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From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.

ABSTRACT: Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer's disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.

SUBMITTER: Stubbs BJ

PROVIDER: S-EPMC8190215 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.

Stubbs Brianna J BJ Koutnik Andrew P AP Volek Jeff S JS Newman John C JC

GeroScience 20201002 3

Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, ...[more]

PMID: 33006708

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Project description:BackgroundFrailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults.ObjectivesThe primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures.MethodsCommunity-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12.ConclusionThis study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.

Project description:BackgroundFrailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that interventions which target common underlying mechanism of aging could ameliorate frailty. Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on inflammatory and metabolic aging pathways in laboratory animal models. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults.ObjectivesThe primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a broad population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures.MethodsCommunity-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n = 30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12.ConclusionThis study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of aging-related endpoints. This data will inform design of larger trials to rigorously test KE effects on aging mechanisms and clinical outcomes relevant to frailty.

Project description:BackgroundMilitary services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members.ObjectiveThe primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3).MethodsARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions.ResultsThis UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders.ConclusionsThe ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges.International registered report identifier (irrid)DERR1-10.2196/51235.

Dataset Information

From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.

Publications

From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.

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