associated with ageing, such as cardiovascular disease (CVD), osteoporosis, and cognitive dysfunction – all of which are common in the uremic phenotype. In Study I, we demonstrate that increased arterial gene expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), a known inducer of cellular senescence, is associated with the presence of CVD and vascular calcification (VC) in CKD patients. Furthermore, there is a positive correlation between CDKN2A expression and the expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2), both of which are involved in osteogenesis. We also show a tentative relationship between a higher degree of VC and increasing p16INK4a expression, a cognate protein of CDKN2A. In Study II, we use telomere length as a biomarker of biological age, showing that CKD patients have shorter telomeres than non-CKD controls. In addition, our results indicate a possible association between longitudinal telomere length, folate, and immunosuppressive treatment in patients undergoing renal transplantation (RTx). This suggests that anti- metabolite therapy may have an impact on biological ageing in RTx patients. In Study III, we show that the global methylation status in dialysis and RTx patients at baseline and after 12 months of renal replacement therapy (RRT) differs at several sites in the genome from that of age- and gender-matched healthy controls. Furthermore, differences in methylation between patients and controls can be found at CpG sites located in genes with known functional relevance to CKD, cellular ageing, CVD and/or metabolic disease. Continuing our investigations of factors affecting epigenetic status, Study IV investigates the association between the degree of self-reported physical activity and global DNA methylation in Swedish seniors. In this study, we demonstrate that individuals who reported higher physical activity had less global DNA methylation than those who were less physically active. Study V describes the application of a multifactorial mathematical model for predicting the presence of inflammation in a dataset generated from 225 incident dialysis patients. Eight of the ten features with the highest predictive factor were single nucleotide polymorphisms (SNPs), suggesting a large genetic influence on inflammation in CKD patients. In Study VI, the interplay between inflammatory status, genotype, and mortality is demonstrated in two cohorts of incident dialysis patients. The mortality was reduced in inflamed individuals carrying a 32 base-pair deletion in the C-C motif chemokine receptor 5 (CCR5) gene compared to individuals who were inflamed but lacked the deletion.