The metabolic regulation of cellular ageing

Abstract

The incidence of obesity and type 2 diabetes (T2D) are increasing in the UK and there is evidencethat these disorders influence the ageing process. The mechanisms by which obesity/diabetesmight regulate ageing are poorly understood. This study aimed to investigate the links betweenbody composition, metabolic disease and ageing, as well as the role of cellular senescence onnutrient homeostasis. Study participants had biochemical and anthropometric measurements taken. DNA analysis was used to measure telomere length (TL) using real-time PCR and plasmawas used to quantify circulating factors using ELISA. Human dermal fibroblasts were madesenescent and conditioned media was collected and used to treat AML-12, C2C12 and 3T3-L1cell lines. Following treatment glucose content of cell media was measured. TL exhibited a significant negative association amongst individuals retaining excess visceral fat(p <0.001) and plasma irisin levels positively correlate and predict TL (p = 0.01) in the controlcohort. There was no significant association between irisin and TL in the T2D cohort (p = 0.333),and a 3-fold higher concentration of irisin was observed in individuals with T2D in comparisonto controls (p < 0.0001). Irisin was a statistically significant predictor of soluble E-selectin (p =0.003) in type 2 diabetics. 40% Conditioned media from senescent HDF reduced the ability ofC2C12 to utilise glucose after 24 and 48 hours and AML-12 hepatocytes after 48 hours (p<0.0001, p <0.01) quantification of circulating glycerol in 3T3-L1 adipocytes following treatmentwith 20% and 40% conditioned media suggests lipotoxic tendencies (p <0.05 and p <0.001). In conclusion this study highlights the importance of maintaining adequate body fat in preservingTL, provides novel data regarding the role of irisin in healthy and obese/type 2 diabeticindividuals and insights into the relation between ageing and insulin resistance.