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[Preprint]. 2024 Sep 18:2024.09.17.24313811.
doi: 10.1101/2024.09.17.24313811.

Exploratory functional and quality of life outcomes with daily consumption of the ketone ester bis-octanoyl (R)-1,3-butanediol in healthy older adults: a randomized, parallel arm, double-blind, placebo-controlled study

Brianna J Stubbs  1 , Elizabeth B Stephens  1 , Chatura Senadheera  1 , Stephanie Roa Diaz  1 , Sawyer Peralta  1 , Laura Alexander  1 , Wendie Silverman-Martin  1 , Jamie Kurtzig  1 , B Ashen Fernando  2 , James T Yurkovich  1   2 , Thelma Y Garcia  1 , Michi Yukawa  3 , Jennifer Morris  3 , James B Johnson  4 , John C Newman  1   5
Affiliations

Exploratory functional and quality of life outcomes with daily consumption of the ketone ester bis-octanoyl (R)-1,3-butanediol in healthy older adults: a randomized, parallel arm, double-blind, placebo-controlled study

Brianna J Stubbs et al. medRxiv. .

Abstract

Background: Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults.

Objectives: Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE (NCT05585762).

Design: Randomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion.

Setting: The Clinical Research Unit at the Buck Institute for Research on Aging, California.

Participants: Community-dwelling older adults (≥ 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30).

Intervention: Subjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil.

Measurements: Longitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables.

Results: There were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes.

Conclusion: Daily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.

Keywords: BO-BD; beta-hydroxybutyrate; cognition; exogenous ketone; frailty; geroscience; ketone di-ester; ketone ester; ketones; physical function; quality of life; strength.

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Conflict of interest statement

Author Declarations and Conflict Management: The Buck Institute holds shares in BHB Therapeutics (Ireland) and Selah Therapeutics. B.J.S. has stock in H.V.M.N Inc, and stock options in Selah Therapeutics Ltd, BHB Therapeutics (Ireland) Ltd., and Juvenescence Ltd. J.C.N. has stock options in Selah Therapeutics Ltd and BHB Therapeutics (Ireland) Ltd. J.C.N and B.J.S. are inventors on patents related to the use of ketone bodies that are assigned to The Buck Institute. Individual and institutional conflict management plans were developed and approved by the Buck Institute and submitted to the reviewing IRB. Actions and decisions important to participant safety and study integrity were carried out by ‘honest brokers’ with no potential financial conflict. Participant consent was obtained by licensed registered nurses (L.A and W.S.M) who have no financial conflict. Decisions on participant enrollment, continuation, and were made by independent medical officers (J.M and M.Y) unaffiliated with Buck Institute and with no financial conflict. All other authors have no conflicts to report.

Figures

Figure 1:
Figure 1:
Study schematic showing the schedule of visits and assessments described in this article. Abbreviations: KE, ketone ester; QoL, quality of life. Created using BioRender.com
Figure 2:
Figure 2:
Change in four functional outcomes from pre- to post- 12 weeks of daily consumption of ketone ester or placebo in n = 23 healthy older adult. A: 1 repmax leg press, B: six minute walk test, C: digit symbol substitution task, D Pittsburgh Fatigability Scale. Change in the composite score resulting from the combination of these four outcomes (E), and characteristics of the composite score (F,G). Abreviations: KE, ketone ester; PLA, placebo; 6MWT, six minute walk test; DSST, digit symbol substitution task, PFS, Pittsburgh Fatigability Scale. Y-axes are oriented so higher is better in all panels.
Figure 3:
Figure 3:
Changes in physical and cognitive function outcomes from pre- to post- 12 weeks of daily consumption of ketone ester or placebo in n = 23 healthy older adults. A: grip strength, B: short physical performance battery, C: leg press reps to fatigue at 70% maximal weight, D: Trails A, E: Trails B, F: Montreal Cognitive Assessment. Abbreviations: KE, ketone ester; PLA, placebo; MoCA, Montreal Cognitive Assessment; SPBB, Short Physical Performance Battery. Y-axes are oriented so higher is better in all panels.
Figure 4:
Figure 4:
Data from wearable health and fitness trackers worn by study participants who completed the 12 week protocol, showing mean and standard error for A) sleeping heart rate, B) sleep minutes, C) daily steps, D) total active minutes for 7 days before baseline visit, and for the remaining 12 weeks of the study. Abbreviations: KE, ketone ester; PLA, placebo.
See this image and copyright information in PMC

References

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