Do Ketone Drinks Improve Immune, Metabolic and Cognitive Health in Older Adults

Investigating the Immunometabolic and Cognitive Effects of 4 Weeks of Ketone Supplementation in Older Adults

The goal of this randomised, double-blinded, placebo-controlled trial is to investigate the immune, metabolic and cognitive effects of four weeks of daily ketone supplementation in adults aged 60 to 80 with stable health. The main objectives are to assess the effects of the intervention versus placebo on markers of metabolic health, inflammation, immune function, adipose tissue, and cognitive performance.

Participants will undergo two weeks of baseline monitoring followed by a four-week supplementation period in which they will drink a ketone monoester drink or taste-matched placebo three times a day. During these periods, participants will record their diet and supplement intake and their physical activity and blood glucose will be monitored using wearable devices. At the beginning and end of the supplementation period, participants will undergo testing in the university physiology laboratories, involving blood, expired air and adipose tissue samples, as well as cognitive tests, physical tests and questionnaires.

Study Overview

• Status: Recruiting
• Conditions: Aging
• Intervention / Treatment: Dietary supplement: Ketone drink; Dietary supplement: Placebo

Detailed Description

Background: Research shows that ketones have beneficial effects on metabolism, inflammation and brain health in humans. In mice, they have also been shown to influence pathways involved in ageing. Ketones are natural molecules that are produced by the body when people fast (abstain from eating) for longer than 16-24 hours or eat a diet low in carbohydrates. It is now possible to consume ketones in the form of a drink.

Aims: This study aims to investigate if consuming a ketone drink for four weeks improves immunometabolic and cognitive health in adults aged 60 to 80 years. The main objectives are to assess the effects of the intervention versus placebo on:

1. Markers of metabolic health, including glucose control, lipid profile, blood pressure and body composition;
2. Systemic inflammation, immune cell activation and pro-inflammatory cytokine production;
3. Gene expression and secretory profile of subcutaneous adipose tissue; and
4. Cognitive performance and physical function.

Methods: The study is a randomised, double-blinded, placebo-controlled trial. Thirty participants (male and female) aged 60 to 80 years old with stable health will be recruited. Participants will undergo two weeks of baseline monitoring followed by a four-week supplementation period in which they will drink a ketone monoester drink or placebo three times a day. During these periods, participants will record their diet and supplement intake and their physical activity and blood glucose will be monitored using wearable devices. For two days in the supplementation period, participants will replicate their food consumption and physical activity so that they match two days in the baseline period (these are known as matched meal and activity days).

At the beginning and end of the supplementation period, participants will come to the physiology laboratories at the University of Bath for testing. Here, measures will be taken of their body weight, body composition, blood pressure, cognitive function and physical function, as well as samples of expired air, fat tissue and blood for analysis. Sleep and quality of life will be assessed via questionnaires.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anna Nicholas; Phone Number: +44 7724 303532; Email: an915@bath.ac.uk
• Study Contact Backup: Name: Dylan Thompson; Phone Number: +44 1225 383177; Email: spsdt@bath.ac.uk

Study Locations

• United Kingdom
  • Somerset
    • Bath, Somerset, United Kingdom, BA2 7AY
      • Recruiting
      • University of Bath
      • Contact: Anna Nicholas; Phone Number: +447724303532; Email: an915@bath.ac.uk
      • Contact: Dylan Thompson; Phone Number: +441225383177; Email: spsdt@bath.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 60 to 80 years
• Postmenopausal women must be >1 year since last menses
• Able to provide informed consent
• Willing and able to comply with all study procedures including randomisation into any of the experimental groups; maintenance of habitual dietary intake, exercise, medication and supplement use over the 28-day intervention period; blood draws and adipose tissue biopsies; and abstinence from alcohol (>24 h), food (>10 h) and strenuous exercise (>3 d) prior to trial days.

Exclusion Criteria:

• Living in a residential care home
• Unstable or clinically active pulmonary, cardiac, hepatic, renal, endocrine, hematologic, immunologic, neurologic, psychiatric or biliary disorders. 'Unstable' refers to complications of a condition that are not controlled by medication or lifestyle and which require frequent monitoring and testing by a health professional. Stable chronic disease is not an exclusion criterion unless specified.
• Diagnosed Type 1 or Type 2 Diabetes Mellitus
• Diagnosed gastrointestinal condition which would potentially impact ability to consume study drink (e.g. inflammatory bowel disease, history of gastrointestinal ulcers or bleeding)
• Diagnosed autoimmune condition
• Previous major cardiovascular event (e.g. heart attack, stroke)
• Past or current cancer diagnosis and treatment excluding non-melanoma skin cancers
• Severe hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥120 mmHg), as defined by blood pressure measured at Visit 1
• Current tobacco or recreational drug use
• Reported changes to use of thyroid, antihypertensive, antidepressant or statin medications within 30 days of Visit 1
• Taking medications that will interfere with the study outcomes
• Known negative reaction to lidocaine anaesthetic and/or taking warfarin
• Currently following a ketogenic diet or taking ketone supplements
• Not weight stable in the prior 3 months (>5% weight change)
• Unable to converse in English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketone drink; Pre-intervention (baseline) and post-intervention measurements will be obtained before and after the 4-week supplementation period. Physical activity and blood glucose will be monitored using wearable devices.	Dietary supplement: Ketone drink; Participants will consume three daily ketone monoester (KME) drinks (0.282g KME/kg body weight/ serving) for 4 weeks.; Other Names: D-β-hydroxybutyrate-R 1,3-Butanediol
Placebo Comparator: Placebo; Pre-intervention (baseline) and post-intervention measurements will be obtained before and after the 4-week supplementation period. Physical activity and blood glucose will be monitored using wearable devices.	Dietary supplement: Placebo; Participants will consume three daily taste-matched calorie-free placebo drinks for 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24hr average glucose area under the curve (AUC)	Glucose control will be measured using a continuous glucose monitoring device worn throughout the baseline period and weeks 3 and 4 of the intervention period. Change in 24h average glucose AUC will be assessed on 'matched meal and activity days' i.e. days during intervention and baseline that are matched for food intake and physical activity.	1 day during baseline period and 1 day during the intervention period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in glycemic variability	Glucose control will be measured using continuous glucose monitoring device worn throughout the baseline period and weeks 3 and 4 of the intervention period. Change in glycemic variability will be assessed on 'matched meal and activity days' i.e. days during intervention and baseline that are matched for food intake and physical activity.	1 day during baseline period and 1 day during the intervention period
Change in serum fructosamine	Measured in fasting blood sample by automated analyser (Daytona Rx)	Pre (day 0) and post (day 29)
Change in fasting plasma glucose	Measured in fasting blood sample by automated analyser (Daytona Rx)	Pre (day 0) and post (day 29)
Change in fasting lipid profile concentrations	Measured in fasting blood sample by automated analyser (Daytona Rx)	Pre (day 0) and post (day 29)
Change in fasting plasma free fatty acids (FFA)	Measured in fasting blood sample by automated analyser (Daytona Rx)	Pre (day 0) and post (day 29)
Change in fasting plasma insulin	Measured in fasting blood sample using a high-sensitivity human insulin enzyme-like immunosorbent assay (ELISA)	Pre (day 0) and post (day 29)
Change in Insulin Sensitivity Index	Calculated from fasting plasma insulin and fasting plasma glucose	Pre (day 0) and post (day 29)
Change in Adipose tissue Insulin Resistance index (Adipo-IR)	Calculated from fasting plasma insulin and fasting plasma FFA	Pre (day 0) and post (day 29)
Change in body mass	Measured using a digital body weight scales	Pre (day 0) and post (day 29)
Change in waist and hip circumference	Measured using a measurement tape	Pre (day 0) and post (day 29)
Change in waist to hip ratio	Calculated from waist and hip circumferences	Pre (day 0) and post (day 29)
Change in fat mass and fat free mass	Assessed by Dual Energy X-ray Absorptiometry (DEXA) scan	Pre (day 0) and post (day 29)
Change in calf muscle density, quality and area	Assessed by calf peripheral Quantitative Computed Tomography (pQCT)	Pre (day 0) and post (day 29)
Change in blood pressure	Measured using an automated blood pressure device. Both systolic and diastolic blood pressure will be measured	Pre (day 0) and post (day 29)
Change in circulating adipokines and inflammatory cytokines	Key inflammatory cytokines including CRP will be quantified by R-plex, U-plex and V-plex kits on a Mesoscale QuickPlex SQ120	Pre (day 0) and post (day 29)
Change in blood immune cell phenotype, function and activation	Peripheral blood mononuclear cells (PBMCs) isolated from whole blood will be incubated with fluorophore-conjugated antibodies and analysed with a flow cytometer to examine the phenotype and cytokine production of immune cells	Pre (day 0) and post (day 29)
Change in adipose tissue immune cell phenotype, function and activation	Adipose tissue stromal vascular fraction (SVF) will be incubated with fluorophore-conjugated antibodies and analysed with a flow cytometer to examine the phenotype and cytokine production of immune cells	Pre (day 0) and post (day 29)
Change adipose tissue adipokine and cytokine concentrations	Adipose tissue explants will be cultured ex vivo for 3h. Concentrations of key adipokines and cytokines in supernatant will be quantified by R-plex, U-plex and V-plex kits on a Mesoscale QuickPlex SQ120	Pre (day 0) and post (day 29)
Change in adipose tissue gene expression	Whole-tissue RNAseq	Pre (day 0) and post (day 29)
Change in Digit-Symbol Substitution Test score	This test will be administered using the computer-based app Inquisit6 Lab (Millisecond). The score reflects the number of correct symbols within the allowed time. Higher is better.	Pre (day 0) and post (day 29)
Change in Stroop Test score	This test will be administered using the computer-based app Inquisit6 Lab (Millisecond). The score reflects the number of correct responses and the response latency. Higher is better.	Pre (day 0) and post (day 29)
Change in Trail Making Task score	This test will be administered using the computer-based app Inquisit6 Lab (Millisecond). The score reflects the time taken to complete trails A and B. Lower is better.	Pre (day 0) and post (day 29)
Change in Digit Span Test score	This test will be administered using the computer-based app Inquisit6 Lab (Millisecond). The score reflects the maximum number of digits recalled correctly. Higher is better.	Pre (day 0) and post (day 29)
Change in score on Montreal Cognitive Assessment (MoCA)	The test will be administered by a trained researcher.	Pre (day 0) and post (day 29)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in physical activity level (PAL)	Physical activity will be assessed using a combined accelerometer and heart rate monitor (Actiheart) worn throughout the baseline period and weeks 3 and 4 of the intervention period	Pre (day 0) and post (day 29)
Change in heart rate	Heart rate will be assessed using an accelerometer (Actiheart) worn throughout the baseline period and weeks 3 and 4 of the intervention period	Pre (day 0) and post (day 29)
Change in score on Pittsburgh Sleep Quality Index	Questionnaire to assess sleep quality	Pre (day 0) and post (day 29)
Change in score on EuroQuol EQ-5D-5L Questionnaire	Questionnaire to assess health-related quality of life	Pre (day 0) and post (day 29)
Change in Short Physical Performance Battery score	Standard set of tests to measure physical function in elderly involving gait speed, chair stand and balance test	Pre (day 0) and post (day 29)
Supplement acceptability as assessed by likability, taste and ease of compliance	Acceptability of the supplement will be assessed via questionnaire using a 7-point Likert scale	Post (day 29)
Change in adipose tissue protein expression	Adipose tissue protein expression will be assessed by targeted immunoblotting.	Pre (day 0) and post (day 29)

Collaborators and Investigators

• Sponsor: University of Bath

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2023
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: September 13, 2023
• First Submitted That Met QC Criteria: September 28, 2023
• First Posted (Actual): October 5, 2023

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: September 28, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Ketone
• Other Study ID Numbers: 23/SW/0067

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No