Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate

Am J Physiol Heart Circ Physiol. 2022 Mar 1;322(3):H466-H473. doi: 10.1152/ajpheart.00486.2021. Epub 2022 Feb 11.


With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body β-hydroxybutyrate (βHB), in lieu of nutrient deprivation. However, suprapharmacological concentrations of 1,3-BD are necessary to significantly increase systemic βHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations. Therefore, we hypothesized that 1,3-BD could be a novel antiaging therapeutic, independent of βHB biosynthesis. To test this hypothesis, we administered a low-dose (5%) 1,3-BD to young and old Wistar-Kyoto (WKY) rats via drinking water for 4 wk and measured indices of vascular function and metabolism posttreatment. We observed that low-dose 1,3-BD was sufficient to reverse age-associated endothelial-dependent and -independent dysfunction, and this was not associated with increased βHB bioavailability. Further analysis of the direct vasodilator mechanisms of 1,3-BD revealed that it is predominantly an endothelium-dependent vasodilator through activation of potassium channels and nitric oxide synthase. In summary, we report that 1,3-BD, at a concentration that does not stimulate βHB biosynthesis, could be a nutraceutical that can reverse the age-associated decline in vascular function. These results emphasize that 1,3-BD has multiple, concentration-dependent mechanisms of action. Therefore, we suggest alternative approaches to study the physiological and cardiovascular effects of βHB.NEW & NOTEWORTHY 1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, β-hydroxybutyrate (βHB), and its purported salubrious effects. Here, we report that a low dose of 1,3-BD (5%) is sufficient to reverse age-associated vascular dysfunction, independent of βHB. Therefore, low-dose 1,3-BD could be a novel therapeutic to increase blood flow and improve the quality of life in the elderly.

Keywords: aging; ketogenesis; metabolism; vascular function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology
  • Animals
  • Butylene Glycols
  • Ketone Bodies*
  • Quality of Life*
  • Rats
  • Rats, Inbred WKY


  • Butylene Glycols
  • Ketone Bodies
  • 1,3-butylene glycol
  • 3-Hydroxybutyric Acid