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

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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.