The geroscience approach of modulating fundamental aging mechanisms holds great promise for generating
effective new therapeutics for complex, multifactorial conditions of aging such as frailty which contribute so much
to functional decline, disability, and loss of independence in older adults. The frailty syndrome is conceptualized
as a condition of progressive functional decline and increased vulnerability to stressors resulting from decreased
functional reserve. The pathophysiology of frailty is complex and not well understood, but is generally thought to
prominently include cellular energy production deficits along with chronic inflammation and immune dysfunction.
Dietary restriction and fasting, interventions closely linked to fundamental mechanisms of aging, promote the
endogenous production of ketone bodies as a means of supplying fat-derived energy to tissues. New advances
in understanding the biological activities of the ketone body beta-hydroxybutyrate (BHB) suggest that both
energy production and signaling activities of BHB may have a mechanistic role in modulating aging, and may be
particularly relevant to the pathophysiology of frailty. Ketone esters have recently emerged as a pharmacological
means of delivering ketone bodies. We have assembled a multidisciplinary team of experts in geroscience,
geriatrics and frailty, ketone body biology, immunosenescence, and ketone body-related clinical trials to carry
out a multi-site, proof-of-concept Phase 2a clinical trial of a ketone ester (KE) targeting frailty in prefrail and mildly
frail older adults. TAKEOFF is a prospective, randomized, double-blind, 12-week study of ketone ester vs.
matched placebo. Aim 1 will test if muscle strength and other clinical frailty- and aging-related outcomes improve
with KE. Aim 2 will determine the safety and tolerability of daily KE in broadly representative pre-frail and frail
older adults. Aim 3 will test the hypothesis that ketone ester impacts the aging immune system, skeletal muscle,
and biomarkers of aging via detailed mechanistic immunophenotyping, muscle metabolism, and biomarker
studies that leverage the strong specialist expertise at the participating institutions. Altogether, this translational
effort will provide crucial information on the safety and efficacy of interventions increasingly being used by the
public despite a paucity of data, and with potential to impact important aging-related conditions to improve the
health and independence of older adults.