12-Weeks of Supplementation with the Short-Chain Fatty Acid Acetate does not Improve Systemic Arterial Stiffness or Blood Pressure in Middle-aged to Older Adults

Cardiovascular disease (CVD) is the leading cause of death in adults and risk is exacerbated by aging. Two key pathophysiological and interrelated antecedents to CVD are arterial stiffening and elevated blood pressure (BP). High-fiber diets can reduce CVD mortality, but they are difficult to implement at a population level. Short-chain fatty acids (SCFAs), especially acetate, are produced from dietary soluble fiber by gut microbiota and may mediate the CV benefits of high-fiber diets. Thus, directly supplementing acetate could provide a feasible alternative for reducing CVD risk in middle-aged to older (MA/O) adults. We have previously shown acetate supplementation reduces aortic stiffness in old mice. This current study represents clinical translation of our previous data, and thus, we hypothesized that acetate supplementation would have similar effects in MA/O adults. We performed a randomized, placebo-controlled, double-blind, parallel-arm clinical trial in adults aged ≥50 years to compare effects of 12 weeks of oral supplementation with calcium acetate (4g Ca-acetate/day [ACE]; age: 61 ± 9; n = 18) vs. a calcium carbonate placebo (2.5g/day to match elemental calcium [PLB]; age: 63 ± 11; n = 14). Individuals with contraindications for calcium supplementation were excluded (e.g., coronary artery disease), but participants had other comorbidities. There were no exclusions based on medications (# of participants per group taking anti-hypertensives: 1 ACE, 5 PLB). The Welch two sample t-test was used to compare changes in all outcome variables between groups. There were no significant differences in sex, body mass index, or race/ethnicity between the two groups (all p > 0.08). There was no effect of ACE supplementation on arterial stiffness, measured by the gold-standard carotid-femoral pulse wave velocity (cfPWV: 823 ± 199 to 828 ± 233 cm/s); whereas, unexpectedly, cfPWV decreased in the PLB group (882 ± 239 to 809 ± 215 cm/s), such that the pre/post reduction in cfPWV was significantly greater with PLB vs. ACE (ΔPLB: -73 ± 89; ΔACE: 5 ± 71 cm/s, p = 0.013). There were no significant changes over the intervention in either group in resting clinic BP (systolic: ΔPLB: -1.3 ± 9.4; ΔACE: -2.9 ± 6.9mmHg, p = 0.6; diastolic: ΔPLB: 0.0 ± 6.4; ΔACE: -0.2 ± 3.6 mmHg, p > 0.9), or in 24-hour ambulatory BP (systolic: ΔPLB: 0.0± 6.6; ΔACE: -1.3 ± 5.5 mmHg, p = 0.6; diastolic: ΔPLB: 0.4 ± 4.3; ΔACE: 0.1 ± 3.9 mmHg, p = 0.9). These findings suggest that supplementing acetate at 4g/day for 12 weeks was insufficient to improve arterial stiffness or BP in our heterogeneous population of MA/O adults. Further study is needed to determine if SCFA supplementation confers improvements with different dosing, longer duration, and/or on other components of arterial health (e.g., endothelial function) that could provide benefits to CVD risk with aging. Funding: R00 HL151818, 5T32DK007135-49, and TL1DK147566-01 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.