Mechanisms of dietary control of the transsulfuration pathway and increased endogenous hydrogen sulfide production

总结 热量限制（CR），或强制减少食物摄入量而不营养不良， 葡萄糖和脂质体内平衡，急性应激抗性和多种实验生物体的寿命。 限制膳食含硫氨基酸蛋氨酸和半胱氨酸，称为蛋氨酸限制（MR），也 在实验啮齿类动物中产生了大部分相同的益处，但没有强制的卡路里限制，因此 潜在地通过不同的潜在机制。 在之前的资助期间，我们发现了一种新的分子机制，这种机制是多效性益处的基础 CR和MR的共同之处：通过呼吸道增加内源性硫化氢气体（H2S）的产生， 进化保守的转硫途径（TSP）。特别是，我们发现， 半胱氨酸的摄入增加了TSP酶胱硫醚γ-裂解酶（CGL）的表达， 硫化氢 H2S的健康益处直到最近才开始受到重视。CGL基因敲除小鼠 缺乏产生足够的内源性H2S的能力，有高血压和对 神经退行性疾病，而外源性H2S添加可以作为血管扩张剂，免疫调节剂， 神经保护剂，甚至增加低等生物的寿命。这个发现 增加内源性H2S对于CR的两个主要健康益处是必要的和足够的，即 增强的抗压能力和跨越进化界限的延长寿命，巩固了这样一个概念， 增加的内源性H2S对许多健康结果非常有益。我们的发现也证明了 这项建议的主要目标，即了解新的干预方法，以增加内源性 H2S生产，并将这些发现应用于临床相关性高的领域。 在这里，我们建议测试的假设，饮食低蛋白质，特别是低硫氨基 在植物来源的蛋白质中发现的氨基酸甲硫氨酸和半胱氨酸，导致CGL表达增加， H2S的产生部分通过激活氨基酸剥夺传感器GCN 2。我们还将测试 假设内源性H2S产生的底物来源于自噬，将这种效应与自噬作用联系起来。 寿命首次有利于H2S生产。最后，我们将探讨H2S在保护中的新作用 造血干细胞对电离辐射，并测试一种新的机制，增加H2S的交付 涉及循环CGL蛋白的内分泌作用的组织如骨髓。

SUMMARY Calorie restriction (CR), or enforced reduced food intake without malnutrition, is highly beneficial on glucose and lipid homeostasis, acute stress resistance and longevity in multiple experimental organisms. Restriction of dietary sulfur amino acids methionine and cysteine, known as methionine restriction (MR), also results in most of the same benefits in experimental rodents, but without enforced calorie restriction, and thus potentially by a different underlying mechanism. In the prior funding period we discovered a novel molecular mechanism underlying pleiotropic benefits common to both CR and MR: increased production of endogenous hydrogen sulfide gas (H2S) via the evolutionarily conserved transsulfuration pathway (TSP). In particular, we found that restriction specifically of cysteine intake increased expression of the TSP enzyme cystathionine γ-lyase (CGL), resulting in increased H2S. The health benefits of H2S have only recently begun to be appreciated. Engineered CGL knockout mice lacking the ability to produce adequate endogenous H2S have high blood pressure and susceptibility to neurodegenerative disease, while exogenous H2S addition can act as a vasodilator, immunomodulator, and neuroprotectant in experimental rodents, and even increase lifespan in lower organisms. Our finding that increased endogenous H2S is necessary and sufficient for two of the major health benefits of CR, namely increased stress resistance and extended longevity across evolutionary boundaries, cements the notion that increased endogenous H2S is highly beneficial to numerous health outcomes. Our findings also justify the major goal of this proposal, namely to understand novel interventional approaches to increasing endogenous H2S production, and applying of these findings to areas of high clinical relevance. Here we propose to test the hypothesis that diets low in protein, and particular low in the sulfur amino acids methionine and cysteine as found in vegetable-derived proteins, result in increased CGL expression and H2S production in part through activation of the amino acid deprivation sensor GCN2. We will also test the hypothesis that the substrate for endogenous H2S production is derived from autophagy, linking this effector of longevity benefits to H2S production for the first time. Finally, we will explore the novel role of H2S in protection of hematopoietic stem cells against ionizing radiation, and test a novel mechanism of increasing H2S delivery to tissues such as bone marrow involving endocrine action of circulating CGL protein.