The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging (“inflammaging”). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor–α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.

Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.

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Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from a Marfan mouse model ( Fbn1 c1039g/+ ) and MFS-patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMCs) by conditional depleting mitochondrial transcription factor A (Tfam) ( Myh11-Cre ERT2 Tfam flox/flox mice). We have used a mouse model of Marfan syndrome to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial-DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1 -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS-patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient-VSMCs mice, lose their contractile capacity, showed aortic aneurysms and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside (NR) rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan Syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

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Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta‐like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1‐null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey‐1 expression compared to wild‐type (WT) littermates. NOTCH1 over‐activation in Dlk1‐null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL‐17A and other related‐inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non‐canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17‐mediated inflammatory response.

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