Variations in Ketone Metabolism

Summary

This outcome of this study will elucidate how the phenotype of the individual modulates the KE metabolic effect. Most studies of KE have been in homogenous populations, usually young, male athletes. However, two striking experiments using identical, body weight adjusted KE doses in healthy and obese individuals found that BHB area under the curve (AUC) and removal was reduced by obesity and poor metabolic health. Similarly, ketone infusion experiments found that diabetes, obesity, and insulin resistance alter BHB metabolism. It is important to determine how obesity affects KE 'sensitivity' (i.e., breakdown and oxidation) because the increasing prevalence of obesity as a function of age. Age may be another important source of variation in ketone metabolism. The genes that control the ketone system are regulated by a cascade of transcription factors and hormones including PPARα and FGF21, which are themselves known to be affected by aging and dietary status, and the cellular protein sensor target of rapamycin (TOR). Aberrant hyperactivation of TOR with aging may reduce ketogenesis, while it was observed that a long-term ketogenic diet specifically up-regulated PPARα activity. Preliminary work revealed substantial changes across mouse lifespan in the expression of ketone-related genes in the liver such as Hmgcs2 (rate limiting for ketone production) and Bdh1 (rate limiting for BHB oxidation) between young, middle-aged, and old mice, with a nadir of gene expression in middle age before increasing again late in life. Substantial age differences were found in response to matched doses of oral KE in mice and in rats. These data may have important implications for treating people of different ages and for translating KE technologies into the Department of VA. Therefore, this project plans to study individual responses to KE ingestion across the lifespan, against the background of varying metabolic health

Conditions

• Ketosis

Interventions

DIETARY_SUPPLEMENT

Ketone Supplement

Participants will be given 360mg/kg

BEHAVIORAL

Beverage Tolerability Questionnaire (BTQ) and satiety visual analogue scale

Beverage Tolerability Questionnaire (BTQ) and satiety visual analogue scale will be administered at beginning and end of testing day to tests palatability of supplement

BIOLOGICAL

Blood Draw

IV cannula will be inserted at the start of Test Day, and removed at the end of Test Day. Blood samples will be collected at 7 timepoints (possibly 1 more). Cannula will be flushed with a small volume of saline after each sample to maintain patency.

OTHER

Urine Analysis

Prior to consumption of the Study Product, participants will be asked to completely void bladder. And hydration status will be determined via urine specific gravity (USG) reporting \<1.025. Urine passed after the ingestion of the study product will be collected in a plastic container; participants will be asked to void their bladder and collect urine at the end of the test day. The volume produced will be recorded at the end of the study and aliquots will be frozen and stored for future analysis

Sponsors & Collaborators

• Buck Institute for Research on Aging

  collaborator OTHER

• Ohio State University

  lead OTHER

Principal Investigators

• Jeff Volek, PhD · Ohio State University

Study Design

Allocation

NA

Purpose

BASIC_SCIENCE

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

20 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-06-20

Primary Completion

2026-11-01

Completion

2027-01-01

Countries

• United States

Study Locations