Abstract
The natural aging process induces subtle, yet significant physiological changes that impact both the skeletal muscle and vascular systems. Age-related functional declines in these systems are often attributed to oxidative stress, wherein excessive production of reactive oxygen species (ROS) leads to oxidative damage to major macromolecules. The oxidative stress hallmark of aging implicates increased ROS generation in the pathophysiology of endothelial cell dysfunction, skeletal muscle deconditioning, and maladaptive responses observed in aging vessels, all which contribute to the development of hypertension.The deconditioning experienced by aging skeletal muscle is often exacerbated by chronic comorbidities, leading to faster progression of cardiovascular diseases (CVD). A predictor of future CVD is hypertension, which also increases in prevalence with advancing age, primarily due to an increase in total peripheral resistance within the vessels. As skeletal muscle is an important site of resistance in the periphery, any vasodilatory decrements within this tissue can alter blood flow and pressure dynamics beyond physiological limits. Under physiological conditions, skeletal muscle continuously produces ROS during contraction, acting as essential mediators and signalling molecules for muscle adaptation. An increase in the production and activity of ROS is suspected to play part in the underlying molecular mechanisms of skeletal muscle deconditioning and endothelial dysfunction, including dysfunctional mitochondria, and the changes in blood pressure that occur during aging.
Hypertension remains a substantial risk factor for CVD, mortality, and stroke. While there is a considerable degree of comprehension surrounding both modifiable and non-modifiable risk factors, the prevailing public health directive emphasises specific lifestyle modifications to reduce compounding risks. However, to continue to optimise the current preventative and therapeutic approaches, it is imperative to delve deeper into the mechanisms underpinning the development of age-related increases in blood pressure and hypertension.
Presented as a thesis containing published works, this doctoral research contains peer-reviewed publications, as well as non-published work, as each thesis chapter. The contents range from a literature review (Chapter Two) to cross-sectional epidemiologic bioinformatic investigations (Chapters Three and Four), to a protocol methodology paper utilising a microdialysis technique (Chapter Five), and the ultimate application of that protocol as an experimental investigation (Chapter Six). A mix of traditional (e.g., age, sex, BMI), non-traditional (inflammation) and emerging risk factors (micro- and macro-vascular endothelial function) were explored, as well as the roles of ROS in skeletal muscle signalling, and their relationship with aging and increasing blood pressure.
The findings of this thesis determined that the risk factors relating to age-related hypertension and associated muscle and vascular changes are likely sex-specific, and include a multifaceted interplay between body composition, inflammation, and oxidative stress responses. Responses to oxidative stress (and ROS more specifically) can be highly individualised and depend on various factors such as the presence or absence of comorbidities, diet, and recent exercise. The experimental study (Chapter Six) assessed microvascular blood flow and endothelium-dependent vasodilation, although larger cohort studies are needed to determine the magnitude of the vasodilatory responses and confirm if any marked functional impairments are evident. In attempts to characterise the ROS profile in a cohort of middle-older age males with and without hypertension, Chapter Six also identified that H2O2 (a less reactive, stable form of ROS) can be detected in the muscle at rest, and although highly variable, is comparable to previous experiments in participants with similar BMI or comorbidities. Overall, the contributions offered by this thesis support abnormal ROS regulation in age-related conditions through multi-system, complex, redox-sensitive pathways, and recognises that additional human research is needed to further understand the pathophysiological processes associated with vascular injury and any direct causal roles of ROS in the pathogenesis of hypertension.
| Date of Award | 2024 |
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| Original language | English |