The goal of this randomized, double-blind, parallel group interventional study is to evaluate the effect of ketone bodies on healthy older adults (65-85 y) during 5 days of bed rest. The main questions it aims to answer are: Does supplementation of ketone bodies prevent the typical decline in muscle protein synthesis, muscle size, muscle function, insulin sensitivity, and muscle mitochondrial function that occurs in response to bed rest? Researchers will compare ketone supplements (KET) to an energy matched control beverage (carbohydrates and fats) to see if the ketones can rescue the decline in muscle protein synthesis rates, muscle loss, muscle function, insulin sensitivity, and mitochondrial function due to 5 days of bed rest. This may positively impact the heath of older adults subjected to bed rest.
Bed rest is a common feature of many clinical environments such as hospitals and long-term care facilities. However, physical inactivity due to bed rest decreases muscle size, muscle strength, and physical performance (i.e. rising from a chair) that can lead to a reduced quality of life and a higher risk of disease and death. Eating protein-rich foods and exercising normally helps to maintain muscle size by building proteins found in muscle. However, during bed rest there is a reduction in the rate at which proteins found in muscle are made and this leads to smaller muscles. Bed rest leads to problems with blood glucose regulation and insulin resistance which can increase the risk for diabetes. Both the loss of muscle size and insulin resistance are linked to problems with parts of our cells called mitochondria. Mitochondria do a lot of important things including keeping our cells full of energy. Bed rest occurs more frequently in older adults and also negatively impacts their health more than in younger adults. Sadly, there are limited options to prevent the problems associated with bed rest. Ketone bodies are molecules that come from fat that are normally produced in the body in response to reduced carbohydrate intake (i.e. a ketogenic diet). Recently ketone supplements have become available, which increase the amount of ketone bodies in the body without the need to limit carbohydrate intake from food. Elevated ketone bodies may help protect muscle size and health during bed rest by enhancing the process of building muscle proteins, improving blood glucose regulation, and helping mitochondria work optimally.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
30
Provided twice a day between meals.
Provided twice a day between meals.
Research Institute - McGill University Health Centre
Montreal, Quebec, Canada
Changes in integrated fractional synthesis rate (%/d) in response to bed rest with and without ketone monoester (KET) supplementation.
Integrative myofibrillar fractional synthesis rate will be calculated during baseline (day 0-5) and bed rest (day 5-10) phases.
Time frame: Day 0-5 and day 5-10
Changes in whole body insulin sensitivity in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken in the fasted state before and after bed rest. Will measure blood glucose and insulin concentration during a hyperinsulinemic-euglycemic clamp.
Time frame: Day-3 and Day 10.
Changes in whole-body lean mass (kg) in response to bed rest with and without ketone monoester (KET) supplementation
Measurements taken in the fasted state using dual-energy x-ray absorptiometry (DXA) following urinary void before and after bed rest.
Time frame: Day-3 and Day 10.
Changes in leg lean mass (kg) in response to bed rest with and without ketone monoester (KET) supplementation
Measurements taken in the fasted state using dual-energy x-ray absorptiometry (DXA) following urinary void before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in quadriceps muscle volume in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest via magnetic resonance imaging (MRI).
Time frame: Day -3 and Day 10.
Changes in maximal voluntary isometric contraction (N/m) of the knee extensors in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest using a Biodex dynamometer.
Time frame: Day -3 and Day 10.
Changes in handgrip strength (kg) in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest using a Jamar hand dynamometer.
Time frame: Day -3 and Day 10.
Changes in physical performance (numerical score) as determined by short physical performance battery (SPPB) in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest
Time frame: Day -3 and Day 10.
Changes in physical performance (numerical score) as determined by 5-item physical performance test in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest
Time frame: Day -3 and Day 10.
Changes in cognitive status in response to bed rest with and without ketone monoester (KET) supplementation.
NIH Toolbox Cognition Battery (computerized). Measurements taken before and after bed rest
Time frame: Day 4 and Day 9.
Changes in markers of inflammation in systemic circulation in response to bed rest with and without ketone monoester (KET) supplementation.
Markers of inflammation including: IL-1 beta, NF-K beta 1, IL-6, TNF-alpha, IFNY, MIP-1 beta will be evaluated. Measurements taken before, during, and after bed rest.
Time frame: Day -3 and Day 10.
Changes in muscle mRNA expression of inflammatory regulators will be assessed in response to bed rest with and without ketone monoester (KET) supplementation.
Muscle mRNA expression of NFKB1, TLR-4,IL-6, TNF-alpha, and IL-1Beta will be evaluated. Measurements taken before and after bed rest
Time frame: Day -3 and Day 10.
Changes in skeletal muscle phenotype in response to bed rest with and without ketone monoester (KET) supplementation.
Muscle cross-sections immunolabeled for type I, IIa, and IIx myosin heavy chains. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in skeletal muscle fiber size in response to bed rest with and without ketone monoester (KET) supplementation.
Muscle cross-sections analyzed for cross-sectional area.
Time frame: Day -3 and Day 10.
Changes in mitochondrial content in response to bed rest with and without ketone monoester (KET) supplementation.
Via the assessment in succinate dehydrogenase activity.
Time frame: Day -3 and Day 10.
Changes in mitochondrial respiration in response to bed rest with and without ketone monoester (KET) supplementation.
Assessed using standard substrate and inhibitor addition protocols in O2k high resolution Respirometer. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in mitochondrial calcium retention capacity (marker of mitochondrial propensity to trigger apoptosis) in response to bed rest with and without ketone monoester (KET) supplementation.
Determined spectrofluorometrically using the Calcium Green probe. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in mitochondrial reactive oxygen species (ROS) production in response to bed rest with and without ketone monoester (KET) supplementation.
Assessed using standard substrate and inhibitor addition protocols in O2k high resolution Respirometer. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in mitochondrial time to the permeability transition pore opening (marker of mitochondrial propensity to trigger apoptosis) in response to bed rest with and without ketone monoester (KET) supplementation.
Determined spectrofluorometrically using the Calcium Green probe. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in the phosphorylation status of anabolic signaling molecules modulating muscle protein synthesis (MPS) in response to bed rest with and without ketone monoester (KET) supplementation.
Western blotting - membranes will be probed with phospho-specific antibodies against IRS-1S527/Thr446, AktSer473, mTORSer2448, 4E-BP1Thr37/46, rpS6Ser240/244, p70S6KThr389. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in the phosphorylation status of catabolic signaling molecules modulating muscle protein breakdown (MPB) in response to bed rest with and without ketone monoester (KET) supplementation.
Western blotting - membranes will be probed with phospho-specific antibodies against FoxO3aThr32, MuRF1, and MAFbx. Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Blood beta-hydroxybutyrate concentrations (mmol/L) in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken at the start and end of bed rest.
Time frame: Day 5 and Day 10
Changes in subjective pain via visual analog scale in response to bed rest with and without ketone monoester (KET) supplementation.
Throughout the 5 day bed rest period.
Time frame: Day 5-10.
Changes in muscle area in response to bed rest with and without ketone monoester (KET) supplementation.
Peripheral quantitative computed tomography (pQCT). Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Changes in muscle density in response to bed rest with and without ketone monoester (KET) supplementation.
Peripheral quantitative computed tomography (pQCT). Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
2H enrichments in body water before and during bed rest with and without ketone monoester (KET) supplementation.
Throughout the baseline and bed rest period.
Time frame: Day -1 to Day 10.
2H-alanine enrichment in venous blood before and during bed rest with and without ketone monoester (KET) supplementation.
Throughout the baseline and bed rest period.
Time frame: Day -1 to Day 10.
Changes in resting metabolic rate (RMR) in response to bed rest with and without ketone monoester (KET) supplementation.
Measurements taken before and after bed rest.
Time frame: Day -3 and Day 10.
Physical activity level via accelerometer before bed rest.
Throughout the baseline period
Time frame: Day 0-4.
Changes in sleep disturbance (numerical score) during bed rest with and without ketone monoester (KET) supplementation.
Via Patient-Reported Outcomes Measurement Information System (PROMIS) Short form 8a. Measured throughout the 5 day bed rest period.
Time frame: Day 5-10.
Changes in sleep quality (numerical score) during bed rest with and without ketone monoester (KET) supplementation.
Via Pittsburgh Sleep Quality Index (PSQI). Measured throughout the 5 day bed rest period.
Time frame: Day 5-10.
Average habitual dietary intake assessed using Keenoa for 3 days (a food tracker application).
Dietary intake will be assessed for total energy (kcals) and macronutrient (protein, carbohydrate, and fat consumption; g) intake.
Time frame: Measured before bed rest.
Changes in Thigh Absolute Synthetic Rate (ASR) in response to bed rest with and without ketone monoester (KET) supplementation.
Changes in Thigh Absolute Synthetic Rate (ASR) will be calculated during baseline (day 0-5) and bed rest (day 5-10) phases.
Time frame: Day 0-5 and day 5-10
Changes in Thigh Absolute Protein Breakdown Rate (ABR) in response to bed rest with and without ketone monoester (KET) supplementation.
Changes in Thigh Absolute Protein Breakdown Rate (ABR) will be calculated during baseline (day 0-5) and bed rest (day 5-10) phases.
Time frame: Day 0-5 and day 5-10
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