Methods of determining glucose hypometabolism-induced energy crisis and treatments thereof

Abstract

The present disclosure provides systems, methods, compositions, and algorithms for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer's disease, Parkinson's disease, or heart failure).

Description

Attorney Docket No. FRD-001 WO METHODS OF DETERMINING GLUCOSE HYPOMETABOLISM-INDUCED ENERGY CRISIS AND TREATMENTS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U. S. Provisional Patent Application No. 63 / 778,052, filed March 26, 2025, and U. S. Provisional Patent Application No.63 / 922,537, filed November 21, 2025, the contents of each of which are hereby incorporated by reference in their entirety.BRIEF SUMMARY

[0002] Described herein is a diagnostic-therapeutic platform for treating a common underlying metabolic mechanism in diverse diseases. Specifically, the disclosure targets glucose hypometabolism and the resultant cellular energy crisis found in neurodegenerative, cardiovascular, and metabolic disorders that were previously considered unrelated. More specifically, described herein are systems, methods, compositions, and algorithms for quantitatively measuring tissue-specific glucose metabolism deficits and administering precisely calibrated exogenous ketone formulations to compensate for these deficits, thereby treating the underlying pathophysiology rather than merely addressing symptoms.FIELD OF THE INVENTION

[0003] This application relates to metabolic diagnostics and therapies, particularly to methods and systems for identifying impaired glucose utilization in tissues and treating conditions characterized by such glucose hypometabolism. This application further relates to a programmable metabolic therapy platform for inducing and controlling a therapeutic titratable ketonemia (“TTK”). In particular, it describes a composition-agnostic and disease agnostic system and method for treating patients by achieving and maintaining a target metabolic state characterized by elevated blood ketone bodies - specifically P-hydroxybutyrate (BHB) and / or acetoacetate (AcAc) - within a defined therapeutic range. The platform leverages feedback-guided dosing of ketone elevating agents to titrate ketone levels to a desired treat-to-target window, independent of strict dietary carbohydrate restriction. The TTK approach is broadly applicable across medical domains, including oncologic, neurologic, psychiatric, and metabolic disorders, as a state-based treatment modality.BACKGROUND

[0004] Diseases and disorders have historically been classified based on presenting symptoms and affected organs rather than underlying molecular and metabolic mechanisms. For example, the symptomatic presentations of Alzheimer's disease (memory loss), heart failure (reducedAttorney Docket No. FRD-001 WO cardiac output), and Parkinson's disease (motor dysfunction) appear entirely distinct, masking their shared metabolic pathophysiology. A unifying feature of these conditions is impaired glucose utilization at the cellular level, often due to reduced glucose uptake or utilization in affected regions. Despite decades of research in each of these disease areas, this unifying mechanism - glucose hypometabolism - has remained unrecognized due to several key factors, including entrenched medical specialization silos, lack of previous cross-disease metabolic comparisons, and technological limitations to precisely measure and quantify tissue-specific glucose metabolism. In Alzheimer's disease, the dominant amyloid hypothesis has guided therapeutic development for decades, despite consistent failures. In Parkinson's disease, focus has remained on dopaminergic therapies despite their inability to modify disease progression. In heart failure, hemodynamic approaches have predominated despite incomplete efficacy. There remains a need to develop a unifying therapeutic approach to address the common underlying pathophysiology - glucose hypometabolism and resultant cellular energy crisis - behind these and other traditionally considered distinct and unrelated disorders, including neurodegenerative, cardiovascular, and metabolic disorders.

[0005] Ketone bodies, namely P-hydroxybutyrate ( HB) and acetoacetate (AcAc), represent an alternative energy source for the brain that can bypass defects in glucose metabolism. During fasting or ketogenic diets, the liver produces ketone bodies which can supply up to two-thirds of the brain’s energy. Importantly, ketones produce more ATP per unit oxygen than glucose and generate fewer reactive oxygen species (ROS) during metabolism, thereby offering a dual benefit of efficient energy and reduced oxidative stress. Preclinical and clinical evidence suggests ketone supplementation can lead to significant cognitive or metabolic improvements in patients with mild cognitive impairment and Alzheimer’ s disease, improvement in non-motor symptoms in patients with Parkinson’s disease, and reduction in hospitalization risk in patients with heart failure.

[0006] Despite recognition that ketones can benefit patients with these conditions, previous metabolic therapy approaches have been limited. Past interventions - such as ketogenic diets or general ketone supplementation trials in Alzheimer’s or Parkinson’s disease - relied on indirect measures and one-size-fits-all dosing, without quantitatively tailoring treatment to an individual’s deficit. For instance, some strategies tracked the ratio of blood glucose to ketones (a “glucose ketone index”) as a broad indicator of metabolic state, but no existing method provides a direct measurement of a patient’s tissue-specific glucose shortfall and then compensates for it with a precisely calibrated alternative fuel.Attorney Docket No. FRD-001 WO

[0007] Ketogenic Diets and Limitations: For nearly a century, ketogenic diets (high-fat, very low-carbohydrate regimens) have been used to induce endogenous ketosis for therapeutic benefit (for example, to reduce seizures in epilepsy). However, dietary ketosis has practical limitations. Maintaining a strict ketogenic diet long-term is challenging for many patients due to palatability issues, lifestyle incompatibility, and side effects (e.g. gastrointestinal discomfort, micronutrient deficiencies, dyslipidemia). Even when patients adhere, diets lack precision: the resulting ketone levels can vary widely between individuals and cannot be fine-tuned easily. There is no convenient way to “dial in” a precise blood ketone concentration through diet alone, and lapses in diet quickly negate the ketosis. Thus, while ketogenic diets demonstrate that ketosis can be therapeutic, they underscore the need for a more controlled and patient-friendly method to achieve and sustain a therapeutic ketotic state.

[0008] Exogenous Ketone Supplements: In recent years, exogenous ketone formulations (such as ketone esters, ketone salts, medium-chain triglycerides (MCTs), and related precursors) have emerged as tools to elevate blood ketone levels without requiring complete carbohydrate restriction. These supplements can induce ketosis pharmacologically - raising blood BHB acutely in a dose-dependent manner. However, prior uses of exogenous ketones have typically been in an open-loop fashion (fixed doses or schedules) rather than as part of a closed-loop “treat-to-targef ’ system. Patients might take a ketone drink or pills and occasionally measure blood BHB (e.g. via fingerstick) to see if they are “in ketosis,” but there is no dynamic adjustment of dosing based on those readings. This contrasts with diabetes care, where glucose levels are continuously monitored and insulin delivery is automated to achieve target glucose levels. In the ketone therapy arena, no established protocol yet exists for automatically maintaining a patient’s ketone level within a specific therapeutic window over time. The lack of feedback-controlled ketosis means sub-therapeutic ketone levels may fail to confer benefit, whereas excessive ketone levels could pose safety risks (e.g. metabolic acidosis), all without a mechanism for automatic correction. A need exists for a tunable, sensor-guided system to induce and maintain therapeutic ketosis reliably and safely.

[0009] Metabolic and Bioenergetic Dysregulation in Disease: A wide range of chronic diseases are characterized by impairments in cellular energy utilization, neurotransmitter imbalances, and redox (oxidation-reduction) disturbances. For example, cancer cells often exhibit Warburg metabolism (heavy reliance on glucose glycolysis), neurodegenerative diseases like Alzheimer’ s involve reduced brain glucose uptake and mitochondrial dysfunction, psychiatric disorders have been linked to neurochemical imbalances and inflammation, and metabolic diseases such as type 2 diabetes are defined by insulin resistance and energy surplus.Attorney Docket No. FRD-001 WO Traditional treatments for these conditions do not directly address the underlying metabolic state of cells. Therapeutic ketosis represents a unifying strategy to counteract these dysfunctions: ketone bodies serve as an alternative high-efficiency fuel, alter the NAD / N ADH ratio toward a more oxidized state, modulate neurotransmitter levels (e.g. increasing GABA relative to glutamate), and reduce systemic inflammation. Despite evidence that ketosis can positively influence these disease pathways, no standardized medical platform exists to intentionally create and sustain a therapeutically optimized ketotic state in patients across different indications. The present disclosure fills this gap by providing methods and systems to programmatically control a patient’s metabolic state (via titratable ketonemia) as a versatile treatment approach.

[0010] In contrast, the present application introduces an integrated platform that, for the first time, quantifies a subject’s glucose hypometabolism and directly addresses it with an optimized ketone therapy. This paradigm shift - from symptom-focused or generic metabolic therapy to a personalized, mechanism-driven treatment - underscores the novelty of the approach.SUMMARY

[0011] Disclosed herein, in certain embodiments, are systems, methods, compositions, and algorithms for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, or heart failure).

[0012] In one aspect provided is a method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:(a) measuring a glucose metabolism deficit (G_Diff) in one or more tissues of the subject using at least one diagnostic technique (for example, positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, or wearable biosensors) to obtain a quantitative indication of the subject’s impaired glucose utilization;(b) calculating a personalized exogenous ketone dosage (K) based on the measured G_Diff, wherein said calculation comprises applying at least one algorithm that correlates the measured G_Diff to the exogenous ketone intake required to at least partially compensate for the subject’s impaired glucose utilization; and(c) administering an exogenous ketone composition to the subject in accordance with the calculated personalized exogenous ketone dosage,wherein the administered exogenous ketone composition provides an alternative metabolic fuel to the affected tissues, thereby addressing the subject’s glucose hypometabolism.Attorney Docket No. FRD-001 WO

[0013] Another aspect of the disclosure provides a system for diagnosing and treating a glucose hypometabolic disorder in a subject, comprising:(a) a diagnostic module configured to measure a glucose metabolism deficit (G_Diff) in the subject’s tissue using at least one diagnostic technique (for example, positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, or wearable biosensors);(b) a computational module, operably connected to the diagnostic module, that applies an algorithm converting the measured G_Diff into a recommended exogenous ketone dosage (K) to compensate for the subject’s impaired glucose utilization; and(c) a ketone delivery apparatus configured to administer the recommended ketone dosage to the subject,wherein the diagnostic module, computational module, and ketone delivery apparatus together provide a unified diagnostic-therapeutic platform to treat the glucose hypometabolic disorder by supplying ketones in proportion to the measured deficit.

[0014] Another aspect of the disclosure provides a kit for diagnosing and treating a glucose hypometabolic disorder in a subject, comprising:(a) instructions for measuring or estimating a glucose metabolism deficit (G_Diff) in the subject using at least one diagnostic technique (for example, positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, or wearable biosensors);(b) an exogenous ketone composition suitable for oral or parenteral administration; and (c) a reference chart or algorithmic guide that translates the measured G_Diff into a recommended personalized exogenous ketone dosage for mitigating the subject’s impaired glucose utilization,wherein the kit enables a practitioner or patient to determine a personalized exogenous ketone dosage that compensates for the subject’s impaired glucose utilization.

[0015] Another aspect of the disclosure provides a non-transitory computer-readable medium containing instructions which, when executed by one or more processors, cause the processor(s) to:(a) receive data corresponding to a measured glucose metabolism deficit (G_Diff) in a subject’s tissue;Attorney Docket No. FRD-001 WO (b) apply at least one mathematical formula to compute a recommended exogenous ketone dosage (K) that partially or fully compensates for the measured deficit, wherein said formula accounts for factors including the relative energy yield of ketones, the subject's efficiency factor (F), and partition factor (p);(c) generate an output specifying how the ketone dosage should be administered to the subject; and(d) optionally transmit the output to a user interface or ketone delivery apparatus, whereby the subject’s measured glucose shortfall is systematically converted into a therapeutic ketone dosage parameter.In general, the disclosed platform can be implemented in a variety of forms and combinations. For instance, the diagnostic and computational functions may be provided as software (e.g., an analysis application or cloud service that takes input from existing hospital imaging devices or laboratory tests), while the therapeutic component may be delivered as a pharmaceutical composition or a wearable infusion device. The system’s modules need not be physically integrated; data can be communicated via wired or wireless means between separate devices. This modular design allows for the embodiments described herein to be integrated into existing clinical workflows or deployed as a stand-alone solution. In some embodiments, the platform further includes a digital health interface (e.g., a patient smartphone application) that synchronizes behavioral or dietary guidance with the ketone therapy and optionally transmits the patient’s metabolic data to a remote server for clinician monitoring. Such flexibility enables the platform to complement standard-of-care treatments (for example, being used alongside conventional Alzheimer’s or heart failure medications) or to be offered as an adjunct service or device. Overall, the disclosure provides a unified yet adaptable solution to glucose hypometabolism, suitable for partnership with pharmaceutical therapies, medical devices, and digital health systems.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG.1 is a schematic diagram of an exemplary closed-loop Therapeutic Titratable Ketonemia system. The figure illustrates a patient connected to a ketone delivery device (such as an infusion pump) and a ketone level sensor. A feedback control unit receives the sensor readings and adjusts the ketone delivery rate in real time to maintain the patient’s blood BHB within the target range. Safety interlocks are integrated, such that the controller will halt infusion if, for example, the ketone level exceeds a set safety threshold or if blood glucose drops below a minimum level.Attorney Docket No. FRD-001 WO

[0017] FIG.2 is a timing chart showing an example treatment schedule in combination with a standard therapy. The graph plots blood BHB concentration (Y-axis) over time (X-axis) and highlights a shaded target range (therapeutic ketosis window, e.g. 1-3 mM BHB). In this example, the patient’s ketone level is raised into the target window prior to a standard-of-care (SOC) treatment (such as chemotherapy or an infusion of a drug) and maintained during and after the SOC therapy session. The timing chart demonstrates how TTK can be synchronized with other treatments - for instance, ketone administration begins a few hours before the SOC therapy to achieve the target ketone level, continues through the therapy period, and tapers off afterwards - maximizing therapeutic synergy.

[0018] FIG.3 is a flowchart of a feedback-based control algorithm for therapeutic ketosis. The flow diagram shows the steps of monitoring the patient’s ketone level, comparing it to the target range, and adjusting dosing accordingly. The algorithm includes safety checks: if ketone levels are below target, dosing is increased (unless limited by other factors); if levels are above target or a safety limit is reached, dosing is decreased or paused. The flowchart also depicts optional inputs (such as glucose measurements) that modulate the control decision, and outputs such as alerts or data logs. This figure illustrates the logic that can be implemented in software or firmware for an automated TTK system.

[0019] FIG.4 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on neuronal viability in Alzheimer’s disease (AD) neurons. Neurons were treated with amyloid beta (A[H-42) and increasing concentrations of AcAc (approximately 0.1 mM, 0.5 mM, 1 mM, 10 mM, and 100 mM). Cell viability was measured using a luminescence-based live / dead assay (CellTiter-Glo). Increasing concentrations of AcAc progressively improve viability relative to untreated AD neurons exposed to A|3, approaching levels observed in healthy control neurons.

[0020] FIG.5 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on reactive oxygen species (ROS) levels in AD neurons. Neurons were treated with amyloid beta (Api-42) and increasing concentrations of AcAc (approximately 0.1 mM to 100 mM). ROS levels were measured using MitoSOX staining. Increasing concentrations of AcAc reduce MitoSOX fluorescence intensity relative to untreated AD neurons, indicating a dose-dependent reduction in oxidative stress.

[0021] FIG.6 is a bar graph showing effects of multiple ketone bodies, including D-P-hydroxybutyrate (D-BHB), L-P-hydroxybutyrate (L-BHB), and acetoacetate (AcAc), on ROS levels in AD neurons under amyloid beta stimulation. Ketone treatment reduces ROS relative to untreated AD neurons, demonstrating a class-wide effect of ketones on oxidative stress reduction.Attorney Docket No. FRD-001 WO

[0022] FIG.7 is a set of fluorescence microscopy images showing mitochondrial structure and oxidative stress in neurons under amyloid beta-induced conditions. Neurons were treated with 1 pM amyloid beta (A01-42) in the presence or absence of 0-hydroxybutyrate (P-OHB) at concentrations of approximately 250 pM and 500 pM. MitoTracker staining (green) indicates mitochondrial structure and integrity, while MitoSOX staining (red) indicates mitochondrial reactive oxygen species (ROS) production. Ketone-treated cells exhibit reduced MitoSOX signal intensity and improved mitochondrial morphology relative to amyloid-treated cells without ketone treatment, indicating reduced oxidative stress and preservation of mitochondrial integrity.

[0023] FIG.8 is a bar graph quantifying mitochondrial oxidative stress in neurons under amyloid beta-induced conditions. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of P-hydroxybutyrate (P-OHB) at concentrations of approximately 250 pM and 500 pM. Reactive oxygen species (ROS) levels were measured using MitoSOX staining and normalized to MitoTracker signal. Treatment with P-OHB reduced MitoSOX fluorescence intensity relative to amyloid-treated cells without ketone treatment, indicating reduced mitochondrial oxidative stress. Lower values correspond to reduced oxidative stress.

[0024] FIG. 9 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on intracellular ATP levels in Alzheimer’s disease (AD) neurons. Neurons were treated with 1 pM amyloid beta (Api-42) and increasing concentrations of AcAc (approximately 0.1 mM, 0.5 mM, 1 mM, 10 mM, and 100 mM). Intracellular ATP levels were measured using an ATP-dependent luminescence assay and are presented relative to healthy control neurons. AD neurons exhibit reduced ATP levels relative to healthy controls, while treatment with increasing concentrations of AcAc results in a dose-dependent increase in ATP levels, indicating restoration of cellular energy metabolism.

[0025] FIG. 10 is a bar graph showing neuronal viability under basal and amyloid betastimulated conditions in AD neurons. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of ketone bodies, including D- -hydroxybutyrate (D-BHB), L-P-hydroxybutyrate (L-BHB), and acetoacetate (AcAc), at approximately 5 mM for 14 days. Cell viability was measured using a CellTiter-Glo Live / Dead assay. Amyloid beta exposure reduces viability relative to basal conditions, while ketone treatment restores viability to varying extents.

[0026] FIG. 11 is a bar graph showing apoptosis levels in AD neurons as measured by Annexin V staining. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of ketone bodies (D-BHB, L-BHB, and AcAc) at approximately 5 mM for 14 days. The percentage of Annexin V-positive cells is increased following amyloid beta exposure and reduced following ketone treatment, indicating decreased apoptotic signaling.Attorney Docket No. FRD-001 WO

[0027] FIG. 12 is a graph showing oxygen consumption rate (OCR) over time in AD neurons as measured by a Seahorse XF Mito Stress Test. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). OCR was measured across sequential additions of mitochondrial modulators, including oligomycin, FCCP, and rotenone / antimycin A. Ketone -treated neurons exhibit increased mitochondrial respiration relative to untreated AD neurons.

[0028] FIG. 13 is a bar graph showing ATP-linked respiration in AD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc) and ATP concentration was measured. Ketone-treated neurons exhibit increased ATP relative to untreated AD neurons.

[0029] FIG. 14 is a bar graph showing basal respiratory capacity in AD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Basal respiration was determined using Seahorse XF Mito Stress Test analysis. Ketone-treated neurons exhibit increased basal respiratory capacity relative to untreated AD neurons, indicating improved mitochondrial function.

[0030] FIG. 15 is a bar graph showing neuronal viability in Parkinson’s disease (PD) neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Cell viability was measured using a CellTiter-Glo Live / Dead assay. PD neurons exhibit reduced viability relative to healthy controls, and ketone treatment improves viability, with AcAc demonstrating a comparatively strong effect.

[0031] FIG.16 is a bar graph showing apoptosis levels in PD neurons as measured by Annexin V staining. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). PD neurons exhibit increased percentages of Annexin V-positive cells relative to healthy controls, and ketone treatment reduces apoptotic signaling.

[0032] FIG.17 is a bar graph showing reactive oxygen species (ROS) levels in PD neurons as measured by MitoSOX staining. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). PD neurons exhibit elevated ROS levels relative to healthy controls, and ketone treatment reduces ROS levels to varying extents.

[0033] FIG. 18 is a graph showing oxygen consumption rate (OCR) over time in PD neurons as measured by a Seahorse XF Mito Stress Test. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). OCR was measured across sequential additions of mitochondrial modulators, including oligomycin, FCCP, and rotenone / antimycin A. Ketone-treated neurons exhibit increased mitochondrial respiration relative to untreated PD neurons.

[0034] FIG.19 is a bar graph showing ATP production in PD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). ATP-linked respiration was derived fromAttorney Docket No. FRD-001 WO Seahorse XF Mito Stress Test measurements. Ketone treatment increases ATP production relative to untreated PD neurons.

[0035] FIG.20 is a bar graph showing basal respiratory capacity in PD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Basal respiration was determined using Seahorse XF Mito Stress Test analysis. Ketone treatment increases basal respiratory capacity relative to untreated PD neurons.

[0036] FIG.21 is a bar graph showing uptake of amyloid beta (Api-42) by microglia treated with ketone esters. Microglia were treated with ketone esters and exposed to fluorescently labeled Api-42 for approximately 1 hour. Following acid wash to remove non -internalized amyloid, intracellular fluorescence was measured. Increased fluorescence intensity indicates enhanced internalization of amyloid beta in ketone-treated microglia relative to untreated controls.

[0037] FIG.22 is a bar graph showing clearance of amyloid beta (Api-42) by microglia following ketone treatment. Microglia were treated with ketone esters and exposed to fluorescently labeled Api-42 for approximately 24 hours. Residual extracellular amyloid beta was quantified by fluorescence analysis. Reduced fluorescence intensity indicates decreased residual amyloid beta and enhanced clearance relative to untreated controls.

[0038] FIG.23 is a line graph showing the relative kinetics of amyloid beta (Api-42) clearance in microglia over time. Microglia were treated with acetoacetate (AcAc) and exposed to amyloid beta, and clearance was monitored over a time course of approximately 0 to 30 hours. Ketone-treated microglia exhibit enhanced uptake at early time points and accelerated clearance relative to vehicle-treated controls, resulting in improved overall amyloid clearance kinetics.

[0039] FIG.24 displays a graph demonstrating the mean time-plasma BHB concentration following a representative compound of Formula (A), TrehaAce, PO dosing in mice.DETAILED DESCRIPTION

[0040] Provided herein, in certain embodiments, are systems, methods, compositions, and algorithms for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, or heart failure). The contemplated systems, methods, compositions, and algorithms disclosed herein are useful in a diagnostic-therapeutic platform for identifying and treating glucose hypometabolism and resultant cellular energy crisis in subjectsAttorney Docket No. FRD-001 WO by quantitatively measuring tissue-specific glucose metabolism deficits and administering precisely calibrated exogenous ketone formulations to compensate for these deficits.Certain Terminology

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with, and techniques of, immunology, oncology, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well-known and commonly used in the art. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational puiposes only and are not to be construed as limiting the subject matter described.

[0042] The articles “a” and “an” are used herein to refer to one or to more than one (z'.e. at least one) of the grammatical objects of the article.Chemical Definitions

[0043] Definitions of specific functional groups and chemical terms are described in more detail below.

[0044] In some embodiments, compounds described herein comprise one or more asymmetric centers, and thus exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0045] In some embodiments, compounds described herein also comprise one or more isotopic substitutions. For example, in some embodiments, H is in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C is any isotopic form, including12C,13C, and14C; O is in any isotopic form, including16O and18O; F is in any isotopic form, including18F and19F; and the like.Attorney Docket No. FRD-001 WO

[0046] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, Cs, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0047] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-C10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-Ce alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-Ce alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0048] As used herein, “alkylene,” refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. In some embodiments, “alkylene” group is substituted or unsubstituted with one or more substituents as described herein.

[0049] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”).

[0050] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5—10 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits.

[0051] In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6Attorney Docket No. FRD-001 WO membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

[0053] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as " Cs-Ciocycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

[0054] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and is saturated or is partially unsaturated. In some embodiments, heterocyclyl bicyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclylAttorney Docket No. FRD-001 WO ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably.

[0055] In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0056] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. In some embodiments, hetero is applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0057] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro.

[0058] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0059] The term “oxo” as used herein refers to =0.Attorney Docket No. FRD-001 WO

[0060] The term “hydroxyl” as used herein refers to -OH.

[0061] In general, the term “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0062] Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.

[0063] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0064] As used herein, the term “about” when modifying a numeric value means within a reasonable range of the stated value, typically ±10% unless otherwise specified. This term accounts for normal experimental or biological variability around the precise value.

[0065] As used herein, “pharmaceutically acceptable excipient” refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). Exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use.

[0066] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaricAttorney Docket No. FRD-001 WO acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0067] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” “individual” and “subject” are used interchangeably herein. None of the terms require the supervision of medical personnel.

[0068] The terms “disease”, “disorder”, and “condition” are used interchangeably herein.

[0069] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition.

[0070] As used herein, and unless otherwise specified, a “therapeutically effective amount” or an “effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount or an effective amount of a compound means an amount of therapeutic agent, alone or in combinationAttorney Docket No. FRD-001 WO with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. In some embodiments, the term “therapeutically effective amount” or “effective amount” encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0071] As used herein, the term “ketone body”, “exogenous ketone” or “exogenous ketone body” means a compound or species which is a ketone or a ketone body precursor, that is, a compound or species which is a precursor to a ketone and which may be converted or metabolized to a ketone. Ketone bodies are produced when fatty acids levels are raised in the body and are metabolized by the body for energy. Ketone bodies have been disclosed as being suitable for reducing the levels of free fatty acids circulating in the plasma of a subject and that ingestion of ketone bodies can lead to various clinical benefits, including an enhancement of cognitive performance and treatment of cardiovascular conditions, diabetes and treatment of mitochondrial dysfunction disorders and in treating muscle fatigue and impairment. Examples of ketone bodies include, but are not limited to, beta-hydroxybutyrate (“PHB”) and acetoacetate (“AcAc”).

[0072] For consistency, the terms “administering” and “delivering” (with respect to providing a therapeutic composition to a subject) are used interchangeably herein. Likewise, terms like “exogenous ketone therapy,” “ketone composition,” or “ketone formulation” refer to the use of one or more ketone compounds (or precursors) administered to the subject as described.

[0073] As used herein, the term “glucose hypometabolic disorder” refers to any disease, disorder, or condition in which one or more tissues exhibit a chronically reduced capacity to utilize glucose relative to normal physiology. Examples of glucose hypometabolic disorders include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any other condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0074] As used herein, the term “glucose metabolism deficit,” abbreviated as “G_Diff,” refers to the quantitative shortfall in glucose utilization by a tissue (or entire subject) compared to a normal or baseline value. G_Diff may be expressed as a percentage below a normal glucose metabolic rate, an absolute deficit in terms of glucose consumption (e.g., milligrams per deciliter lower than normal), or an energy equivalent. For example, a G_Diff of 20% indicates the tissue is only achieving about 80% of the glucose uptake / usage observed in a healthy reference under the same conditions.Attorney Docket No. FRD-001 WO

[0075] The term “module” (as in “diagnostic module,” “computational module,” etc.) refers broadly to a component or combination of components — implemented in hardware, software, firmware, or any combination thereof — configured to perform a specified function. For example, a “diagnostic module” may be a physical device or instrument (such as an imaging scanner or a biosensor array) or a software algorithm that processes data from an instrument to yield a diagnostic result. Modules can be distributed or integrated; a module’s function can be executed on a local machine or via a remote / cloud-based service, as long as it performs the recited function.

[0076] The phrase “Therapeutic Titratable Ketonemia (TTK)” refers to a metabolic state of a patient characterized by elevated ketone body levels (principally P-hydroxybutyrate and / or acetoacetate) that are maintained within a predefined therapeutic range through controlled induction and titration. “Titratable” in this context means the ketone levels are actively adjusted (increased or decreased via dosing) to reach and stay in the target window, rather than fluctuating freely.

[0077] The phrase “Therapeutic Ketonemic State” refers to a physiological condition of ketosis that is deliberately induced and maintained for therapeutic purposes. It is typically defined quantitatively by a target range of blood BHB (and optionally Ac Ac) concentrations that has been determined to confer therapeutic benefit for a given condition. In many embodiments, a therapeutic ketonemic state might be, for example, a blood BHB level of about 1-3 mM sustained for several hours per day, with an associated AcAc level in a physiologic ratio (e.g. BHB: AcAc on the order of 3: 1 to 5: 1). This state is distinct from pathological ketosis (ketoacidosis) in that it is lower in magnitude and actively regulated for safety.

[0078] The phrase “Ketone-Elevating Agent” refers to any composition or intervention that can raise blood ketone levels. This includes exogenous ketone bodies (such as BHB or AcAc in salt, ester, or other chemically modified forms), metabolic precursors that the body converts into ketones (e.g. medium-chain fats like C8 / C10 triglycerides, which are converted to ketones by the liver), ketogenic amino acids, as well as devices or genetic therapies that induce ketogenesis. The agent can be formulated for various delivery routes (oral, intravenous, subcutaneous, transdermal, etc.).

[0079] The phrase “Ketone Monitor” refers to a device or system for measuring ketone levels in a patient. This could be a blood ketone meter (BHB sensor via fingerstick), a continuous ketone monitor (similar to a continuous glucose monitor, measuring interstitial BHB), or any sensor that provides data on the patient’s metabolic state (including indirect measures like breathAttorney Docket No. FRD-001 WO acetone sensors or urine ketone strips, though blood BHB is the primary controlled variable in TTK).

[0080] “The phrase “time -in-range” refers to the fraction of therapy time that the patient’s ketone level is within the target range. The phrase “Exposure -time” refers to the cumulative duration of ketosis exposure (which could be measured daily or over the course of weeks). These metrics are used to guide and assess therapy; for instance, a protocol may specify achieving at least 12 hours per day in the target ketone range, or a certain ketone AUC (area under curve) per 24-hour period.Exogenous Ketone Compounds and CompositionsCompounds

[0081] Disclosed herein, in certain embodiments, the exogenous ketone composition is a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0082] As generally defined above R1is a polyol, amino acid, or a derivative thereof. In certain embodiments, R1is a polyol. A polyol is a compound containing two or more hydroxy (OH) groups. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodiesAttorney Docket No. FRD-001 WO to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0083] In certain embodiments, R1is a polyol which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosedAttorney Docket No. FRD-001 WO with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0084] In certain embodiments, R1is a carbohydrate. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.Attorney Docket No. FRD-001 WO

[0085] In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0086] In certain embodiments, R1is an amino acid or a derivative thereof. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subjectAttorney Docket No. FRD-001 WO diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0087] In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucoseAttorney Docket No. FRD-001 WO hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0088] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine.

[0089] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.

[0090] As generally defined above, X is a covalent linker joining selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, — O~, -NH-,— S—, and -S-S-. In certain embodiments, X is -O-C(O)-. In certain embodiments, X is -C(O)-O- In certain embodiments, X is -C(O)-NH-. In certain embodiments, X is -NH-C(O)-. In certain embodiments, X is -C(O)-S- In certain embodiments, X is -S-C(O)-. In certain embodiments, X is -O-C(O)-O-. In certain embodiments, X is -O-C(O)-NH- or -NH-C(O)-O-. In certain embodiments, X is -O-P(O2)-O-. In certain embodiments, X is -O-SO2-O-. In certain embodiments, X is -C=N- In certain embodiments, X is -C=N-NH-. In certain embodiments, X is -O-. In certain embodiments, X is -NH-. In certain embodiments, X is -S-. In certain embodiments, X is-S-S-. In preferred embodiments, X is -O- or -NH-.

[0091] As generally defined above R2is a ketone body moiety selected from 0-hydroxybutyryl (BHB), acetoacetyl (AcAc), or a derivative thereof. In certain embodiments, R2is 0-hydroxybutyryl (BHB) or a derivative thereof. In certain embodiments, R2is P-hydroxybutyryl (BHB). In certain embodiments, R2is a acetoacetyl (AcAc) or a derivative thereof. In certainAttorney Docket No. FRD-001 WO O OHembodiments, R2is a acetoacetyl (Ac Ac). In certain embodiments, R2is[ncertain OH 0 0embodiments, R2isx. In certain embodiments, R2is. In certainOembodiments,R2is.

[0092] As generally defined above, n is an integer from 1 to 50. In certain embodiments, n is an integer from 1 to 20. In specific embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments n is 1. In certain embodiments n is 2. In certain embodiments n is 3. In certain embodiments n is 4. In certain embodiments n is 5. In certain embodiments n is 6. In certain embodiments n is 7. In certain embodiments n is 8. In certain embodiments n is 9. In certain embodiments n is 10. In certain embodiments n is 11. In certain embodiments n is 12. In certain embodiments n is 13. In certain embodiments n is 14. In certain embodiments n is 15. In certain embodiments n is 16. In certain embodiments n is 17. In certain embodiments n is 18. In certain embodiments n is 19. In certain embodiments n is 20. In certain embodiments, n is an integer which is equal to the number of hydroxy groups in R1.

[0093] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-. -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0094] In certain embodiments, the compound is compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine;X is -O- or -NH-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0095] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is trehalose, myo-inositol, or D-ribose;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 8, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0096] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is trehalose, myo-inositol, or D-ribose;Attorney Docket No. FRD-001 WO X is -O-C(O)-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 8, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0097] In certain embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. It is understood that each of these compounds may exist in partially esterified / amidated forms where not all available hydroxyl or amine groups are conjugated to ketone bodies. Additionally, mixed conjugates are contemplated wherein some / attachment sites contain P-hydroxybutyrate moi Oe T \ties while others contain acetoacetate moieties ) J o oon the same carrier moleculexT o\= — / y o p —Table 1. List of compounds. ° — \ / \CompoundName J S ° ° O 7 OtrNo. ° °Ju vcture1 HO,Hcrj HO~A ftOF\ A \ HOV0o J V JK Trehalose-BHBH0AO, X 0,,01 O | 0 | | oEster (TrehaBHB)'0^0^° \ / 0Hn o \OH O / F'OHTrehalose- 2 Acetoacetate Ester(TrehaAce)Attorney Docket No. FRD-001 WO CompoundName Structure No.HO^ / 1 HOH01?Inositol-BHB Ester o^o^^o73 I I,o (InosBHB) £>"' OHox— (OH ° / ^°VoHHO^0^0 0 OHD-Ribose-BHB4Ester (RiboBHB)X^X-yO OyOOH 0 \ / °HHOY HOY°Y oJ% ^^o-Z 01 0 °yO ° \_ / 0HT v0HoxZ 1 OH ^^O^J \ _ / Inulin-BHB Ester5,o (FibraBHB), 0x ^0HO-Z \ V x°H \ X / 0H \ °Y [ 'H0Y 2-60 0 OH0o-^X °'N— Z 0 r^o ° f° °x^° / 0HZH y0HL / OH \Attorney Docket No. FRD-001 WO CompoundName StructureNo.NHCreatine-BHB6 N N H Ester (CreaBHB)2OH O 1Glycine- H?7 AcetoacetateAmide (GlyAce) o oo’Carnitine- 0"^ 0 08 Acetoacetate Ester(CarnAce) oV OD C — / Nt / O rZ < o o CD CD —Taurine- ) y pO ' °=K ° —A Z ) o o o p o —- 9 Acetoacetate ° A — \ \\ V(o°O O=p\- — / —OHAmide (TaurAce) Z \ / oo O o—-") o ° — / ( ( o oo O y-.y( 'ooo==— / o o O=\ Inositol- z o 10 Acetoacetate Ester(InosAce)Glycerol- 11 Acetoacetate Ester(GlycAce)Allulose- 12 Acetoacetate Ester(AllAce)Attorney Docket No. FRD-001 WOCompoundName StructureNo.OAspartic Acid-HOYV13 Acetoacetate Ester O NH< OH(AspAce)OH O O OHGlycerol- BHB14Ester (GlycBHB)HO^ JCarnosine-BHB H H 9 15 Ester0 0(CarnosBHB) \ NHN=s /

[0098] The compounds of Formula (A) described herein offer certain advantages over simpler ketone supplements (such as monomeric ketone esters or salts). By attaching multiple ketone body moieties (R2) to a single polyol backbone (R1), a single compound can deliver a higher payload of ketone equivalents per molecule, potentially increasing the efficiency of raising blood ketone levels. Additionally, the use of a polyol backbone can impart favorable pharmacokinetic properties - for instance, as the conjugate is metabolized, it may release ketone bodies gradually, acting as a built-in sustained-release mechanism. This could help maintain therapeutically relevant ketone concentrations over a longer duration compared to a rapid spike from a simple ketone salt. In some embodiments, such multi-ketone conjugates may also improve tolerability or palatability: by distributing the ketone load across a larger molecule, peak gastrointestinal irritation or the strong taste associated with free ketones or salts might be reduced. While the invention is not bound by theory, these potential benefits illustrate the innovative nature of the polyol-based ketone conjugates, which go beyond conventional monomeric ketone compounds.Compositions

[0099] In certain embodiments, the exogenous ketone composition is a composition comprising one or more compounds of Formula (A).Atorney Docket No. FRD-001 WO

[0100] In certain embodiments, the composition comprises at least two compounds of Formula (A). In certain embodiments, the comprises at least two compounds from Table 1.

[0101] In certain embodiments, the composition comprises Compound 1 and Compound 2. In certain embodiments, the composition comprises Compound 1 and Compound 3. In certain embodiments, the composition comprises Compound 1 and Compound 4. In certain embodiments, the composition comprises Compound 1 and Compound 5. In certain embodiments, the composition comprises Compound 1 and Compound 6. In certain embodiments, the composition comprises Compound 1 and Compound 7. In certain embodiments, the composition comprises Compound 1 and Compound 8. In certain embodiments, the composition comprises Compound 1 and Compound 9. In certain embodiments, the composition comprises Compound 1 and Compound 10. In certain embodiments, the composition comprises Compound 1 and Compound 11. In certain embodiments, the composition comprises Compound 1 and Compound 12. In certain embodiments, the composition comprises Compound 1 and Compound 13. In certain embodiments, the composition comprises Compound 1 and Compound 14. In certain embodiments, the composition comprises Compound 1 and Compound 15.

[0102] In certain embodiments, the composition comprises Compound 2 and Compound 3. In certain embodiments, the composition comprises Compound 2 and Compound 4. In certain embodiments, the composition comprises Compound 2 and Compound 5. In certain embodiments, the composition comprises Compound 2 and Compound 6. In certain embodiments, the composition comprises Compound 2 and Compound 7. In certain embodiments, the composition comprises Compound 2 and Compound 8. In certain embodiments, the composition comprises Compound 2 and Compound 9. In certain embodiments, the composition comprises Compound 2 and Compound 10. In certain embodiments, the composition comprises Compound 2 and Compound 11. In certain embodiments, the composition comprises Compound 2 and Compound 12. In certain embodiments, the composition comprises Compound 2 and Compound 13. In certain embodiments, the composition comprises Compound 2 and Compound 14. In certain embodiments, the composition comprises Compound 2 and Compound 15.

[0103] In certain embodiments, the composition comprises Compound 3 and Compound 4. In certain embodiments, the composition comprises Compound 3 and Compound 5. In certain embodiments, the composition comprises Compound 3 and Compound 6. In certain embodiments, the composition comprises Compound 3 and Compound 7. In certain embodiments, the composition comprises Compound 3 and Compound 8. In certainAttorney Docket No. FRD-001 WO embodiments, the composition comprises Compound 3 and Compound 9. In certain embodiments, the composition comprises Compound 3 and Compound 10. In certain embodiments, the composition comprises Compound 3 and Compound 11. In certain embodiments, the composition comprises Compound 3 and Compound 12. In certain embodiments, the composition comprises Compound 3 and Compound 13. In certain embodiments, the composition comprises Compound 3 and Compound 14. In certain embodiments, the composition comprises Compound 3 and Compound 15.

[0104] In certain embodiments, the composition comprises Compound 4 and Compound 5. In certain embodiments, the composition comprises Compound 4 and Compound 6. In certain embodiments, the composition comprises Compound 4 and Compound 7. In certain embodiments, the composition comprises Compound 4 and Compound 8. In certain embodiments, the composition comprises Compound 4 and Compound 9. In certain embodiments, the composition comprises Compound 4 and Compound 10. In certain embodiments, the composition comprises Compound 4 and Compound 11. In certain embodiments, the composition comprises Compound 4 and Compound 12. In certain embodiments, the composition comprises Compound 4 and Compound 13. In certain embodiments, the composition comprises Compound 4 and Compound 14. In certain embodiments, the composition comprises Compound 4 and Compound 15.

[0105] In certain embodiments, the composition comprises Compound 5 and Compound 6. In certain embodiments, the composition comprises Compound 5 and Compound 7. In certain embodiments, the composition comprises Compound 5 and Compound 8. In certain embodiments, the composition comprises Compound 5 and Compound 9. In certain embodiments, the composition comprises Compound 5 and Compound 10. In certain embodiments, the composition comprises Compound 5 and Compound 11. In certain embodiments, the composition comprises Compound 5 and Compound 12. In certain embodiments, the composition comprises Compound 5 and Compound 13. In certain embodiments, the composition comprises Compound 5 and Compound 14. In certain embodiments, the composition comprises Compound 5 and Compound 15.

[0106] In certain embodiments, the composition comprises Compound 6 and Compound 7. In certain embodiments, the composition comprises Compound 6 and Compound 8. In certain embodiments, the composition comprises Compound 6 and Compound 9. In certain embodiments, the composition comprises Compound 6 and Compound 10. In certain embodiments, the composition comprises Compound 6 and Compound 11. In certain embodiments, the composition comprises Compound 6 and Compound 12. In certainAtorney Docket No. FRD-001 WO embodiments, the composition comprises Compound 6 and Compound 13. In certain embodiments, the composition comprises Compound 6 and Compound 14. In certain embodiments, the composition comprises Compound 6 and Compound 15.

[0107] In certain embodiments, the composition comprises Compound 7 and Compound 8. In certain embodiments, the composition comprises Compound 7 and Compound 9. In certain embodiments, the composition comprises Compound 7 and Compound 10. In certain embodiments, the composition comprises Compound 7 and Compound 11. In certain embodiments, the composition comprises Compound 7 and Compound 12. In certain embodiments, the composition comprises Compound 7 and Compound 13. In certain embodiments, the composition comprises Compound 7 and Compound 14. In certain embodiments, the composition comprises Compound 7 and Compound 15.

[0108] In certain embodiments, the composition comprises Compound 8 and Compound 9. In certain embodiments, the composition comprises Compound 8 and Compound 10. In certain embodiments, the composition comprises Compound 8 and Compound 11. In certain embodiments, the composition comprises Compound 8 and Compound 12. In certain embodiments, the composition comprises Compound 8 and Compound 13. In certain embodiments, the composition comprises Compound 8 and Compound 14. In certain embodiments, the composition comprises Compound 8 and Compound 15.

[0109] In certain embodiments, the composition comprises Compound 9 and Compound 10. In certain embodiments, the composition comprises Compound 9 and Compound 11. In certain embodiments, the composition comprises Compound 9 and Compound 12. In certain embodiments, the composition comprises Compound 9 and Compound 13. In certain embodiments, the composition comprises Compound 9 and Compound 14. In certain embodiments, the composition comprises Compound 9 and Compound 15.

[0110] In certain embodiments, the composition comprises Compound 10 and Compound 11. In certain embodiments, the composition comprises Compound 10 and Compound 12. In certain embodiments, the composition comprises Compound 10 and Compound 13. In certain embodiments, the composition comprises Compound 10 and Compound 14. In certain embodiments, the composition comprises Compound 10 and Compound 15.

[0111] In certain embodiments, the composition comprises Compound 11 and Compound 12. In certain embodiments, the composition comprises Compound 11 and Compound 13. In certain embodiments, the composition comprises Compound 11 and Compound 14. In certain embodiments, the composition comprises Compound 11 and Compound 15.Attorney Docket No. FRD-001 WO

[0112] In certain embodiments, the composition comprises Compound 12 and Compound 13. In certain embodiments, the composition comprises Compound 12 and Compound 14. In certain embodiments, the composition comprises Compound 12 and Compound 15.

[0113] In certain embodiments, the composition comprises Compound 13 and Compound 14. In certain embodiments, the composition comprises Compound 13 and Compound 15.

[0114] In certain embodiments, the composition comprises Compound 14 and Compound 15.

[0115] In certain embodiments, each compound of Formula (A) has the same R1and X.

[0116] As generally defined above R1is a polyol, amino acid, or a derivative thereof. In certain embodiments, R1is a polyol. A polyol is a compound containing two or more hydroxy (OH) groups.

[0117] In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucoseAttorney Docket No. FRD-001 WO hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0118] In certain embodiments, R1is a polyol which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0119] In certain embodiments, R1is a carbohydrate. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable ofAttorney Docket No. FRD-001 WO delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0120] In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucoseAttorney Docket No. FRD-001 WO hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0121] In certain embodiments, R1is an amino acid or a derivative thereof. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0122] In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucoseAttorney Docket No. FRD-001 WO hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0123] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine.

[0124] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine.Attorney Docket No. FRD-001 WO

[0125] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.

[0126] As generally defined above, X is a covalent linker joining selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, - O-, -NH-,— S—, and -S-S-. In certain embodiments, X is -O-C(O)-. In certain embodiments, X is -C(O)-O- In certain embodiments, X is -C(O)-NH-. In certain embodiments, X is -NH-C(O)-. In certain embodiments, X is -C(O)-S- In certain embodiments, X is -S-C(O)-. In certain embodiments, X is -O-C(O)-O-. In certain embodiments, X is -O-C(O)-NH- or -NH-C(O)-O-. In certain embodiments, X is -O-P(O2)-O-. In certain embodiments, X is -O-SO2-O-. In certain embodiments, X is -C=N- In certain embodiments, X is -C=N-NH-. In certain embodiments, X is -O-. In certain embodiments, X is -NH-. In certain embodiments, X is -S-. In certain embodiments, X is-S-S-. In preferred embodiments, X is -O- or -NH-.

[0127] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.

[0128] In certain embodiments, the composition comprises at least two unique compounds of Formula (A). In certain embodiments, the composition comprises one unique compound of Formula (A) is:or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;Attorney Docket No. FRD-001 WO X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from β-hydroxybutyryl or a derivative thereof; and n is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1, andwherein the other unique compound of Formula (A) is:or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-. -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from acetoacetyl (AcAc) or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0129] The compounds of Formula (A) may be formulated as pharmaceutical compositions by combining the compound with pharmaceutically acceptable carriers, excipients, and / or diluents. Such compositions may be formulated for oral, enteral, parenteral, or intravenous administration.

[0130] For oral administration, the compounds may be formulated as tablets, capsules, powders, solutions, suspensions, or emulsions. For parenteral administration, the compounds may be formulated as solutions, suspensions, or emulsions in aqueous or oil vehicles.Therapeutic Applications and Advantages

[0131] The compounds and compositions of the present disclosure provide significant therapeutic advantages for treating glucose hypometabolic disorders:Attorney Docket No. FRD-001 WO

[0132] Enhanced Bioavailability: By conjugating ketone bodies to carrier molecules via stable linkers (e.g., ester or amide bonds), the compounds and compositions exhibit improved absorption, extended circulation time, and enhanced tissue penetration compared to free ketone bodies.

[0133] Increased Ketone Payload: In certain embodiments, the multi-esterification design allows delivery of multiple ketone moieties per carrier molecule, maximizing the therapeutic effect while minimizing excipient load.

[0134] Targeted Delivery: Specific carrier molecules can preferentially direct ketones to tissues most affected by glucose hypometabolism. For example, trehalose-based conjugates may have enhanced blood-brain barrier penetration for neurological conditions.

[0135] Controlled Release: The linkers (e.g., the ester or amide bonds) are enzymatically hydrolyzed in vivo, providing sustained release of ketone bodies over time rather than the sharp peaks and troughs seen with direct ketone salt administration.

[0136] Synergistic Effects: The carrier molecules themselves often have complementary therapeutic effects. For example, inositol supports membrane stabilization and signaling, while creatine enhances cellular energy reserves.

[0137] Reduced Side Effects: The conjugate formulations minimize gastrointestinal distress and electrolyte imbalances commonly associated with ketone salt administration.

[0138] Dosing Convenience: The stable solid formulations allow for convenient oral dosing, improving patient compliance compared to liquid formulations or dietary interventions.Mechanisms of Action

[0139] The compounds and compositions of the present disclosure work through multiple complementary mechanisms:

[0140] Metabolic Bypass: The released ketone bodies provide an alternative energy substrate that bypasses the impaired glucose metabolism pathways seen in conditions like Alzheimer's disease, Parkinson's disease, and heart failure.

[0141] Enhanced Energetic Efficiency: Ketone bodies produce more ATP per oxygen molecule compared to glucose (2.5 vs 2.25 ATP / O), providing energetic advantages in oxygen-limited or mitochondrially compromised tissues.

[0142] Reduced Oxidative Stress: Ketone metabolism produces fewer reactive oxygen species than glucose or fatty acid oxidation, reducing oxidative damage in affected tissues.Attorney Docket No. FRD-001 WO

[0143] Signaling Effects: Beyond serving as energy substrates, ketone bodies (particularly β-hydroxybutyrate) activate beneficial signaling pathways, including those related to mitochondrial biogenesis, antioxidant defense, and epigenetic regulation through histone deacetylase inhibition.

[0144] Neuroprotection: In neurodegenerative conditions, ketone bodies provide neuroprotection through multiple mechanisms, including reduced excitotoxicity, enhanced GABA signaling, and stabilization of neuronal membrane potentials.

[0145] Cardiac Protection: In heart failure, ketone bodies improve cardiac efficiency, reduce fibrosis, and enhance calcium handling in cardiomyocytes.Methods

[0146] Disclosed herein, in certain embodiments, are methods of treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, or heart failure). In certain embodiments, the method comprises administering a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-. -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0147] Also disclosed herein, in certain embodiments, are methods for diagnosing and quantifying glucose hypometabolism in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WO or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0148] In one aspect, provided herein a method for treating Alzheimer's disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0149] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0150] In another aspect, provided herein is a method for treating Parkinson’s disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0151] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0152] In another aspect, provided herein is a method for treating Huntington’ s disease, the method comprising administering to a subject a therapeutically effective amount of compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0153] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0154] In another aspect, provided herein is a method for treating heart failure, the method comprising administering to a subject a therapeutically effective amount of compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0155] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0156] In another aspect, provided herein is a method for treating stroke, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):I R1TR2'!n7(A),or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0157] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0158] In another aspect, provided herein is a method for treating spinal cord injury, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0159] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0160] In another aspect, provided herein is a method for treating type 2 diabetes, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):I R1TR2'!n7(A),or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0161] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0162] In another aspect, provided herein is a method for treating obesity, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0163] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0164] In another aspect, provided herein is a method for treating non-alcoholic fatty liver disease (NAFLD), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0165] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0166] In another aspect, provided herein is a method for treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0167] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0168] In another aspect, provided herein is a method for treating polycystic ovarian syndrome (PCOS), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0169] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0170] In another aspect, provided herein is a method for treating epilepsy, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0171] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0172] In another aspect, provided herein is a method for treating traumatic brain injury (TBI), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0173] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0174] In another aspect, provided herein is a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0175] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0176] In another aspect, provided herein is a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):I R1TR2'!n7(A),or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0177] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0178] In another aspect, provided herein is a method for treating cancer cachexia, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0179] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0180] In another aspect, provided herein is a method for treating peripheral vascular disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0181] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0182] In another aspect, provided herein is a method for treating mitochondrial disorders, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0183] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0184] In another aspect, provided herein is a method for treating chronic fatigue syndrome, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0185] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0186] In another aspect, provided herein is a method for treating metabolic syndrome, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0187] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0188] In another aspect, provided herein is a method for treating bipolar disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):I R1TR2'!n7(A),or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0189] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0190] In another aspect, provided herein is a method for treating major depressive disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0191] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0192] In another aspect, provided herein is a method for treating anxiety disorders, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0193] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0194] In another aspect, provided herein is a method for treating schizophrenia, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0195] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0196] In another aspect, provided herein is a method for treating autism spectrum disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0197] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0198] In another aspect, provided herein is a method for treating attention deficit hyperactivity disorder (ADHD), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-001 WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)-O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0199] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WO

[0200] In another aspect, provided herein is a method for treating any condition in which a subject’s tissue exhibits a quantifiable reduction in glucose utilization, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, - C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O-, -O-C(O)-NH- or -NH-C(O)- O-, -O-P(O2)-O-, -O-SO2-O-, -C=N-, -C=N-NH-, -O-, -NH-,-S-, and -S-S-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0201] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-001 WOPrecise Measurement of Glucose Hypometabolism Across ConditionsAttorney Docket No. FRD-001 WO

[0202] Comprehensive, quantitative evidence demonstrates remarkably consistent patterns of glucose hypometabolism across diverse disorders:Alzheimer's Disease:

[0203] FDG-PET studies demonstrate 15-25% lower regional glucose metabolism in temporal, parietal, and posterior cingulate regions compared to age-matched controls. Early-onset AD shows even more dramatic declines, with 40-45% global cerebral metabolic rate glucose reduction. The degree of hypometabolism correlates strongly with cognitive impairment, with correlation coefficients between regional FDG uptake and cognitive scores of r ~ 0.5-0.7.Hypometabolism manifests 5-10 years before clinical dementia in sporadic AD and 13 years before expected symptom onset in familial AD.Parkinson's Disease:

[0204] Substantia nigra shows 15-20% lower FDG uptake in PD patients compared to controls (effect size d~l.0). The PD-related metabolic pattern (PDRP) network expression correlates with motor UPDRS scores at r = 0.62, p<0.005. Correlation between glucose metabolism deficits and dopaminergic neuron loss (DAT binding r ~0.6)Heart Failure:

[0205] Cardiac glucose oxidation rates in failing hearts are 30-40% lower than in healthy hearts. Glucose's contribution to cardiac ATP production falls from approximately 30% in healthy hearts to 10-15% in severe heart. Myocardial phosphocreatine-to-ATP ratio (PCr / ATP) is reduced by 25-30% in dilated cardiomyopathy, correlating with LVEF at r -0.6.Convergent Enzymatic and Mitochondrial Defects

[0206] A particularly surprising finding is the convergent pattern of enzymatic deficiencies across these diverse conditions:Attorney Docket No. FRD-001 WO Table 2. Comparison of Enzymatic Deficiencies in Alzheimer’s Disease, Parkinson’s Disease, and Heart FailurePrimary Key Enzyme Magnitude of Energy Reserve DiseaseTissue Defect Defect DeficitAlzheimer's -20% ATP Brain cortex PDH complex -50% reductionDisease reductionParkinson's Substantia -10-15% ATP Complex I -30% reductionDisease nigra reduction30-40% reduced -30% ATP Heart Failure Cardiac tissue PDH complexflux reduction

[0207] In one aspect, provided herein a method of treating a glucose hypometabolic disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0208] In certain embodiments, the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, heart failure, stroke, spinal cord injury, type 2 diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovary syndrome (PCOS), epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer, cancer cachexia, peripheral vascular disease, mitochondrial disorders, chronic fatigue syndrome, metabolic syndrome, bipolar disorder, major depressive disorder, anxiety disorders, schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0209] In certain embodiments, the glucose hypometabolic disorder is Alzheimer’s disease. In certain embodiments, the glucose hypometabolic disorder is Parkinson’s disease. In certain embodiments, the glucose hypometabolic disorder is Huntington’s disease. In certain embodiments, the glucose hypometabolic disorder is heart failure. In certain embodiments, the glucose hypometabolic disorder is stroke. In certain embodiments, the glucose hypometabolic disorder is spinal cord injury. In certain embodiments, the glucose hypometabolic disorder is type 2 diabetes. In certain embodiments, the glucose hypometabolic disorder is obesity. In certain embodiments, the glucose hypometabolic disorder is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the glucose hypometabolic disorder is non-alcoholicAttorney Docket No. FRD-001 WO steatohepatitis (NASH). In certain embodiments, the glucose hypometabolic disorder is polycystic ovary syndrome (PCOS). In certain embodiments, the glucose hypometabolic disorder is epilepsy. In certain embodiments, the glucose hypometabolic disorder is traumatic brain injury. In certain embodiments, the glucose hypometabolic disorder is amyotrophic lateral sclerosis. In certain embodiments, the glucose hypometabolic disorder is cancer. In certain embodiments, the glucose hypometabolic disorder is cancer cachexia. In certain embodiments, the glucose hypometabolic disorder is peripheral vascular disease. In certain embodiments, the glucose hypometabolic disorder is a mitochondrial disorder. In certain embodiments, the glucose hypometabolic disorder is chronic fatigue syndrome. In certain embodiments, the glucose hypometabolic disorder is metabolic syndrome. In certain embodiments, the glucose hypometabolic disorder is bipolar disorder. In certain embodiments, the glucose hypometabolic disorder is major depressive disorder. In certain embodiments, the glucose hypometabolic disorder is an anxiety disorder. In certain embodiments, the glucose hypometabolic disorder is schizophrenia. In certain embodiments, the glucose hypometabolic disorder is autism spectrum disorder. In certain embodiments, the glucose hypometabolic disorder is attention deficit hyperactivity disorder (ADHD). In certain embodiments, the glucose hypometabolic disorder is any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0210] In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0211] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased byAttorney Docket No. FRD-001 WO about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0212] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0213] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%,. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0214] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%.Attorney Docket No. FRD-001 WO In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0215] In another aspect, provided herein is a method of treating Alzheimer's Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0216] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0217] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, theAttorney Docket No. FRD-001 WO glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0218] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0219] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by aboutAttorney Docket No. FRD-001 WO 45%. In some embodiments, the production of ATP is increased by about 50%. In another aspect, provided herein is a method of treating Parkinson’s Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0220] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0221] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In someAttorney Docket No. FRD-001 WO embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0222] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0223] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0224] In another aspect, provided herein is a method of treating Huntington’ s Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0225] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35%Attorney Docket No. FRD-001 WO to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0226] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0227] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0228] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0229] In another aspect, provided herein is a method of treating heart failure in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises heart tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0230] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments,Attorney Docket No. FRD-001 WO the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0231] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0232] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0233] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0234] In another aspect, provided herein is a method of treating stroke in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0235] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0236] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,Attorney Docket No. FRD-001 WO about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0237] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0238] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0239] In another aspect, provided herein is a method of treating spinal cord injury in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0240] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0241] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolismAttorney Docket No. FRD-001 WO is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0242] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0243] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0244] In another aspect, provided herein is a method of treating type 2 diabetes in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0245] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-001 WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0246] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0247] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0248] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0249] In another aspect, provided herein is a method of treating obesity in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0250] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.Attorney Docket No. FRD-001 WO

[0251] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0252] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0253] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0254] In another aspect, provided herein is a method of treating non-alcoholic fatty liver disease (NAFLD) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0255] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0256] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In someAttorney Docket No. FRD-001 WO embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0257] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0258] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0259] In another aspect, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0260] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35%Attorney Docket No. FRD-001 WO to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0261] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0262] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0263] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0264] In another aspect, provided herein is a method of treating polycystic ovarian syndrome (PCOS) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0265] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased byAttorney Docket No. FRD-001 WO about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0266] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0267] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0268] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%.Attorney Docket No. FRD-001 WO In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0269] In another aspect, provided herein is a method of treating epilepsy in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0270] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0271] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In someAttorney Docket No. FRD-001 WO embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0272] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0273] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.Attorney Docket No. FRD-001 WO

[0274] In another aspect, provided herein is a method of treating traumatic brain injury (TBI) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0275] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0276] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by aboutAttorney Docket No. FRD-001 WO 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0277] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0278] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0279] In another aspect, provided herein is a method of treating amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0280] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-001 WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0281] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0282] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0283] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0284] In another aspect, provided herein is a method of treating cancer in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0285] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.Attorney Docket No. FRD-001 WO

[0286] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0287] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0288] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0289] In another aspect, provided herein is a method of treating cancer cachexia in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0290] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0291] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, theAttorney Docket No. FRD-001 WO glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0292] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0293] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0294] In another aspect, provided herein is a method of treating peripheral vascular disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0295] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, aboutAttorney Docket No. FRD-001 WO 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0296] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0297] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%. about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments,Attorney Docket No. FRD-001 WO the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0298] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0299] In another aspect, provided herein is a method of treating mitochondrial disorders in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0300] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% toAttorney Docket No. FRD-001 WO 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0301] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0302] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0303] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments,Attorney Docket No. FRD-001 WO the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0304] In another aspect, provided herein is a method of treating chronic fatigue syndrome in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0305] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0306] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, theAttorney Docket No. FRD-001 WO glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0307] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0308] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0309] In another aspect, provided herein is a method of treating metabolic syndrome in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.Attorney Docket No. FRD-001 WO

[0310] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0311] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0312] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0313] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0314] In another aspect, provided herein is a method of treating bipolar disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0315] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments,Attorney Docket No. FRD-001 WO the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0316] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0317] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In someAttorney Docket No. FRD-001 WO embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0318] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0319] In another aspect, provided herein is a method of treating major depressive disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0320] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0321] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,Attorney Docket No. FRD-001 WO about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0322] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0323] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0324] In another aspect, provided herein is a method of treating anxiety disorders in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0325] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0326] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by aboutAttorney Docket No. FRD-001 WO 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0327] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0328] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0329] In another aspect, provided herein is a method of treating schizophrenia in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0330] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-001 WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0331] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0332] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0333] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0334] In another aspect, provided herein is a method of treating autism spectrum disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0335] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In someAttorney Docket No. FRD-001 WO embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0336] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0337] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0338] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATPAttorney Docket No. FRD-001 WO is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0339] In another aspect, provided herein is a method of treating attention deficit hyperactivity disorder (ADHD) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0340] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0341] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolismAttorney Docket No. FRD-001 WO is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0342] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0343] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0344] In another aspect, provided herein is a method of treating any condition in which a subject’s tissue exhibits a quantifiable reduction in glucose utilization, the method comprising increasing glucose metabolism in one or more tissues of the subjectAttorney Docket No. FRD-001 WO

[0345] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0346] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0347] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP isAttorney Docket No. FRD-001 WO increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0348] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0349] In certain embodiments, the method disclosed herein results in an increase in ATP production, restoration of cellular energy metabolism, compensation for glucose hypometabolism, improvement in metabolic efficiency, improvement in mitochondrial respiration, improvement in basal respiratory capacity, improvement in mitochondrial function, increase in oxygen consumption rate (OCR), improvement in neuronal viability, reduction in neuronal cell death, reduction in apoptosis, protection against amyloid-induced toxicity, promotion of neuronal survival, reduction in reactive oxygen species (ROS), reduction in oxidative stress, improvement in mitochondrial integrity, increased microglial uptake of amyloid beta, increased clearance of amyloid beta, acceleration of amyloid clearance kinetics, improvement in cognitive function, stabilization of cognitive decline, improvement in memory, improvement in alertness, improvement in language function, improvement in overall cognitive performance, improvement in cardiac output, improvement in cardiac function, improvement in ejection fraction, reduction in blood glucose levels, improvement in glycemic control, reductionAttorney Docket No. FRD-001 WO in HbAlc, improvement in insulin sensitivity, reduction in insulin requirements, reduction in body weight, reduction in fat mass, reduction in liver fat, improvement in liver function, reduction in hepatic inflammation, increased time -in-range for glucose control, stabilization of metabolic parameters, increased energy levels, reduced fatigue, reduced sugar cravings, improved quality of life, sustained elevation of blood ketone levels, improved tolerability, and controlled or prolonged ketone release.

[0350] In certain embodiments, the method disclosed herein results in an increase in ATP production. In certain embodiments, the method disclosed herein results in restoration of cellular energy metabolism. In certain embodiments, the method disclosed herein results in compensation for glucose hypometabolism. In certain embodiments, the method disclosed herein results in improvement in metabolic efficiency. In certain embodiments, the method disclosed herein results in improvement in mitochondrial respiration. In certain embodiments, the method disclosed herein results in improvement in basal respiratory capacity. In certain embodiments, the method disclosed herein results in improvement in mitochondrial function. In certain embodiments, the method disclosed herein results in an increase in oxygen consumption rate (OCR). In certain embodiments, the method disclosed herein results in improvement in neuronal viability. In certain embodiments, the method disclosed herein results in reduction in neuronal cell death. In certain embodiments, the method disclosed herein results in reduction in apoptosis. In certain embodiments, the method disclosed herein results in protection against amyloid-induced toxicity. In certain embodiments, the method disclosed herein results in promotion of neuronal survival. In certain embodiments, the method disclosed herein results in reduction in reactive oxygen species (ROS). In certain embodiments, the method disclosed herein results in reduction in oxidative stress. In certain embodiments, the method disclosed herein results in improvement in mitochondrial integrity. In certain embodiments, the method disclosed herein results in increased microglial uptake of amyloid beta. In certain embodiments, the method disclosed herein results in increased clearance of amyloid beta. In certain embodiments, the method disclosed herein results in acceleration of amyloid clearance kinetics. In certain embodiments, the method disclosed herein results in improvement in cognitive function. In certain embodiments, the method disclosed herein results in stabilization of cognitive decline. In certain embodiments, the method disclosed herein results in improvement in memory. In certain embodiments, the method disclosed herein results in improvement in alertness. In certain embodiments, the method disclosed herein results in improvement in language function. In certain embodiments, the method disclosed herein results in improvement in overall cognitive performance. In certain embodiments, the method disclosed herein results in improvement in cardiac output. In certain embodiments, the method disclosed herein results inAttorney Docket No. FRD-001 WO improvement in cardiac function. In certain embodiments, the method disclosed herein results in improvement in ejection fraction. In certain embodiments, the method disclosed herein results in reduction in blood glucose levels. In certain embodiments, the method disclosed herein results in improvement in glycemic control. In certain embodiments, the method disclosed herein results in reduction in HbAlc. In certain embodiments, the method disclosed herein results in improvement in insulin sensitivity. In certain embodiments, the method disclosed herein results in reduction in insulin requirements. In certain embodiments, the method disclosed herein results in reduction in body weight. In certain embodiments, the method disclosed herein results in reduction in fat mass. In certain embodiments, the method disclosed herein results in reduction in liver fat. In certain embodiments, the method disclosed herein results in improvement in liver function. In certain embodiments, the method disclosed herein results in reduction in hepatic inflammation. In certain embodiments, the method disclosed herein results in increased time-in-range for glucose control. In certain embodiments, the method disclosed herein results in stabilization of metabolic parameters. In certain embodiments, the method disclosed herein results in increased energy levels. In certain embodiments, the method disclosed herein results in reduced fatigue. In certain embodiments, the method disclosed herein results in reduced sugar cravings. In certain embodiments, the method disclosed herein results in improved quality of life. In certain embodiments, the method disclosed herein results in sustained elevation of blood ketone levels. In certain embodiments, the method disclosed herein results in improved tolerability. In certain embodiments, the method disclosed herein results in controlled or prolonged ketone release.

[0351] This previously unrecognized pattern of convergent enzymatic deficiencies at remarkably similar magnitudes (30-50% reductions) strongly supports a common metabolic pathophysiology and points to potential common therapeutic targets.Preserved Ketone Metabolism: The Critical Therapeutic Opportunity

[0352] The most significant and therapeutically relevant finding is that ketone metabolism remains intact or is enhanced across these conditions despite impaired glucose utilization:Alzheimer's Disease

[0353] Three independent PET studies using radiolabeled ketones confirmed that AD brains readily oxidize ketones at normal rates despite significant glucose hypometabolism.Parkinson's DiseaseAttorney Docket No. FRD-001 WO

[0354] PD brain ketone utilization appears preserved, with preclinical models showing ketones effectively utilized and providing neuroprotection.Heart Failure

[0355] Failing hearts demonstrate ~2x higher ketone uptake and utilization than normal hearts, with upregulation of ketone-specific enzymes (BDH1, SCOT) and transporters

[0356] This differential preservation of ketone metabolism despite glucose hypometabolism represents a critical therapeutic opportunity that forms the core of the present disclosure.Therapeutic Efficacy Across Diverse Conditions

[0357] Robust clinical evidence demonstrates that addressing the common glucose hypometabolism through ketone therapy produces significant and consistent benefits across these diverse conditions:Controlled Clinical Evidence of EfficacyAlzheimer's Disease:

[0358] In one randomized controlled clinical study (n=152), APOE-s4-negative patients on ketogenic compound AC-1202 improved by +4.7 points versus placebo on the ADAS-Cog at Day 45 (p=0.0005) and by +3.4 points at Day 90 (p=0.0148). Even in the overall intention-to-treat sample, a 1.9-point ADAS-Cog improvement (p=0.02) was observed. 5 of 7 clinical studies of ketogenic interventions in MCI / AD showed significant cognitive or metabolic improvements.Parkinson's Disease:

[0359] In one randomized controlled clinical study (n=47), 8-week ketogenic diet produced 41% improvement in non-motor symptoms (MDS-UPDRS Part I) versus 11% with low-fat diet (p<0.001). Therapeutic ketosis led to improved P-hydroxybutyrate levels of ~2-3 mM, associated with symptom improvements.Heart Failure:

[0360] In clinical settings, administration of intravenous P-hydroxybutyrate to achieve blood concentrations of approximately 3 mM increased cardiac output by 2.0 L / min (-30% increase) without increasing myocardial oxygen consumption. SGLT2 inhibitors (which induce mildAttorney Docket No. FRD-001 WO ketosis) demonstrated -25% reductions in HF hospitalization risk. Animal models: 4-week ketone ester improved ejection fraction by -15 percentage points.Dose-Response Relationship Across Conditions

[0361] A key finding supporting the unified mechanism is a consistent dose-response relationship between circulating ketone levels and clinical improvement across multiple disease states. For example, higher serum ketone levels are associated with greater cognitive improvement in subjects with Alzheimer’s disease. Similarly, in Parkinson’s disease, ketone levels in the range of approximately 2-3 mM are associated with greater improvement in clinical symptoms. In heart failure, blood 0-hydroxybutyrate levels of approximately 3 mM are associated with increases in cardiac output on the order of approximately 30%. This consistent relationship between ketone levels and clinical improvement across diverse conditions strongly supports the mechanistic validity of the disclosed approach.Mechanistic DetailsMetabolic Bypass Mechanism

[0362] The disclosure leverages the critical insight that ketone bodies (P-hydroxybutyrate, acetoacetate) can bypass the glucose-specific metabolic blockade observed in these conditions:

[0363] In Alzheimer's and heart failure, pyruvate dehydrogenase (PDH) complex activity is reduced by 30-50%, creating a bottleneck for glucose-derived pyruvate to enter the TCA cycle. Ketone bodies are metabolized to acetyl-CoA via a distinct enzymatic pathway (|3-hydroxybutyrate dehydrogenase — > acetoacetate — > acetoacetyl-CoA — > acetyl-CoA) that entirely bypasses the PDH complex. In Parkinson's disease, Complex I deficiency (-30% reduced) limits NADH oxidation from glucose metabolism; ketone metabolism generates FADH2 that can enter the electron transport chain at Complex II, bypassing the Complex I deficiency. This metabolic bypass mechanism explains why ketone therapy is effective across these seemingly disparate conditions.Energy Yield and Efficiency Advantages

[0364] The disclosure further leverages previously unappreciated energetic advantages of ketone metabolism. Ketone bodies produce more ATP per oxygen molecule consumed compared to glucose (2.5 vs 2.25 ATP / O), providing energetic efficiency in oxygen-limited conditions. Ketone metabolism produces fewer reactive oxygen species than glucose or fatty acid oxidation, reducing oxidative stress that is common across these conditions. Ketones have direct signaling effects that activate mitochondrial biogenesis and antioxidant pathways (e.g., Nrf2), providing benefits beyond simple energy provision.Attorney Docket No. FRD-001 WO Methods of Treatment

[0365] One aspect of the disclosure provides a method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:(a) measuring a glucose metabolism deficit (G_Diff) in one or more tissues of the subject using at least one diagnostic technique to obtain a quantitative indication of the subject’s impaired glucose utilization;(b) calculating a personalized exogenous ketone dosage (K) based on the measured G_Diff, wherein said calculation comprises applying at least one algorithm that correlates the measured G_Diff to the exogenous ketone intake required to at least partially compensate for the subject’s impaired glucose utilization; and(c) administering an exogenous ketone composition to the subject in accordance with the calculated personalized exogenous ketone dosage,wherein the administered exogenous ketone composition provides an alternative metabolic fuel to the affected tissues, thereby addressing the subject’s glucose hypometabolism.

[0366] In certain embodiments, the at least one diagnostic technique is selected from positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, and wearable biosensors.

[0367] In certain embodiments, the calculation in step (b) comprises computing the personalized exogenous ketone dosage (K) using Formula (I):K = G_Diff x (4 / 4.7) x F x p(I)wherein,G_Diff is the measured glucose deficit in grams or equivalent energy units;(4 / 4.7) is a factor accounting for relative energy yields of glucose versus ketones; F is an efficiency factor (F 5= 1) reflecting systemic overhead or disease-specific factors; and p is a partition factor (0 < p1) representing tissue-specific ketone uptake capacity.

[0368] It will be appreciated that Formula (I) is one exemplary approach to determining the ketone dosage K based on G_Diff. In other embodiments, the personalized ketone dosage can be calculated using different algorithms or computational techniques. For instance, a machine learning model (trained on data from numerous patients) may predict an optimal ketone dose byAttorney Docket No. FRD-001 WO taking the measured G_Diff as well as additional patient-specific parameters into account (such as the patient’s age, liver function, current diet, or oxygen saturation). In another embodiment, a simple lookup table or an iterative titration protocol is used: the system might start at a baseline ketone dose and adjust upward or downward in controlled increments until the patient’s metabolic markers reach target ranges. The computational module performing the dose calculation can be implemented locally (e.g., on a wearable device or pump controller) or remotely (e.g., a cloud server that receives the diagnostic data and returns a dosing recommendation). In all cases, the core principle is that the dose is quantitatively based on the measured glucose deficit, regardless of the specific mathematical model used. This ensures that even if different formulae or algorithms are employed, they fall within the scope of using G_Diff to inform therapy.

[0369] In certain embodiments, the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization. In certain embodiments, the glucose hypometabolic disorder is Alzheimer’s disease. In certain embodiments, the glucose hypometabolic disorder is Parkinson’s disease. In certain embodiments, the glucose hypometabolic disorder is heart failure.

[0370] In certain embodiments, the method further comprises classifying the subject’s disease severity into one or more metabolic stages (Stage 0 through 4) based on the measured G_Diff, and increasing the exogenous ketone dosage for each advancing metabolic stage to at least partially offset the subject’s progressively reduced glucose utilization.

[0371] In certain embodiments, measuring the glucose metabolism deficit (G_Diff) comprises performing a fluorodeoxyglucose PET (FDG-PET) scan to quantify local or global glucose uptake in the subject’s tissue, and comparing the measured local or global glucose uptake to a reference level to determine a magnitude of G_Diff, wherein the calculated personalized exogenous ketone dosage (K) in step (b) is directly proportional to the measured impaired glucose utilization.

[0372] In certain embodiments,...

Claims

1. Attorney Docket No. FRD-001 WO CLAIMSWhat is claimed is:

1. A method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:(a) measuring a glucose metabolism deficit (G_Diff) in one or more tissues of the subject using at least one diagnostic technique to obtain a quantitative indication of the subject’s impaired glucose utilization;(b) calculating a personalized exogenous ketone dosage (K) based on the measured G_Diff, wherein said calculation comprises applying at least one algorithm that correlates the measured G_Diff to the exogenous ketone intake required to at least partially compensate for the subject’s impaired glucose utilization; and(c) administering an exogenous ketone composition to the subject in accordance with the calculated personalized exogenous ketone dosage,wherein the administered exogenous ketone composition provides an alternative metabolic fuel to the affected tissues, thereby addressing the subject’s glucose hypometabolism.

2. The method of claim 1, wherein the at least one diagnostic technique is selected from positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, and wearable biosensors.

3. The method of claim 1, wherein the calculation in step (b) comprises computing the personalized exogenous ketone dosage (K) using Formula (I):K = G_Diff x (4 / 4.7) x F x p(I)wherein,G_Diff is the measured glucose deficit in grams or equivalent energy units;(4 / 4.7) is a factor accounting for relative energy yields of glucose versus ketones; F is an efficiency factor (F 5= 1) reflecting systemic overhead or disease-specific factors; and p is a partition factor (0 < p1) representing tissue-specific ketone uptake capacity.

4. The method of claim 1, wherein the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

5. The method of claim 1, further comprising classifying the subject’s disease severity into one or more metabolic stages (Stage 0 through 4) based on the measured G_Diff, and increasingAttorney Docket No. FRD-001 WO the exogenous ketone dosage for each advancing metabolic stage to at least partially offset the subject’s progressively reduced glucose utilization.

6. The method of claim 1, wherein measuring the glucose metabolism deficit (G_Diff) comprises performing a fluorodeoxyglucose PET (FDG-PET) scan to quantify local or global glucose uptake in the subject’s tissue, and comparing the measured local or global glucose uptake to a reference level to determine a magnitude of G_Diff, wherein the calculated personalized exogenous ketone dosage (K) in step (b) is directly proportional to the measured impaired glucose utilization.

7. The method of claim 1, further comprising concurrently administering at least one standard-of-care therapy for the glucose hypometabolic disorder, wherein the exogenous ketone composition provides an unexpectedly synergistic improvement in clinical or functional outcomes relative to the standard-of-care therapy alone.

8. The method of claim 1, wherein the exogenous ketone composition comprises delivering an amount sufficient to raise the subject’s blood beta-hydroxybutyrate ( HB) concentration to at least about 0.5 millimolar (mM), wherein a therapeutic level of ketosis is induced thereby alleviating the measured glucose metabolism deficit (G_Diff).

9. The method of claim 1, wherein the exogenous ketone composition is administered orally, enterally, parenterally, or intravenously, and the exogenous ketone composition is selected from the group consisting of: beta-hydroxybutyrate (| HB) salts, beta-hydroxybutyrate (0HB) bound to any carrier molecule, acetoacetate (AcAc) salts, acetoacetate (AcAc) bound to any carrier molecule, 1,3-butanediol, glycerol tributyrate or other glycerol-butyric acid esters, medium-chain triglycerides (MCTs) capable of conversion to ketone bodies, ketone amides, ketone ethers, ketone analogs, and any pharmaceutically acceptable derivatives or combinations thereof, andwherein the administered exogenous ketone composition provides a therapeutically effective level of ketones that at least partially compensates for the subject’s measured glucose metabolism deficit.

10. A system for diagnosing and treating a glucose hypometabolic disorder in a subject, comprising:(a) a diagnostic module configured to measure a glucose metabolism deficit (G_Diff) in the subject’s tissue using at least one diagnostic technique;(b) a computational module, operably connected to the diagnostic module, that applies an algorithm converting the measured G Diff into a recommended exogenous ketone dosage (K) to compensate for the subject’s impaired glucose utilization; andAttorney Docket No. FRD-001 WO (c) a ketone delivery apparatus configured to administer the recommended ketone dosage to the subject,wherein the diagnostic module, computational module, and ketone delivery apparatus together provide a unified diagnostic-therapeutic platform to treat the glucose hypometabolic disorder by supplying ketones in proportion to the measured deficit.

11. The system of claim 10, wherein the at least one diagnostic technique is selected from positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, and wearable biosensors.

12. The system of claim 10, wherein the computational module calculates the personalized exogenous ketone dosage (K) using Formula (I):K = G_Diff x (4 / 4.7) x F x p(I)wherein:G_Diff is the measured glucose deficit in grams or equivalent energy units;(414.7) is a factor accounting for relative energy yields of glucose versus ketones; F is an efficiency factor (F1) reflecting systemic overhead or disease-specific factors; and p is a partition factor (0 < p1) representing tissue-specific ketone uptake capacity.

13. The system of claim 10, wherein the ketone delivery apparatus comprises an automated infusion pump that dynamically adjusts the exogenous ketone flow rate based on real-time feedback of the subject’s glucose or ketone levels, maintaining a target therapeutic ketone range that partially or fully offsets the measured G_Diff.

14. A kit for diagnosing and treating a glucose hypometabolic disorder in a subject, comprising:(a) instructions for measuring or estimating a glucose metabolism deficit (G_Diff) in the subject using at least one diagnostic technique;(b) an exogenous ketone composition suitable for oral or parenteral administration; and (c) a reference chart or algorithmic guide that translates the measured G_Diff into a recommended personalized exogenous ketone dosage for mitigating the subject’s impaired glucose utilization,wherein the kit enables a practitioner or patient to determine a personalized exogenous ketone dosage that compensates for the subject’s impaired glucose utilization.

15. The kit of claim 14, wherein the at least one diagnostic technique is selected from positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, and wearable biosensors.Attorney Docket No. FRD-001 WO 16. The kit of claim 14, wherein said reference chart or algorithmic guide includes guidance on applying a partition factor (p) representing tissue-specific ketone uptake capacity, thereby adjusting the recommended ketone dosage to match the subject’s particular organ demands or disease severity.

17. The kit of claim 14, wherein the reference chart or algorithmic guide comprises computing the personalized exogenous ketone dosage (K) using Formula (I):K = G_Diff x (4 / 4.7) x F x p(I)wherein:G_Diff is the measured glucose deficit in grams or equivalent energy units;(4 / 4.7) is a factor accounting for relative energy yields of glucose versus ketones; F is an efficiency factor (F 1) reflecting systemic overhead or disease-specific factors; and p is a partition factor (0 < p =£ 1) representing tissue-specific ketone uptake capacity.

18. A non-transitory computer-readable medium containing instructions which, when executed by one or more processors, cause the processor(s) to:(a) receive data corresponding to a measured glucose metabolism deficit (G_Diff) in a subject’s tissue;(b) apply at least one mathematical formula to compute a recommended exogenous ketone dosage (K) that partially or fully compensates for the measured deficit, wherein said formula accounts for factors including the relative energy yield of ketones, the subject’s efficiency factor (F), and partition factor (p);(c) generate an output specifying how the ketone dosage should be administered to the subject; and(d) optionally transmit the output to a user interface or ketone delivery apparatus, whereby the subject’s measured glucose shortfall is systematically converted into a therapeutic ketone dosage parameter.

19. The non-transitory computer-readable medium of claim 18, wherein the formula used to compute the ketone dosage (K) is:K = G_Diff x (4 / 4.7) x F x psuch that G_Diff is multiplied by (4 / 4.7) to account for energy differences between glucose and ketones, F is an efficiency factor, and p is a partition factor reflecting tissue-specific ketone uptake potential.

20. A method for diagnosing and quantifying glucose hypometabolism in a subject, comprising:Attorney Docket No. FRD-001 WO (a) performing an FDG-PET scan to measure regional glucose uptake;(b) performing magnetic resonance spectroscopy to measure lactate / pyruvate ratios in the same regions;(c) measuring at least three blood biomarkers selected from insulin, glycated albumin, fructosamine, pyruvate, lactate, and glucose variability indices; and(d) integrating data from steps (a), (b), and (c) using a machine learning algorithm to calculate a comprehensive Glucose Metabolism Index (GMI) that quantifies the subject's tissuespecific and global glucose utilization capacity, wherein the calculated GMI provides a more accurate basis for ketone dosage calculation than any single measurement alone.

21. A method for non-invasively diagnosing glucose hypometabolism in a subject, comprising:(a) measuring a panel of at least five biomarkers in the subject's blood, wherein said biomarkers comprise glucose, insulin, lactate, pyruvate, and at least one inflammatory marker;(b) measuring the subject's exhaled breath for volatile organic compounds associated with altered glucose metabolism;(c) collecting continuous glucose monitoring data for at least 72 hours; and(d) applying a diagnostic algorithm to the collected data to diagnose the presence and severity of glucose hypometabolism, wherein the diagnosis enables ketone therapy without requiring more invasive or expensive diagnostic procedures.

22. A method of stratifying subjects for personalized ketone therapy, comprising:(a) determining the subject's genotype for at least three genetic markers selected from APOE, PPAR-gamma, MCT1, BDH1, SCOT, and HMGCS2;(b) measuring the subject's baseline ketone metabolism by administering a test dose of exogenous ketones and measuring blood ketone levels at predetermined intervals;(c) calculating a Ketone Responsiveness Index (KRI) based on the genetic profile and metabolic test results; and(d) stratifying the subject into one of at least three ketone therapy protocol groups based on the calculated KRI, wherein each protocol group is associated with a different dosing regimen, formulation type, or administration schedule to optimize therapeutic outcomes.

23. A method of stratifying subjects based on metabolic phenotype for ketone therapy, comprising:Attorney Docket No. FRD-001 WO (a) measuring the subject's insulin sensitivity using a glucose tolerance test;(b) measuring the subject's baseline ketone production capacity using a controlled fast; (c) assessing the subject's mitochondrial function using a standardized exercise capacity test; and(d) classifying the subject into one of at least four metabolic phenotypes based on the measured parameters, wherein the metabolic phenotype classification determines the subject's ketone therapy protocol, including dosage, timing, and formulation.

24. A method of predicting a subject's response to ketone therapy, comprising:(a) collecting at least ten data parameters from the subject, wherein said parameters include age, disease type, disease duration, glucose metabolism measurements, inflammatory markers, genetic markers, and baseline cognitive or physical performance metrics;(b) inputting the collected parameters into a trained machine learning model that has been developed using data from at least 100 previous ketone therapy recipients; and(c) generating a predicted response score that indicates the likelihood of the subject achieving at least a 30% improvement in at least one primary outcome measure, wherein the predicted response score guides therapy decisions and personalized dosing strategies.

25. A method of predicting and optimizing a subject's response to ketone therapy over time, comprising:(a) establishing baseline measurements for the subject, including glucose metabolism, ketone metabolism, and clinical symptoms;(b) initiating ketone therapy according to an initial dosing protocol;(c) collecting response data at predetermined intervals during treatment;(d) inputting the response data into a reinforcement learning algorithm that dynamically updates the predicted optimal dosing protocol; and(e) adjusting the ketone therapy based on the algorithm's recommendations, wherein the dynamic response algorithm improves therapeutic outcomes by at least 20% compared to static dosing protocols.

26. A method of monitoring and optimizing ketone therapy in a subject, comprising:(a) utilizing a wearable device that continuously monitors at least three parameters selected from glucose levels, ketone levels, heart rate variability, and physical activity;Attorney Docket No. FRD-001 WO (b) transmitting the monitored data to a computational system that applies an algorithm to assess therapeutic adequacy;(c) generating alerts when measured parameters fall outside target ranges; and (d) providing automated dosing recommendations to maintain optimal therapeutic levels, wherein the continuous monitoring system improves adherence to therapy and clinical outcomes by at least 25% compared to periodic monitoring.

27. A method of monitoring response to ketone therapy, comprising(a) measuring a panel of biomarkers before initiating ketone therapy to establish baseline values;(b) re-measuring the same biomarker panel at predetermined intervals during ketone therapy;(c) calculating a Treatment Response Index (TRI) based on changes in the biomarker panel; and(d) adjusting the ketone therapy protocol based on the calculated TRI, wherein the biomarker panel comprises markers of inflammation, oxidative stress, mitochondrial function, and glucose-ketone metabolism, and wherein improvements in the TRI correlate with clinical improvement.

28. A closed-loop system for ketone therapy, comprising:(a) a continuous monitoring component that measures the subject's blood ketone levels at intervals not exceeding 15 minutes;(b) a computational component that processes the measured ketone levels and compares them to target ranges determined by the subject's measured glucose metabolism deficit;(c) a delivery component capable of adjusting ketone administration rates based on signals from the computational component; and(d) a user interface that displays real-time data and alerts, wherein the closed-loop system maintains blood ketone levels within ±15% of target values for at least 80% of the treatment period.

29. A method of implementing closed-loop ketone therapy, comprising:Attorney Docket No. FRD-001 WO (a) continuously monitoring the subject’s glucose levels, ketone levels, and at least one additional physiological parameter selected from heart rate, blood pressure, and body temperature;(b) processing the monitored parameters using an algorithm that calculates optimal ketone levels based on current glucose levels and the additional physiological parameter;(c) automatically adjusting ketone delivery rates to maintain the calculated optimal ketone levels; and(d) recording all data for subsequent efficacy analysis, wherein the multi-parameter monitoring enables more precise therapeutic control than ketone monitoring alone.

30. A method of enhancing ketone therapy efficacy, comprising:(a) administering exogenous ketones according to a personalized dosage protocol; (b) providing the subject with a digital therapeutic application that delivers behavioral interventions synchronized with the ketone dosing schedule;(c) collecting adherence and symptom data through the digital therapeutic application; and(d) adjusting the ketone therapy based on the collected data, wherein the combined physical-digital therapeutic approach improves clinical outcomes by at least 35% compared to ketone therapy without the digital component.

31. A method of optimizing ketone therapy across a population, comprising:(a) collecting anonymized treatment and outcome data from multiple subjects receiving personalized ketone therapy;(b) analyzing the collected data using a machine learning algorithm to identify patterns associated with optimal responses;(c) generating updated treatment protocols based on the identified patterns; and (d) implementing the updated protocols for new subjects, wherein the iterative optimization process continuously improves treatment efficacy and reduces adverse effects across the treated population.

32. A method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:(a) measuring a glucose metabolism deficit (G_Diff) in one or more tissues of the subject using at least one diagnostic technique;Attorney Docket No. FRD-001 WO (b) calculating a personalized exogenous ketone dosage (K) based on the measured G_Diff using Formula (I)K = G_Diff x (4 / 4.7) x F x p,(I)wherein F is an efficiency factor and p is a partition factor representing tissue-specific ketone uptake capacity; and(c) administering an exogenous ketone composition to the subject in accordance with the calculated dosage, wherein the administered exogenous ketone composition provides an alternative metabolic fuel that compensates for the subject's glucose hypometabolism.

33. The method of claim 32, the method further comprising optionally administering hyperbaric oxygen therapy (HBOT) to the subject at a pressure of between 1.5 and 3.0 atmospheres absolute (ATA), wherein the combined administration of exogenous ketones and HBOT may produce enhanced cellular energy production by simultaneously addressing both fuel substrate deficiency and oxygen availability.

34. The method of claim 32, wherein the glucose hypometabolic disorder is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, Parkinson's disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject's tissue exhibits a quantifiable reduction in glucose utilization.

35. The method of claim 32, the method further comprising classifying the subject's glucose hypometabolic disorder into one of the following metabolic stages based on the measured G_Diff:(a) Stage 0 corresponding to normal glucose metabolism;(b) Stage 1 corresponding to mild hypometabolism with a G_Diff of 5-20% below normal;(c) Stage 2 corresponding to moderate hypometabolism with a G_Diff of 20-40% below normal;(d) Stage 3 corresponding to severe hypometabolism with a G_Diff of 40-70% below normal; orAttorney Docket No. FRD-001 WO (e) Stage 4 corresponding to extreme hypometabolism with a G_Diff greater than 70% below normal, wherein both the optional HBOT parameters and the calculated ketone dosage may be progressively adjusted based on the metabolic stage.

36. The method of claim 32, wherein for subjects classified in more advanced metabolic stages (Stage 3-4), the optional HBOT is administered according to parameters adjusted to the severity of glucose hypometabolism.

37. The method of claim 32, wherein when HBOT is administered in conjunction with ketone therapy, the efficiency factor (F) in the ketone dosage calculation formula may be adjusted to account for the potential synergistic effects of combined therapy.

38. A system for treating a glucose hypometabolic disorder in a subject, comprising:(a) a diagnostic module configured to measure a glucose metabolism deficit (G_Diff) in one or more tissues of the subject;(b) a computational module that calculates a personalized ketone dosage using the formula K = G_Diff x (4 / 4.7) x F x p;(c) a ketone delivery apparatus configured to administer the calculated ketone dosage; and(d) optionally, a hyperbaric oxygen chamber configured to deliver oxygen at an elevated pressure determined based on the measured G_Diff, wherein the system provides treatment that addresses the fuel component of glucose hypometabolism, with optional enhancement through oxygen therapy.

39. A kit for treating a glucose hypometabolic disorder in a subject, comprising:(a) an exogenous ketone composition;(b) instructions for measuring or estimating a glucose metabolism deficit (G_Diff); (c) a reference guide that translates the measured G_Diff into a recommended ketone dosage using the formula K = G_Diff x (4 / 4.7) x F x p; and(d) optionally, an HBOT protocol guide that specifies recommended parameters for optional adjunctive hyperbaric oxygen therapy based on the measured G_Diff and classified metabolic stage, wherein the kit enables implementation of the core ketone therapy with guidance for optional HBOT enhancement.

40. A method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:Attorney Docket No. FRD-001 WO (a) administering to the subject an exogenous ketone composition in an amount sufficient to achieve and maintain a sustained blood ketone level of at least about 0.5 mM P-hydroxybutyrate ( HB) for a therapeutically effective duration; and(b) periodically measuring or estimating the subject’s ketone levels by one or more suitable techniques,wherein said sustained blood ketone level alleviates or improves one or more clinical symptoms of the glucose hypometabolic disorder, independent of explicitly measuring any glucose metabolism deficit in the subject.

41. The method of claim 40, wherein the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

42. The method of claim 40, wherein the exogenous ketone composition comprises a sustained-release or slow-release fonnulation, thereby maintaining the blood ketone level at or above about 0.5 mM for at least about 4 hours following a single administration.

43. The method of claim 40, wherein the periodic measurement or estimation of the subject’s ketone levels is performed using any invasive or non-invasive technique, including but not limited to finger-stick blood testing, continuous or intermittent ketone monitoring devices, breath ketone analysis, transdermal sensors, saliva testing, or urine ketone measurements.

44. The method of claim 40, further comprising adjusting a dosage or frequency of administration of the exogenous ketone composition based on said measured or estimated ketone levels, thereby maintaining a therapeutic blood ketone concentration between about 0.5 mM and about 5.0 mM.

45. A method of treating a patient in need of therapy by establishing a therapeutic ketonemic state, the method comprising: administering one or more ketone-elevating agents to the patient and controlling the patient’s blood -hydroxybutyrate (BHB) level to maintain BHB within a target range effective for therapy, for a duration sufficient to achieve a therapeutic benefit, wherein said therapeutic ketonemic state is achieved without requiring the patient to adhere to a ketogenic diet.

46. The method of claim 45, wherein the patient’s blood BHB concentration is maintained within the target range for at least a predetermined portion of each day, for example at leastAttorney Docket No. FRD-001 WO about 8-12 hours per 24-hour period, thereby ensuring sustained time-in-range exposure to therapeutic ketone levels.

47. The method of claim 45, wherein maintaining the therapeutic ketonemic state is accomplished via feedback-guided titration, comprising continuously or periodically monitoring the patient’s ketone level (such as via a blood or interstitial BHB sensor) and automatically adjusting the dosage or delivery rate of the ketone-elevating agent to keep the BHB level within the target range.

48. The method of claim 45, further comprising implementing safety interlocks during said maintaining of the ketonemic state, including: (i) halting or reducing ketone administration if the patient's BHB level exceeds a safety threshold (e.g., about 5 mM) to prevent excessive hyperketonemia; (ii) monitoring the patient’s blood glucose and pausing ketone delivery if blood glucose falls below a threshold to reduce risk of hypoglycemia: and (iii) monitoring for signs of metabolic acidosis (via blood pH or bicarbonate) and adjusting or stopping ketone delivery if acidosis is detected, wherein the method optionally includes providing an alert or automated countermeasure if any of these safety conditions occur.

49. The method of claim 45, wherein the therapeutic ketonemic state is administered in combination with a second therapy directed to the patient’ s condition, such that the patient is maintained within the target ketone range during a time window overlapping with administration of the second therapy, thereby enhancing the efficacy of the second therapy. Examples: maintaining 1-3 mM BHB during chemotherapy or immunotherapy for cancer; maintaining therapeutic ketosis during administration of a neuroprotective drug for Alzheimer’ s disease; or maintaining therapeutic ketosis alongside an antidepressant regimen for depression.

50. The method of claim 45, wherein the patient’s condition is selected from the group consisting of: a cancer, a neurodegenerative disease, a psychiatric disorder, a metabolic or endocrinological disease, or a cardiovascular disease, and wherein maintaining the therapeutic ketonemic state yields a clinical improvement in the selected condition. Examples: the condition is cancer and sustained ketonemia impairs tumor growth; the condition is Alzheimer' s disease and ketonemia improves cognitive function; the condition is type 2 diabetes and ketonemia improves glycemic control.

51. The method of claim 45, wherein the patient is identified as a candidate for ketonemia therapy by the presence of a biomarker or metabolic indicator predictive of therapeutic responsiveness, and the target BHB range is selected based on said biomarker. Examples: selecting a cancer patient whose tumor exhibits low expression of ketone -utilizing enzymesAttorney Docket No. FRD-001 WO (0XCT1 and / or BDH1) and treating them by maintaining therapeutic ketonemia to preferentially affect tumor cells; or selecting a neurological patient with evidence of brain glucose hypometabolism and prescribing a target ketone level sufficient to supplement brain energy metabolism.

52. The method of claim 45, wherein inducing and maintaining the ketonemic state causes at least one beneficial physiological effect selected from the group consisting of: an increase in the patient’s NAD / NADH ratio in blood or tissue; a reduction in pro-inflammatory cytokine levels; an increase in the brain GABA-to-glutamate ratio; or an improvement in mitochondrial ATP production efficiency, thereby contributing to the therapeutic outcome.

53. A system for inducing and maintaining therapeutic titratable ketonemia in a patient, the system comprising: (a) a ketone delivery device configured to administer a ketone body or ketone precursor to the patient in a controllable manner; (b) at least one sensor configured to measure the patient’s ketone level in real time or near-real time, and optionally to measure additional metabolic parameters including glucose and / or pH; (c) a control unit comprising a processor executing an algorithm that receives input from said sensor and regulates the ketone delivery device to maintain the patient’s ketone level within a target range; and (d) a user interface or communication module to allow clinicians to set target ranges and to display patient data and alerts, wherein the system is configured to automatically maintain the patient in a therapeutic ketonemic state safely and effectively.

54. The system of claim 53, wherein the ketone delivery device comprises an infusion pump for intravenous or subcutaneous administration of a ketone solution, and the sensor comprises a continuous ketone monitor providing frequent BHB readings to the control unit. The control algorithm is a closed-loop feedback controller that modulates the infusion rate based on deviation from the target BHB range and includes integrated safety rules to halt infusion if the BHB level exceeds a predetermined maximum or if a concurrent glucose measurement falls below a minimum threshold.

55. A computer-implemented method for maintaining a target metabolic state of therapeutic ketosis in a patient, the method comprising: receiving, via one or more electronic sensors, current patient data including at least a ketone level; comparing, by a programmed processor, the current ketone level to a predetermined target range; and automatically controlling a dosing mechanism to administer a ketone-elevating agent to the patient or adjust a delivery rate, wherein the dosing is increased if the ketone level is below the target range and decreased or paused if the ketone level is at or above the target range, such that the patient’s ketone level is driven toward and maintained within the target range over time.Attorney Docket No. FRD-001 WO 56. The method of claim 55, wherein the programmed processor further receives glucose level data and is configured to reduce or stop administration of the ketone-elevating agent if the patient's glucose falls below a threshold, and to resume administration when the patient’s glucose returns to a safe level, thereby incorporating a hypoglycemia safeguard into the control algorithm. The method also includes generating an alert signal if either the ketone or glucose reading falls outside permissible limits despite the dosing adjustments.

57. A kit for implementing therapeutic titratable ketonemia in a patient, the kit comprising: (i) a supply of at least one exogenous ketone composition (for example, a ketone ester liquid or a plurality of ketone salt packets, or an injectable ketone formulation) in an amount sufficient for a treatment course: (ii) a ketone monitoring device (for example, a blood ketone meter with test strips or a wearable ketone sensor patch with a reader); and (iii) instructions for use that detail a treat-to target protocol including a defined target ketone level or range to achieve (within a range of therapeutically effective BHB concentration) and a dosing schedule or algorithm to titrate the composition so as to reach and maintain that range. The instructions may further include guidance on adjusting doses based on ketone readings (in an open-loop mode) and safety guidelines for the patient to follow during therapy.

58. The kit of claim 57, wherein the ketone composition comprises multiple formulations for different times of day (for example, a fast-acting ketone ester for morning dosing and a slow-release formulation for overnight ketosis), and the ketone monitoring device is a continuous BHB monitor linked to a software application. The instructions included with the kit are tailored to the patient’s indication and treatment plan, and optionally the kit further comprises ancillary items selected from the group consisting of: electrolyte supplements for use during ketosis, nutritional guidelines to follow while on TTK therapy, and a logging tool or application to record ketone levels and symptoms.

59. An exogenous ketone body composition for use in treating a chronic disease or condition in a human subject, wherein the treatment comprises inducing and maintaining a therapeutic ketonemic state in the subject by elevating the subject’s blood P-hydroxybutyrate (BHB) concentration to between about 1 mM and 5 mM for a therapeutically effective duration each day, thereby alleviating one or more symptoms of the disease or condition.

60. The exogenous ketone composition for use according to claim 59, for use in treating a patient diagnosed with a ketone-responsive cancer, wherein the patient is identified as having a tumor with low expression of a ketone -utilizing enzyme, and wherein the treatment comprises maintaining the patient’s blood BHB level within about 1-3 mM to selectively impair tumor cell metabolism while sustaining normal tissue metabolism.Attorney Docket No. FRD-001 WO 61. A medical system comprising a ketone delivery apparatus, a ketone level sensor, and a controller for use in the treatment of a patient suffering from a disease associated with metabolic dysregulation, wherein the system is configured to maintain the patient’ s blood ketone level within a predetermined therapeutic range during the treatment, and wherein the system includes safety controls that suspend ketone delivery if the patient’s BHB level exceeds a preset maximum or if the patient’s blood glucose falls below a preset minimum, thereby ensuring safe operation during the course of treatment.

Images