Abstract
Background and Aims
There appears to be an accelerated ageing process seen among patients with end stage kidney disease. They often exhibit prematurely aged phenotypes which include frailty, sarcopenia and protein energy wasting. These phenotypes are associated with increased morbidity and mortality. The exact reason for premature ageing in this cohort is poorly understood. We hypothesised that biomarkers of cellular senescence and biological age may be associated with phenotypes of ageing observed in dialysis patients; in particular the frailty phenotype. Both telomere length (TL) and DNA methylation (DNAm) status have been recognised as predictors of biological age. The aim of the study was to investigate the relationship between TL and DNAm status with frailty phenotype among patients on dialysis.
Method
This was a single centre prospective observational study among eligible haemodialysis (HD) and peritoneal dialysis (PD) patients as per the inclusion and exclusion criteria. All recruited patients had their DNA extracted from peripheral leucocytes and frailty was measured by using the Fried Frailty Phenotype criteria. Extracted DNA was used to measure TL by quantitate polymerase chain reaction according to the modified Cawthon protocol. DNAm status was measured by sodium bisulphite conversion with targeted sequencing of 48 CpG sites. All baseline demographic data were obtained from electronic patient record.
Results
Between the period of December 2015 to July 2018, 239 dialysis (125 HD, 114 PD) patients were recruited. The age range of the study recruits were 23 to 83 years of age with a mean age of 54.3 years. There were 44 and 43 females in the HD and PD group respectively. All patients had TL measured and 228 patients (118 in HD, 110 in PD) had DNAm status measured successfully. Frailty assessments at baseline were completed in 213 patients (110 in HD, 103 in PD). A decrease in mean TL (p<0.001) and increased mean DNAm age (p<0.001) was observed in the frail group. TL and DNAm status were significantly associated with frailty in a univariate analysis, p=0.010 and p=0.014 respectively but only TL remained significant in a multivariate analysis to predict frailty, p=0.018. Increased frailty was observed in dialysis patients with shorter TL which remained significant following multivariate logistic regression analysis. A receiver operating characteristic curve analysis demonstrated that TL was a significant predictor of frailty, p<0.001 with an area under the curve of 0.64. A decrease of TL by one standard deviation was associated with a 52.2% increase risk of frailty when adjusted for age and gender in this dialysis cohort.
Conclusion
The study supports the hypothesis that TL; a biomarker of ageing is better associated with frailty, an ageing phenotype in comparison to DNAm status in dialysis patients. This is the first study to show a significant association between TL and frailty status in the dialysis patients. DNAm status is derived from an individual’s chronological age and may not be the best surrogate for chronological age. Therefore, to use this measure seems rather counter intuitive as the incorporation of chronological age might mask clinically significant associations that exist when the DNAm status is considered in isolation. These findings provide a preliminary proof of concept validation that TL is associated with frailty and may provide the basis of future research. The use of targeted methylation CpG sites may be a better predictor of frailty in this cohort which is an area that has sparked an interest.
Genetic Prediction of Biological Age: A Meta-Analysis on Telomere Length, DNA Methylation, and All-Cause Mortality
