Grant Abstract: Translational Studies of Age-Associated Arterial Dysfunction, Western Diet and Aerobic Exercise: Role of the Gut Microbiome

Grant Number: 5R01HL134887-02
PI Name: Seals
Project Title: Translational Studies of Age-Associated Arterial Dysfunction, Western Diet and Aerobic Exercise: Role of the Gut Microbiome

Abstract: Age-related arterial dysfunction is the primary risk factor for cardiovascular diseases (CVD). Recently, we have used short-term and lifelong studies in mice to determine how a Western-style diet (WD; high fat and sugar, low fiber and nutrient density) and aerobic exercise (EX), common lifestyle factors, interact with aging to influence stiffening of the large elastic arteries and endothelial dysfunction. We found that WD accelerates, and EX prevents, these key features of arterial aging by modulating oxidative stress and inflammation. The gut microbiome is a strong modulator of host physiology that is influenced by age, diet and EX, but there is little information about its effects on arterial function in these or other settings. Thus, the purpose of our parent R01 (HL134887-01) is to determine the potential causal role of the gut microbiome in mediating the effects of aging, WD and EX on arterial function, and gain insight into the underlying mechanisms. We are employing three innovative, complementary, translational approaches: 1) mechanistic mouse studies involving mouse-to-mouse transfer of microbiota, 2) a human feeding study assessing the time course of diet-induced changes in the microbiome vs. arterial function, and 3) humanized mouse studies to discern cause-and-effect. In initial studies, we have discovered a key role of the atherosclerosis-linked gut-derived metabolite trimethylamine N-oxide (TMAO) in mediating age- and WD-associated arterial dysfunction. Further, our pilot data demonstrate that inhibition of TMAO with recently discovered 3,3-dimethyl-1-butanol (DMB) reverses arterial dysfunction in both old and WD-fed mice. However, it is not yet known whether DMB would prevent the development of arterial dysfunction when initiated in midlife, a strategy which is likely to have a greater public health impact on reducing CVD-related morbidity and mortality. DMB is a naturally-occurring phytochemical found (to varying extents) in foods, including some balsamic vinegars, red wines, and extra virgin olive oils; however, the amounts and types of DMB-rich foods that should be eaten to suppress TMAO is unclear. Instead, development of DMB as a dietary supplement shows promise. DMB is not yet available for use in humans, but has no known adverse effects, making it an excellent candidate for translation. The purpose of this administrative supplement, through the NIH Office of Dietary Supplements, is to investigate the efficacy of the food-derived phytochemical DMB initiated in midlife (i.e., before the onset of dysfunction) for preventing the development of arterial stiffening and endothelial dysfunction in sedentary mice fed a WD or normal chow. Use of a mouse model of human aging affords a unique opportunity to assess the long-term preventive effects of DMB. As DMB is not yet available for use in humans, this study represents a critical step in the development of this promising dietary supplement and its translation to humans. Furthermore, this research will address an important strategic research priority of NHLBI: identify a novel therapeutic strategy to prevent and treat age-associated arterial dysfunction, thereby reducing risk of CVD.

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