Compositions and methods for treating neurodegenerative diseases

Abstract

Provided herein are methods and compositions utilizing a urolithin A agent, a fisetin agent, and an isoflavone agent for treatment of neurodegenerative diseases.

Description

Attorney Docket No : 40978-0774WO1COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVEDISEASESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 679,792, filed on August 6, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Neurodegenerative diseases of the central nervous system (CNS) cause progressive loss of neuronal structure and function and are devastating diseases for affected patients and their families. While various agents are known or have been suggested for treating neurodegenerative diseases, effective therapies are scarce or non-existent. Thus, there is need for improved approaches for treating neurodegenerative diseases.SUMMARY

[0003] The present disclosure provides certain insights regarding, and technologies for, treatment and / or prevention of neurodegenerative diseases. Among other things, the present disclosure provides certain combinations of agents with unexpected and / or synergistic effects in treatment and / or prevention of neurodegenerative disease. The present disclosure also identifies the source of a problem with certain conventional or proposed strategies for treating and / or preventing neurodegenerative disease, for example in failing to appreciate importance and / or benefit of certain combination therapies.

[0004] The present disclosure specifically provides combinations of a urolithin A agent, a fisetin agent, and an isoflavone agent (e.g., ipriflavone), and demonstrates surprising features of combination therapy with such a combination of agents in the treatment or prevention of neurodegenerative disease. The present disclosure further documents usefulness of such combination therapy when further combined with additional agents.

[0005] In some embodiments, provided herein are methods of treating or preventing a neurodegenerative disease in a subject in need thereof, the methods include administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure provides a method of reducing pathogenic microglial pro-inflammatory activation in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure providesAttorney Docket No : 40978-0774WO1 a method of promoting microglial Ap> clearance in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure provides a method of reducing pathogenic microglial pro-inflammatory' activation and promoting microglial A clearance in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent.

[0006] In some embodiments, the present disclosure provides methods of treating, preventing, or decreasing neuroinflammation. In some embodiments, neuroinflammation can be caused by or associated with neurodegenerative disorders (e.g., those described herein), other diseases, disorders, and conditions, such as viral infection, autoimmune disorders, mental stress (e.g.. stress caused from overworking, lack of sleep, and the like), metabolic disorders, and injury, or aging. In some embodiments, neuroinflammation is caused by or associated with a viral infection. In some embodiments, a viral infection is a SARS-CoV-2 infection. In some embodiments neuroinflammation is characterized by microglia activation in the subject.

[0007] In some embodiments, the present disclosure provides methods of treating or preventing a symptom or feature associated with a neurodegenerative disease. In some embodiments, a symptom or feature of a neurodegenerative disease is memory loss, cognitive decline, brain fog, increased Ap plaque production and / or increased Ap plaque levels.

[0008] In some embodiments, the present disclosure provides methods of treating or preventing brain fog. In some embodiments, brain fog is not associated with any particular clinical disease, disorder, or condition. In some embodiments, brain fog is associated with lack of sleep, stress, and the like. In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, a polyglutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander disease, Alpe’s disease, ataxia telangiectasia. Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple system atrophy, Pelizaeus- Merzbacher disease. Pick’s disease, primary lateral sclerosis, Refsum’s disease, Sandhoff disease, Schilder’s disease, spinal cord injury, spinal muscular atrophy. SteeleRichardson- Olszewski disease, Tabes dorsalis, or frototemporal dementia.

[0009] In some embodiments, provided compositions are useful for improving cognitive health of a subject. In some embodiments, provided compositions are useful for improving cognitive health of a healthy subject. In some embodiments, provided compositions are usefulAttorney Docket No : 40978-0774WO1 for supporting memory and recall in a subject. In some embodiments, the present disclosure provides a composition that maintains cognitive function in a subject. In some embodiments, the present disclosure provides a composition that prevents cognitive decline in a subject. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age-related.

[0010] In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote A|3 uptake and / or reduce pro- inflammatory cytokine production. In some embodiments, the present disclosure provides a method for improving cognitive health of a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an A uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0011] In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Ap uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the present disclosure provides a method for supporting memory and recall in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an A uptake promoter, and the other of the first agent or the second agent reduces pro-mflammatoiy cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0012] In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote Ap uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the present disclosure provides a method for maintaining cognitive function in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an Ap uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprisesAttorney Docket No : 40978-0774WO1 administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject.

[0013] In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein the first agent and the second agent each independently promote A(3 uptake and / or reduce pro-inflammatory cytokine production. In some embodiments, the present disclosure provides a method for preventing cognitive decline in a subject comprising administering a first agent and a second agent, wherein one of the first agent or the second agent is an A|3 uptake promoter, and the other of the first agent or the second agent reduces pro-inflammatory cytokine production. In some embodiments, a method described herein further comprises administration of one or more additional compounds as described herein. In some embodiments, a subject is a healthy subject. In some embodiments, cognitive decline is age- related.

[0014] In some embodiments, the present disclosure provides compositions for use in provided methods. In some embodiments, provided compositions are in an oral dosage form. In some embodiments, the present disclosure provides a kit comprising an oral dosage form of a provided composition.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 is a graph demonstrating the dose-response increase in A(3 uptake by Urolithin A in microglial BV2 cells, measured by Af> ELISA.

[0016] FIG. 2A is a graph showing the dose-response decrease of TNFa by urolithin A.

[0017] FIG. 2B is a graph showing the dose-response decrease of TNFa by fisetin.

[0018] FIG. 3 is a graph showing microglial A(342 uptake / clearance in response to cotreatment with urolithin A (Uro) and fisetin, as compared to fisetin alone.

[0019] FIG. 4A is a graph showing toxicity in BV2 microglial cells in response to treatment with urolithin A (Uro) and fisetin (Fis), alone or in combination, as measured using an LDH assay.

[0020] FIG. 4B is a graph showing TNFa levels in BV2 microglial cells in response to treatment with urolithin A (Uro) and fisetin (Fis), alone or in combination, as measured by ELISA.

[0021] FIG. 5 is a graph showing TNFa levels secreted by BV2 microglial cells in response to varying doses of urolithin A and fisetin, alone or in combination.Attorney Docket No : 40978-0774WO1

[0022] FIG. 6A-6E are graphs showing TNFa concentration upon treatment with nicotinamide riboside (#101) at 20 pM. cat's claw (#134) at 34 pg / rnL, urolithin A (#144) at lOpM, fisetin (NP-82) at 5pM or quercetin (NP-162) at 7.5pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0023] FIG. 7A-7C are graphs show ing TNFa concentration upon treatment with nicotinamide riboside (#101) at 20 pM. cat's claw (#134) at 25 pg / mL, urolithin A (#144) at 20pM, fisetin (NP-82) at lOpM or quercetin (NP-162) at 7.5pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0024] FIG. 8 is a graph showing toxicity upon treatment with nicotinamide riboside (#101) at 20pM, cat's claw (#134) at 40pg / mL. urolithin A (#144) at lOpM, fisetin (NP-82) at 5pM or quercetin (NP-162) at 7.5pM, alone or in combination.

[0025] FIG. 9 is a graph showing A(3 uptake upon treatment with nicotinamide riboside (#101) at 20pM, cat's claw (#134) at 40pg / mL, urolithin A (#144) at lOpM, fisetin (NP-82) at 5pM or quercetin (NP-162) at 7.5pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0026] FIG. 10A is a graph showing A(3 uptake upon treatment with cat's claw at 25 pg / mL or 40pg / mL in water or DMSO. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0027] FIG. 10B is a graph showing Af> uptake upon treatment with cat's claw (#134) at 25pg / mL or 40pg / mL in water in combination with urolithin A (#144) at 25pM or 40pM. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0028] FIG. IOC is a graph showing shows A(3 uptake upon treatment with cat's claw (#134) at 25pg / mL or 40pg / mL in DMSO in combination with urolithin A (#144). A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0029] FIG. 11A is a graph showing toxicity upon treatment with nicotinamide riboside (#101) at 20pM, cat's claw (#134) at 30pg / mL, urolithin A (#144) at 20pM, fisetin (NP-82) at lOpM or quercetin (NP-162) at 7.5pM, alone or in combination.Attorney Docket No : 40978-0774WO1

[0030] FIG. 11B-11D are graphs showing TNFa levels upon treatment with urolithin A (#144) at 20pM, fisetin (NP-82) at 7.5pM or quercetin (NP-162) at lOpM, and cat's claw (#134) at 30pg / mL, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0031] FIG. 12A-12F are graphs showing TNFa levels upon treatment with cat's claw (#134) at 30pg / mL, urolithin A (#144) at 20pM. fisetin (NP-82) at 7pM or quercetin (NP-162) at lOpM. alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0032] FIG. 13 -13E are graphs showing TNFa levels upon treatment with nicotinamide riboside (#101) at 25pM, cat's claw (#134) at 30pg / mL, urolithin A (#144) at 20pM, and fisetin (NP-82) at 7 pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0033] FIG. 14A is a graph showing A|3 uptake upon treatment with urolithin A (#144 or # 144 A) at 40pM or ipriflavone (NP- 182) at 20pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0034] FIG. 14B is a graph showing Ap uptake upon treatment with cat's claw (#134) at 30pg / mL, urolithin A (#144 or #144 A) at 40pM or ipriflavone (NP-182) at 20pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0035] FIG. 14C is a graph showing Ap uptake upon treatment with cat's claw (#134) at 30pg / mL, urolithin A (#144 or #144 A) 40pM or ipriflavone (NP-182) at 20pM, alone or in combination. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0036] FIG. 15A is a graph showing toxicity upon treatment with cat's claw (#134) at a range of concentrations, in DMSO or in H2O, as measured using an LDH assay.

[0037] FIG. 15B is a graph showing toxicity upon treatment with cat's claw (#134) at a range of concentrations, in DMSO or in H2O, as measured using a BCA assay.

[0038] FIG. 15C is a graph showing A uptake upon treatment with cat's claw (#134) at a range of concentrations, in DMSO or in H2O. Fluticasone propionate (#7) was used as a positive control. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.Attorney Docket No : 40978-0774WO1

[0039] FIG. 16A is a graph showing Ap uptake upon treatment with cat's claw (#134) at a 25pg / mL or 40pg / mL, in DMSO or in H2O. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0040] FIG. 16B is a graph showing A uptake upon treatment with urolithin A (#144) at 40pg / mL cat's claw (#134) at a 25pg / mL, alone or in combination, in H2O. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0041] FIG. 16C is a graph showing Ap uptake upon treatment with urolithin A (#144) at 40pg / mL cat's claw (#134) at a 25pg / mL, alone or in combination, in DMSO. A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0042] FIG. 17A is a graph showing TNFa concentration upon treatment with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0043] FIG. 17B is a graph showing Ap uptake upon treatment of BV2 cells with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0044] FIG. 17C is a graph showing Ap uptake upon treatment of BV2 cells with vary ing doses of ipriflavone (NP-182).

[0045] FIG. 17D is a graph showing Ap uptake upon treatment of P2D3 cells with varying doses of ipriflavone (NP-182). A greater number of stars indicates a greater statistical significance, "ns" indicates a difference that is not statistically significant.

[0046] FIG. 17E is a graph showing Ap uptake upon treatment of P2D3 cells with varying doses of ipriflavone (NP-182).

[0047] FIG. 18A is a graph summarizing observations of behavior (from left to right: hyperactivity, distance, rearings (size), rearings (number), and number of fecal boli) in Open Field testing of test animals, presented in order from left to right for each observation: wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B). and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0048] FIG. 18B is a graph summarizing observations of behavior (activity, left, and thigmotaxis, right) in Open Field testing of test animals, presented in order from left to right for each observation: wild type control group treated with vehicle (group A), a 5xFAD mutatedAttorney Docket No : 40978-0774WO1 group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin. and quercetin (group I).

[0049] FIG. 19 is a graph summarizing observations of nest building behavior for animals of a wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0050] FIG. 20 is a pair of graphs summarizing observations in Morris Water Maze testing of test animals, including number of target zone crossings during the probe trial (top) and abidance in target quadrant during the probe trial (bottom), and abidance in each quadrant (NE quadrant was target quadrant). In each panel, data is presented for each treatment group from left to right in the following order: wild type control group treated with vehicle (group A); a 5xFAD mutated group treated with vehicle (group B); and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I).

[0051] FIGs. 21A-21B are graphs providing measurements of TNF-a levels in cortex and hippocampus samples (results from cortex and hippocampus samples are paired with cortex on the left and hippocampus on the right) obtained from animals of wild type control group treated with vehicle (group A), a 5xFAD mutated group treated with vehicle (group B), and a 5xFAD mutated group treated with ipriflavone, urolithin A, fisetin, and quercetin (group I). *p<0.05 relative to group B, **p<0.01 relative to group B, ***p<0.001 relative to group B.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0052] The provided disclosure provides, among other things compositions useful for treatment or prevention of neurodegenerative disorders such as those described herein. In some embodiments, provided methods comprise administering to a subject a urolithin A agent, a fisetin agent, and an isoflavone agent. The present disclosure further encompasses the surprising discovery that combinations of a urolithin A agent, a fisetin agent, and an isoflavone agent exhibit particular synergistic features with respect to amyloid (3 uptake and inflammatory cytokine production. Such unexpected benefits are particularly useful for the treatment of neurodegenerative diseases, disorders, and conditions, including, for example, Alzheimer’s Diseases.DefinitionsAttorney Docket No : 40978-0774WO1

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The methods and materials described herein are exemplary, and methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0054] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherw ise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0055] Certain ranges are presented herein with numerical values being preceded by the term “about”. The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0056] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, Ci-s, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0057] The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at leastAttorney Docket No : 40978-0774WO1 one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0058] The term ‘‘alkoxy’’ refers to the group — O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy.

[0059]

[0060] The term “aryl” refers to an optionally substituted monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-C ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a nonaromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include

[0061] As used herein, the term “cycloalkyd” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0062] The term “halogen” or “halo” means F, Cl, Br, or I.

[0063] Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

[0064]

[0065] Neurodegenerative Disorders

[0066] Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. Although there are several medicines currently approved for managing neurodegenerative diseases, a large majority of them only help with associated symptoms. Neurodegenerative diseases such as Alzheimer’s disease and dementia continue to be a clinical concern in most older people.Attorney Docket No : 40978-0774WO1

[0067] Amyloid beta (AP) plaque accumulation is considered one of the key drivers of Alzheimer’s disease pathophysiology. A elimination can be triggered by selectively activating microglia-mediated Ap clearance. However, chronic and excessive reactive microgliosis (a process of expansion and activation of microglia) can also be detrimental in brain disorders such as Alzheimer’s disease. For example, reactive microglia secrete pro-inflammatory cytokines, which induce astrogliosis, and contribute to brain cell death during late stages of Alzheimer’s disease. Common anti-inflammatory drugs have been tested in Alzheimer’s disease patients, but their efficacy in reducing reactive microgliosis has not been proven.

[0068] Applicant has discovered that the combination of a urolithin A agent, a fisetin agent, and an isoflavone agent demonstrate a synergistic effect in treating or preventing neurodegenerative diseases in subjects in need thereof. Surprisingly, Applicant has discovered that the combination of a urolithin A agent, a fisetin agent, and an isoflavone agent can concomitantly promote microglial Ap clearance and reduce pathogenic microglial pro- inflammatory activation. Described combination therapy solves problems associated with previous therapies (in particular the failure to achieve both promotion of microglial Ap clearance and reduction of pathogenic microglial pro-inflammatory activation). Applicant has also discovered that nicotinamide riboside, quercetin and cat’s claw extracts have beneficial effects in promoting microglial Ap clearance and reduce pathogenic microglial pro- inflammatory activation. Such additional agents (e.g.. nicotinamide riboside, quercetin and cat’s claw extracts) can be combined with administration of a urolithin A agent, a fisetin agent, and a isoflavone agent to treat or prevent neurodegenerative diseases, disorders, or conditions.

[0069] Applicant has surprisingly discovered that, while each of a urolithin A agent, a fisetin agent, and / or an isoflavone agent may provide some benefit in isolation for promoting microglial Ap clearance or reducing pathogenic microglial pro-inflammatory activation, when the agents are combined, both of these effects are promoted in a manner that is more than simply additive. The effect of promoting microglial Ap clearance can be illustrated through the measurement of Ap concentration in particular assays, such as those described in Examples 1 and 2. Further, the effect of reducing pathogenic microglial pro-inflammatory activation can be illustrated through the measurement of TNFa concentration in particular assays, such as those described in Examples 1 and 2. As illustrated in these Examples, when comparing the impact of a urolithin A agent, a fisetin agent, and / or an isoflavone agent on one or both of promoting microglial Ap clearance or reducing pathogenic microglial pro-inflammatoryAttorney Docket No : 40978-0774WO1 activation, Applicant has demonstrated that this combination of agents is surprisingly synergistic, having an effect that is more than simply additive.

[0070] Without wishing to be bound by theory, it is understood that this synergistic effect of a urolithin A agent, a fisetin agent, and an isoflavone agent, when used in combination to promote microglial A|3 clearance and reduce pathogenic microglial pro-inflammatory activation, is useful for the treatment of neurodegenerative disorders, and in particular achieve beneficial effects where other treatments to date have failed. As used herein, the terms “synergy’’ or “synergies” refers to the effect that two or more agents have that is more than simply additive. That is, the effect observed when two or more agents are used is greater than when the agents are used in isolation or in other combinations. In some embodiments, synergies are measured quantitatively, such as by an assay described herein. In some embodiments, synergies may not show a quantitative change, but an overall improvement in, for example, treatment or prevention of a particular disease, disorder, or condition, is improved, relative to administration of an agent alone.

[0071] Accordingly, the present disclosure provides methods of treating or preventing (e.g.. treating) neurodegenerative diseases comprising administering to the subject a urohthin A agent, a fisetin agent, and an isoflavone agent.

[0072] In some embodiments, the present disclosure provides methods of treating or preventing a symptom or feature associated with a neurodegenerative disease. In some embodiments, a symptom or feature of a neurodegenerative disease is memory loss, cognitive decline, brain fog, increased Ap plaque production and / or increased A plaque levels. In some embodiments, a symptom or feature of a neurodegenerative disease is memory’ loss. In some embodiments, a symptom or feature of a neurodegenerative disease is brain fog. In some embodiments, a symptom or feature of a neurodegenerative disease is increased Ap plaque production. In some embodiments, a symptom or feature of a neurodegenerative disease is increased Ap plaque levels.

[0073] In some embodiments, the present disclosure provides methods of treating or preventing brain fog. In some embodiments, brain fog is not associated with any particular clinical disease, disorder, or condition. In some embodiments, brain fog is associated with lack of sleep, stress, and the like. Without wishing to be bound by any particular theory, the present disclosure proposes that provided combination(s) (e.g., that comprise and / or deliver a urohthin A agent, a fisetin agent, and / or an isoflavone agent, and optionally one or more additional agents), may be particularly useful and / or effective to alleviate or improve brain fog. AsAttorney Docket No : 40978-0774WO1 described herein, brain fog can refer to confusion, forgetfulness, lack of focus, lack of mental clarity, and the like.

[0074] In some embodiments, the present disclosure provides methods of treating, preventing, or decreasing neuroinflammation. In some embodiments, neuroinflammation can be caused by or associated with neurodegenerative disorders (e.g., those described herein), other diseases, disorders, and conditions, such as viral infection, autoimmune disorders, mental stress (e.g.. stress caused from overworking, lack of sleep, and the like), metabolic disorders, and injury, or aging. In some embodiments, neuroinflammation is caused by or associated with a viral infection. In some embodiments, a viral infection is a SARS-CoV-2 infection. In some embodiments neuroinflammation is characterized by microglia activation in the subject. In some embodiments, the present disclosure provides a method of treating, preventing, or decreasing neuroinflammation in a subject comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure provides a method of treating, preventing, or decreasing neuroinflammation in a subject comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent in combination with one or more additional components descnbed herein.

[0075] Also contemplated herein are methods of treating or preventing (e g., treating) neurodegenerative diseases in a subject in need thereof, comprising administering to the subject a urolithin A precursor, e.g., ellagi tannin or ellagic acid in combination with a fisetin agent and an isoflavone agent, wherein the method can further include determining or having determined that the subject is capable of metabolizing ellagitannin or ellagic acid into urolithin A.

[0076] Also provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof, comprising administering to the subject an ellagitannin or ellagic acid, in combination with a fisetin agent and an isoflavone agent, and one or more bacterial species that are associated with urolithin A production.Urolithin A Agents

[0077] Urolithin A agents can be utilized for the treating or preventing (e g., treating) of neurodegenerative diseases as disclosed herein.

[0078] In some embodiments, the urolithin A agents have a structure of Formula I:Attorney Docket No : 40978-0774WO1Formula I or a pharmaceutically acceptable salt thereof, whereinR1is -H, -OH, or -OR4;R2is -H, -OH, -OR4, -NH2, -NHR4, -SH, -SR4, -F, -Cl, -Br, -CN, -OCN, -O(CH2)nNH2, -O(CH2)nCH3, -Ci to Cio alkyl, C3-C6cycloalkyl, -C6to Ci2aiyl, -SOCH3, -SO2, -ONO2, -NO2, and -N3;R3is -H, -OH, or -OR4;R4is a Ci to Cio alkyl;R5is -H or -OR4; n is from 1 to 10, wherein each alkyl, cycloalkyl, and aryl ofR2is optionally substituted with one or more substituents selected from halogen, Ci to Cio alkyl, C3to Cs cycloalkyl, and Ce to C12 aryl.In some embodiments of Formula I, R1is -H, R2is -OH, R3is -OH, and R5is -H.In some embodiments, the urolithin A agent is urolithin A:or a pharmaceutically acceptable salt thereof.

[0079] Urolithin A (3,8-dihydroxy-6 / 7-benzo[b,d]pyran-6-one) is produced, e.g., as a metabolite resulting from the transformation of ellagitannins by the gut bacterial. Ellagitannins are hydrolyzed in the gut to release ellagic acid, which in turn, is further processed by the gut microflora into urolithins. Urolithin A is commercially available (see, e.g., Sigma-Aldrich, SML1791) and can also be obtained by methods known to the skilled artisan.Attorney Docket No : 40978-0774WO1

[0080] In some embodiments, urolithin A is obtained from natural sources, including, for example, nuts, berries and pomegranate using conventional isolation methods.

[0081] In other embodiments, urolithin A is synthesized using conventional organic synthesis methods. For example, urolithin A can be prepared by combining in an alkaline aqueous solution the following starting materials and reagents: a copper-containing catalyst, 2-bromo-5 -hydroxy benzoic acid, and resorcinol, which produces the salt of urolithin A, followed by protonating such salt of urolithin A to yield urolithin A. (See. e.g. WO2019168972).

[0082] In some embodiments, a urolithin A agent is not urolithin A, but is instead a urolithin A analog. As described herein, a urolithin A analog is one represented by Formula I, wherein R1is not -H, R2is not -OH. R3is not -OH, and R5is not -H. As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity7with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete way(s). In some embodiments, an analog is a substance that can be generated from the reference substance, e.g.. by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0083] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof. R1is -H, R2is -OH, R3is -H, and R5is -H.

[0084] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -H, R2is -OCH?, R3is -H, and R5is -H.

[0085] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -OH, R2is -OH, R3is -H, and R5is -H.

[0086] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof. R1is -OCH3. R2is -OCH3, R3is -H. and R5is -H.

[0087] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -H, R2is -OH, R3is -OH, and R5is -H.

[0088] In some embodiments of the compound of Fomiula I, or a pharmaceutically acceptable salt thereof. R1is -H. R2is -OCH3. R3is -OCH3. and R5is -H.Attorney Docket No : 40978-0774WO1

[0089] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof. R1is -OH, R2is -OH, R3is -OCH3, and R5is -OCH3.

[0090] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -H, R2is -OH, R3is -OCH3, and R5is -H.

[0091] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof. R1is -OH, R2is -OH, R3is -OH, and R5is -H.

[0092] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -OCH3, R2is -OCH3, R3is -OCH3, and R5is -H.

[0093] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof. R1is -H, R2is -OH, R3is -OCH3, and R5is -OCH3.

[0094] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1is -OH, R2is -OH, R3is -OCH3, and R5is -H.

[0095] In some embodiments, a urolithin A agent is one described in Noshadi, B., et al., Chem. Biodiversity 2020, 17, e2000197, which is incorporated herein by reference in its entirety.

[0096] In some embodiments, urolithin A agents include, but are not limited to:

[0097] (8-Hydroxy-6-oxo-6H-benzo [c]chromen-3-yl (tert butoxycarbonyl)tryptophanate) with the structure, dibenzo[b,d]pyran-6-one,3-Methoxy-6H-benzo[c]chromen-6-one(=3-Methoxy-6H- dibenzo[b,d]pyran-6-one, l,3-Dihydroxy-6H-benzo[c]chromen-6-one(=l,3-Dihydroxy-6H- dibenzo[b,d]pyran-6-one, l,3-Dimethoxy-6H-benzo[c]chromen-6-one(=l,3-Dimethoxy-6H- dibenzo[b,d]pyran-6-one, 3,8-Dimethoxy-6H-benzo[c]chromen-6-one(=3,8-Dimethoxy-6H- dibenzo[b,d]pyran-6-one, l .3-Dihydroxy-8.9-dimethoxy-6H-benzo|c|chromen-6-one(=l .3-Dihydroxy-8,9-dimethoxy-6H-dibenzo[b,d]pyran-6-one, 3-Hydroxy-8-methoxy-6H- benzo[c]chromen-6-one(=3-Hydroxy-8-methoxy-6H-dibenzo[b,d]pyran-6-one, 1,3,8-Attorney Docket No : 40978-0774WO1Trihydroxy-6H-benzo[c]chromen-6-one(=l,3,8-Trihydroxy-6H-dibenzo[b,d]pyran-6-one, l,3,8-Trimethoxy-6H-benzo[c]chromen-6-one (=l .3.8-Trimethoxy-6H-dibenzo|b.d|pyran-6- one, 3-Hydroxy-8,9-dimethoxy-6H-benzo[c]chromen-6-one (=3-Hydroxy-8,9-dimethoxy-6H- dibenzo[b,d]pyran-6-one, l,3-Dihydroxy-8-methoxy-6H-benzo[c]chromen-6-one(=l,3- Dihydroxy-8-methoxy-6H-dibenzo[b,d]pyran-6-one, urolithin A-glucuronide, urolithin A- sulfate, and urolithin A-aglycone, and methylated urolithin A.

[0099] In some embodiments, urolithin A precursors, or analogs or metabolites thereof, may be utilized in accordance with the present disclosure. In some embodiments, the present disclosure encompasses methods of delivering a urolithin A agent to a subject via a precursor, analog, or metabolite.

[0100] In some embodiments, the precursor of urolithin A include ellagitannins and ellagic acid. In some embodiments, an analog or metabolite of an ellagitannin or ellagic acid, may be useful in accordance with the present disclosure. Those skilled in the art will be aware of a variety of analogs or metabolites of ellagitannins or ellagic acid. Ellagitannins useful for the present disclosure can include monomeric ellagitannins, C-glycosidic ellagitannins with an open-chain glucose core, condensates of C-glycosidic tannins with flavan-3-ol (complex tannin), and oligomers which are produced through intermolecular C-0 or C-C bonds between monomers. Exemplary7ellagitannins include punicalagin, sanguiin H6, lambertianin C, pedunculagin, vescalagin, castalagin, casuarictin and potentillin.

[0101] In some embodiments, one or more urolithin A precursors, e.g., ellagitannins or ellagic acid, or their analogs and metabolites are administered to urolithin A producers, which are individuals that are capable of metabolizing ellagitannins or ellagic acid into urolithin A. For example, some individuals are able to produce urolithin A via their gut bacteria while others can also produce Isourolithin A and urolithin B. Bacterial species that are associated with urolithin A production are known in the art. For example, bacterial species belonging to the Clostridiales and Ruminococcaceae family, and Gordonibacter urolithinfaciens , Ellagibacter isourolithinifaciens, and Akkermansia muciniphilia have been known to show' increased abundance in urolithin A producers. Accordingly, the present disclosure also provides methods comprising administering ellagitannins and / or ellagic acid to a subject where the methods can further include determining or having determined that the subject is a urolithin A producer. Subjects can be determined to be urolithin A producers via analysis of their gut microbiota through blood, urine or fecal samples and detection of one or more bacterial species associated with urolithin A production.Attorney Docket No : 40978-0774WO1Fisetin Agents

[0102] Fisetin agents can be utilized for the treating or preventing (e.g., treating) of neurodegenerative diseases as disclosed herein. Fisetin (3,3',4',7-tetrahydroxyflavone) is a plant flavonol from the flavonoid group of polyphenols and has the following structure:

[0103] Fisetin is commercially available (see, e.g., Sigma-Aldrich, PHL82542) and can be obtained by methods known to the skilled artisan.In some embodiments, a fisetin agent has a structure of Formula II:or a pharmaceutically acceptable salt thereof, whereinR7is H, CF3, OCH3, Cl, Br;R8is H, CF3. OH, OCH3. F, Cl, Br, or t-Bu;R9is H, CF3, Cl, Br, OH, Ci to G, alkoxy, C3to G, cycloalkyl. Ci to G alkyl, or SCF3;R10is H, OH, CF3, CI to Cg alkoxy, C3to Ce cycloalkyl, or Ci to Ce alkyd;R11is H or NO2;R12is H, CH3, OH. OCH3, Cl or Br;R13is H, CH3, F, Cl or Br; andR14is H or OH.In some embodiments of the compound of Formula II, or a pharmaceutically acceptable salt thereof,Attorney Docket No : 40978-0774WO1R7is H, CF3, OCH3, Cl, Br;R8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu;R9is H, CF3, Cl, Br, OH, Ci to C6 alkoxy, C3to C6 cycloalkyl, Ci to Ce alkyl, or SCF3;R10is H, CF3, CI to Ce alkoxy, C3to Ce cycloalkyl, or Ci to Ce alkyd;R11is H or NCh;R12is H, CH3, OH, OCH3, Cl or Br;R13is H, CH3, F. Cl or Br; andR14is H or OH.In some embodiments, a fisetin agent is fisetin, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, fisetin is obtained from natural sources, including from fruits and vegetables, such as strawberry, apple, persimmon, grape, onion and cucumber.

[0105] In other embodiments, fisetin is synthesized using conventional organic synthesis methods. For example, fisetin can be prepared using methods described in Giynkiewicz and Demchuk, New Perspectives for Fisetin. Front. Chem. 7:697 (2019).

[0106] In some embodiments, the fisetin agent is quercetin, or a pharmaceutically acceptable salt thereof.

[0107] Quercetin (3,3’,4’,5,7-pentahydroxyflavone) is an antioxidant flavonoid and has the following structure:

[0108] Quercetin is commercially available and can be obtained by methods known to the skilled artisan.

[0109] In some embodiments, quercetin is obtained from natural sources, including from fruits and vegetables, such as apples, onions, grapes, berries, cherries, broccoli, and citrus fruits.

[0110] In some embodiments, a fisetin agent has a structure of Formula Ila:Attorney Docket No : 40978-0774WO1Formula Ila wherein R9is H, Ci to Cg alkoxy, or C3 to Cg cycloalkylR10is H, OH, Ci to Cg alkoxy, or C3 to Cg cycloalkyl .[OlH] In some embodiments, a fisetin agent is one described in US11591305B2, which is incorporated herein by reference in its entirety.

[0112] In some embodiments, a fisetin agent is a glucuronide conjugate of fisetin or 3'- methoxylated metabolite of fisetin (e g. geraldol).

[0113] In some embodiments, a fisetin agent is a sulfate conjugate of fisetin.

[0114] In some embodiments, a fisetin agent has a structure of Formula lib:or a pharmaceutically acceptable salt thereof, whereinR7is H, CF3, OCH3, Cl, Br;R8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu;R9is H, CF3, Cl, Br, OH, Ci to Cg alkoxy, C3 to Cg cycloalkyl, Ci to Cg alkyl, or SCF3; andR10is H, CF3, Ci to Cg alkoxy. C3 to Cg cycloalkyl, or Ci to Cg alkyl.In some embodiments of the compound of Formula lib, or a pharmaceuticallyAttorney Docket No : 40978-0774WO1 acceptable salt thereof. R7is H, R8is H, R9is H, and R10is H.

[0115] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof R7is H, R8is OCH3, R9is H, and R10is H.

[0116] In some embodiments of the compound of Formula Uh, or a pharmaceutically acceptable salt thereof, R7is H, R8is H, R9is SCF3, and R10is H.

[0117] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof. R7is Cl. R8is H, R9is Br. and R10is H.

[0118] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof, R7is CF3, R8is H, R9is CF3, and R10is H.

[0119] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof. R7is H, R8is CF3. R9is H, and R10is CF3.

[0120] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof, R7is H, R8is H, R9is OBn, and R10is H.

[0121] In some embodiments of the compound of Formula lib, or a pharmaceutically acceptable salt thereof. R7is OCH3, R8is H. R9is OCH3, and R10is OCH3.

[0122] In some embodiments, the fisetin agent has a structure of Formula lie:or a pharmaceutically acceptable salt thereof, whereinR8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu;R9is H, CF3, Cl, Br, OH. Ci to Cg alkoxy, C3 to Cg cycloalkyl, Ci to Cg alkyl, or SCF3; andR10is H, CF3, Ci to Cg alkoxy, C3 to Cg cycloalkyl, or Ci to Cg alkyl.In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof. R8is H, R9is Cl, and R10is H.In some embodiments of the compound of Formula lie. or a pharmaceuticallyAttorney Docket No : 40978-0774WO1 acceptable salt thereof. R8is H, R9is OCH3. and R10is H.

[0123] In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof, R8is Br, R9is OCH3, and R10is OCH3.

[0124] In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof, R8is H, R9is H, and R10is t-Bu.

[0125] In some embodiments, the fisetin agent has a structure of Formula lid:Formula lid or a pharmaceutically acceptable salt thereof, wherein R9is H, CFs, Cl, Br, OH, Ci to Ce alkoxy, C3 to Ce cycloalkyl, Ci to Ce alkyl, or SCF3.

[0126] In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof. R9is Br.

[0127] In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof, R9is t-Bu.

[0128] In some embodiments, the fisetin agent has a structure of Formula lie:or a pharmaceutically acceptable salt thereof, whereinR7is H, CF3, OCH3, Cl, Br;R8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu;Attorney Docket No : 40978-0774WO1R9is H. CF3, Cl, Br, OH, Ci to Cg alkoxy, C3 to Cg cycloalkyl, Ci to Cg alkyl, or SCF3;R10is H, OH. CF3, Ci to Ce alkoxy, C3 to Cg cycloalkyl, or Ci to Cg alkyl; andR12is H, CH3, OH, OCH3, Cl or Br.In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof, R7is H, R8is H, R9is H, R10is H, and R12is Br.In some embodiments of the compound of Formula lie. or a pharmaceutically acceptable salt thereof. R7is H, R8is OCH3. R9is H, R10is H, and R12is Br.In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof, R7is H, R8is F, R9is OEt, R10is H, and R12is Cl.In some embodiments of the compound of Formula lie, or a pharmaceutically acceptable salt thereof. R7is OCH3, R8is H. R9is OCH3, R10is OCH3, and R12is Cl.In some embodiments, a fisetin agent has a structure of Formula Ilf:or a pharmaceutically acceptable salt thereof, whereinR8is H, CF3, OH, OCH3, F, Cl, Br, or t-Bu;R9is H, CF3, Cl, Br, OH. Ci to Cg alkoxy, C3 to Ce cycloalkyl, Ci to Ce alkyl, or SCF3;R10is H, OH. CF3, Ci to Cg alkoxy, C3 to Cg cycloalkyl, or Ci to Cg alkyl; andR13is H, CH3, F, Cl or Br.In some embodiments of the compound of Formula Ilf, or a pharmaceutically acceptable salt thereof. R8is H, R9is OCH3. R10is OCH3. and R13is Br.In some embodiments of the compound of Formula Ilf. or a pharmaceutically acceptable salt thereof, R8is H, R9is Cl, R10is H, and R13is F.In some embodiments of the compound of Formula Ilf, or a pharmaceutically acceptable salt thereof, R8is OCH3, R9is OCH3, R10is OCH3, and R13is F.In some embodiments, the fisetin agent has a structure of Formula Ilg:Attorney Docket No : 40978-0774WO1or a pharmaceutically acceptable salt thereof, wherein R9is H, CF3, Cl, Br, OH, Ci to Ce alkoxy, C3 to Cg cycloalkyl, Ci to Ce alkyl, or SCF3.

[0129] In some embodiments of the compound of Formula Ilg, or a pharmaceutically acceptable salt thereof, R9is t-Bu.

[0130] In some embodiments of the compound of Formula Ilg, or a pharmaceutically acceptable salt thereof. R9is OBn.

[0131] In some embodiments, the fisetin agent has a structure of Formula Hh:or a pharmaceutically acceptable salt thereof.

[0132] As described herein, reference to a fisetin agent is intended to refer to one or two fisetin agents are administered in combination with a urolithin A agent and an isoflavone agent, unless specified otherwise. For example, in some embodiments, a method described herein comprises administration of a urolithin A agent, a first fisetin agent, a second fisetin agent, and an isoflavone agent. In some embodiments, a method described herein comprises administration of a urolithin A agent, a first fisetin agent that is fisetin. a second fisetin agent that is quercetin, and an isoflavone agent. In some embodiments, the present disclosure further encompasses compositions comprising one or two fisetin agents. For example, in some embodiments, the present disclosure provides a composition comprising a urolithin A agent, a first fisetin agent, a second fisetin agent, and an isoflavone agent. In some embodiments, theAttorney Docket No : 40978-0774WO1 present disclosure provides a composition comprising a urolithin A agent a first fisetin agent that is fisetin, a second fisetin agent that is quercetin, and an isoflavone agent.Isoflavone Agents

[0133] Isoflavone agents can be utilized for the treating or preventing (e.g., treating) of neurodegenerative diseases as disclosed herein. In some embodiments, an isoflavone agent is represented by Formula III:or a pharmaceutically acceptable salt thereof, wherein Rl ais H. OH, CF3, Ci to Ce alkoxy, C3 to Ce cycloalkyl, or Ci to Ce alkyl. In some embodiments, an isoflavone agent of Formula III is represented by Formula III- A:III-A or a pharmaceutically acceptable salt thereof, wherein Rlais H, OH, CF3, Ci to Ce alkoxy, C3 to Ce cycloalkyl, or Ci to Ce alkyl.

[0134] In some embodiments. Rlais H. OH, or Ci to Ce alkoxy. In some embodiments. Rlais H. In some embodiments, Rlais OH. In some embodiments, Rlais Ci to Ce alkoxy. In some embodiments, Rlais -O-C(H)(CH3)2.

[0135] In some embodiments, an isoflavone agent is ipriflavone:or a pharmaceutically acceptable salt thereof. Ipriflavone is a synthetic isoflavone that is also sold under the brand name Yambolap.Nicotinamide RibosideAttorney Docket No : 40978-0774WO1

[0136] Nicotinamide riboside or a pharmaceutically acceptable salt thereof can be utilized for the treating or preventing (e.g.. treating) of neurodegenerative diseases as disclosed herein.

[0137] Nicotinamide riboside is a member of the Vitamin B3 family and has the following structure:

[0138] Nicotinamide riboside is an NAD1precursor, which is an essential coenzyme that plays important roles in various metabolic pathways. The importance of NAD+is reflected through the activity of NAD+-depleting enzy mes, the mediators of aging, which are mostly induced by stress factors, such as DNA damage, oxidative stress, and inflammation.Pharmaceutically acceptable salts of nicotinamide riboside include, e.g., nicotinamide-P-d-riboside chloride, nicotinamide-P-d-riboside bromide, thionicotinamide-P-d- riboside bromide, nicotinamide-P-d-riboside triacetate bromide, and thionicotinamide-P-d- riboside triacetate bromide.

[0139] Nicotinamide riboside or pharmaceutically acceptable salts thereof are commercially available (e.g., Tru Niagen®) and can be obtained by methods known to the skilled artisan.Cat ’s claw

[0140] Cat’s claw (Uncaria tomentosa) is a woody vine that can be found in the Amazon rain forest. Cat’s claw extracts or components thereof can be utilized for the treating or preventing (e.g., treating) of neurodegenerative diseases as disclosed herein.

[0141] Cat’s claw extracts can be prepared from cat’s claw bark using conventional extraction methods. For example, the extraction process can involve use of 70% ethanol / distilled water at a ratio of 5: 1. Components from cat’s claw extracts can be isolated using conventional methods, including, e.g., affinity fractionation and high-pressure liquidAttorney Docket No : 40978-0774WO1 chromatography (HPLC). The methods can also include assessment of the purity of the individual components using HPLC, mass spectroscopy and / or nuclear magnetic resonance (NMR) spectroscopy. The identity of individual components can be assessed using HPLC, -ve ion electrospray mass spectroscopy (relative intensity of the molecular ion given as a percentage), fourier transfer mass spectroscopy, ultraviolet spectroscopy,1H NMR,13C NMR, electrospray ionization time-of-flight mass spectroscopy (ESI-TOF), electron impact (El) initiated mass spectroscopy, fast atom bombardment (FAB) mass spectroscopy, homonuclear correlation spectroscopy (COSY), constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation spectroscopy (CIGAR) and / or heteronuclear correlation spectroscopy (HETCOR).

[0142] In some embodiments, the cat's claw component is a polyphenol. In some embodiments, the cat’s claw component is epicatechin dimers and variants thereof (known as proanthocyanidins). For example, the cat’s claw component can be proanthocyanidin B2 (epicatechin-4B-8-epicatechin), proanthocyanidin B4 (i.e. catechin-4a 8-epicatechin), proanthocyanidin Cl (i.e. epicatechin-40^ 8-epicatechin-40 8-epicatechin). In some embodiments, the cat’s claw component is an epicatechin tnmer (i.e. epicatechin-40 8- epicatechin-40 — > 8-epicatechin), epiafzelechin-40 8-epicatechin, or an epi catechin tetramer (i.e. epicatechin-40 — > 8-epicatechin-40 — >• 8-epicatechin-40 — ► 8-epicatechin). In some embodiments, the cat’s claw extract is PTI-00703 (Percepta).Methods of Treatment

[0143] Provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof by administering or otherwise delivering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent either individually or in combination. In some embodiments, the present disclosure provides a method of reducing pathogenic microglial pro-infl ammatory activation in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure provides a method of promoting microglial A0 clearance in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent. In some embodiments, the present disclosure provides a method of reducing pathogenic microglial pro-inflammatory activation and promoting microglial A0 clearance in a subject, the method comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent.Attorney Docket No : 40978-0774WO1

[0144] Thus, among other things, the present disclosure documents that provided technologies (e.g., combinations of a urolithin A agent, a fisetin agent, and an isoflavone agent) achieve reduction in inflammation, including specifically of microglial inflammation. In some embodiments, the present disclosure documents that such provided technologies reduce pro- inflammatory activation, e.g., microglial pro-inflammatory activation, specifically including pathogenic microglial pro-inflammatory activation.

[0145] In some embodiments, provided methods involve combination therapy with at least a urolithin A agent, a fisetin agent, and an isoflavone agent. Those skilled in the art will appreciate that combination therapy (e.g., a urolithin A agent, a fisetin agent, and an isoflavone agent combination therapy) involves delivery' of one or more of a plurality of agents to a subject, so that the subject is exposed to all of them. In some embodiments, each agent of the combination is administered or otherwise delivered to the subject. In some embodiments, one or more agents is administered or otherwise delivered to a subject who has already received, is receiving, or will receive (e.g., via an overlapping administration regimen) the remaining agent(s) of the combination.

[0146] In some embodiments, combination therapy involves administration of one or more pharmaceutical compositions as described herein (i.e., that comprise and / or otherwise deliver a relevant agent as described herein), each of which comprises and / or delivers one or more agent(s) of a combination. In some embodiments, different agent(s) are delivered from different pharmaceutical compositions (i.e., from distinct dosage forms). In some embodiments, each agent is delivered as part of a single combination dose (e.g., from a single dosage form).

[0147] In some embodiments, provided methods include administration or other delivery of one or more agents in addition to urolithin A agents, fisetin agents, and isoflavone agents. In some embodiments, such one or more additional agents is selected from nicotinamide riboside or a pharmaceutically acceptable salt thereof, and cat’s claw extracts or components thereof. As used herein, reference to urolithin A agents, fisetin agents, and / or isoflavone agents is intended to refer to one or more agents of each category’ of agents, as described herein. For example, reference to “urolithin A agents” is intended to refer to one or more urolithin A agents. Similarly, reference to fisetin agents or isoflavone agents is intended to refer to one or more of fisetin agents or isoflavone agents, respectively.

[0148] In some embodiments, provided methods include administering a combination of urolithin A agents, fisetin agents, and isoflavone agents. In some embodiments, providedAttorney Docket No : 40978-0774WO1 methods include administering a combination of urolithin A agents, fisetin agents, isoflavone agents, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of urolithin A agents, fisetin agents, isoflavone agents, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of urolithin A agents, fisetin agents, isoflavone agents, nicotinamide riboside or a pharmaceutically acceptable salt thereof and a cat’s claw extract or component thereof.

[0149] In some embodiments, provided methods include administering a combination of urolithin A, fisetin, quercetin, and ipriflavone. In some embodiments, provided methods include administering a combination of urolithin A, fisetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of urolithin A, fisetin, quercetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of urolithin A, fisetin, quercetin, ipriflavone, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of urolithin A, fisetin, ipriflavone, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of urolithin A, fisetin, quercetin, ipriflavone. nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof.

[0150] Also provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof, comprising administering or otherwise delivering to the subject an ellagitannin or ellagic acid, or an analog or metabolite thereof, alone or in combination with a fisetin agent and an isoflavone agent, wherein the method can further include determining or having determined that the subject is a urolithin A producer. In some embodiments, provided methods include administration or other delivery of one or more agents in addition to an ellagitannin or ellagic acid, or an analog or metabolite thereof and fisetin agents and isoflavone agents. In some embodiments, such one or more additional agents is one or both of nicotinamide riboside or pharmaceutically acceptable salts thereof, and cat’s claw extracts or components thereof.

[0151] In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, and isoflavone agents. In some embodiments, provided methods include administering a combination of anAttorney Docket No : 40978-0774WO1 ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, isoflavone agents, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, isoflavone agents, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, isoflavone agents, nicotinamide riboside or a pharmaceutically acceptable salt thereof and a cat’s claw extract or component thereof.

[0152] In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, and ipriflavone. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin. quercetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, ipriflavone, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, ipriflavone, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof.

[0153] The present disclosure also provides methods of treating neurodegenerative diseases in a subject, comprising administering or otherwise delivering to the subject an ellagitannin or ellagic acid, or an analog or metabolite thereof, alone or in combination with a fisetin agent and an isoflavone agent, where the method can further include administering a composition comprising one or more bacterial species that are associated with urolithin A production. In some embodiments, provided methods include administration or other delivery of one or more agents in addition to an ellagitannin or ellagic acid, or an analog or metabolite thereof and fisetin agents and isoflavone agents. In some embodiments, such one or moreAttorney Docket No : 40978-0774WO1 additional agents is one or both of nicotinamide riboside or pharmaceutically acceptable salts thereof, and cat's claw extracts or components thereof.

[0154] In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof and fisetin agents and isoflavone agents. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, isoflavone agents, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, isoflavone agents, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin agents, nicotinamide riboside or a pharmaceutically acceptable salt thereof and a cat’s claw extract or component thereof. For example, in some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, and ipriflavone. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, ipriflavone, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, ipriflavone, and nicotinamide riboside or a pharmaceutically acceptable salt thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, ipriflavone, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof. In some embodiments, provided methods include administering a combination of an ellagitannin or ellagic acid, or an analog or metabolite thereof, fisetin, quercetin, ipriflavone, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof.

[0155] Also provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof by administering or otherwise delivering to the subject a urolithin A agent, a fisetin agent, an isoflavone agent, and one orAttorney Docket No : 40978-0774WO1 both of nicotinamide riboside or a pharmaceutically acceptable salt thereof, and a cat’s claw extract or component thereof.

[0156] Non-limiting examples of neurodegenerative diseases that can be treated or prevented using the methods disclosed herein include Alzheimer’s disease (AD), Parkinson's disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), spinocerebellar ataxia (e.g.. type 1, ty pe 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease. Alper's disease, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, SteeleRichardson-Olszewski disease, and Tabes dorsalis.

[0157] As is understood by those skilled in the art, effective prevention can involve delay of onset (e.g., of expected onset, as may be determined, for example, based on genetic, lifestyle, biomarker, or other factor(s)) of one or more features of a relevant disease, disorder or condition (e.g, of a neurodegenerative disease, as described herein); effective treatment can involve delay of onset (e.g., of expected onset) and / or reduction in frequency and / or severity of one or more such features.

[0158] Methods described in the present disclosure can include treatment of a disease or disorder per se, as well as treatment for one or more symptoms of the disease or disorder. “Treating” a disease does not require 100% abolition of the disease or disease symptoms in the subject. In some embodiments, treatment achieves relief or reduction in severity of one or more symptoms or features of the disease; typically, relevant relief or reduction is determined, for example, by a significant effect in an appropriate system (e.g., a model system) and / or an appropriate population (e.g, of human subjects or of animal models). In some embodiments, a composition described herein shown to be effective in preventing or reducing cognitive decline as evidenced in a 5xFAD mouse model. For example, in some embodiments, a provided composition, when administered to a 5xFAD mouse, demonstrates substantiallyAttorney Docket No : 40978-0774WO1 similar behavior as a wild-ty pe mouse. A 5xFAD mouse model can also be used to assess cognitive health in a mouse as compared to a wild type mouse A 5xFAD mouse model can also be used to assess memory and recall in a mouse as compared to a wild type mouse A 5xFAD mouse model can also be used to assess cognitive function in a mouse as compared to a wild type mouse In some embodiments, “treating” may be or comprise a delay in onset of symptoms or delay in progression of symptoms or the loss of function associated with the disease; alternatively or additionally, in some embodiments, “treating” may be or comprise a reduction in frequency and / or severity of one or more symptoms or features of the disease; alternatively or additionally, “treating” may be or comprise eliminating or reducing one or more side effects of a treatment or eliminating or reducing one or more direct or indirect effects of disease progression. In some embodiments, a subject who receives treatment in accordance with the present disclosure may not exhibit signs of the disease but may be at risk for the disease.

[0159] In some embodiments, provided methods include selection of a subject, for example, by obtaining a sample from a candidate subject and testing the sample for an indication that the subject is suitable for selection. In some instances, the subject can be confirmed or identified, e g. by a health care professional, as having a condition or disease or at risk for developing the condition or disease. In some instances multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some instances, subjects can be selected and / or referred by a medical practitioner (e.g., a general practitioner). Samples can include, for example, cells or populations of cells.

[0160] The terms “administer”, “administering”, or “administration” as used herein refers to causing a subject to receive (i.e., to be exposed to) a relevant agent and, in some embodiments, can involve one or more of, e.g., ingesting, injecting, implanting, absorbing, or inhaling, the agent, without restriction to a particular form. In some embodiments, one or more of the compounds disclosed herein can be administered to a subject by ingestion orally and / or topically (e.g.. nasally). For example, in some embodiments, provided methods include administration of an effective amount of an agent or combination of agents to achieve the desired or stated effect. Specific dosage and treatment regimens for any particular subject may depend upon a variety of factors, including the activity’ of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion,Attorney Docket No : 40978-0774WO1 drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0161] Those skilled in the art, reading the present specification, will appreciate that, where combination therapy is involved, an “effective amount” of a particular agent included in the combination therapy is an amount that is effective (e.g., has been demonstrated to be effective, for example, through appropriate testing in relevant system(s) [e.g., model system(s)] and / or population(s) [e.g., patient population(s)]; where an amount has been demonstrated to be effective in a particular model system, those skilled in the art will be aware that appropriate adjustment establishes a corresponding amount for delivery [e.g., administration] to a subject [e.g, ahuman subject]) in the context of such combination; such amount may be different from, and in particular embodiments may be lower than and / or less frequent than, that which would be required to achieve a particular effect if such agent were delivered other than as part of relevant combination therapy.

[0162] In some embodiments, following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some embodiments, treatment can continue until a change (e.g.. reduction) in the level of disease in the subject is detected. In some embodiments, treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and / or after treatment.

[0163] Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary or desired. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0164] The term “subject,” as used herein, refers to any animal. In some instances, the subject is a mammal. In some instances, the term “subject”, as used herein, refers to a human (e.g., a man, a woman, or a child).Alzheimer ’s Disease

[0165] In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the loss of neurons and synapses in the cerebral cortex and atrophy in the temporal and parietal lobes. Histopathological findings of AD can include abnormal aggregates of amyloid plaques and neurofibrillary tangles.Attorney Docket No : 40978-0774WO1

[0166] Provided herein are methods of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a combination of a urolithin A agent and a fisetin agent. The methods can be used to treat at least one symptom of AD, reduce AD disease progression, reduce the deterioration of, maintain, or improve one or more bodily functions affected by AD, treat dementia or mild cognitive impairment (MCI) (e.g. dementia or MIC due to AD), or reduce the progressive decline of cognitive functions, including loss of declarative and procedural memory, decreased learning ability, reduced attention span, severe impairment in thinking ability, judgment, and decision making. Also provided are methods of increasing the survival time of a subject having one or more symptoms of AD or reducing the levels of one or more biomarkers in a subject with AD (e g., total tau or phospho-tau).

[0167] In some embodiments, the subject exhibits one or more symptoms associated with AD, have been diagnosed with AD, be suspected as having AD, or at risk for developing AD. The methods of treatment can further include determining or having determined that a subject has AD, has one or more symptoms associated with AD, or is at risk for developing AD.

[0168] Methods of diagnosing AD are known in the art. The subject can be diagnosed based on clinical history, family history, physical or neurological examinations. The subject can be confirmed or identified by a healthcare professional as having AD. Diagnosis of AD or determination of the risk of developing AD can be based upon neuroimaging, one or more cognitive tests (e.g., ADAS-Cog, MoCA, DSRS. MADCOMS, FAQ, or NPI-Q), or the presence of one or more biomarkers in the subject’s cerebrospinal fluid or blood samples. Exemplary biomarkers include amyloid-P 42 (A|342), total tau (T-tau), phosphorylated tau (P- tau), AP42 / 40 or amyloid precursor protein (APP) 669-711 / AP42 ratios, neurogranin, neurofilament light, and soluble insulin receptor. Diagnosis can also be based on detection of mutations in one or more genes associated with AD, for example, the presence of APOEs4 alleles or mutations in APP, Presenilin 1 (PSEN1), or Presenilin 2 (PSEN2). Inflammation within the brain, including increased reactivity of the resident microglia towards amyloid deposits, has been implicated in the pathogenesis and progression of AD. Therefore, diagnosis can also be based on the presence of markers of neuro-inflammation.

[0169] The treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing AD), at symptom onset or immediately following detection of AD symptoms, or upon observation of any one or more symptoms that would lead a skilledAttorney Docket No : 40978-0774WO1 practitioner to suspect that the subject may be developing AD (e.g., decline in cognitive functions, memory loss, reduced attention span). Treatment can also be initiated at later stages.Administration of ellagitannin or ellagic acid

[0170] The present disclosure also provides methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof, comprising administering or otherwise delivering to the subject an ellagitannin (e.g., any ellagitannin disclosed herein or known in the art) or ellagic acid, or an analog or metabolite thereof, a fisetin agent, and an isoflavone agent, wherein the method can further include determining or having determined that the subject is a urolithin A producer.

[0171] Whether a subject is a urolithin A producer can be determined based on the presence of one or more bacterial species in their gut microbiota (e.g., from blood, urine or fecal samples) that are associated with urolithin A production. Bacterial species that are associated with urolithin A production can be those known in the art, including, for example, those belonging to the Clostridiales and Ruminococcaceae family, and Gordonibacter urolithinfaciens . Ellagibacter isour olithinifaciens, and Akkermansia muciniphilia.

[0172] Also provided herein are methods of treating or preventing (e.g., treating) neurodegenerative diseases in a subject in need thereof, comprising administering to the subject an ellagitannin or ellagic acid, or an analog or metabolite thereof, in combination with a fisetin agent, and a composition comprising one or more bacterial species that are associated with urolithin A production (e g., any of the bacteria species disclosed herein or known in the art). A bacterial composition can be prepared in a variety' of forms, such as capsules, tablets, suppositories, food, or drink. The ellagitannin or ellagic acid, or the analog or metabolite thereof, the fisetin agent, the isoflavone agent, and the composition comprising one or more bacterial species can be administered concurrently or separately and can be administered at the same or different frequencies.Dosing

[0173] The compounds of the present disclosure can generally be administered in a therapeutically effective amount. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutically effective amount can be one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease orAttorney Docket No : 40978-0774WO1 disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i. e. , an effective dosage) depends on the therapeutic compounds selected. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity' of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.

[0174] In some embodiments, a provided therapy is a regulated therapy, wherein its commercialization is supported by clinical trial(s) and / or is otherwise subjected to government regulation and / or oversight. Alternatively or additionally, in some embodiments, a provided therapy may be commercialized without regulatory review and / or approval.

[0175] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i. e. , the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

[0176] The agents provided herein can be administered separately or concurrently, including as a part of a regimen of treatment. For example, urolithin A agents, fisetin agents, isoflavone agents, and one or more additional agents (e.g., nicotinamide riboside or pharmaceutically acceptable salts thereof or cat’s claw extracts or components thereof) disclosed herein can be administered separately in separate dosage forms, or concurrently as part of a single dosage form. The agents provided herein can be administered daily, weekly, monthly, or quarterly . In some embodiments, they are administered once a day, twice a day, or three times a day or more. They can be administered over a period of weeks, months, or years. For example, the compounds can be administered over a period of at least or about 1 week. 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more.Attorney Docket No : 40978-0774WO1

[0177] Urolithin A has been reported to be safe and / or useful when administered in those amounts within a range of 500 mg to 1000 mg daily (see e.g., Cell Rep Med. 2022 May 17; 3(5): 100633). In some embodiments, urolithin A may be administered or delivered in such amounts and / or according to such regimens in accordance with the present disclosure. Alternatively or additionally, in some embodiments, urolithin A may be utilized in accordance with the present disclosure in alternative dose amount and / or according to alternative regimens, For example, in some embodiments, urolithin A may be utilized in lower dose amount(s) and / or with less frequent administration than that at which it has been utilized when administered alone.

[0178] Urolithin A can be administered at a dose of about 1 mg to about 2500 mg (e.g., about 1 mg to about 1000 mg, about 50 mg to about 2500 mg, about 10 mg to about 2400 mg, about 100 mg to about 2300 mg, about 130 mg to about 2100 mg, about 160 mg to about 1900, about 190 mg to about 1700 mg, about 220 mg to about 1500 mg, about 240 mg to about 1300 mg, about 260 mg to about 1100 mg, about 280 mg to about 1000 mg, about 300 mg to about 900 mg, about 1 mg, about 10 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg. about 350 mg, about 400 mg. about 450 mg. about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, urolithin A is administered in an amount that is about 50 mg. about 75 mg. about 100 mg, about125 mg, or about 150 mg per day. In some embodiments, urolithin A is administered in an amount that is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg per day, about 175 mg per day, about 200 mg per day. about 225 mg per day, or about 250 mg per day.In some embodiments, urolithin A is administered at a dose of about 100 mg per day. In some embodiments, urolithin A is administered at a dose of about 125 mg per day. In some embodiments. urolithin A is administered at a dose of about 150 mg per day. In some embodiments, urolithin A is administered at a dose of about 175 mg per day. In some embodiments, urolithin A is administered at a dose of about 200 mg per day. In some embodiments, urolithin A is administered at a dose of about 225 mg per day. In some embodiments, urolithin A is administered at a dose of about 250 mg per day. In some embodiments, urolithin A is administered in an amount that is about 900 mg to about 1500 mg per day. In some embodiments, urolithin A is administered in an amount that is about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg. about 950 mg, about 955 mg, about 960 mg, about 965Attorney Docket No : 40978-0774WO1 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, or about 1000 mg per day. Urolithin A can be administered once a day, twice a day, or three or more times a day. For example, urolithin A can be administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. Urolithin A can be administered at an amount of about 100 mg to about 5000 mg daily (e.g., about 100 mg to about 250 mg, about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg. about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 700 mg, about 725 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg daily). In some embodiments, urolithin A is administered at an amount of about 1000 mg daily (e.g.. about 500 mg twice a day). In some embodiments, urolithin A is administered in an amount that is from about 1 mg to about 1000 mg per day.

[0179] As described herein, urolithin A can be administered once a day, twice a day, or three or more times a day. For example, in some embodiments, urolithin A is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. In some embodiments, urolithin A is administered at a dose of about 100 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 125 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 150 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 175 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 200 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 225 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 250 mg twice per day. In some embodiments, urolithin A is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, urolithin A is administered at a dose of about 100 mg once per day. In some embodiments, urolithin A is administered at a dose of about 125 mg once per day. In some embodiments, urolithin A is administered at a dose of about 150 mg once per day. In some embodiments, urolithin A is administered at a dose of about 175 mg once per day. In some embodiments, urolithin A is administered at a dose of about 200 mg once per day. In some embodiments, urolithin A is administered at a dose of about 225 mg once per day. In some embodiments, urolithin A is administered at a dose of about 250 mg once per day.Attorney Docket No : 40978-0774WO1

[0180] In some embodiments, the present disclosure provides a composition that comprises about 100 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 125 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 150 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 175 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 200 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 225 mg of urolithin A. In some embodiments, the present disclosure provides a composition that comprises about 250 mg of urolithin A.

[0181] In some embodiments, urolithin A is administered at a dose of about 0.5 to about 65 mg / kg of the subject’s body weight (e.g., about 1 to about 60. about 1.5 to about 55, about 2 to about 50, about 2.5 to about 45, about 3 to about 40, about 3.5 to about 35, about 4 to about 30, about 4.5 to about 25, about 5 to about 20, about 5.5 to about 15, about 6 to about 12, or about 6.5 to about 10 mg / kg of the subject’s body weight). In some embodiments, urolithin A is administered at a dose that is about 1.5 mg / kg to about 2 mg / kg of the subject’s body weight. In some embodiments, urohthin A is administered at a dose that is about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, or about 2 mg / kg of the subject’s body weight.

[0182] Urohthin A agents other than urolithin A can be administered at a dose that corresponds with a dose for urohthin A as disclosed herein, where correspondence can be established, for example, by comparable results and in appropriate assessment, as will be understood by those skilled in the art.

[0183] Fisetin can be administered at a dose of about 0.5 mg to about 2500 mg (e.g., about 0.5 mg to about 20 mg, about 1 mg to about 10 mg, about 2 mg to about 6 mg, about 25 mg to about 500 mg, about 50 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, about 400 mg to about 750 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg. about 500 mg, about 550 mg, about 600 mg, about 650 mg. about 700 mg, about 750 mg. about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, fisetin is administered in an amount that is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 80 mg, about 85 mg, about 90 mg. about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120Attorney Docket No : 40978-0774WO1 mg, about 125 mg, about 130 mg, or about 135 mg. In some embodiments, fisetin is administered in an amount of about 25 mg. In some embodiments, fisetin is administered in an amount of about 50 mg. In some embodiments, fisetin is administered in an amount of about 75 mg. In some embodiments, fisetin is administered in an amount of about 100 mg. In some embodiments, the present disclosure provides a composition that comprises about 25 mg of fisetin. In some embodiments, the present disclosure provides a composition that comprises about 50 mg of fisetin. In some embodiments, the present disclosure provides a composition that comprises about 75 mg of fisetin. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of fisetin.

[0184] Fisetin can be administered once a day, twice a day, or three or more times a day. For example, fisetin can be administered at a dose of about 0.5 mg to about 2000 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. In some embodiments, fisetin is administered at a dose of about 25 mg twice per day. In some embodiments, fisetin is administered at a dose of about 50 mg twice per day. In some embodiments, fisetin is administered at a dose of about 75 mg twice per day. In some embodiments, fisetin is administered at a dose of about 100 mg twice per day. In some embodiments, fisetin is administered at a dose of about 25 mg to about 2500 mg (e g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, fisetin is administered at a dose of about 25 mg once per day. In some embodiments, fisetin is administered at a dose of about 50 mg once per day. In some embodiments, fisetin is administered at a dose of about 75 mg once per day. In some embodiments, fisetin is administered at a dose of about 100 mg once per day. Fisetin can be administered at an amount of about 1 mg to about 5000 mg daily (e.g., about 1 mg to about 40 mg. about 2 mg to about 20 mg, about 4 mg to about 12 mg, about 50 mg to about 1000 mg. about 100 mg to about 800 mg, about 150 mg to about 500 mg, about 200 mg to about 400 mg, about 500 mg to about 2000 mg, about 700 mg to about 1800 mg, or about 800 mg to about 1500 mg daily). In some embodiments, fisetin is administered at an amount of about 8 mg daily (e.g., about 4 mg twice a day). In some embodiments, fisetin is administered in an amount that is from about 400 mg to about 500 mg per day. In some embodiments, fisetin is administered in an amount that is about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, or about 500 mg per day. In some embodiments, fisetin is administered in an amount that is about 25 mg. about 30Attorney Docket No : 40978-0774WO1 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. about 95 mg, or about 100 mg per day. In some embodiments, fisetin is administered at an amount that is about 100 mg daily (e.g., about 50 mg twice a day). In some embodiments, fisetin is administered in an amount that is from about 1 mg to about 1000 mg per day. In some embodiments, fisetin is administered in an amount that is about 25 mg. about 50 mg. about 75 mg. about 100 mg, about 125 mg, about 150 mg per day. about 175 mg per day, or about 200 mg per day. In some embodiments, fisetin is administered in an amount that is about 100 mg to about 1500 mg per day. In some embodiments, fisetin is administered in an amount that is about 25 mg per day. In some embodiments, fisetin is administered in an amount that is about 50 mg per day. In some embodiments, fisetin is administered in an amount that is about 75 mg per day. In some embodiments, fisetin is administered in an amount that is about 100 mg per day. In some embodiments, fisetin is administered in an amount that is about 150 mg per day. In some embodiments, fisetin is administered in an amount that is about 200 mg per day.

[0185] Fisetin agents other than fisetin can be administered at a dose that corresponds with a dose for fisetin as disclosed herein, where correspondence can be established, for example, by comparable results and in appropriate assessment, as will be understood by those skilled in the art.

[0186] In some embodiments, fisetin is administered at an amount of about 0.05 to about 60 mg / kg of the subject’s body weight (e.g., about 0.05 to about 0.15. about 0.4 to about 12, about 0.6 to about 10, about 0.8 to about 8, about 1 to about 6, about 1 .5 to about 26, about 2 to about 24, about 2.5 to about 22, or about 3 to about 20 mg / kg of the subject’s body weight). In some embodiments, fisetin is administered in an amount of about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg or about 1.0 mg / kg of the subject’s body weight.

[0187] Quercetin can be administered at a dose of about 1 mg to about 2500 mg (e.g., about 25 mg to about 100 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 100 mg to about 600 mg, about 150 to about 500 mg, about 200 mg to about 300 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg. about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg. about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, quercetin is administered in an amount that is from about 1 mg to about 1000 mg. In someAttorney Docket No : 40978-0774WO1 embodiments, quercetin is administered in an amount that is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg. about 175 mg, or about 200 mg. In some embodiments, quercetin is administered in an amount of about 25 mg. In some embodiments, quercetin is administered in an amount of about 50 mg. In some embodiments, quercetin is administered in an amount of about 75 mg. In some embodiments, quercetin is administered in an amount of about 100 mg. In some embodiments, the present disclosure provides a composition that comprises about 25 mg of quercetin. In some embodiments, the present disclosure provides a composition that comprises about 50 mg of quercetin. In some embodiments, the present disclosure provides a composition that comprises about 75 mg of quercetin. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of quercetin.

[0188] As described herein, quercetin can be administered once a day, twice a day, or three or more times a day. For example, quercetin can be administered at a dose of about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg. about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg. about 85 mg, about 90 mg, about 95 mg. about 100 mg. about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, or about 500 mg once per day or twice per day. In some embodiments, quercetin is administered at a dose of about 25 mg twice per day.In some embodiments, quercetin is administered at a dose of about 50 mg twice per day. In some embodiments, quercetin is administered at a dose of about 75 mg twice per day. In some embodiments, quercetin is administered at a dose of about 100 mg twice per day. In some embodiments, quercetin is administered at a dose of about 25 mg once per day. In some embodiments, quercetin is administered at a dose of about 50 mg once per day. In some embodiments, quercetin is administered at a dose of about 75 mg once per day. In some embodiments, quercetin is administered at a dose of about 100 mg once per day. In some embodiments, quercetin is administered in an amount that is about 100 mg to about 1500 mg per day. In some embodiments, quercetin is administered in an amount that is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg. about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, or about135 mg per day. In some embodiments, quercetin is administered in an amount that is about 25 mg per day. In some embodiments, quercetin is administered in an amount that is about 50 mg per day. In some embodiments, quercetin is administered in an amount that is about 75 mgAttorney Docket No : 40978-0774WO1 per day. In some embodiments, quercetin is administered in an amount that is about 100 mg per day. In some embodiments, quercetin is administered in an amount that is about 150 mg per day. In some embodiments, quercetin is administered in an amount that is about 200 mg per day. In some embodiments, quercetin is administered in an amount that is about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg. about 475 mg. about 480 mg, about 485 mg, about 490 mg. about 495 mg, or about 500 mg per day. In some embodiments, quercetin is administered in an amount that is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg. about 80 mg, about 85 mg, about 90 mg, about 95 mg. or about 100 mg per day.

[0189] In some embodiments, quercetin is administered at an amount of about 0.05 to about 60 mg / kg of the subject’s body weight (e.g., about 0.05 to about 0.15, about 0.4 to about 12, about 0.6 to about 10, about 0.8 to about 8, about 1 to about 6, about 1.5 to about 26, about 2 to about 24, about 2.5 to about 22, or about 3 to about 20 mg / kg of the subject's body weight). In some embodiments, quercetin is administered in an amount of about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg or about 1.0 mg / kg of the subject’s body weight.

[0190] In some embodiments, ipriflavone is administered in an amount that is about 1 mg to about 1500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg to about 1000 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg to about 500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 300 mg to about 800 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 600 mg to about 800 mg per day. In some embodiments, ipriflavone is administered in an amount that is about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg. or about 800 mg per day. In some embodiments, ipriflavone is administered in an amount of about 100 mg per day. In some embodiments, ipriflavone is administered in an amount of about 150 mg per day. In some embodiments, ipriflavone is administered in an amount of about 200 mg per day. In some embodiments, ipriflavone is administered in an amount of about 250 mg per day. In someAttorney Docket No : 40978-0774WO1 embodiments, ipriflavone is administered in an amount of about 300 mg per day. In some embodiments, the present disclosure provides a composition that comprises about 100 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 125 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 150 mg of ipriflavone. In some embodiments, the present disclosure provides a composition that comprises about 200 mg of ipriflavone.

[0191] As described herein, ipriflavone can be administered once a day, twice a day, or three or more times a day. For example, in some embodiments, ipriflavone is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) twice a day. In some embodiments, ipriflavone is administered at a dose of about 100 mg twice per day. In some embodiments, ipriflavone is administered at a dose of about 125 mg twice per day. In some embodiments, ipriflavone is administered at a dose of about 150 mg twice per day. In some embodiments, ipriflavone is administered at a dose of about 50 mg to about 2500 mg (e.g. any of the subranges or doses within this range disclosed herein) once a day. In some embodiments, ipriflavone is administered at a dose of about 100 mg once per day. In some embodiments, ipriflavone is administered at a dose of about 125 mg once per day. In some embodiments, ipriflavone is administered at a dose of about 150 mg once per day. In some embodiments, ipriflavone is administered at an amount of about 100 mg to about 5000 mg daily (e.g., about 100 mg to about 250 mg, about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg, about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 700 mg, about 725 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg daily). In some embodiments, ipriflavone is administered at an amount that is about 1000 mg daily (e.g., about 500 mg twice a day).

[0192] In some embodiments, ipriflavone is administered in an amount that is about 1.0 to about 5.0 mg / kg of the subject’s body weight. In some embodiments, ipriflavone is administered in an amount that is about 1.0 mg / kg, about 1.5 mg. kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg. about 4.0 mg / kg. about 4.5 mg / kg, or about 5.0 mg / kg.

[0193] In some embodiments, when administered in combination with urolithin A for treating or preventing (e.g., treating) a neurodegenerative disease, the dosage of fisetin and / or ipriflavone can be reduced as compared to the dosage used when fisetin and / or ipriflavone are administered alone. For example, the amount of fisetin and / or ipriflavone administered inAttorney Docket No : 40978-0774WO1 combination with urolithin A can be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%. about 50%, or about 55% compared to the dosage used when fisetin and / or ipriflavone are administered alone.

[0194] In some embodiments, when administered in combination with fisetin for treating or preventing (e.g., treating) a neurodegenerative disease, the dosage of urolithin A and / or ipriflavone can be reduced as compared to the dosage used when urolithin A and / or ipriflavone are administered alone. For example, the amount of urolithin A administered in combination with fisetin and / or ipriflavone can be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 55% compared to the dosage used when urolithin A is administered alone.

[0195] In some embodiments, when administered in combination with ipriflavone for treating or preventing (e.g., treating) a neurodegenerative disease, the dosage of urolithin A and / or fisetin can be reduced as compared to the dosage used when urolithin A and / or fisetin are administered alone. For example, the amount of ipriflavone administered in combination with fisetin and / or ipriflavone can be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%. about 50%, or about 55% compared to the dosage used when urolithin A is administered alone.

[0196] In some embodiments, urolithin A is administered at an amount of about 1 mg to about 1100 mg daily and fisetin is administered at an amount of about 4 mg to about 12 mg daily. In some embodiments, urolithin A is administered in an amount that is about 100 mg to about 1000 mg per day and fisetin is administered in an amount that is about 4 mg to about 12 mg per day.

[0197] In some embodiments, urolithin A is administered at an amount from about 1 mg to about 2500 mg per day. fisetin is administered at an amount from about 1 mg to about 2500 mg per day, quercetin is administered at an amount of about 1 mg to about 2500 mg per day, and ipriflavone is administered in an amount that is about 1 mg to about 1500 mg per day. In some embodiments, urolithin A is administered at an amount from about 1 mg to about 1000 mg per day, fisetin is administered at an amount from about 25 mg to about 500 mg per day, quercetin is administered at an amount from about 25 mg to about 500 mg per day, and ipriflavone is administered in an amount from about 100 mg to about 500 mg per day.

[0198] In some embodiments, urolithin A is administered at an amount from about 50 mg to about 200 mg per day, fisetin is administered at an amount from about 25 mg to about 250 mg per day, quercetin is administered at an amount from about 25 mg to about 250 mg per day,Attorney Docket No : 40978-0774WO1 and ipriflavone is administered in an amount that is about 100 mg to about 300 mg per day. In some embodiments, urolithin A is administered at an amount of about 100 mg per day, fisetin is administered at an amount of about 50 mg per day, quercetin is administered at an amount of about 50 mg per day, and ipriflavone is administered in an amount of about 150 mg per day. In some embodiments, urolithin A is administered at an amount of about 200 mg per day, fisetin is administered at an amount of about 100 mg per day, quercetin is administered at an amount of about 100 mg per day, and ipriflavone is administered in an amount of about 300 mg per day.

[0199] In some embodiments, urolithin A is administered in an amount that is about 50 to about 150 mg per day, fisetin is administered in an amount that is about 25 mg to about 75 mg per day, and ipriflavone is administered in an amount that is about 100 mg to about 200 mg per day. In some embodiments, urolithin A is administered in an amount that is about 800 mg to about 1500 mg per day, fisetin is administered in an amount that is about 350 mg to about 500 mg per day, and ipriflavone is administered in an amount that is about 650 mg to about 900 mg per day.

[0200] Nicotinamide riboside can be administered at a dose of about 1 mg to about 2500 mg (e g., about 10 mg to about 1000 mg about 50 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 500 mg). For example, nicotinamide riboside can be administered at a dose of about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg per day.

[0201] Cat’s claw extracts can be administered at a dose of about 1 mg to about 2500 mg (e.g., about 100 mg to about 1200 mg about 200 mg to about 1100 mg, about 300 mg to about 1000 mg, about 400 mg to about 900 mg, about 600 mg to about 800 mg. or about 750 mg).

[0202] In some embodiments, when administering urolithin A. fisetin. and ipriflavone in combination with one or more of nicotinamide riboside, cat’s claw, or quercetin for treating a neurodegenerative disease, the dosage of urolithin A, fisetin, and / or ipriflavone can be reduced as compared to the dosage used when only administering urolithin A, fisetin, and ipriflavone. For example, the amount of urolithin A, fisetin, and / or ipriflavone can be reduced by about 5%, about 10%, about 15%, about 20%. about 25%. about 30%, about 40%, about 50%. or about 55%.Pharmaceutical CompositionAttorney Docket No : 40978-0774WO1

[0203] When employed as pharmaceuticals, agents of the disclosure can be administered in the form of pharmaceutical compositions which comprise and / or deliver relevant compound(s).

[0204] A pharmaceutical composition refers to a combination of one or more compounds of the present disclosure, and at least one pharmaceutically acceptable carrier.

[0205] Those skilled in the art, reading the present disclosure, will appreciate that the term "‘pharmaceutical’7(and its cognates such as “pharmaceutically”, etc) does not require or imply review of or approval by any governmental agency charged with granting marketing approval for active agents and / or products with therapeutic or biologic activity'. Rather, the term references a degree of such therapeutic or biologic activity, absent significant or otherwise problematic (e.g., in the context of a risk / benefit analysis as is understood in the art) toxicity when administered to a relevant population (e.g., a population in need of or that would otherwise benefit from such therapeutic or biologic activity'). Specifically, those skilled in the art will appreciate that the term, as used herein, may refer, in some embodiments, to approved pharmaceutical agents. Alternatively or additionally, in some embodiments, the term may refer to what are sometimes referred to as nutraceutical agents or other “over-the counter” products. Of course, if the recipient (or recipient population) is other than human, the term may refer to veterinary' agents.

[0206] For example, the present disclosure provides pharmaceutical compositions, and / or combinations of pharmaceutical compositions that together comprise one or more agents selected from urolithin A agent, fisetin agents, isoflavone agents, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and cat’s claw extracts or components thereof, individually or in combination, and optionally comprising one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise a combination of urolithin A agents, fisetin agents, and isoflavone agents, and optionally comprising one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise urolithin A, fisetin, ipriflavone, and optionally one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise urolithin A, quercetin, ipriflavone, and optionally one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise urolithin A, fisetin, ipriflavone, and one or more additional agents selected from quercetin, nicotinamide riboside or a pharmaceutically acceptable salt thereof, and cat’s claw extracts or components thereof, and optionally one or more excipients. These compositions can be prepared in a manner well known in the pharmaceutical art, and can beAttorney Docket No : 40978-0774WO1 administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Pharmaceutical compositions of the present disclosure may be for administration to healthy subjects. Pharmaceutical compositions of the present disclosure may be nutraceutical compositions.

[0207] Pharmaceutical compositions are ty pically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (subcutaneous, intracutaneous. intravenous, intradermal, intramuscular, intra-articular. intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0208] Pharmaceutical compositions can be in the form of a solution or powder. Suitable powders may include those that are substantially soluble in water. Pharmaceutical compositions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.

[0209] Pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to. powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions, or hydrogel formulations. In the case of powders for oral administration, the powders can be substantially dissolved in water prior to administration. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, may be added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added. An example earner is FenuMAT™.

[0210] Pharmaceutical compositions can also be administered by' nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyd alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0211] In some embodiments, provided herein are oral compositions comprising one or more agents selected from urolithin A agents, fisetin agents, nicotinamide riboside or pharmaceutically acceptable salts thereof, and cat’s claw extracts or components thereof,Attorney Docket No : 40978-0774WO1 optionally comprising one or more excipients. In some embodiments, the oral composition is capsules, soft gels, or tablets.

[0212] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. In some embodiments, the invention provides kits that include the bile acid and phenylbuty rate compounds. The kit may also include instructions for the physician and / or patient, syringes, needles, box, bottles, vials, etc.

[0213] In some embodiments, a composition comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, and ipriflavone, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, and quercetin, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises an amount of urolithin A that is from about 1 mg to about 2500 mg, an amount of fisetin that is from about 0.5 mg to about 2500 mg, an amount of ipriflavone that is from about 1 mg to about 1500 mg, and an amount of quercetin that is from about 1 mg to about 2500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 1 mg to about 1000 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 2500 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 200 mg, an amount of fisetin that is from about 25 mg to about 250 mg, an amount of ipriflavone that is from about 100 mg to about 200 mg, and an amount of quercetin that is from about 25 mg to about 100 mg. In some embodiments, the composition comprises an amount of urolithin A that is from about 50 mg to about 2500 mg, an amount of fisetin that is from about 25 mg to about 500 mg, an amount of ipriflavone that is from about 100 mg to about 500 mg, and an amount of quercetin that is from about 100 mg to about 500 mg. In some embodiments, the composition comprises an amount of urolithin A that is about 100 mg, an amount of fisetin that is about 50 mg, an amount of ipriflavone that is about 150 mg, and an amount of quercetin that is about 50 mg.Attorney Docket No : 40978-0774WO1Combination Therapy

[0214] As discussed herein and understood by those skilled in the art, combination therapy (e.g., urolithin A agent, fisetin agent, and isoflavone agent combination therapy) or, interchangeably, “combination treatment” or “combination” in reference to a pharmaceutical composition, involves administration or other delivery7of one or more of a plurality7of agents to a subject, so that the subject is exposed to all of them. In some embodiments, each agent of the combination is administered or otherwise delivered to the subject. In some embodiments, one or more agents is administered or otherwise delivered to a subject who has already received, is receiving, or will receive (e.g., via an overlapping administration regimen) the remaining agent(s) of the combination.

[0215] In some embodiments, combination therapy involves administration of one or more pharmaceutical compositions (z.e., that comprise and / or otherwise deliver an active agent, e.g., as described herein), each of which comprises and / or delivers one or more agent(s) of a combination. In some embodiments, different agent(s) are delivered from different pharmaceutical compositions (i.e., from distinct dosage forms). In some embodiments, two or more agents may be delivered from the same pharmaceutical composition (i.e., may be included in the same dosage form). In some embodiments, pharmaceutical compositions that delivery7different agents are administered according to overlapping dosing regimens, determined to achieve exposure to all agents of a combination. In some embodiments, a combination is a single pharmaceutical composition comprising two or more agents. In some embodiments, a combination is two or more pharmaceutical compositions each comprising one or more agents.

[0216] In some embodiments, combination therapy in accordance with the present disclosure is or comprises urolithin A agent, fisetin agent, and isoflavone agent combination therapy. In some embodiments, combination therapy involves combination of a urolithin A agent and / or a fisetin agent and / or an isoflavone agent with one or more additional therapeutic agents. As noted, in some embodiments, such additional therapeutic agents can be combined with the compounds disclosed herein in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, additional agents include those known for treating or preventing (e.g., treating) neurodegenerative diseases. For example, in some embodiments, suitable agents for use in combination therapy as described herein may include one or more of donepezil (Aricept®). tacrine (Cognex®),Attorney Docket No : 40978-0774WO1 rivastigmine (Exelon®), galantamine (Nivalin® and Razadyne®), memantine (Namenda®), anti-amyloid vaccine, A(3-lowering therapies, and mental exercise or stimulation.

[0217] In some cases, treatment with a urolithin A agent and / or a fisetin agent and / or an isoflavone agent as described herein may reduce the need for treatment with one or more additional therapeutic agents or reduce the dose or frequency required for the additional therapeutic agents to obtain the same treatment effect. For example, the amount of the additional therapeutic agent administered to the subject can be reduced by at least about 10% (e.g., at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%) compared to the dosage amount used when the additional therapeutic agent(s) is administered alone.

[0218] In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, and ipriflavone, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, and quercetin, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises urolithin A, or a pharmaceutically acceptable salt thereof, fisetin, or a pharmaceutically acceptable salt thereof, ipriflavone, or a pharmaceutically acceptable salt thereof, quercetin, or a pharmaceutically acceptable salt thereof, and dolutegravir, or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, a kit comprises oral dosage forms of the provided agents. In some embodiments, a kit further comprises instructions to consume one or two oral dosage forms daily. In some embodiments, a kit comprises instructions to consume one oral dosage form daily. In some embodiments, a kit comprises instructions to consume two oral dosage form daily.EXAMPLES

[0220] The following examples are provided by way of illustration of certain embodiments of the present disclosure and are not in any way intended to limit the scope of this disclosure or the claims.Example 1: Effects of urolithin A and flsetin on microglial AB clearance and the release of pro-inflammatory cytokines.Attorney Docket No : 40978-0774WO1

[0221] Urolithin A was identified as a top-tier enhancer of AB clearance by microglia in an unbiased (and biased) screening of natural product compounds. Cellular assay models based on BV2 microglial cells were used to assess the ability of microglia to phagocytose synthetic AB42 peptides, a major pathogenic AB isoform of Alzheimer’s disease AB species (microglial uptake / clearance). FIG. 1 shows a representative result where urolithin A increases microglial AB uptake / clearance in a dose-dependent manner in the cell culture model. EC 50 for AB42 uptake is 1.243e-005 M in this model system. As shown in FIG. 3, microglial AB uptake / clearance is dramatically increased by co-treatment of urolithin A and fisetin, as compared to fisetin alone.

[0222] Effects of urolithin A and fisetin on the reduction of pro-inflammatory cytokines levels, such as TNFa, were assessed in an unbiased library screening. BV2 microglial cells were converted to a pro-inflammatory activation state by acute treatment with 1 pg / mL of Lipopolysaccharide (LPS) for 5 hours in the presence of a vehicle or urolithin A or fisetin. Effects on inflammation were assessed by measuring levels of a representative pro- inflammatory cytokine, TNFa, via an ELISA assay on the conditioned cell media. FIGs. 2A and 2B show representative results of the dose-response reduction of TNFa after treatment with LPS and urolithin A and fisetin, respectively. While each of urolithin A and fisetin reduce TNFa release by LPS-activated microglia in a dose-dependent manner, fisetin has an EC50 of 8 pM and urolithin A of 21 pM, indicating that fisetin is a more effective drug in this assay.

[0223] Next. BV2 microglial cells were treated with urolithin A at 10 pM and fisetin at 7.5 pM, alone or in combination. Drug toxicity during cell treatment was measured by monitoring the levels of lactate dehydrogenase released in the conditioned media, expressed as Vehicle % (FIG. 4A). The combination treatment did not impact cell viability as shown in FIG. 4A. Reduction of TNFa in BV2 microglial cells was measured by ELISA (FIG. 4B).

[0224] BV2 microglial cells were next treated with 1 pg / mL of LPS for 5 hours in the presence of urolithin A and fisetin at different concentrations, alone or in combination (FIG. 5). Levels of TNFa secreted by the microglial cells into the conditioned cell media were measured using ELISA.

[0225] Co-treatment of urolithin A and fisetin dramatically reduced LPS-induced microglial pro-infl ammatory activation, as measured by TNFa levels (FIG. 4B and FIG. 5). The combination of urolithin A and fisetin unexpectedly and dramatically increases the ability of fisetin to reduce LPS-induced microglial pro-inflammatory activation, as measured by TNFa levels, significantly beyond fisetin, alone. The combination led to a more than additive effectAttorney Docket No : 40978-0774WO1 in the reduction of LPS-induced microglial pro-inflammatory activation. Specifically, as shown in FIG. 4B, while Fisetin alone significantly reduced TNFa levels by roughly 75% in LPS- treated BV2 microglia cells, the combination of urolithin A at 10 pM and fisetin at 7.5 pM reduced TNFa levels to almost under-detectable levels.Example 2: Effects of urolithin A, fisetin, nicotinamide riboside, cat’s claw, quercetin, and ipriflavone on microglial AB clearance and the release of pro-inflammatory cytokine

[0226] Effects of urolithin A. fisetin, nicotinamide riboside, cat's claw, quercetin, and ipriflavone, alone or in combination, on TNFa concentration were assessed (FIGs. 6A-6E,7A- 7C, and 17A). BV2 microglial cells were converted to a pro-inflammatory activation state by acute treatment with 1 pg / mL of Lipopolysaccharide (LPS) for 5 hours in the presence of a vehicle or nicotinamide riboside (#101), cat's claw (#134), urolithin A (#144), fisetin (NP-82), quercetin (NP-162) or ipriflavone (NP-182). alone or in combination. Effects on inflammation were assessed by measuring levels of TNFa, via an ELISA assay on the conditioned cell media. As shown in FIGs. 6A-6E and 7A-7C, the combination of the five agents was able to reduce TNFa release to a greater extent compared to each agent alone. Moreover, as shown in FIGs. 6C-6E, urolithin A (#144). fisetin (NP-82) and quercetin (NP-162) in combination can reduce TNFa release to a greater extent compared to each of the three agents alone. Toxicity was assessed by monitoring the levels of lactate dehydrogenase released in the conditioned media, and the results demonstrated that viability7was not impacted by the treatments (FIG. 8).

[0227] The ability of the agents, alone or in combination, to increase microglial AB uptake was also assessed (FIG. 9). Cat’s claw significantly increased AB uptake compared to vehicle (FIGs. 9 and 10A). Ipriflavone also significantly increased A(3 uptake compared to vehicle (FIGs. 17B-17E). Furthermore, the combination of cat’s claw (#134) and urolithin A (#144) was able to increase AB uptake more than cat’s claw7and urolithin A alone (FIGS. 10B and 10C). FIGs. 11B-11D and FIGs. 12A-12F show TNFa levels in response to treatment with cat’s claw (#134), urolithin A (#144), fisetin (NP-82) and quercetin (NP-162), alone or in various combinations.

[0228] FIGs. 13A-13E and 17A show7TNFa levels in response to treatment with nicotinamide riboside (#101). cat’s claw (#134), urolithin A (#144), fisetin (NP-82), and ipriflavone (NP-182), alone or in various combinations.Attorney Docket No : 40978-0774WO1Example 3: In vivo assessment of provided combinations

[0229] Cohort I: A total of 20 transgenic male and female (mixed sex) 5xFAD mice at an age of 5 months ±2 weeks, as well as 10 wild type littermates of same sex and age were randomly allocated to the study groups as shown in the table below:

[0230] Cohorts II-V: In each cohort, a total of 20 transgenic male and female (mixed sex) 5xFAD mice at an age of 5 months ±2 weeks, as well as 10 wild type littermates of same sex and age were randomly allocated to the study groups as shown in the table below:

[0231] All animals were treated per oral (p.o.) gavage for 18 weeks with either different combination treatments or vehicle (5% DMSO, 40% PEG300, 5% Tween-80, 50% Saline) on a daily basis for 18 weeks. Wild type animals from group A (n=10) and 5x FAD transgenic animals from group B (n=10) were treated p.o. with vehicle. Transgenic animals from group I (n=10 / group) received a combination treatment of Ipriflavone, Urolithin A, Fisetin. and Quercetin (150 mg / kg, 200 mg / kg, 100 mg / kg, and 100 mg / kg, respectively) via p.o. gavage daily for 18 weeks.Attorney Docket No : 40978-0774WO1

[0232] At the end of the 18 weeks treatment period, all animals were subjected to a behavioral test battery. Exploratory behavior was assessed in the Open Field test, spatial learning and memory was tested in the Morris Water Maze, and general health and fine motor behavior was assayed in the Nest Building test.

[0233] After 18 weeks of treatment, all animals were sacrificed -3-4 hours (time-sensitive) after final dosing on last treatment day. CSF was collected from the cistema magna and snap frozen on dry ice and stored at -80 °C for biochemical analysis. Terminal blood was collected by heart puncture in EDTA coated tubes. Blood plasma was collected by centrifugation (3000 x g for 10 minutes at room temperature) and plasma aliquots were transferred to 1.5 mL tubes, frozen on dry' ice, and stored at -80 °C for biochemical analysis. Following transcardial perfusion with 0.9% saline, brains were removed and hemisected. The right hemibrains were post-fixed in 4 % paraformaldehyde in phosphate buffer (PFA / PB, pH 7.4) for two hours at room temperature, processed and embedded in cryomolds for histological evaluations. The left hemibrain of each animal was further dissected into cortex, hippocampus, and remaining brain, all parts were weighed, snap frozen on dry ice, and stored at -80°C for biochemical analysis.

[0234] For histological analysis, 8 brains per treatment group were then cryo-sectioned (12 levels with 5 sections each). 5 sections per animal were then used for quantitative immunofl uorescent labeling of amyloid plaques (6E10 or ThioS), microgliosis (Ibal), astrocytosis (GFAP), macrophages and monocytes (CD68) in cortex and subiculum. Additionally, 5 sections per animal were used for quantitative immunofluorescent labeling of synaptic health (synaptophysin, PSD95), and neuronal loss (NeuN) in cortex and subiculum.

[0235] For biochemical analyses, soluble and insoluble protein fractions were extracted from the left cortex and hippocampus of 8 brains per group (72 animals x 4 sample types, n=288 samples in total). Abeta 1-40 and abeta 1-42 levels were analyzed separately in soluble and insoluble cortical and hippocampal fractions using assays from Mesoscale Discovery (72 animals x 4 sample types = total of 288 samples per assay). In addition, a commercially available ELISA kit for Human [3 Amyloid (1-42. Wako) was used for analysis of abeta 1-42 levels in soluble and insoluble cortical and hippocampal fractions (4 sample types x 72 samples = 288 samples in total). TNFa levels were measured in duplicates in hippocampus and cortex homogenates using the V-PLEX Custom MouseAttorney Docket No : 40978-0774WO1Cytokine assay by Mesoscale Discovery (2 x 72 samples = 144 samples in total as duplicates).

[0236] Measurements of Neurofilament light chain (NF-L) levels in terminal CSF samples were performed using the NF-L ELISA by Uman Diagnostics (total n= 72 samples as singlets).

[0237] Bodyweight: Animals of all groups generally exhibited constant body weight throughout the in-life phase after some body weight fluctuations in the first two treatment weeks, indicating that treatment was tolerated well.

[0001] Behavioral Test Battery

[0238] Open Field: The Open Field Test is a sensorimotor test that may be used to determine general activity levels, gross locomotor activity, and exploration habits in rodent models of central nervous system disorders indicating changes in anxiety7, depression or motor performance. In this test, animals are exposed to a novel open space and the animal' s exploration activity7is measured. For instance, differences in time spent in the center area (for rodents the most ‘’threatening” part of the Open Field box) vs. the outside area may reflect strong differences in anxiety levels. Animals that spend a higher proportion of time in the outside area (higher thigmotaxis) may be considered more anxious. Changes in activity levels (e g., distance traversed, activity and hyperactivity7as well as duration and number of rearings) may also reflect emotional changes, as well as motor related changes. Reduced levels of these exploration parameters may be indicative of anxiety7and depression.

[0239] An opaque Open Field Box (45 x 45 x 23.5 cm) in combination with a computerized video tracking system was used. Spontaneous activity and anxiety were assessed in the Open Field at the end of the 18 weeks treatment period by evaluating the following parameters for all animals: hyperactivity7[s] , activity7[s] , distance [m], rearings [s], rearings [n] and thigmotaxis [s], and number of fecal boli [n]. The open field test was performed prior to treatment on the testing day. The mice were brought to the room at least 45 minutes before the start of the testing. Each test session lasted for 5 minutes to check the mice's behavior in the new surroundings, as the first minutes of the Open Field test were the most suitable to display the exploratory7behavior of the animals. After the testing session, the number of fecal boli was counted, as a measure of emotionality. The Open Field was cleaned with 70% Isopropanol after each mouse to get rid of odor traces. Testing wasAttorney Docket No : 40978-0774WO1 performed under standard room lighting conditions during the light phase of the circadian cycle.

[0240] 5xFAD mice of group B displayed significant age-dependent decreases in behavioral habituation to a novel environment. Animals of treatment group I displayed recovery of certain metrics of behavioral habituation to a novel environment relative to group B. Observations are summarized in the table below and in FIGs 18A-18B.

[0241] Nest Building Behavior: Nesting behavior is an intrinsic behavior shown by rodents of both sexes that requires fine motor skills. The nest building test is a simple and versatile behavioral test performed in the home cage environment without the presence of the experimenter. In some cases, it is suitable for the evaluation of motor deficits, as well as changes in general health or welfare. It may be sensitive to environmental and physiological challenges, genetic mutations, and pharmacological interventions.

[0242] Mice were housed in cages containing wood chip bedding and a new 'nestlet', a 5 - 5 cm square of pressed cotton (treatment week 18). Mice were habituated to single-housing for at least one week prior to testing. No other nesting material (e.g. wood wool) was present. The nestlet was introduced on the day before testing, about 2 to 3 hours before the dark phase was initiated, and the nest building behavior was evaluated on the following day within 2 to 3 hours after the light phase started. The time span between introduction of the cotton square and evaluation of the nest status was the same for all examinations. The following morning the nests w ere assessed and rated by the experimenter according to a five-point scale (Deacon, NATURE PROTOCOLS, VOL. l, 2006, 1117):1. Nestlet not noticeably touched (more than 90% intact).2. Nestlet partially tom (50-90% remaining intact).Attorney Docket No : 40978-0774WO13. Nestlet mostly shredded but often no identifiable nest site: less than 50% of the Nestlet remains intact, but less than 90% is within a quarter of the cage floor area; i.e., the cotton is not gathered into a nest but is spread around the cage.4. An identifiable but flat nest: more than 90% of the Nestlet is tom and the material is gathered into a nest, but the nest is flat, with walls higher than mouse body height (of a mouse curled up on its side) for less than 50% of its circumference.5. A (near) perfect nest: more than 90% of the Nestlet is tom and the nest is a crater, w ith walls higher than mouse body height for more than 50% of its circumference.5xFAD mice of group B displayed significant age-dependent degradation of nest building behavior. Vehicle treated transgenic animals (group B) exhibited lower mean nesting scores compared to vehicle treated wild type animals (group A). Animals treated with the combination treatment Ipriflavone / Urolithin A / Fisetin / Quercetin (group I) showed a trend towards improved nest building performance compared to vehicle treated transgenic animals. Certain observations are summarized in the table below7and in FIG. 19.

[0243] Morris Water Maze (MWM): The Morris water maze (MWM) is a widely used behavioral test to study spatial learning and memory7in rodents. Typically, an animal learns to escape from the water by locating a hidden platform with help of visual cues. Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex have been shown to impair MWM accomplishment. As part of the test, escape latency, swim distance and thigmotaxis (indicative of strategy learning) were assessed during training days 1-4. Motor performance and emotional status (swim speed / velocity and floating, respectively) were assessed. Furthermore, target zone crossings and abidance in the target quadrant were quantified during the probe trial (day 5), and searching strategies during the acquisition training and probe trials w ere analyzed using the pathfinder software. Analysis was performed for all animals (mixed-sex) and separated for sex.Attorney Docket No : 40978-0774WO1

[0244] During treatment week 17, 4 MWM trials were performed on 4 consecutive days, plus 1 probe trial on day 5, using a computerized video tracking system. Escape latency, swim distance, and thigmotaxis (indicative of strategy learning), motor performance (swim speed / velocity) and emotional status (floating) were assessed. The MWM was performed prior to treatment on the respective testing days using the following pattern: four trials on each of four consecutive days were performed. In all trials, the platform was located in the northeast (NE) quadrant of the pool. Mice started from predefined positions (southeast (SE), southwest (SW), northwest (NW)). A single trial lasted for a maximum of 60 seconds. In case the mouse did not find the hidden, transparent platform within this time, the experimenter guided the mouse to the target. Mice were allowed to rest on the platform for 10-15 sec to orientate in the surrounding. Artificial landmarks were mounted above the walls of the pool to help the animals with their orientation. After the first 4 MWM trials (treated as training days), all mice were tested in a single probe trial on day 5, with the platform removed from the pool.

[0245] In some cases, mean performance of the animals during the first trial (trial 1) on each training day may be more reflective of long term memory capacity that is not masked by additional short term learning (during subsequent trials 2-4 on each training day). On the first trial day, wild ty pe animals (group A) exhibited a slight trend towards improved learning behavior on all determined parameters compared to other treatment groups.

[0246] Target zone crossings and abidance in the target quadrant were quantified during the probe trial (day 5), and searching strategies during the acquisition training and probe trials were analyzed using the Pathfinder software. The number of crossings of the northeast (NE) target zone, the abidance in the NE target quadrant, as well as the abidance in all quadrants, were analyzed. Wild type animals of group A and transgenic animals of treatment group I exhibited increased target zone crossings and length of stay (abidance) in the target quadrant. When considering swim strategies based in their relevance to hippocampus-associated spatial learning using the Pathfinder tool, vehicle treated wild ty pe animals (group A) exhibited highest cognitive scores per day during the training phase compared to all transgenic 5xFAD treatment groups, reaching statistical significance on training day 3 and 4 compared to vehicle treated transgenic animals (group B). The results are summarized in the table blow and in FIG. 20.Attorney Docket No : 40978-0774WO1

[0247] Vehicle-treated wild-type control animals (group A) exhibited significantly higher hippocampus-dependent search patterns on training days two. three, and four compared to vehicle-treated transgenic animals (group B). Ipriflavone / Urolithin A / Fi setin / Quercetin treatment (group I) exhibited increased use of hippocampal search strategies on training day 4 compared to vehicle treated transgenic animals (group B). Certain observations of search strategies exhibited by animals of the various treatment group are provided in the table below.Attorney Docket No : 40978-0774WO1Hippocampus dependent Hippocampus independentAttorney Docket No : 40978-0774WO1Attorney Docket No : 40978-0774WO1Hippocampus dependentHippocampus independent

[0002] Biochemical and Histological Analysis

[0248] After 18 weeks of treatment, once all behavioral tests were completed, all animals were euthanized ~3-4 hours (time-sensitive) after a final dosing on the last treatment day by pentobarbital injection (600mg / kg). CSF, blood (plasma), and brain samples were collected as described below.

[0249] CSF Sampling: After confirmation of deep anesthesia. CSF was obtained by dissection of the muscles and exposure of the foramen magnum. Upon exposure, a Pasteur pipette was inserted in an approximate depth of 0.3 - 1 mm into the cistema magna. CSF was collected by suction and capillary action until flow fully ceased in 0.2 ml polypropylene PCR tubes. The tubes were spun briefly and immediately frozen in an upright position on dry ice. The tubes were stored at -80 °C. CSF quality was documented as scores from 0 (no visible blood contamination) to 3 (severe blood contamination), and amount of CSF was estimated in pL.

[0250] Blood sampling: The thorax was opened and blood was collected by heart puncture with a 23-gauge needle. The needle was removed and the blood was transferred to the sample tube (MiniCollect® K2EDTA (potassium ethylenediaminetetraacetic acid). The tube was inverted thoroughly to facilitate homogeneous distribution of the EDTA and prevent clotting. The blood samples were centrifuged at 3,000 x g for 10 minutes at room temperature (22 °C). Plasma was transferred to pre-labeled 1.5 ml LoBin d Eppendorf tubes (40 pl + 15 pl + rest aliquot), frozen on dry ice and stored at -80 °C.

[0251] Brain sampling: Animals were transcardially perfused with 0.9 % saline. To this end a 23-gauge needle connected to a bottle with 0.9% saline was inserted into the left ventricle. The thoracic aorta - between the lungs and the liver - was clamped withAttorney Docket No : 40978-0774WO1 hemostatic forceps to block the blood flow from the heart to the abdomen but allowing the blood flow to the brain. The right atrium was opened with scissors. A constant pressure of 100 to 120 mm Hg was maintained on the perfusion solution by connecting the solution bottle to a manometer-controlled air compressor. Perfusion was continued until the skull surface had turned pale and only perfusion solution instead of blood was exiting of the right atrium. Following transcardial perfusion with 0.9% saline, brains were removed and hemisected. The left hemibrain of each animal was further dissected into cortex, hippocampus, and remaining brain. All parts were weighed, snap frozen on dry ice, and stored at -80°C for biochemical analysis. Soluble and insoluble protein fractions were extracted from the left cortex and hippocampus of 8 brains per group (72 animals x 4 sample types, n=288 samples in total). A|3 1-40 and A 1-42 levels were analyzed separately in soluble and insoluble cortical and hippocampal fractions using assays from Mesoscale Discovery (72 animals x 4 sample types = total of 288 samples per assay). In addition, a commercially available ELISA kit for Human P Amyloid (1-42, Wako) was used for analysis of Ap 1-42 levels in soluble and insoluble cortical and hippocampal fractions (4 sample types x 72 samples = 288 samples in total). TNFa levels were measured in duplicates in soluble hippocampal and cortical samples using the V-PLEX Custom Mouse Cytokine assay by Mesoscale Discovery’ (2 x 72 samples = 144 samples in total as duplicates).

[0252] Biochemical analysis: Frozen hippocampus and cortex samples were processed and homogenized by adding 19 volumes (hippocampus) or 9 volumes (cortex) of tissue homogenization buffer (THB; 250 mM Sucrose, 1 mM EDTA, 1 rnM EGTA, 20 mM Tris pH 7.4) including lx protease inhibitor (Calbiochem), to hippocampus / cortex samples. The tissue was homogenized with a beadmill (UPHO, Geneye) at 55Hz for 50sec. Three aliquots were stored at -80 °C until further use. For extraction of non-plaque associated proteins, 1 aliquot of THB homogenate was mixed with 1 part diethylamine (DEA) solution (0.4% DEA, lOOmM NaCl). The mixture was centrifuged for 120 min at 20,000x g, 4 °C. The supernatant was neutralized with 1 / 10 of the volume 0.5 M Tris-HCl, pH 6.8 and vortexed briefly. Aliquots were stored at -80 °C as DEA fraction (soluble fraction). Total protein content was determined using Pierce™ BC A Protein Assay Kit (ThermoFisher), or extraction of deposited proteins, a second aliquot of THB homogenate was mixed with 2.2 parts cold formic acid (FA), sonicated for 30 sec on ice and centrifuged for 120 min at 20,000x g, 4 °C. The supernatant was mixed with 19 parts FA Neutralization Solution (IMAttorney Docket No : 40978-0774WO1Tris, 0.5 M Na2HPO4, 0.05% NaN3). Aliquots were stored at -80°C as FA fraction (insoluble fraction). For measurement of inflammation markers, the third aliquot of homogenate was substituted with Triton X-100 so that the final concentration was 1% in the homogenate. After vortexing and 10 min incubation on ice, the homogenates were cleared from cell debris by centrifugation at 20,800 x g at 4°C for 10 minutes in a tabletop centrifuge and the supernatants were collected for the measurement of cytokines and stored at -80°C until further use.

[0253] Human |3 Amyloid (1-42) levels were measured with ELISA Kit for Human Amyloid 1-42 (Wako, 296-64401) in soluble and insoluble fractions of hippocampus and cortex. DEA samples were diluted 1 :2500, FA samples 1:3000-1: 10.000. Ap levels in study samples were evaluated in comparison to calibration curves provided in the kit and are expressed as pg or ng per mg brain wet weight. Homogenates were analyzed for TNF-a in duplicates with a commercially available immunosorbent assay kit (K152QWD Mesoscale Discovery ) according to the instructions of the manufacturer and evaluated in comparison to calibration curves provided in the kit and are expressed as pg / pg total protein or pg per mg brain wet weight.

[0254] TNFa levels were measured in duplicates in hippocampal and cortical protein fractions.

[0255] Transgenic animals of treatment group I exhibited a substantial effect on TNF-a production in the hippocampus extract in comparison to transgenic animals treated with vehicle (group B). This effect was especially significant when the level was normalized by total protein. Certain observations of levels of TNF-a in cortex and hippocampus (HC) extract are provided in FIG. 21A and FIG. 21B.

[0256] The NF-light® (Neurofilament-light) ELISA 10-7001 CE from Uman Diagnostics was used for analysis of NF-L levels in CSF samples (n=72). CSF samples were diluted 1 :30 in assay buffer and analyzed according to the manufacturers protocol in single replicates.

[0257] NF-L levels in CSF were significantly increased in vehicle treated transgenic animals (group B) compared to vehicle treated wild type animals (group A).

[0258] Histological Analysis: following fixation by immersion in freshly prepared 4% paraformaldehyde in phosphate buffer (PB; pH 7.4) for 2 hours at room temperature, right hemibrains of each animal (total n = 90 hemi brains) w ere transferred to 15 % sucrose / PBS and stored at 4 °C until sample was sunk to the bottom of the tube to ensure cryoprotectionAttorney Docket No : 40978-0774WO1(usually overnight). Tissue blocks were then trimmed as needed, transferred to cryomolds, embedded in OCT medium, frozen in dry ice-cooled isopentane and stored in an ultra-deep freezer (set at -80 °C).

[0259] Frozen hemibrains from 8 animals per group (total n = 72 animals) were sectioned sagittally at 10 pm thickness on a Leica CM1950 or a Thermo Scientific NX70 cry otome, using following section scheme: five consecutive cryosections were collected and the next 25 sections per level were discarded. This collection scheme was repeated for 12 levels and was somewhat modified if required by unusual brain size. In total 12 x 5 = 60 sections were collected per hemibrain. Sectioning levels were chosen according to the brain atlas of Paxinos and Franklin (“The Mouse Brain in Stereotaxic Coordinates”, 2ndedition. 2001). Collection of sections started at a level ~0.2 mm lateral from midline and extend through the hemisphere, in order to ensure systematic random sampling through the target regions. Sections were stored at -20°C.

[0260] No significant differences between treatment groups were observed in the size of the different areas investigated, suggesting that section sampling was unbiased.

[0261] Immunofluorescence: For each incubation a uniform systematic random set of five sections per mouse was selected (one section each from levels 2, 4, 6, 8, 10). All sections were counterstained with the nuclear dye DAPI. Binding of primary' antibodies was visualized using highly cross-absorbed secondary antibodies.

[0262] Protocol of Exp4711 : CD68 + GFAP + Ibal + B-Amyloid + DAPI: All steps were executed in Dulbecco's phosphate buffered saline pH 7.5 (PBS) at room temperature unless noted otherwise.1. cryo-sections were air-dried for 45 minutes and then washed in PBS for 10 minutes2. reduction of autofluorescence by 4 minutes in cold 1 mg / ml sodium borohydride in PBS3. sections were washed 3 x 5 minutes each in PBS4. unspecific binding sites were blocked with M.O.M. blocking reagent (Vector Laboratories) 0. 1% Tergitol in PBS for 60 minutes in a damp chamber5. sections were washed 3 x 5 minutes each in PBS6. sections were incubated with primary' antibodies in M.O.M. diluent (Vector Laboratories) overnight at 4 °C in a damp chamber• rat anti-CD68 monoclonal [FA-11] antibody (BioRad, MCA 1957), 1 : 10000Attorney Docket No : 40978-0774WO1• goat anti-GFAP polyclonal (abeam, ab53554), 1 : 1000• guinea pig anti-Ibal monoclonal |Gp311H9] antibody (Synaptic Systems, 234308), 1:3000• mouse anti-BAmyloid monoclonal [6E10] antibody (BioLegend, B803001), 1 : 10007. sections were washed 3 x 5 minutes each in PBS8. sections were incubated with secondary antibodies in M.O.M. diluent (Vector Laboratories) for 60 minutes in a damp chamber (light protected)• donkey anti-rat IgG H+L DyLight 755-conjugated (Thermo Fisher, SA5- 10031), 1 :500• donkey anti-goat IgG H+L Alexa Fluor 488-conjugated (abeam, abl50129), 1 :500• donkey anti-guinea pig IgG H+L Cy3-conjugated, (Jackson Immunoresearch, 706-165-148), 1:500• donkey anti -mouse IgG H+L DyLight 650-conjugated (Thermo Scientific, SA5-10169), 1 :5009. sections were washed 3 x 5 minutes each in PBS (light protected)10. sections were incubated with DAPI working solution for 15 minutes (light protected)11. sections were washed 2 x 5 minutes in PBS (light protected)12. sections were washed for 5 minutes in ddH2O (light protected)13. sections were automatically covered with Mowiol and coverslips (light protected) using a Leica CV5030 coverslipper.

[0263] Protocol of Exp4718: NeuN + PSD95 + Synaptophysin + DAPI: All steps were executed in Dulbecco's phosphate buffered saline pH 7.5 (PBS) at room temperature unless noted otherwise.1. cryo-sections were air-dried for 45 minutes and then washed in PBS for 10 minutes2. unspecific binding sites were blocked with M.O.M. blocking reagent (Vector Laboratories in 0. 1% Tergitol in PBS for 60 minutes in a damp chamber3. sections were washed 3 x 5 minutes each in PBS4. sections were incubated with primary' antibodies in M.O.M. diluent (Vector Laboratories overnight at 4 °C in a damp chamberAttorney Docket No : 40978-0774WO1• rabbit anti-NeuN polyclonal antibody (Merck Millipore, ABN78). 1:500• guinea pig anti-PSD95 monoclonal [Gpl08E10] antibody (Synaptic Systems, 124 308), 1:800• mouse anti-Synaptophysin monoclonal [SY38] antibody (Abeam, ab8049), 1 : 1005. sections were washed 3 x 5 minutes each in PBS6. sections were incubated with secondary antibodies in M.O.M. diluent (Vector Laboratories for 60 minutes in a damp chamber (light protected)• donkey anti-rabbit IgG H+L Alexa Fluor 750-conjugated (abeam, abl75728), 1:500• donkey anti-guinea pig IgG H+L Cy3-conjugated (Jackson Immunoresearch, 706-165-148), 1:500• donkey anti -mouse IgG H+L Dy Light 650-conjugated (Thermo Scientific, SA5-10169), 1 :5007. sections were washed 3 x 5 minutes each in PBS (light protected)8. sections were incubated with DAPI working solution for 15 minutes (light protected)9. sections were washed 2 x 5 minutes in PBS (light protected)10. sections were washed for 5 minutes in ddH2O (light protected)11. sections were automatically covered with Mowiol and coverslips (light protected) using a Leica CV5030 coverslipper.

[0264] Imaging and Quantification: Whole slide scans of the stained sections were recorded on aZeiss automatic microscope AxioScan Z1 with high aperture lenses, equipped with aZeiss Axiocam 506 mono and a Hitachi 3CCD HV-F202SCL camera and Zeiss ZEN 3.7 software. Image analysis was done with Image Pro 10 (Media Cybernetics). At the beginning the target areas (cortex and subiculum) were identified by drawing regions of interest (ROI) on the images. Additional ROIs excluded wrinkles, air bubbles, or any other artifacts interfering with the measurement. Afterwards, signal of 6E10, Ibal, GFAP, CD68, PSD95, Synaptophysin, and NeuN were quantitatively evaluated within the identified areas, or quantification we used background correction if necessary and detected immunoreactive objects by adequate thresholding and morphological filtering (size, shape). Different object features were then quantified, among them the percentage of cumulative object area based on ROI size (immunoreactive area; this is the most comprehensiveAttorney Docket No : 40978-0774WO1 parameter indicating whether there are differences in immunoreactivity), the number of objects normalized to ROI size (object density), the mean signal intensity of identified objects (mean intensity; this indicates if there are differences in the cellular expression level of target proteins), and the size of above-threshold objects. Once the parameters of the targeted objects had been defined in a test run, the quantitative image analysis ran automatically so that the results were operator-independent and fully reproducible. Statistical analysis was performed using GraphPad Prism software.

[0265] No significant differences among any of the groups were observed in levels of Ibal , CD68, NeuN, Synaptophysin, or PSD95.

Claims

Attorney Docket No : 40978-0774WO1CLAIMS1. A method of treating or preventing a neurodegen erative disease in a subject in need thereof, comprising administering to the subject a urolithin A agent, a fisetin agent, and an isoflavone agent.

2. The method of claim 1, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, a polyglutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander disease, Alpe’s disease, ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration. Creutzfeldt- Jakob disease, ischemia stroke. Krabbe disease, Lewy body dementia, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, Refsum’s disease, Sandhoff disease, Schilder’s disease, spinal cord injury', spinal muscular atrophy, SteeleRichardson-Olszewski disease, or Tabes dorsalis.

3. The method of claims 1 or 2, wherein the urolithin A agent, the fisetin agent, and the isoflavone agent are administered concurrently.

4. The method of claims 1 or 2, wherein the urolithin A agent, the fisetin agent, and the isoflavone agent are administered separately.

5. The method of any one of claims 1-4, wherein the urolithin A agent, the fisetin agent, and the isoflavone agent are administered daily.

6. The method of any one of claims 1-5, wherein the urolithin A agent, the fisetin agent, and the isoflavone agent are administered once per day, twice per day, or three or more times per day.

7. The method of any one of claims 1-6, wherein the urolithin A agent is urolithin A.

8. The method of claim 7, wherein urolithin A is administered to the subject in an amount that is from about 1 mg to about 2500 mg.Attorney Docket No : 40978-0774WO19. The method of claim 8, wherein urolithin A is administered to the subject in an amount that is from 1 mg to about 1500 mg per day.

10. The method of claim 9, wherein urolithin A is administered to the subject at a dose of about 300 mg to about 900 mg twice per day.

11. The method of claim 9, wherein urolithin A is administered to the subject in an amount that is from about 50 mg to about 300 mg per day.

12. The method of claim 9, wherein urolithin A is administered to the subject in an amount of about 100 mg per day.

13. The method of claim 9, wherein urolithin A is administered to the subject in an amount of 200 mg per day.

14. The method of claim 9, wherein urolithin A is administered to the subject in an amount of 300 mg per day.

15. The method of claim 9, wherein urolithin A is administered to the subject at a dose of about 50 mg per day to about 300 mg once per day.

16. The method of claim 9, wherein urolithin A is administered to the subject at a dose of about 50 mg per day to about 300 mg twice per day.

17. The method of claim 9, wherein urolithin A is administered to the subject at a dose of about 100 mg once per day.

18. The method of claim 9, wherein urolithin A is administered to the subject at a dose of about 100 mg twice per day.

19. The method of any one of claims 1-18, wherein the fisetin agent is fisetin.Attorney Docket No : 40978-0774WO120. The method of claim 19, wherein fisetin is administered to the subject at in an amount that is from about 0.5 mg to about 2500 mg.

21. The method of claim 20, wherein fisetin is administered to the subject in an amount that is from about 1 mg to about 500 mg per day.

22. The method of claim 21. wherein the fisetin is administered in in an amount that is from about 25 mg to about 150 mg per day.

23. The method of claim 22, wherein the fisetin is administered in an amount of about 50 mg per day.

24. The method of claim 22, wherein the fisetin is administered in an amount of about 100 mg per day.

25. The method of claim 21. wherein the fisetin is administered in in an amount that is from about 25 mg to about 150 mg once per day.

26. The method of claim 21, wherein the fisetin is administered in in an amount that is from about 25 mg to about 150 mg twice per day.

27. The method of claim 21, wherein the fisetin is administered in in an amount that is about 50 mg once per day.

28. The method of claim 21, wherein the fisetin is administered in in an amount that is about 50 mg twice per day.

29. The method of any one of claims 1-28, wherein the fisetin agent is a first fisetin agent, and the method further comprises administering a second fisetin agent.

30. The method of claim 19, wherein the second fisetin agent is quercetin.Attorney Docket No : 40978-0774WO131. The method of claim 30, wherein quercetin is administered to the subject in an amount that is from about 1 mg to about 1000 mg.

32. The method of claim 31, wherein quercetin is administered to the subject in an amount that is about 1 mg to about 500 mg per day.

33. The method of claim 32. wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg per day.

34. The method of claim 33, wherein the quercetin is administered in an amount of about 50 mg per day.

35. The method of claim 33, wherein the quercetin is administered in an amount of about 100 mg per day.

36. The method of claim 32. wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg once per day.

37. The method of claim 32, wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg twice per day.

38. The method of claim 32, wherein the quercetin is administered in an amount that is about 50 mg once per day.

39. The method of claim 32, wherein the quercetin is administered in an amount that is about 50 mg twice per day.

40. The method of any one of claims 1-39, wherein the isoflavone agent is ipriflavone.

41. The method of claim 40, wherein ipriflavone is administered to the subject in an amount that is from about 1 mg to about 1500 mg per day.Attorney Docket No : 40978-0774WO142. The method of claim 41, wherein ipriflavone is administered to the subject in an amount that is about 100 mg to about 1000 mg per day.

43. The method of claim 42, wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg per day.

44. The method of claim 42. wherein the ipriflavone is administered in an amount of about 150 mg per day.

45. The method of claim 42, wherein the ipriflavone is administered in an amount of about 300 mg per day.

46. The method of claim 42, wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg once per day.

47. The method of claim 42. wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg twice per day.

48. The method of claim 42, wherein the ipriflavone is administered in an amount that is about 150 mg once per day.

49. The method of claim 42, wherein the ipriflavone is administered in an amount that is about 150 mg twice per day.

50. The method of any one of claims 1-49, wherein the method comprises administering to the subject a combination of urolithin A, fisetin, and ipriflavone.

51. The method of any one of claims 1-50, wherein the method comprises administering to the subject a combination of urolithin A, fisetin. quercetin, and ipriflavone.

52. The method of any one of claim 1-51, wherein the method further comprises administering to the subject one or both of nicotinamide riboside or a pharmaceutically acceptable salt thereof, and cat's claw extracts or components thereof.Attorney Docket No : 40978-0774WO153. The method of claim 52, wherein the method further comprises administering to the subject nicotinamide riboside.

54. The method of claim 53, wherein nicotinamide riboside is administered at an amount that is from about 100 mg to about 800 mg.

55. The method of any one of claims 52-54, wherein the method further comprises administering to the subject a cat’s claw extract.

56. The method of claim 55. wherein the cat's claw extract is administered at an amount of about 100 to about 1200 mg.

57. The method of any one of claims 1-56, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

58. The method of any one of claims 1-57, wherein the subject is at risk for developing the neurodegenerative disease.

59. The method of any one of claims 1-58, further comprising, prior to administration, determining or having determined that the subject has one or more symptoms associated with the neurodegenerative disease.

60. The method of any one of claims 1-59, further comprising, prior to administration, determining or having determined that the subject is at risk for developing the neurodegenerative disease.

61. A method of treating or preventing a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an ellagitannin or ellagic acid, a fisetin agent, and an isoflavone agent.

62. The method of claim 61, wherein the subject is a urolithin A producer.Attorney Docket No : 40978-0774WO163. The method of claims 61 or 62, further comprising, prior to administration, determining or having determined that the subject is a urolithin A producer.

64. The method of claim 63, comprising detecting or having detected one or more bacterial species associated with urolithin A production in a biological sample of the subject.

65. The method of claim 64. wherein the bacterial species is Gordonibacter urolithinfaciens or Ellagibacter isourolithinifaciens .

66. The method of any one of claims 61-65, wherein the neurodegenerative disease is Alzheimer’s disease. Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, a poly glutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander disease, Alpe’s disease, ataxia telangiectasia, Batten disease, Canavan disease. Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease. Lewy’ body dementia, multiple system atrophy, Pelizaeus- Merzbacher disease. Pick’s disease, primary lateral sclerosis. Refsum’s disease, Sandhoff disease, Schilder’s disease, spinal cord injury, spinal muscular atrophy, SteeleRichardson- Olszewski disease, or Tabes dorsalis.

67. The method of any one of claims 61-66. wherein the ellagitannin or ellagic acid, the fisetin agent, and the isoflavone agent are administered concurrently.

68. The method of any one of claims 61-66, wherein the ellagitannin or ellagic acid, the fisetin agent, and the isoflavone agent are administered separately.

69. The method of any’ one of claims 61-68, wherein the ellagitannin or ellagic acid, the fisetin agent, and / or the isoflavone agent are administered daily.

70. The method of any one of claims 61-69. wherein the ellagitannin or ellagic acid, the fisetin agent, and / or the isoflavone agent are administered once a day, twice a day, or three or more times a day.

71. The method of any one of claims 61-70. wherein the fisetin agent is fisetin.Attorney Docket No : 40978-0774WO172. The method of claim 71, wherein fisetin is administered to the subject at in an amount that is from about 0.5 mg to about 2500 mg.

73. The method of claim 72, wherein fisetin is administered to the subject in an amount that is from about 1 mg to about 500 mg per day.

74. The method of claim 73, wherein the fisetin is administered in an amount that is from about 25 mg to about 150 mg per day.

75. The method of claim 73. wherein the fisetin is administered in an amount of about 50 mg per day.

76. The method of claim 73, wherein the fisetin is administered in an amount of about 100 mg per day.

77. The method of claim 73, wherein the fisetin is administered in an amount that is from about 25 mg to about 150 mg once per day.

78. The method of claim 73. wherein the fisetin is administered in an amount that is from about 25 mg to about 150 mg twice per day.

79. The method of claim 73, wherein the fisetin is administered in an amount that is about 50 mg once per day.

80. The method of claim 73, wherein the fisetin is administered in an amount that is about 50 mg twice per day.

81. The method of any one of claims 61-80, wherein the fisetin agent is a first fisetin agent, and the method further comprises administering a second fisetin agent.

82. The method of claim 81, wherein the second fisetin agent is quercetin.Attorney Docket No : 40978-0774WO183. The method of claim 82, wherein quercetin is administered to the subject in an amount that is from about 1 mg to about 1000 mg.

84. The method of claim 83, wherein quercetin is administered to the subject in an amount that is about 1 mg to about 500 mg per day.

85. The method of claim 84. wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg per day.

86. The method of claim 84, wherein the quercetin is administered in an amount of about 50 mg per day.

87. The method of claim 84, wherein the quercetin is administered in an amount of about 100 mg per day.

88. The method of claim 84. wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg once per day.

89. The method of claim 84, wherein the quercetin is administered in an amount that is from about 25 mg to about 150 mg twice per day.

90. The method of claim 84, wherein the quercetin is administered in an amount that is about 50 mg once per day.

91. The method of claim 84, wherein the quercetin is administered in an amount that is about 50 mg twice per day.

92. The method of any one of claims 61-91, wherein the isoflavone agent is ipriflavone.

93. The method of claim 92, wherein ipriflavone is administered to the subject in an amount that is from about 1 mg to about 1500 mg per day.Attorney Docket No : 40978-0774WO194. The method of claim 93, wherein ipriflavone is administered to the subject in an amount that is about 100 mg to about 1000 mg per day.

95. The method of claim 94, wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg per day.

96. The method of claim 94. wherein the ipriflavone is administered in an amount of about 150 mg per day.

97. The method of claim 94, wherein the ipriflavone is administered in an amount of about 300 mg per day.

98. The method of claim 94, wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg once per day.

99. The method of claim 94. wherein the ipriflavone is administered in an amount that is from about 100 mg to about 500 mg twice per day.

100. The method of claim 94, wherein the ipriflavone is administered in an amount that is about 150 mg once per day.

101. The method of claim 94, wherein the ipriflavone is administered in an amount that is about 150 mg twice per day.

102. The method of any one of claims 61-101, wherein the method comprises administering to the subject a combination of an ellagitannin or ellagic acid, fisetin, and ipriflavone.

103. The method of any one of claims 61-102, wherein the method comprises administering to the subject a combination of an ellagitannin or ellagic acid, fisetin. quercetin, and ipriflavone.Attorney Docket No : 40978-0774WO1104. The method of any one of claim 61-103, wherein the method further comprises administering to the subject one or both of nicotinamide riboside or a pharmaceutically acceptable salt thereof, or cat’s claw extracts or components thereof.

105. The method of claim 104, wherein the method further comprises administering to the subject nicotinamide riboside.

106. The method of claim 105, wherein nicotinamide riboside is administered at an amount that is from about 100 mg to about 800 mg.

107. The method of any one of claims 104-106, wherein the method further comprises administering to the subject a cat’s claw extract.

108. The method of claim 107, wherein the cat’s claw extract is administered at an amount of about 100 to about 1200 mg.

109. The method of any one of claims 61-108, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

110. The method of any one of claims 61-109, wherein the subject is at risk for developing the neurodegenerative disease.

111. The method of any one of claims 61-109, further comprising, prior to administration, determining or having determined that the subject has one or more symptoms associated with the neurodegenerative disease.

112. The method of any one of claims 61-109 and 111, further comprising, prior to administration, determining or having determined that the subject is at risk for developing the neurodegenerative disease.

113. The method of any one of claims 61-112, wherein the method comprises administering to the subject a therapeutically effective amount of a combination of an ellagitannin or ellagic acid, fisetin, and ipriflavone.Attorney Docket No : 40978-0774WO1114. A method of treating or preventing a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an ellagitannin or ellagic acid, a fisetin agent, an isoflavone agent, and a composition comprising one or more bacterial species associated with urolithin A production.

115. The method of claim 114, wherein the bacterial species is Gordonibacter urolithinfaciens or Ellagibacter isourolithinifaciens .

116. The method of claims 114 or 115, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson’s disease. Huntington’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, a poly glutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander disease, Alpe’s disease, ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple system atrophy. Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, Refsum’s disease. Sandhoff disease, Schilder’s disease, spinal cord injury, spinal muscular atrophy, SteeleRichardson-Olszewski disease, or Tabes dorsalis.

117. The method of any one of claims 114-116. wherein the ellagitannin or ellagic acid, the fisetin agent, the isoflavone agent, and the composition comprising one or more bacterial species are administered concurrently.

118. The method of any one of claims 114-117, wherein the ellagitannin or ellagic acid, the fisetin agent, the isoflavone agent, and the composition comprising one or more bacterial species are administered separately.

119. The method of any one of claims 114-118, wherein the ellagitannin or ellagic acid, the fisetin agent, and the isoflavone agent are administered daily.

120. The method of any one of claims 114-119, wherein the ellagitannin or ellagic acid, the fisetin agent, and the isoflavone agent are administered once a day, twice a day, or three or more times a day.Attorney Docket No : 40978-0774WO1121. The method of any one of claims 114-120, wherein the fisetin agent is fisetin.

122. The method of claim 121, wherein fisetin is administered to the subject at in an amount that is from about 0.5 mg to about 2500 mg.

123. The method of claim 122, wherein fisetin is administered to the subject in an amount that is from about 1 mg to about 500 mg per day.

124. The method of any one of claims 114-123, wherein the fisetin agent is a first fisetin agent, and the method further comprises administering a second fisetin agent.

125. The method of claim 124, wherein quercetin is administered to the subject in an amount that is from about 1 mg to about 1000 mg.

126. The method of claim 125, wherein quercetin is administered to the subject in an amount that is about 1 mg to about 500 mg per day.

127. The method of any one of claims 114-126, wherein the isoflavone agent is ipriflavone.

128. The method of claim 127, wherein ipriflavone is administered to the subject in an amount that is from about 1 mg to about 1500 mg per day.

129. The method of claim 128, wherein ipriflavone is administered to the subject in an amount that is about 100 mg to about 1000 mg per day.

130. The method of any one of claims 114-129, wherein the method comprises administering to the subject a combination of an ellagitannin or ellagic acid, fisetin, ipriflavone and a composition comprising one or more bacterial species associated with urolithin A production.

131. The method of any one of claims 114-130, wherein the method comprises administering to the subject a combination of an ellagitannin or ellagic acid, fisetin, quercetin, ipriflavoneAttorney Docket No : 40978-0774WO1 and a composition comprising one or more bacterial species associated with urolithin A production.

132. The method of any one of claim 114-131, wherein the method further comprises administering to the subject one or both of nicotinamide riboside or a pharmaceutically acceptable salt thereof, or cat’s claw extracts or components thereof.

133. The method of claim 132, wherein the method further comprises administering to the subject nicotinamide riboside.

134. The method of claim 133, wherein nicotinamide riboside is administered at an amount that is from about 100 mg to about 800 mg.

135. The method of any one of claims 132-134, wherein the method further comprises administering to the subject cat’s claw extracts or components thereof.

136. The method of claim 135, wherein the cat’s claw extracts or components thereof is administered at an amount of about 100 to about 1200 mg.

137. The method of any one of claims 114-136, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

138. The method of any one of claims 114-137, wherein the subject is at risk for developing the neurodegenerative disease.

139. The method of any one of claims 114-137, further comprising, prior to administration, determining or having determined that the subject has one or more symptoms associated with the neurodegenerative disease.

140. The method of any one of claims 1 14-139, further comprising, prior to administration, determining or having determined that the subject is at risk for developing the neurodegenerative disease.Attorney Docket No : 40978-0774WO1141. A composition comprising a urolithin A agent, a fisetin agent, and an isoflavone agent.

142. The composition of claim 141, wherein the urolithin A agent is urolithin A.

143. The composition of claim 142, wherein the composition comprises from about 1 mg to about 2500 mg of urolithin A.

144. The composition of claim 143, wherein the composition comprises from about 50 mg to about 300 mg urolithin A.

145. The composition of claim 143, wherein the composition comprises about 100 mg urolithin A.

146. The composition of any one of claims 141-145, wherein the fisetin agent is fisetin.

147. The composition of claim 146, wherein the composition comprises from about 1 mg to about 1000 mg of fisetin.

148. The composition of claim 147, wherein the composition comprises from about 25 mg to about 150 mg fisetin.

149. The composition of claim 147, wherein the composition comprises about 50 mg fisetin.

150. The composition of any one of claims 141-149, wherein the isoflavone agent is ipriflavone.

151. The composition of claim 150. wherein the composition comprises from about 1 mg to about 1500 mg of ipriflavone.

152. The composition of claim 151, wherein the composition comprises from about 100 mg to about 500 mg ipriflavone.Attorney Docket No : 40978-0774WO1153. The composition of claim 151, wherein the composition comprises about 50 mg ipriflavone.

154. The composition of any one of claims 141-153, wherein the fisetin agent is a first fisetin agent and the composition further comprises a second fisetin agent.

155. The composition of claim 154. wherein the second fisetin agent is quercetin.

156. The composition of claim 155, wherein the composition comprises from about 1 to about 1000 mg of quercetin.

157. The composition of claim 156, wherein the composition comprises from about 25 mg to about 150 mg quercetin.

158. The composition of claim 156, wherein the composition comprises about 50 mg quercetin.

159. The composition of any one of claims 141-158, wherein the composition further comprises nicotinamide riboside, or a pharmaceutically acceptable salt thereof.1 0. The composition of claim 159, wherein the composition comprises from about 100 mg to about 800 mg of nicotinamide riboside.

161. The composition of any one of claims 141-160, wherein the composition further comprises cat’s claw extracts or components thereof.

162. The composition of claim 161, wherein the composition comprises from about 100 to about 1200 mg of cat’s claw extract, or components thereof.

163. A composition comprising: urolithin A, or a pharmaceutically acceptable salt thereof; fisetin, or a pharmaceutically acceptable salt thereof; quercetin, or a pharmaceutically acceptable salt thereof; andAttorney Docket No : 40978-0774WO1 ipriflavone, or a pharmaceutically acceptable salt thereof.

164. The composition of claim 163 comprising: from about 50 mg to about 300 mg urolithin A; from about 25 mg to about 150 mg fisetin; from about 25 mg to about 150 mg quercetin; and from about 100 mg to about 500 mg ipriflavone.

165. The composition of claim 163 comprising: about 100 mg urolithin A; about 50 mg fisetin; about 50 mg quercetin; and about 150 mg ipriflavone.

166. The composition of any one of claims 141-165, wherein the composition is in a unit dosage form.

167. The composition of claim 168, wherein the unit dosage form is an oral dosage form.

169. A kit comprising the composition of any one of claims 141-167.

169. The kit of claim 168, wherein the composition is provided is in an oral dosage form and the kit further comprises instructions to consume one oral dosage form daily.

170. The kit of claim 168, wherein the composition is provided is in an oral dosage form and the kit further comprises instructions to consume two oral dosage forms daily.

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