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Human ageing is accompanied by characteristic metabolic and endocrine changes, including altered hormone profiles, insulin resistance and deterioration of skeletal muscle. Obesity and diabetes may themselves drive an accelerated ageing phenotype. Untangling the causal web between ageing, obesity and diabetes is a priority in order to understand their aetiology and improve prevention and management. The role of biological ageing in determining the risk of obesity and associated conditions has often been examined using mean leukocyte telomere length (LTL), a marker of replicative fatigue and senescence. However, considering phenotypes which represent different domains of biological and functional ageing as exposures for obesity and related traits could allow the elucidation of new understudied phenotypes relevant to cardio-metabolic risk in the wider population. This PhD considers the causal role of (1) hand grip strength (HGS), a marker of overall strength and physical functioning, and (2) resting energy expenditure, an indicator of overall energy metabolism and the major component of daily energy expenditure, in cardio-metabolic risk. I also characterise a new and readily-quantifiable marker of age-related genomic instability, mosaic loss of the Y chromosome (mLOY). Observational evidence implicates each of these phenotypes in cardio-metabolic conditions and intermediate phenotypes. However, it is not possible to infer causality from these observational associations due to confounding and reverse-causality. Mendelian randomisation offers a solution to these limitations and can allow the causal nature of these relationships to be investigated. Using population-based data including UK Biobank, this thesis presents the first large-scale genetic discovery effort for each trait and provides new biological insight into their shared and separate aetiology. I used identified variants to investigate the bidirectional causal associations of each trait with cardio-metabolic outcomes, intermediate phenotypes and other related traits such as frailty and mortality. In total I identified 16 loci for hand grip strength, 19 for mLOY, and one signal for REE. I have shown that HGS is likely to be causally linked to fracture risk, and I have identified the important shared genetic architecture between mLOY, glycaemic traits and cancer. I have also demonstrated that at least one known genetic variant contributing to obesity risk acts partially via reduced REE. Overall the findings of my PhD contribute to our wider understanding of the aetiological role of ageing processes in metabolic dysfunction, and have implications for both basic science and translational applications.

This thesis examines 'improvement' of wetland commons in early modern England as a contested process of rapid environmental change. As a flagship project of agrarian improvement, drainage sought to alchemise pastoral fen commons into arable enclosed terra firma and promised manifold benefits for crown, commoners, and commonwealth alike. In practice, however, improvement schemes generated friction between the political and fiscal agendas of governors and projectors and local communities' customary ways of knowing and using wetland commons, provoking the most sustained and violent agrarian unrest of the seventeenth century. This thesis situates the first state-led drainage project in England, in the northern fens of Hatfield Level, in the context of the local politics of custom, national legal and political developments, and international movements of capital, expertise, and refugees; all of which intersected to reshape perceptions and management of English wetlands. Drawing on the analytic perspectives of environmental history, this thesis explores divergent ideas and practices generating conflict over the making of private property, reorganisation of flow, and reconfiguration of lived environments. This thesis argues that different 'environing' practices - both mental and material - distinguished what was seen as an ordered or disordered landscape, determined when and how water was understood as a resource or risk, and demarcated different scales and forms of intervention. Rival visions of the fenscape, ways of knowing land and water, and concepts of value and justice were productive of, and produced by, different practices of management, ownership, and use. Drainage disputes therefore crossed different spheres of discourse and action, spanning parliament, courtroom, and commons to bring improvement into dialogue with fen custom and generate a contentious environmental politics. In seven substantive chapters, this thesis investigates how improvement was imagined, legitimised, and enacted; how fen communities experienced and navigated rapid environmental transformation; and how political, social, and spatial boundaries were reforged in the process. By grounding improvement in the early modern fenscape, this thesis reintegrates agency into accounts of inexorable socio-economic change, illuminates ideas at work in social contexts, and deepens understandings of environmental conflict.