Importance of cellular senescence for metabolic dysfunction and pharmacological intervention of aged mice

Abstract

Cellular senescence, a state of cell cycle arrest, is a hallmark of ageing and has emerged as a potential mediator in pathophysiology of age-related diseases, including type 2 diabetes. Senescent cells contribute to protective and detrimental effects depending on their persistence. Their accumulation promotes tissue dysfunction, primarily through secretion of pro-inflammatory molecules. Understanding the role of cellular senescence in ageing and in the development and progression of diseases is essential for enabling correct interventions to prevent or treat accelerated ageing and diseases. This thesis examines the relationship between cellular senescence, ageing and metabolic dysfunction with a focus on adipose tissue and liver. In papers I and II, the relationship between cellular senescence and function was investigated in adipocytes and hepatocytes, respectively. Senescent adipocytes exhibited markedly reduced insulin-stimulated glucose uptake accompanied by reduced levels of glucose transporter GLUT4, while lipolytic and insulin signalling capacity remained largely intact. Hepatocyte senescence was associated with altered glucose and lipid metabolism, including increased triglyceride content and capacity for lipid uptake, increased glycogen content and VLDL-TAG secretion, and reduced capacity for de novo lipogenesis. In paper III, the effect of the SGLT2 inhibitor dapagliflozin and FGF21 on metabolic function and cellular senescence in adipose and liver tissue in naturally aged mice was assessed. While both interventions exerted beneficial effects on metabolic parameters and reduced senescence primarily in adipose tissue, FGF21 had a more pronounced effect on metabolic control while dapagliflozin exerted a stronger effect on cellular senescence in adipose tissue and liver in aged mice. In conclusion, these findings indicate that adipocyte and hepatocyte senescence results in metabolic dysfunction. Many of the observed metabolic changes recapitulate metabolic features observed in adipocytes and hepatocytes in obesity, type 2 diabetes and MASLD. Moreover, the results in this thesis suggest that both FGF21 and SGLT2 inhibitor dapagliflozin are promising interventions to improve metabolic control and attenuate the progression of cellular senescence in ageing.