WO2020160618A1 - An anti-cell-senescence composition and method of use - Google Patents

An anti-cell-senescence composition and method of use Download PDF

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Publication number
WO2020160618A1
WO2020160618A1 PCT/AU2020/050093 AU2020050093W WO2020160618A1 WO 2020160618 A1 WO2020160618 A1 WO 2020160618A1 AU 2020050093 W AU2020050093 W AU 2020050093W WO 2020160618 A1 WO2020160618 A1 WO 2020160618A1
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composition
extract
schinopsis
formulated
tocotrienol
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PCT/AU2020/050093
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French (fr)
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Raymond Denis PALMER
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Helium 3 Biotech Pty Ltd
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Priority claimed from AU2019900345A external-priority patent/AU2019900345A0/en
Application filed by Helium 3 Biotech Pty Ltd filed Critical Helium 3 Biotech Pty Ltd
Publication of WO2020160618A1 publication Critical patent/WO2020160618A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates to an anti-cell-senescence composition and a method of use thereof.
  • senescent cells accumulate in the tissues of organs. Such senescent cells are thought to be associated with age-related dysfunction of such organs. Additionally, senescent cells are also associated with the development of morbidities within the ageing populations world-wide.
  • compositions that will mitigate an effect of cell senescence when administered in a therapeutically effective dose to a subject in need thereof and a method of using such a composition.
  • Senescent cells accumulate in multicellular organisms, such as humans, with the passage of time. Accumulation of senescent cells is associated with deleterious effects that are typically termed “ageing”. These deleterious effects, including a deterioration of cell function, lead to an increase of ageing-related pathologies and inevitably accelerate mortality. Purging of senescent cells may delay onset of ageing- related negative effects on the health of an individual and contribute to economic benefits insofar as the costs associated with an increase in the ageing populations world-wide may be diminished.
  • the present disclosure in one aspect sets forth a composition including a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol, the composition formulated to mitigate a condition associated with cell senescence of a subject.
  • the present disclosure in another aspect a method of mitigating a condition associated with cell senescence of a subject, the method including administering to a subject in need thereof a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
  • the present disclosure is directed to a composition that mitigates an effect of senescence in one or more cell of a multicellular organism, such as humans, that may arise with the passage of time.
  • the present disclosure also relates to a method of use of the composition.
  • the term“senescent” and derivatives thereof, e.g.,“senescence”, should be understood for the purposes herein to define that stage of a cell’s lifecycle where the cell is neither in interphase nor cell division stages.
  • compositions for mitigating at least one condition associated with cell senescence in a subject including a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
  • mitigation e.g., mitigating
  • mitigating in this context is expressed relative to a non-senescent cell, i.e., a cell that is either in interphase or undergoing cell division.
  • a therapeutically effective dose refers to an amount of a composition administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • each of the fisetin, quercetin, extract of Schinopsis sp., Fragaria sp. extract, and tocotrienol will depend on a preferred route of administration, the rate and expected duration of release of the composition, and the nature of the condition, disease or disorder to be treated or prevented.
  • each of the fisetin, quercetin, extract of Schinopsis sp., Fragaria sp. extract, and tocotrienol is present in an amount of 20 - 150 mg.
  • fisetin is present in an amount of 100 mg.
  • the quercetin is present in an amount of 50 mg.
  • the extract of Schinopsis sp. is present in an amount of 50 mg. In a further preferred embodiment, the extract of Fragaria sp. is present in an amount of 50 mg. In a further preferred embodiment, the tocotrienol is present in an amount of 50 mg.
  • the extract of Schinopsis sp. is an extract of Schinopsis balansaeado.
  • the extract of Schinopsis sp. is an extract of Schinopsis brasiliensis.
  • the extract of Schinopsis sp. is an extract of Schinopsis haenkeana.
  • the extract of Schinopsis sp. is an extract of Schinopsis heterophylla.
  • the extract of Schinopsis sp. is an extract of Schinopsis lorentzii.
  • the extract of Schinopsis sp. is an extract of Schinopsis marginata.
  • the extract of Fragaria sp. is an extract of Fragaria x ananassa.
  • the tocotrienol is a-tocotrienol. In another preferred embodiment, the tocotrienol is b-tocotrienol. In another preferred embodiment, the tocotrienol is y-tocotrienol. In another preferred embodiment, the tocotrienol is d-tocotrienol.
  • the composition is formulated for enteral administration.
  • the composition herein disclosed may be delivered to a subject in need thereof by any one of several routes.
  • the composition may be delivered via buccal, infusion (e.g., a bolus infusion), inhalation, intracranial injection, enteral, intradermal, intramuscular, intranasal, intraocular, intraperitoneally, intravenously, orally, rectal, rectal, subcutaneously, sublingual, topically, transdermal, vaginal, or any combination thereof.
  • the composition may be formulated for enteral administration.
  • composition herein disclosed may be formulated for delayed release (also termed sustained or slow release, timed release, delayed release, or controlled release).
  • delayed release also termed sustained or slow release, timed release, delayed release, or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site in a delayed release manner.
  • Delayed-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling barrier.
  • a particularly preferred embodiment of the composition may be formulated in an enteric coating layer.
  • the enteric coating layer may include one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates.
  • composition disclosed herein may be formulated with a buffering agent to protect the compound from low pH of the gastric environment and/or an enteric coating.
  • the composition may, when administer orally, buccally, or sublingually, may be formulated with a flavouring agent, e.g., in a liquid, solid or semi-solid formulation.
  • Preferred embodiments may include one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment.
  • Preferred embodiments will include at least one excipient that is biocompatible and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the excipient facilitates absorption. In yet a further particularly preferred embodiment, the excipient enhances solubility.
  • the composition may be a tablet formulation.
  • the composition may be a powder formulation.
  • the powder formulation may be in a capsule.
  • the composition may be a liquid formulation.
  • the composition may be formulated for parenteral administration.
  • the composition may be formulated for subcutaneous administration.
  • the composition may be formulated for intramuscular administration.
  • the composition may be formulated for intravenous administration.
  • the composition may be formulated for intradermal administration.
  • the composition may be formulated for transdermal administration.
  • composition disclosed herein will be administered for a sufficient amount of time to selectively purge senescent cells from one or more tissue in a subject, wherein the purging of such cells does not lead to a cancer.
  • purging of senescent cells may ameliorate at least one symptom associated with a number of pathologies.
  • Such pathologies may include age-related loss of pulmonary function, Alzheimer's disease, angina, aortic aneurysm, arrhythmia, arteriosclerosis, asthma, atherosclerosis, atopic dermatitis, brain aneurysm, bronchiectasis, cardiac diastolic dysfunction, a cancer, cardiac fibrosis, cardiac stress resistance, cardiomyopathy, carotid artery disease, cataracts, chronic obstructive pulmonary disease, chronic renal failure, congestive heart failure, coronary artery disease, coronary thrombosis, cutaneous lupus, cutaneous lymphomas, cystic fibrosis, dementia, diabetes, diabetic ulcer, diseases and disorders related to photosensitivity or photoaging, dysesthesia, eczema, eczematous eruptions, emphysema, endocarditis, eosinophilic dermatosis, fibrohistocytic proliferations of skin, frailty, glaucoma,
  • composition will be administered for a time sufficient and in an amount sufficient that selectively ameliorates at least one symptom associated with insufficient Klotho production and/or distribution as a functional integral protein in an organelle and/or cell membrane.
  • a method for mitigating a condition associated with cell senescence of a subject including administering to a subject in need thereof a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
  • the method may include a treatment course no longer than (a) one month, or (b) no longer than two months, or (c) no longer than three months.
  • each treatment course is no longer than (a) five days, (b) seven days, (c) ten days, (d) fourteen days, or (e) twenty-one days.
  • the composition is administered every second day or every third day of each treatment course.
  • the composition is administered once daily during each treatment course.
  • the composition is administered twice daily during each treatment course. Suitable interval periods between treatments will be known to a person skilled in the art.
  • the subject may be a multicellular animal.
  • the multicellular animal is a human.

Abstract

The present invention relates to pharmaceutical compositions comprising a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol, and the use of these in a method of mitigating a condition associated with cell senescence.

Description

AN ANTI-CELL-SENESCENCE COMPOSITION AND METHOD OF USE
Field of Invention
The present disclosure relates to an anti-cell-senescence composition and a method of use thereof.
Background of Invention
As animals, including humans, age, senescent cells accumulate in the tissues of organs. Such senescent cells are thought to be associated with age-related dysfunction of such organs. Additionally, senescent cells are also associated with the development of morbidities within the ageing populations world-wide.
Given the afore-mentioned dysfunction and morbidities within the ageing populations around the world, a need exists for a composition that will mitigate an effect of cell senescence when administered in a therapeutically effective dose to a subject in need thereof and a method of using such a composition.
Summary
Senescent cells accumulate in multicellular organisms, such as humans, with the passage of time. Accumulation of senescent cells is associated with deleterious effects that are typically termed “ageing”. These deleterious effects, including a deterioration of cell function, lead to an increase of ageing-related pathologies and inevitably accelerate mortality. Purging of senescent cells may delay onset of ageing- related negative effects on the health of an individual and contribute to economic benefits insofar as the costs associated with an increase in the ageing populations world-wide may be diminished.
The present disclosure in one aspect sets forth a composition including a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol, the composition formulated to mitigate a condition associated with cell senescence of a subject.
The present disclosure in another aspect a method of mitigating a condition associated with cell senescence of a subject, the method including administering to a subject in need thereof a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
The reference to any prior art in this specification is not and should not be taken as an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia or in any other country. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed, unless otherwise stated. In the present specification and claims, the word“comprising” and its derivatives including“comprises” and“comprise” include each of the stated integers but does not exclude the inclusion of one or more integers. The claims as filed with this application are hereby incorporated by reference in the description.
Detailed Description
The present disclosure is directed to a composition that mitigates an effect of senescence in one or more cell of a multicellular organism, such as humans, that may arise with the passage of time. The present disclosure also relates to a method of use of the composition. The term“senescent” and derivatives thereof, e.g.,“senescence”, should be understood for the purposes herein to define that stage of a cell’s lifecycle where the cell is neither in interphase nor cell division stages.
In a preferred embodiment, there is provided a composition for mitigating at least one condition associated with cell senescence in a subject. The composition including a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
A skilled person will appreciate that the mitigation, and derivatives thereof, e.g., mitigating, in this context is expressed relative to a non-senescent cell, i.e., a cell that is either in interphase or undergoing cell division.
Without wishing to be bound by theory, a therapeutically effective dose refers to an amount of a composition administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
It will be appreciated that the amount of each of the fisetin, quercetin, extract of Schinopsis sp., Fragaria sp. extract, and tocotrienol will depend on a preferred route of administration, the rate and expected duration of release of the composition, and the nature of the condition, disease or disorder to be treated or prevented. In a preferred embodiment, each of the fisetin, quercetin, extract of Schinopsis sp., Fragaria sp. extract, and tocotrienol is present in an amount of 20 - 150 mg. In a further preferred embodiment, fisetin is present in an amount of 100 mg. In a further preferred embodiment, the quercetin is present in an amount of 50 mg. In a further preferred embodiment, the extract of Schinopsis sp. is present in an amount of 50 mg. In a further preferred embodiment, the extract of Fragaria sp. is present in an amount of 50 mg. In a further preferred embodiment, the tocotrienol is present in an amount of 50 mg.
In a preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis balansaeado. In another preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis brasiliensis. In another preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis haenkeana. In another preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis heterophylla. In another preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis lorentzii.
In another preferred embodiment, the extract of Schinopsis sp. is an extract of Schinopsis marginata. In another preferred embodiment, the extract of Fragaria sp. is an extract of Fragaria x ananassa.
In yet another preferred embodiment, the tocotrienol is a-tocotrienol. In another preferred embodiment, the tocotrienol is b-tocotrienol. In another preferred embodiment, the tocotrienol is y-tocotrienol. In another preferred embodiment, the tocotrienol is d-tocotrienol.
In another preferred embodiment, the composition is formulated for enteral administration. A person skilled in the art will appreciate that the composition herein disclosed may be delivered to a subject in need thereof by any one of several routes. By way of non-limiting example, the composition may be delivered via buccal, infusion (e.g., a bolus infusion), inhalation, intracranial injection, enteral, intradermal, intramuscular, intranasal, intraocular, intraperitoneally, intravenously, orally, rectal, rectal, subcutaneously, sublingual, topically, transdermal, vaginal, or any combination thereof. Preferably, the composition may be formulated for enteral administration.
It will be appreciated that the composition herein disclosed may be formulated for delayed release (also termed sustained or slow release, timed release, delayed release, or controlled release). Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site in a delayed release manner. Delayed-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling barrier.
A particularly preferred embodiment of the composition may be formulated in an enteric coating layer. In a preferred embodiment, the enteric coating layer may include one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates.
A skilled person will appreciate that the composition disclosed herein may be formulated with a buffering agent to protect the compound from low pH of the gastric environment and/or an enteric coating. Furthermore, the composition may, when administer orally, buccally, or sublingually, may be formulated with a flavouring agent, e.g., in a liquid, solid or semi-solid formulation. Preferred embodiments may include one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment. Preferred embodiments will include at least one excipient that is biocompatible and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
In a particularly preferred embodiment, the excipient facilitates absorption. In yet a further particularly preferred embodiment, the excipient enhances solubility.
In a further preferred embodiment, the composition may be a tablet formulation.
In a further preferred embodiment, the composition may be a powder formulation. In a particularly preferred embodiment, the powder formulation may be in a capsule.
In a further preferred embodiment, the composition may be a liquid formulation. Preferably, the composition may be formulated for parenteral administration. In a particularly preferred embodiment, the composition may be formulated for subcutaneous administration. In a further particularly preferred embodiment, the composition may be formulated for intramuscular administration. In a further particularly preferred embodiment, the composition may be formulated for intravenous administration. In a further particularly preferred embodiment, the composition may be formulated for intradermal administration. In a further particularly preferred embodiment, the composition may be formulated for transdermal administration.
A skilled person will appreciate that the composition disclosed herein will be administered for a sufficient amount of time to selectively purge senescent cells from one or more tissue in a subject, wherein the purging of such cells does not lead to a cancer. A skilled person will also appreciated that such purging of senescent cells may ameliorate at least one symptom associated with a number of pathologies. Such pathologies may include age-related loss of pulmonary function, Alzheimer's disease, angina, aortic aneurysm, arrhythmia, arteriosclerosis, asthma, atherosclerosis, atopic dermatitis, brain aneurysm, bronchiectasis, cardiac diastolic dysfunction, a cancer, cardiac fibrosis, cardiac stress resistance, cardiomyopathy, carotid artery disease, cataracts, chronic obstructive pulmonary disease, chronic renal failure, congestive heart failure, coronary artery disease, coronary thrombosis, cutaneous lupus, cutaneous lymphomas, cystic fibrosis, dementia, diabetes, diabetic ulcer, diseases and disorders related to photosensitivity or photoaging, dysesthesia, eczema, eczematous eruptions, emphysema, endocarditis, eosinophilic dermatosis, fibrohistocytic proliferations of skin, frailty, glaucoma, hearing loss, herniated intervertebral disc, Huntington's disease, hypercholesterolemia, hyperlipidemia, hyperpigmentation, hypertension, hypertension, immunobullous dermatosis, impaired angiogenesis, impaired endothelium-dependent vasodilation, inflammatory bowel disease, klotho-associated vitamin D metabolic abnormalities, kyphosis, liver fibrosis, macular degeneration, metabolic syndrome, mild cognitive impairment, mitral valve prolapse, motor neuron dysfunction, muscle fatigue, myocardial infarction, nevi, rashes, obesity, oral mucositis, oral submucosa fibrosis, osteoarthritis, osteoarthritis, osteoporosis, osteoporosis, pathologies associated with the cardiovascular system through endothelium-derived NO production, pancreatic fibrosis, Parkinson's disease, pathologies associated with cellular calcium homeostasis, pathologies associated with perturbed TRPV5, i.e., transient receptor potential cation channel subfamily v member 5, pathologies of the skin, pemphigoid, pemphigus, peripheral vascular disease, presbyopia, pruritis, psoriasis, pulmonary fibrosis, pulmonary fibrosis, reactive neutrophilic dermatosis, renal disease, renal failure, rhytides, sarcopenia, skin conditions, skin wound healing, stroke, urticaria, and vision loss.
As described herein it will be appreciated that the composition will be administered for a time sufficient and in an amount sufficient that selectively ameliorates at least one symptom associated with insufficient Klotho production and/or distribution as a functional integral protein in an organelle and/or cell membrane.
In another embodiment, a method for mitigating a condition associated with cell senescence of a subject. The method including administering to a subject in need thereof a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
In preferred embodiments of the method disclosed herein, the method may include a treatment course no longer than (a) one month, or (b) no longer than two months, or (c) no longer than three months. In further preferred embodiments, each treatment course is no longer than (a) five days, (b) seven days, (c) ten days, (d) fourteen days, or (e) twenty-one days. In further preferred embodiments, the composition is administered every second day or every third day of each treatment course. In another specific embodiment, the composition is administered once daily during each treatment course. In another preferred embodiment, the composition is administered twice daily during each treatment course. Suitable interval periods between treatments will be known to a person skilled in the art.
In a preferred embodiment, the subject may be a multicellular animal. Preferably, the multicellular animal is a human.
The features described with respect to one embodiment may be applied to other embodiments, or combined with, or interchanged with, the features of other embodiments without departing from the scope of the present invention.
Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

What is claimed is:
1. A composition comprising a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol, the composition formulated to mitigate a condition associated with cell senescence of a subject.
2. The composition of claim 1 , wherein each of the fisetin, quercetin, extract of Schinopsis sp., Fragaria sp. extract, and tocotrienol is present in an amount of 20 - 150 mg.
3. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis balansaeado.
4. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis brasiliensis.
5. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis haenkeana.
6. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis heterophylla.
7. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis lorentzii.
8. The composition of either claim 1 or claim 2, wherein the extract of Schinopsis sp. is an extract of Schinopsis marginata.
9. The composition of either claim 1 or claim 2, wherein the extract of Fragaria sp. is an extract of Fragaria x ananassa.
10. The composition of either claim 1 or claim 2, wherein the tocotrienol is a- tocotrienol.
1 1. The composition of either claim 1 or claim 2, wherein the tocotrienol is b- tocotrienol.
12. The composition of either claim 1 or claim 2, wherein the tocotrienol is y- tocotrienol.
13. The composition of either claim 1 or claim 2, wherein the tocotrienol is d- tocotrienol.
14. The composition of any one of claims 1 to 13, formulated for enteral administration.
15. The composition of claim 14, formulated for delayed release.
16. The composition of claim 15, formulated in an enteric coating layer.
17. The composition of claim 16, wherein the enteric coating layer includes one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates.
18. The composition of any one of claims 1 to 17, further comprising one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment.
18. The composition of claim 18, wherein the excipient facilitates absorption.
19. The composition of claim 18, wherein the excipient enhances solubility.
20. The composition of any one of claims 1 to 19, wherein the composition is a tablet formulation.
21. The composition of any one of claims 1 to 19, wherein the composition is a powder formulation.
22. The composition of claim 21 , wherein the powder formulation is in a capsule.
23. The composition of any one of claims 1 to 19, wherein the composition is a liquid formulation.
24. The composition of any one of claims 1 to 13 and 23, formulated for parenteral administration.
25. The composition of claim 24, formulated for subcutaneous administration.
26. The composition of claim 24, formulated for intramuscular administration.
27. The composition of claim 24, formulated for intravenous administration.
28. The composition of claim 24, formulated for intradermal administration.
29. The composition of claim 24, formulated for transdermal administration.
30. A method of mitigating a condition associated with cell senescence of a subject, the method comprising administering to a subject in need thereof a therapeutically effective dose of each of fisetin, quercetin, an extract of Schinopsis sp., a Fragaria sp. extract, and a tocotrineol.
31. The method of claim 30, wherein the subject is a human.
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