Supporting Healthy Aging with a Phytochemical Combination that Acts at Multiple Control Points in the Nrf2 Activation Pathway

通过作用于 Nrf2 激活途径多个控制点的植物化学组合支持健康衰老

• 批准号: 9256011
• 负责人: BROOKS MICHAEL HYBERTSON
• 金额: $ 20.99万
• 依托单位: PATHWAYS BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256011
• 关键词: Advocate; Age; Aging; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Biological Markers; Biological Sciences; Cell Survival; Cells; Chronic Disease; Data; Diet; Dietary Supplementation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Health Status; Individual; Life Style; Liver; Location; Longevity; Measurement; Mind; Molecular Conformation; Mus; Outcome; Pathway interactions; Phase; Phytochemical; Play; Protein Biosynthesis; Proteins; Research; Risk Factors; Role; Safety; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Societies; Stress; Testing; Toxicology; United States; Up-Regulation; Work; age effect; age related; anti aging; base; catalase; dietary supplements; experimental study; healthy aging; improved; in vivo; inflammatory marker; innovation; macrophage; mouse model; muscle physiology; nuclear factor-erythroid 2; protein degradation; proteostasis; response

The average lifespan and the number of older individuals is increasing in the US, but because age is a primary risk factor for most chronic disease, there is an accompanying increase in the burden of chronic disease in the US. Diet and lifestyle choices, including dietary supplementation, may be useful approaches to slowing the aging process and increasing healthspan, and also may be the best strategy for minimizing the burden of many chronic diseases. One promising approach to supporting healthy aging is protecting the body by inducing upregulation of its own cell survival genes through dietary supplementation with phytochemical combinations that activate the Nrf2 (NFE2L2, Nuclear Factor Erythroid 2-Like 2) cell signaling pathway. At Pathways Bioscience we are developing a dietary supplement combination (PB125) that synergistically activates the Nrf2 cell signaling pathway which in turn upregulates antioxidant anti-inflammatory, and other cell protective genes and is a promising candidate for improving health status during aging. The phytochemicals in PB125 were specifically selected because they act at different control points on the Nrf2 activation pathway, so that small amounts of each are able to work synergistically together to create relevant Nrf2 activation responses and gene expression. This is an innovative approach being developed by Pathways Bioscience. Our preliminary data indicates that the active components of PB125 upregulate Nrf2 signaling and the expression of Nrf2-dependent genes more than two-fold higher than would be predicted by the adding the responses of each agent individually, that dietary PB125 in mice increases liver catalase activity and Nrf2-dependent HMOX1 gene expression, and decreases markers of inflammation in cultured mouse macrophages. In this project we will expand upon the preliminary data to create an optimized ratio of active components and test the PB125 dietary supplement in vivo in a mouse model of aging based on the measurement of protein homeostasis (proteostasis), which refers to cellular control of the concentration, location, and conformation of individual proteins to achieve stability. The ability to maintain proteostasis is a key outcome in aging and chronic disease research. This makes deficiencies in proteostasis a biomarker associated with aging, and also a target for anti-aging strategies such as PB125-induced Nrf2 activation.

美国的平均寿命和老年人的数量正在增加，但由于 年龄是大多数慢性病的主要危险因素， 美国的慢性病负担。饮食和生活方式的选择，包括饮食 补充，可能是有用的方法，以减缓衰老过程， 健康跨度，也可能是最大限度地减少许多慢性疾病负担的最佳策略。 疾病一种支持健康衰老的有希望的方法是通过以下方式保护身体： 通过膳食补充诱导其自身细胞存活基因的上调， 激活Nrf2（NFE2L2，核因子红细胞2样2）的植物化学组合 细胞信号通路在Pathways Bioscience，我们正在开发一种膳食补充剂 组合（PB125），其协同激活Nrf2细胞信号传导途径， 上调抗氧化剂抗炎和其他细胞保护基因，是一种很有前途的 在衰老过程中改善健康状况的候选人。PB125中的植物化学物质是 因为它们作用于Nrf2活化途径上的不同控制点， 因此少量的每一种都能够协同地一起产生相关的Nrf2 激活反应和基因表达。这是一种创新的方法， Pathways Bioscience.我们的初步数据表明，PB125的活性成分 上调Nrf2信号传导和Nrf2依赖性基因的表达超过两倍 高于通过单独添加每个代理的响应所预测的， 小鼠饮食中PB125增加肝脏过氧化氢酶活性和Nrf2依赖性HMOX1基因 表达，并减少培养的小鼠巨噬细胞中的炎症标志物。在这 项目，我们将扩大初步数据，以创造一个优化的比例，积极 在小鼠衰老模型中体内测试PB125膳食补充剂， 蛋白质稳态（proteostasis）的测量，是指细胞对蛋白质稳态的控制。 浓度、位置和单个蛋白质的构象以实现稳定性。的能力 维持蛋白质稳态是衰老和慢性病研究的一个关键成果。这使得 蛋白质稳态缺陷是与衰老相关的生物标志物，也是抗衰老的靶点 例如PB125诱导的Nrf2激活的策略。