Investigating the effect of endurance exercise on mitochondrial function in the ageing heart

PhD ThesisMitochondria are organelles present in most cells of the body responsible for the production of cellular energy in the form of adenosine triphosphate (ATP), through oxidative phosphorylation (OXPHOS). Mitochondrial function is particularly important in the heart due to its high requirement for ATP, and a decline in mitochondrial function with age is implicated in the pathogenesis of age-related cardiovascular disease. Exercise interventions can induce mitochondrial biogenesis and increase OXPHOS capacity; however, it is unknown whether such interventions are successful if started in later life. I wanted to investigate the effect of an endurance exercise intervention in 2 mouse models; 1) a model of accelerated ageing due to enhanced mitochondrial DNA mutagenesis (PolgAmut/mutmice); 2) C57Bl6/J mouse model of physiological age at 14 months of age. Study 1: Following baseline characterisation of PolgAmut/mutmice compared with age-matched controls, male PolgAmut/mutmice underwent a 6-month endurance exercise programme from 16 weeks of age to investigate the effects of exercise on physiological phenotype, behavioural activity, and cardiac mitochondrial function. I found no improvement in clinical score, locomotor activity, cardiac hypertrophy and fibrosis and mitochondrial function in the exercised mice. This suggests that six months of endurance exercise is unable to improve the clinical phenotype and cardiac mitochondrial function in PolgAmut/mutmice due to the severity of the genetic defect. Study 2: To investigate whether starting an exercise programme in later life is beneficial, I first characterised the effect of age on cardiac function in sedentary mice. Between 14 and 22 months of age, I found a significant decline in neuromuscular coordination, decreased cardiac function (measured by cardiac MRI), and diminished aerobic capacity. Six months of endurance exercise improved physiological function and neuromuscular coordination, decreased cardiac fibrosis and apoptosis and improved mitochondrial OXPHOS activity. This suggests that starting an exercise programme later in life can still have beneficial effects.The MRG, CAV and Barbour foundatio

How good is the evidence that cellular senescence causes skin ageing?

Skin is the largest organ of the body with important protective functions, which become compromised with time due to both intrinsic and extrinsic ageing processes. Cellular senescence is the primary ageing process at cell level, associated with loss of proliferative capacity, mitochondrial dysfunction and significantly altered patterns of expression and secretion of bioactive molecules. Intervention experiments have proven cell senescence as a relevant cause of ageing in many organs. In case of skin, accumulation of senescence in all major compartments with ageing is well documented and might be responsible for most, if not all, the molecular changes observed during ageing. Incorporation of senescent cells into in-vitro skin models (specifically 3D full thickness models) recapitulates changes typically associated with skin ageing. However, crucial evidence is still missing. A beneficial effect of senescent cell ablation on skin ageing has so far only been shown following rather unspecific interventions or in transgenic mouse models. We conclude that evidence for cellular senescence as a relevant cause of intrinsic skin ageing is highly suggestive but not yet completely conclusive