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The aorta stiffens with aging in both men and women and predicts cardiovascular mortality. Stiffening occurs largely due to aortic wall structural remodeling induced, in part, by chronic low-grade inflammation. Use of animal models in biomedical research is essential for screening interventions for safety/efficacy and providing mechanistic insight that is difficult, or impossible, to obtain in humans. Male C57Bl/6N mice are an established model of aortic aging and have predominantly been used to determine mechanisms of and investigate interventions for mitigating age-related vascular changes. Although some studies have investigated mechanisms of artery stiffening in female mice in midlife, there is still a paucity of information regarding whether female mice are an appropriate model of age-related aortic stiffening/structural remodeling, especially in late life. Purpose: To determine if female C57Bl/6N mice are an appropriate model (i.e., reflective of the human condition) of age-related aortic stiffening, associated structural remodeling and systemic inflammation. Methods and Results: Data are mean ± SE. Aortic stiffness (pulse wave velocity) was higher in old (O; 27-29 mo) vs. young adult (Y; 6-7 mo) male (M) and female (F) C67Bl/6N mice (cm/sec: YM: 347±27, YF: 345±23, OM: 401±32, OF: 413±45; p0.15). Aortic elasticity was inversely related to IL-6 (r2=0.49, p NIH T32 AG000279, F31 FHL160173A, K99 HL159241 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aging is the main risk factor for cardiovascular diseases (CVD) due in part to stiffening of large elastic arteries (e.g., aorta). High-fiber diets (H-FIB) are associated with reduced risk of CVD, but most people do not meet guidelines for adequate fiber intake. Short-chain fatty acids (SCFA), which are produced by gut microbiome-dependent fermentation of soluble fiber, are thought to mediate many of the benefits of a H-FIB. Acetate, the most prevalent SCFA in circulation, may be an adherable intervention as an oral supplement for improving age-related arterial stiffening and reducing the risk of CVD. PURPOSE: To determine if oral acetate supplementation can reduce age-related aortic stiffness comparably to a H-FIB. METHODS: Young (Y: 3mo; N=11-12/group) and old (O: 24mo; N=24-27/group) C57Bl/6N mice were split into 3 groups per age: 1) controls (YC/OC): standard chow (15% total, 2.5% soluble fiber) and normal drinking water; 2) acetate supplemented (YA/OA): standard chow and 100mM of calcium acetate in drinking water; and 3) H-FIB (YF/OF): chow supplemented with fiber (20% total, 8% soluble fiber) and normal drinking water. Aortic pulse wave velocity (aPWV; standard reference method of in vivo aortic stiffness) and blood pressure (BP; tail cuff) were measured before and after 8 weeks of intervention. Thoracic aortas were harvested to measure: elastic modulus (aEM) of aortic rings (structural measurement of stiffness dependent on engagement of collagen fibers); aortic wall thickness (structural contributor to arterial stiffening); and collagen abundance by immunofluorescence (pro-stiffening structural protein). RESULTS: Data are mean ± SE. aPWV was higher in old vs. young mice at baseline (O: 404±10 vs. Y: 335±4 cm/sec, p FUNDING: K99/R00 HL151818, CU Boulder BSI Scholarship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aging is the primary risk factor for cardiovascular diseases (CVD), the leading cause of death worldwide. Vascular endothelial dysfunction, a key antecedent to CVD, is primarily mediated by excess superoxide-related oxidative stress and decreased nitric oxide (NO) bioavailability. High-fiber diets (H-FIB) are associated with lower CVD-related morbidity/mortality, but adherence to guidelines for recommended dietary fiber intake is poor. Benefits of H-FIB are likely mediated by fermentation of soluble fiber into short-chain fatty acids (SCFAs) in the gut, which may improve endothelial function. Thus, supplementing SCFAs may be a more practical/effective intervention to reduce CVD risk with aging. PURPOSE: To determine if oral supplementation with acetate, the most prevalent SCFA in circulation, reverses vascular endothelial dysfunction in old mice as effectively as a H-FIB. METHODS: Old (O: 24mo) and young (Y: 3mo) male C57BL/6 mice (N=10-17/group) were randomized into 3 groups per age: 1) standard chow (15% total & 2.5% soluble fiber) + normal drinking water (YC/OC); 2) standard chow + 100mM calcium acetate supplemented in drinking water (YA/OA); or 3) H-FIB (20% total & 8% soluble fiber [inulin added to the standard chow]) + normal drinking water (YF/OF). Endothelium-dependent dilation (EDD; ex vivo carotid artery dilation to increasing doses of acetylcholine) and associated mechanisms were assessed following 8 weeks of intervention. RESULTS: Data are mean ± SE. Age-related impairments in peak EDD (YC: 92±1%; OC: 81±2%, p0.8 vs. YC), suggesting that the interventions effects are specific to aging. There were no differences in smooth muscle sensitivity to NO (peak dilation to sodium nitroprusside; OC: 98±1%; OA: 99±0%; OF: 99±0%, p=0.1), indicating that differences in EDD were endothelium-dependent. Instead, these changes were likely NO-mediated, as addition of the endothelial NO synthase inhibitor L-NAME abolished differences in peak EDD (OC: 51±4%; OA: 47±8%; OF: 54±6%, p=0.8). Aortic superoxide production (electron paramagnetic resonance spectroscopy) was lower in old acetate-treated mice (OC: 50±7; OA: 29±3 AU, p=0.04), and tended to be lower in H-FIB mice (OC vs. OF: 33 AU, p=0.18). Incubation with the superoxide scavenger TEMPOL improved peak EDD in OC mice (OC: 81±2%; OC+TEMPOL: 93±2%, p K99/R00 HL151818, F31 HL164004 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.