Dietary restriction intervention to protect against abdominal aortic aneurysm

An abdominal aortic aneurysm (AAA) is defined as a localized dilation of the aorta, most commonly occurring in the infrarenal segment. Its prevalence increases with age and is higher in men. In the first chapter of this thesis, we established a mouse AAA model induced by perivascular appli-cation of elastase combined with oral β-aminopropionitrile fumarate (BAPN) administration. Mor-phological, transcriptomic and immunohistological analyses revealed that this model, reproduces the progressive structural, molecular and immune alterations observed in human AAA. Consistent with the human clinical data, aged mice exhibited greater dilation, extracellular matrix degradation, and inflammation, and female mice were protected. In the second chapter of this thesis, we explored the role of hydrogen sulfide (H2S) in AAA for-mation. Contrary to its known anti-inflammatory and antioxidant properties, H2S aggravated AAA growth and rupture. H2S promoted matrix metalloproteinase 9 (MMP9+) neutrophil accumulation, extracellular matrix degradation, and vascular smooth muscle cell senescence, leading to impaired AAA repair. These findings highlight the context-dependent effects of H2S and raise safety concerns regarding H2S donor administration in individuals at risk for AAA development. In the final chapter of this thesis, our work investigated the protective effects of time-restricted feed-ing (TRF) on AAA progression. Two weeks of TRF markedly reduced AAA development in both young and aged mice, associated with enhanced mitochondrial metabolism and reduced inflammation within AAA tissue. This protection was dependent on FGF21, as it was lost in Fgf21-/- mice, high-lighting its role in TRF-induced metabolic adaptation. Overall, TRF emerges as a promising metabolic intervention that limits AAA progression by improving vascular metabolism and stability through FGF21-dependent mechanisms. Together, these studies provide novel insights into the molecular and metabolic mechanisms underly-ing AAA progression and identify potential therapeutic targets and interventions to prevent or miti-gate this life-threatening vascular disease.