Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8343
Molecular Mechanisms Underlying Cardiometabolic Disease in Aging
Fanjul, Victor CNIC
Date of defense
Aging is the main risk factor for developing cardiovascular and metabolic diseases, which have become a global concern as the world population is progressively aging. The identification of the hallmarks of aging and the cumulative knowledge on the molecular foundations underlying cardiometabolic diseases show that these processes are deeply interconnected and can be modulated. Many advancements have been made in this field through the study of Hutchinson-Gilford progeria syndrome (HGPS or progeria), an extremely rare genetic disease characterized by cardiometabolic disorders and premature aging. Interestingly, age-related comorbidities such as cancer or neurodegeneration are absent in progeria, and environmental risk factors seem to have a minimal implication in disease progression. Hence, the analysis of HGPS provides an opportunity to elucidate the molecular mechanisms that drive cardiometabolic diseases during aging. Consequently, HGPS animal models constitute a unique tool for this purpose and to develop rejuvenation strategies. In this Doctoral Thesis we sought to evaluate cardiometabolic disease in mouse models of premature and normal aging, to identify which mechanisms are common or specific to each condition, and to study the interplay between the local and systemic environments during disease progression. We found that both premature and normal aging models present similar cardiac electrical abnormalities, and high throughput proteomics in the heart of these animals revealed increased global oxidation as well as deregulated energy metabolism, proteostasis, gene expression and cardiac muscle contraction. Nevertheless, while old mice become overweight, progeric mice develop cachexia and impaired body temperature regulation. Moreover, progeric mice develop bradycardia and lipodystrophy, which are promoted by systemic mechanisms, since these features are absent in mice with heart or adipose tissue-specific progerin expression. Finally, we propose the use of Pparg agonists as a new therapeutic strategy in HGPS, targeting adipose tissue to restore energy balance and alleviate age-related cardiometabolic disease.
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