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

在美国，老年人的平均寿命和数量正在增加，但因为 年龄是大多数慢性病的主要危险因素，伴随而来的是 在美国，慢性病的负担。饮食和生活方式选择，包括饮食 补充，可能是有效的方法来减缓衰老过程和增加 健康跨度，也可能是将许多慢性疾病负担降至最低的最佳策略 疾病。支持健康衰老的一个有希望的方法是通过以下方式保护身体 通过饮食补充诱导自身细胞生存基因的上调 激活Nrf2的植物化学组合(NFE2L2，核因子红素2样蛋白2) 细胞信号通路。在Path Bioscience，我们正在开发一种膳食补充剂 结合(PB125)，协同激活Nrf2细胞信号通路，进而 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 之所以特别选择是因为它们作用于NRF2激活途径上的不同控制点， 以便每一方中少量成员能够协同工作以创建相关的NRF2 激活反应和基因表达。这是一种由 路径生物科学。我们的初步数据表明PB125的活性成分 上调Nrf2信号和Nrf2依赖基因的表达超过两倍 比通过单独添加每个代理的响应来预测的更高，即 饮食PB125提高小鼠肝脏过氧化氢酶活性和Nrf2依赖的Hmox1基因 表达，并减少培养的小鼠巨噬细胞的炎症标志物。在这 我们将扩大项目的初步数据，以创建一个优化的活跃比率 在小鼠衰老模型上测试PB125膳食补充剂的成分和体内试验 蛋白质稳态的测量，指的是细胞对蛋白质的控制 单个蛋白质的浓度、位置和构象以实现稳定性。有能力 维持蛋白质平衡是衰老和慢性病研究的关键成果。这使得 蛋白质平衡缺陷是与衰老相关的生物标记物，也是抗衰老的目标 如PB125诱导Nrf2激活等策略。

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.