(R/S)-1,3-Butanediol
(R/S)-1,3-Butanediol (racemic ketone precursor, beta-hydroxybutyrate prodrug)
Written by Aaron CuhaReviewed Sep 2026
Also known as: 1,3-Butanediol, 1,3-BD, BD, 1,3-Butylene glycol, Butane-1,3-diol
The Interventions Testing Program's most equivocal result: a 2 percent female median gain that depended on which sites were included, a 9 percent male median gain that reached significance only by the Gehan test, and 10 percent of the diet by weight to get either. In people it raises blood ketones for a few hours, caused moderate to severe gut symptoms in 5 of 9 cyclists, and did not improve their time trial.
Overview
1,3-Butanediol is a small alcohol that the liver converts to beta-hydroxybutyrate, so drinking it produces a state of mild ketosis without fasting or a ketogenic diet. It is an approved food additive solvent, the backbone of several commercial ketone ester drinks, and is sold on its own in some ketone supplements. It appears here because the NIA Interventions Testing Program tested it, and because the ketone body it produces is the subject of a large and contradictory longevity literature in animals.
In people the published record is short-term and metabolic. In a randomised crossover in 9 trained male cyclists, 0.35 g/kg of racemic 1,3-butanediol before and during 85 minutes of steady exercise raised blood D-beta-hydroxybutyrate to 0.44 to 0.79 mmol/L during exercise (placebo 0.11 to 0.16) and 1.38 mmol/L an hour afterwards, increased oxygen consumption early in exercise, produced moderate to severe gastrointestinal symptoms in 5 of the 9, dizziness, nausea or euphoria in 2, and did not change time trial duration (28.7 versus 28.5 minutes, p = 0.62) or power output. Esters of (R)-1,3-butanediol have a larger record: a 28-day randomised trial of a bis-hexanoyl ester in 59 healthy adults found no tolerability difference from placebo at 12.5 then 25 g a day and no safety laboratory changes; kinetic studies show blood beta-hydroxybutyrate rising to 0.8 to 1.7 mM for a few hours. Those are different molecules that release 1,3-butanediol in the gut, so they bear on its safety at gram doses but not on the racemate itself. No human study has run longer than 28 days or measured any ageing endpoint.
In mice, the Interventions Testing Program mixed racemic 1,3-butanediol into chow at 100,000 ppm, which is 10 percent of the diet by weight, from 6 months of age in the 2017 cohort. Pooled across three sites, female median lifespan was 2 percent higher (p = 0.04), with the effect concentrated at two sites (7 percent at The Jackson Laboratory, 4 percent at UT); the authors state that the female result held only if the site with unusually short-lived control mice was included, and 90th percentile survival was unchanged. Males showed a 9 percent median gain that was not significant by log-rank (p = 0.11). The 2024 Gehan reanalysis reversed the picture: the male effect became significant (Gehan p = 0.025, proportional hazards not violated) and the female log-rank effect was no longer significant by Gehan. The reanalysis authors group it with the compounds whose benefit is limited to midlife. A separate 2023 Aging Cell study found that a 1,3-butanediol diet started early in life increased midlife mortality in normal mice but extended lifespan when started in aged mice, and prevented the early deaths of mice lacking the ketogenesis enzyme HMGCS2.
1,3-Butanediol is not a drug. It is permitted as a food additive and sold in supplements; it is not approved for any medical indication.
Mechanism of action
1,3-Butanediol is oxidised in the liver by alcohol and aldehyde dehydrogenases to beta-hydroxybutyrate, the main circulating ketone body. The (R) enantiomer yields the physiological D-beta-hydroxybutyrate; the (S) enantiomer yields the L form, which is metabolised differently and whose effects are less studied, and the racemate the ITP used produces both. In people, a single dose raises D-beta-hydroxybutyrate to roughly 0.5 to 1.5 mmol/L for a few hours, lowers glucose and free fatty acids, and at gram doses commonly causes gastrointestinal upset; being an alcohol, it also produces mild intoxication-like symptoms in some people. The longevity rationale is that beta-hydroxybutyrate signals as well as fuels: in rodents and cells it inhibits class I histone deacetylases, suppresses the NLRP3 inflammasome and alters gene expression in ways that overlap with caloric restriction. Whether chronic exogenous ketosis reproduces the effects of endogenous ketosis is disputed in the animal literature, where the same 1,3-butanediol diet shortened or lengthened mouse life depending on the age it started.
Human evidence
Short-term metabolic and tolerability studies only. The racemate itself has one published randomised crossover in 9 cyclists; esters of the (R) enantiomer have randomised trials up to 28 days in about 60 healthy adults. Nothing longer, nothing in older adults, nothing measuring ageing.
- 9 trained male cyclists, 0.35 g/kg racemic 1,3-butanediol, crossover: ketones raised to 0.44 to 1.38 mmol/L; gut symptoms moderate to severe in 5 of 9; no change in time trial time or power.
- 59 healthy adults, 28 days, (R)-1,3-butanediol diester at up to 25 g a day: tolerability and safety labs no different from placebo. Manufacturer funded, different molecule.
- 8 healthy adults, ester kinetics: R-beta-hydroxybutyrate 0.8 to 1.7 mM for up to five hours; glucose and free fatty acids fell; a non-physiological S isomer appeared at low concentration.
- 18 adults, a (R)-1,3-butanediol monoester, crossover: no change in the fat-tissue hormones asprosin and leptin over 150 minutes.
- No study has given 1,3-butanediol or its esters to people for longer than 28 days, to older adults specifically, or with any ageing endpoint.
What this does not tell you: The human data establish that 1,3-butanediol raises blood ketones for a few hours and that the racemate at athletic doses upsets the gut in most people. They say nothing about years of use, about the (S) enantiomer's effects, or about whether exogenous ketosis does in a person what endogenous ketosis is thought to do. The ITP mice ate 10 percent of their diet as 1,3-butanediol for life, a dose that has no human counterpart.
Reading the research record
The NIA Interventions Testing Program runs each compound in parallel at three sites (The Jackson Laboratory, the University of Michigan and UT Health San Antonio) in genetically heterogeneous UM-HET3 mice, tests both sexes, analyses them separately, pools the sites in a site-stratified log-rank test, and publishes every result whether or not the compound worked. It is publicly funded by the National Institute on Aging with no pharmaceutical sponsorship. In the 2017 cohort 1,3-butanediol produced the programme's most equivocal result. The female median gain of 2 percent was significant by log-rank at p = 0.04 but the authors themselves write that it appeared only when the analysis included the site whose control females were unusually short-lived; 90th percentile survival did not move. The male median gain of 9 percent did not reach significance by log-rank (p = 0.11).
"Gehan-only" needs explaining because it is a weaker and more specific claim than "extended lifespan". The ITP's protocol test is the log-rank test, which weights every death equally and is most sensitive when a treatment lowers mortality by a constant proportion across the whole lifespan. In 2024 a group at UT Health San Antonio reanalysed all ITP survival data from 2004 to 2022, 132 compound by sex comparisons, with the Gehan test, which weights deaths by how many animals are still alive and so gives more weight to early and midlife deaths. Five compounds that had failed the log-rank test passed the Gehan test: metformin, enalapril and 17-DMAG in males, CAPE and green tea extract in females. The authors are explicit that this pattern is what you would expect from a compound that lowers mortality before midlife and then stops helping, that these effects are "limited to midlife and may not be effective at older ages", and no correction for the number of comparisons is reported. A Gehan-only result therefore means: fewer mice died young, the survival curves converged later, and the effect on maximum lifespan was nil.
For 1,3-butanediol the reanalysis swapped the sexes: the male result became significant by Gehan (p = 0.025) and the female result stopped being significant. A compound whose sex-specific positive changes depending on which test and which sites you use has not shown a robust effect, and the reanalysis authors accordingly group it with compounds whose benefit is confined to midlife. The wider animal literature adds a warning rather than support: the 2023 Aging Cell study found the same kind of diet increased midlife mortality in normal mice when started young and extended life when started old. Nobody funds long human trials of a bulk chemical, so the question of what chronic exogenous ketosis does to a person is open in both directions.
The evidence, charted
Fig. 1 · evidence composition
3of 6 citations (50%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2019 to 2024, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Not approved
AU
Not approved
CA
Not approved
Not approved in any of the four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2022
Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice
ITP 2017 cohort. (R/S)-1,3-butanediol at 100,000 ppm in chow from 6 months. Females (134 treated, 276 controls): median +2 percent, p = 0.04 pooled, driven by two sites (+7 percent TJL, +4 percent UT), and dependent on including the site with unusually short-lived controls; 90th percentile +4 percent, not significant. Males (145 treated, 285 controls): median +9 percent, log-rank p = 0.11, not significant. NIA funded.
Aging Cell - Animal2024
The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: metformin, enalapril, caffeic acid phenethyl ester, green tea extract, and 17-DMAG
1,3-butanediol males: median +9 percent, log-rank p = 0.11, Gehan p = 0.025, proportional hazards not violated. The female effect that was significant by log-rank was not significant by Gehan. Grouped by the authors with compounds whose benefit is limited to midlife. NIA funded.
GeroScience - Human2019
The effect of 1,3-butanediol on cycling time-trial performance
Randomised crossover, 9 trained male cyclists, 0.35 g/kg racemic 1,3-butanediol or placebo before and during 85 minutes of steady exercise then a time trial. Blood D-beta-hydroxybutyrate 0.44 to 0.79 mmol/L during exercise (placebo 0.11 to 0.16), peak 1.38 mmol/L after. Moderate to severe gastrointestinal symptoms in 5 of 9; dizziness, nausea or euphoria in 2. Time trial 28.7 versus 28.5 minutes, p = 0.62; power 286 versus 290 W, p = 0.50. No performance benefit. Academic study.
International Journal of Sport Nutrition and Exercise Metabolism - Human2021
Tolerability and safety of a novel ketogenic ester, bis-hexanoyl (R)-1,3-butanediol: a randomized controlled trial in healthy adults
59 healthy adults, 28 days, double-blind, 12.5 g a day for a week then 25 g a day of a (R)-1,3-butanediol diester or taste-matched placebo. No difference in gastrointestinal or systemic tolerability scores, no clinically meaningful changes in vital signs or laboratory safety measures; blood ketones rose after each dose. Manufacturer funded; a related molecule, not the racemate.
Nutrients - Human2023
Bis hexanoyl (R)-1,3-butanediol, a novel ketogenic ester, acutely increases circulating R- and S-beta-hydroxybutyrate concentrations in healthy adults
8 healthy adults, three randomised crossover conditions. Plasma R-beta-hydroxybutyrate rose to 0.8 to 1.7 mM for up to five hours, dose dependent; the non-physiological S form rose to 20 to 60 microM; glucose and free fatty acids fell. Kinetics of the ester, not the racemate. Manufacturer funded.
Journal of the American Nutrition Association - Animal2023
Ketone bodies: a double-edged sword for mammalian life span
Mice lacking the ketogenesis enzyme HMGCS2 died early, which a 1,3-butanediol diet prevented. In normal mice the same diet started early in life increased midlife mortality, while started in aged mice it extended lifespan and prevented atherosclerosis deaths in ApoE-deficient mice. An ad libitum ketogenic diet markedly increased mortality. Independent Japanese group.
Aging Cell
Frequently asked questions
Did 1,3-butanediol extend lifespan in the ITP?
Equivocally. Females gained 2 percent at the median (p = 0.04), but the authors state this depended on including one site with unusually short-lived controls, and late survival did not change. Males gained 9 percent at the median, not significant by the protocol log-rank test (p = 0.11) but significant by the Gehan test (p = 0.025) in a 2024 reanalysis, which simultaneously made the female result non-significant. The dose was 10 percent of the diet by weight.
What does it do in people?
It raises blood beta-hydroxybutyrate to roughly 0.5 to 1.5 mmol/L for a few hours. In the one trial of the racemate, 0.35 g/kg gave 5 of 9 cyclists moderate to severe gut symptoms and did not improve performance. Esters of the (R) form were tolerated for 28 days at 25 g a day in 59 healthy adults in a manufacturer-funded trial. No human study has looked at ageing.
Is 1,3-butanediol the same as a ketone ester?
No. Commercial ketone esters are (R)-1,3-butanediol chemically joined to beta-hydroxybutyrate or to fatty acids; they release (R)-1,3-butanediol on digestion. The ITP fed the free racemic alcohol, which also produces the L form of beta-hydroxybutyrate from its (S) enantiomer. The human safety data on esters bear on 1,3-butanediol exposure but are not data on the racemate.
Do ketones extend lifespan?
In mice the answer depends on timing: a 2023 study found a 1,3-butanediol diet increased midlife mortality when started young and extended life when started old, and an unrestricted ketogenic diet increased mortality. No human data address the question.