Targeting Aging With a Ketone Ester for Function in Frailty

This study aims to find out if a food supplement that contains a naturally occurring substance, ketones, can help to improve strength and general wellness in adults at, or over the age of 65 years who are experiencing a slight decline in their physical function. Participation will involve a screening visit and 4 additional study visits over the course of 20 weeks. After being assessed for eligibility, study participants will be sorted into two groups at random and consume either a ketone or placebo supplement at home every day for 20 weeks. Both study products can cause gastro-intestinal side effects in some individuals. At all study visits, subjects will provide blood samples. At three study visits, subjects will be asked to complete physical performance tests, provide blood, stool and urine samples. They will also complete questionnaires during three study visits to assess physical function, markers of inflammation, and other aspects of general well-being. The study enrolls at three sites across the United States, in California (Buck Institute), Ohio (Ohio State University), and Connecticut (University of Connecticut). The study is coordinated by the San Francisco Coordinating Center (California Pacific Medical Center).

Screening (Phone and Visit 0): Subjects are screened for eligibility by telephone for major exclusion criteria. They then attend a screening visit. At the start of the visit subjects must meet pre-test requirements. During this visit, consent is obtained, followed by a medical history interview, a physical assessment and fasting blood samples are collected for screening analysis. Subjects who meet all the inclusion and none of the exclusion criteria will be scheduled for a Baseline (Visit 1) and at the end of Visit 1 will be randomized into one of the two experimental groups (ketone ester or placebo). Subjects will be shown and instructed on the use of the equipment for the physical function testing and complete a brief familiarization. A 24h diet log will be provided to complete before the next visit. A stool collection kit will also be provided along with use instructions to complete 3 days before Baseline visit. Baseline Visit (Visit 1- Week 0): Subjects must meet pre-test requirements. Changes to the subject's health and medication/supplement use will be assessed, and subject's compliance with inclusion/exclusion criteria will be reviewed. Fasted blood samples are collected. A clean catch urine sample is collected for archiving and additional plasma is banked for future aging biomarker analysis. After this a physical assessment will be conducted, including vital signs (after 5 minutes of rest), body weight and waist circumference. Investigators will reassess Katz's Activities of Daily Living (ADL) and Lawton's Instrumental Activities of Daily Living (IADLs) and CSHA Frailty Score (Canadian Study of Health and Aging). Then subjects will complete the following paper questionnaires: Profile of Mood States (Short form), Short Form Health Survey-36, Pittsburgh Sleep Quality Index, Pittsburgh Fatiguability Scale, Geriatric Depression Scale, Lower Urinary Tract Symptom Questionnaire. Subjects will complete cognitive function testing: Montreal Cognitive Assessment, Digit Symbol Substitution Task and Trails A and B. Subjects will complete physical function testing: Short Physical Performance Battery, 1 rep max leg press, sub maximal leg press repetitions to failure, 6-minute walk test and grip strength. Subjects will be given a stool sample collection kit to take home for at-home sample between Week 0 and 1; samples are returned by mail. Subject will be given a month's supply of study product to take home. Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). Subjects will be given a wearable actigraphy device and instructed on its use during the study. At home procedures (Week 0 - 20): Each day at home, subjects should consume their first meal of the day at a similar time and consume the study product with that first meal. For the first 7 days of the study, subjects will consume a 12.5 gram dose of study product. From day 8 onwards subjects will consume 25 grams of study product. From Week 3 onwards, they will consume a second serving (Week 3 = 12.5 grams, Week 4 - 20 = 25 grams) with their final meal of the day. The goal is to consume a 25 gram dose twice a day, one dose each with the first and last meal of the day. Subjects will complete the Study Log to confirm they consumed their study product. The Study Log will query the presence of specific symptoms in the hours after consumption of the study product with a beverage tolerance questionnaire (BTQ). Between days 6 - 9, subjects will collect a stool sample using the provided kit. Every 2 weeks (excepting the site visits) the subjects will schedule a phone call with the Study Team in which they will verbally complete the BTQ for symptoms occurring in the preceding 2-week period. Compliance will be assessed, and AEs will also be assessed with an open-ended question. Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). After Week 16 check in, subjects will be mailed a stool sample collection kit for sample collection up to 3 days ahead of Visit 4. From Week 5 onwards, a full BTQ is not completed daily. There is space in the Study Log to note any symptoms, these notes will be used to assess tolerance by interview for the previous 2-week interval; at Visit 2, during phone check-ins (Week 2, 6, 8, 10, 14, 16 and 18) and at Visits 3 and 4. Study product will be provided at one month intervals, it will be distributed directly during Visit 2 (week 4) and Visit 3 (week 12) and it will be shipped to subject's homes to arrive in week 8 and 16. Intermediate Visit (Visit 2- Week 4): Subjects must meet pre-test requirements on arrival for Visit 2 (fasting ≥ 10 h, no alcohol ≥ 10 h, no exercise ≥ 10 h, no cannabis products ≥ 10 h); a reminder email (or telephone call if preferred by the subject) will be sent out ahead of the visit. On arrival, changes to medication/supplement use will be assessed, and the subject's compliance with inclusion/exclusion criteria will be reviewed. Subjects will be queried to ensure compliance with study instructions. Subjects will be asked to provide any unused product to assess compliance of Study Product consumption, and the Study Log (Part I) will be reviewed and collected. Adherence will be assessed, and adverse events (AEs) will also be assessed with an open-ended question. After this a physical assessment will be conducted, including vital signs (after 5 minutes of rest), body weight, body composition (using bioelectrical impedance), and waist circumference. Fasting blood samples will be collected for the following analysis: clinical chemistry, lipid panel, hematology and liver function. Additional samples will be retained to bank for possible future mechanistic investigations. Then, subjects will be asked to collect a urine sample for archiving. Subjects will verbally complete the BTQ for symptoms occurring in the preceding 2-week period. Subjects will be reminded of study instructions (for study product consumption, daily Study Log completion, and to maintain habitual exercise, meal/diet, and medication/supplementation use). Subjects will be given a stool sample collection kit (instructions insert shown in Appendix) to take home for at-home sample collection up to 3 days after Visit 2, the stool sample will be returned to investigators using a prepaid mailer. Finally, subjects will be given a 4-week supply of study product to take home and Study Log (Part II). On this day, subjects will be asked to consume study products with their next meal after the test visit is complete. Visit 3: Interim Endpoints Visit (Visit 4 - Week 12) and Final Visit (Visit 5- Week 20): Follows identical testing procedures to Baseline Visit (Visit 3- Week 0).