Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging. 

/pdf/targeting-the-biology-of-aging-with-mtor-inhibitors-mlurlz4b.pdf

Targeting the biology of aging with mTOR inhibitors

Increased blood concentrations of phenylalanine in patients with trauma and sepsis are common but unexplained. We examined the potential relationship between serum concentrations of phenylalanine and the immune activation marker neopterin in 84 specimens of 18 patients (14 males and 4 females) post-trauma during 12-14 days of follow up. Compared to healthy controls, average phenylalanine and neopterin concentrations were elevated in patients, and there existed a positive correlation between concentrations of the two analytes (r (s) = 0.375, p < 0.001). No such association existed between neopterin and tyrosine concentrations (r (s) = -0.018), but neopterin concentrations correlated to the phenylalanine to tyrosine ratio (r (s) = 0.328, p = 0.001). Increased phenylalanine implies insufficient conversion by phenylalanine (4)-hydroxylase (PAH). Oxidative stress due to immune activation and inflammation may destroy cofactor 5,6,7,8-tetrahydrobiopterin and impair PAH activity. This assumption is further supported by the correlation found between higher neopterin concentrations and higher phenylalanine to tyrosine ratio, which estimates efficacy of PAH.

Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations

59 KOKKUVÕTE 61 REFERENCES 63 APPENDIX 75 I Materials and methods 75 II Curriculum vitae 77 III Elulookirjeldus 80

Inhibition of platelet aggregation with combination of antiplatelet agents

Oxidative stress in the vasculature has been suggested to contribute to the development of endothelial dysfunction via different mechanisms including LDL oxidation, nitric oxide (NO) scavenging, or oxidation of tetrahydrobiopterin, a critical cofactor of endothelial NO synthase (eNOS). Antioxidants may interfere with these processes and protect NO formed in the endothelium. In particular, ascorbic acid at high concentrations seems to be a prerequisite for sufficient NO bioavailability. Moreover, there is accumulating evidence that ascorbic acid improves tetrahydrobiopterin availability in the vasculature most probably via recycling oxidized tetrahydrobiopterin back to the fully reduced pterin. In addition, ascorbic acid may reduce the α-tocopheroxyl radical and may be required for beneficial vascular effects of α-tocopherol. Recent data have shown that apart from indirect protection of NO from inactivation, α-tocopherol exerts a direct stimulatory effect on eNOS activation via serine 1177 phosphorylation. This effect was amplified by ascorbic acid suggesting that both compounds may act synergistically in optimizing endothelial NO synthesis. The data obtained in cell culture and animal studies are promising, but human long-term studies are needed to determine whether the described mechanisms are active in vivo and may provide a rationale for optimizing dietary or supplementary intake of antioxidant vitamins in certain subsets of patients.

Antioxidants and endothelial nitric oxide synthesis

Nitric oxide (NO), a central regulator of vascular tone and homeostasis, is generated upon activation of endothelial NO synthase (eNOS), which is mediated by an increase of intracellular calcium and/or by eNOS phosphorylation. A reduction of NO bioavailability leads to endothelial dysfunction that has been shown to be improved by alpha-tocopherol in certain conditions. The underlying mechanisms, however, are not completely clarified. The present study was performed to investigate whether alpha-tocopherol is able to affect endothelial NO synthesis. The formation of NO was measured in human umbilical vein endothelial cells using citrulline (coproduct) and cGMP (product of the NO-activated soluble guanylate cyclase) as indicator molecules. alpha-Tocopherol (10-200 microM, 24 hr) increased ionomycin-induced citrulline and cGMP formation in intact cells in a concentration-dependent manner. In parallel, ionomycin-stimulated phosphorylation of eNOS at serine 1177, known to support enzyme activation, was increased by alpha-tocopherol, suggesting that this was the mechanism responsible for enhanced NO formation. The effect of alpha-tocopherol was dependent on its hydrophobic structure because it was mimicked by gamma-tocopherol but not by trolox, a hydrophilic derivative of alpha-tocopherol. Coincubation with ascorbic acid (100 microM, 24 hr) amplified the effects of alpha-tocopherol on eNOS phosphorylation and NO formation, which is possibly related to the regeneration of oxidized alpha-tocopherol by ascorbate. Our data suggest that vasoprotective effects of alpha-tocopherol in vivo may be related to an increase of NO formation. The effect of alpha-tocopherol seems to be dependent on tissue saturation with ascorbic acid, and both vitamins may act synergistically to provide optimal conditions for endothelial NO formation.

α-Tocopherol and Endothelial Nitric Oxide Synthesis

Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.


 
 
 Pulmonary hypertension (PH) is a chronic disease characterized by persistently increases pulmonary arterial pressure, leading on the long term to right ventricular overload and ultimately right heart failure. Until now, therapy focuses on alleviating symptoms and hence the development of a novel strategy for the treatment of this disease remains highly relevant.
 
 
 
 The importance of pro-inflammatory cytokines in progression of PH has already been established. Interestingly, patients with increased plasma levels of inflammatory markers present with more severe disease. Regnase-1 is a newly identified endoribonuclease cleaving the mRNA of pro-inflammatory cytokines therefore diminishing their levels of expression. Hence, we hypothesize that regnase-1 overexpression in lung tissue can be translated into a novel therapeutic approach for PH.
 
 
 
 In vitro experiments were performed in human lung endothelial cells (HUVECs). For our in vivo study, mice were subjected to hypoxic conditions (10% O2) for 3 weeks. Regnase-1 overexpression was achieved in lung endothelial cells by transduction with targeted adeno-associated virus serotype 2 (AAV2-ESGHGYF), administered systemically by tail vein injection 3 days after exposure to hypoxia (early therapy approach). AAV2-EGFP treated mice served as controls. Right ventricular function was monitored by echocardiography and right ventricular systolic pressure was measured by right heart catheterization. The degree of pro-inflammatory cell infiltration was monitored by immunohistochemistry. Induction of fetal gene programme in the right ventricle was measured by real time qPCR. Fibrosis deposition in lung tissue was determined by Sirius Red staining of frozen sections.
 
 
 
 Regnase-1 overexpression led to a significantly decreased level of hypoxia-induced pro-inflammatory cytokines in HUVECs. Importantly, we could show decreased regnase-1 levels in lung endothelial cells of mice subjected to hypoxia for 3 weeks. On the other hand, regnase-1 reintroduction led to a significant improvement in right ventricular function and decreased pulmonary pressure in mice placed under hypoxic conditions. Moreover, the described gene therapy approach induced normalization of fetal gene programme in the cardiac tissue and reduced pro-inflammatory cell infiltration in lungs. Additionally, we could determine mitigation of pulmonary extracellular matrix deposition and fibrosis development in mice receiving AAV2-regnase1 as compared to controls.
 
 
 
 AAV-mediated regnase-1 overexpression in lung endothelial cells results in amelioration of pathological events leading to PH in mice subjected to hypoxia, when the therapeutic AAV is delivered 3 days after disease induction. Further experiments will determine whether this method can be successful used for reversing already established PH.
 
 
 
 Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK


/pdf/regnase-1-overexpression-as-a-novel-gene-therapy-approach-3hr5u1m5.pdf

Regnase-1 overexpression as a novel gene therapy approach for pulmonary hypertension

α-Tocopherol Amplifies Phosphorylation of Endothelial Nitric Oxide Synthase at Serine 1177 and its Short-Chain Derivative Trolox Stabilizes Tetrahydrobiopterin

Role of CD40 ligand-mediated endothelial cell-monocyte interaction at atherosclerosis predilection sites.

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Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.

Regnase-1 overexpression as a novel gene therapy approach for pulmonary hypertension

α-Tocopherol Amplifies Phosphorylation of Endothelial Nitric Oxide Synthase at Serine 1177 and its Short-Chain Derivative Trolox Stabilizes Tetrahydrobiopterin

Role of CD40 ligand-mediated endothelial cell-monocyte interaction at atherosclerosis predilection sites.