Acetate Improves Age-Related Arterial Dysfunction. Oral Supplementation with the Short-Chain Fatty Acid Acetate Ameliorates Age-Related Arterial Dysfunction in Mice

Background Adverse changes in the gut microbiome with aging are an emerging mediator of arterial dysfunction, which contributes to cardiovascular disease development. We investigated, for the first time, the therapeutic potential of enhancing bioavailability of gut-derived short-chain fatty acids (SCFAs; produced from dietary fiber) for improving age-related arterial dysfunction. Methods We performed in-depth characterization of gut bacterial features and functional pathways (metagenomics) in young (3mo) and old (24mo) male C57BL/6N mice, to identify changes with aging under controlled environmental conditions and relations to arterial function. We then supplemented young and old mice with the SCFA acetate in drinking water vs. controls and vs. a high-fiber diet (to assess relative efficacy to a more established intervention) for 8-10 weeks. Results SCFA-producing capacity (abundance of features and pathways) was lower in old mice and was related to worse arterial function after adjusting for age (other groupings were not independently related). Acetate supplementation and high-fiber diet reversed ~30% of the age-related increase in aortic stiffness (pulse wave velocity) and fully restored carotid artery endothelium-dependent dilation to young levels. Using innovative siRNA-based approaches to knockdown pathways in isolated arteries, we found that improvements were likely mediated by enhanced free fatty acid receptor-3 and suppressed early growth response-1 signaling. Acetate and high-fiber diet also reduced age-related increases in systemic inflammation. There were no effects in young mice. Conclusions Acetate supplementation was comparably effective for ameliorating arterial dysfunction with aging as a high-fiber diet and thus shows promise for reducing cardiovascular disease risk in older adults.