Oral Supplementation with the Short-Chain Fatty Acid Acetate Ameliorates Age-Related Aortic Stiffening in Mice

Abstract

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<0.01), and was reduced comparably by both interventions in the old mice (OA: 379±5, p=0.04 vs. OC: 403±8 cm/sec; OF: 379±5 cm/sec, p=0.04 vs. OC). Post-intervention systolic blood pressure (OC: 83.1±3.2, OA: 87.5±4.7, OF: 85.4±5.9 mmHg, p=0.82) and aortic wall thickness (OC: 0.05±0.002, OA: 0.05±0.004, OF: 0.05±0.002 μM, p=0.77) were not different between groups, suggesting that neither factor explained the intervention effects on aPWV. Conversely, aortic collagen abundance (measured in a subset of mice, N=4/group), which was higher in old mice (OC: 964±118 vs. YC: 644±25 AU, p=0.02), was reduced to young levels by acetate supplementation (OA: 671±18 vs. YC: 644±25 A.U., p=0.41). Both acetate and H-FIB reduced aEM in old mice (OC: 3640±229 vs. OA: 2291±274 kPA, p=0.002; OF: 2600±321 kPA, p=0.06 vs. OC). There were no differences across groups in young mice. CONCLUSION: Oral acetate supplementation and H-FIB were similarly effective at mitigating age-related aortic stiffening; effects may be mediated in part by reduced collagen content in the arterial wall. Acetate supplementation may be a promising treatment for preventing age-related aortic stiffening and subsequent CVD risk. 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.