FIELD

[0001] The field of the disclosure relates generally to compositions for the treatment of benign prostatic hypertrophy (also referred to as benign prostatic hyperplasia, BPH). More specifically, the field of disclosure relates generally to compositions for the treatment of BPH that include mammalian target of rapamycin (mTOR) inhibitors optionally combined with thyroid hormones.

BACKGROUND

[0002] Benign prostatic hypertrophy, a benign overgrowth of prostate tissue, is generally a disease that affects men as they age and can cause affected men to experience urinary symptoms including impeded flow of urine and/or semen, frequent and/or urgent need to urinate, nocturia, inability to urinate, and incomplete voiding of the bladder. The disease can be a significant factor in the development of bladder, urinary tract and kidney diseases. The urethra, which carries urine from the bladder, passes from the bladder and directly through the prostate gland. When the prostate gland becomes enlarged, it applies pressure on the urethra and/or the bladder, which can impede the flow of urine and/or semen either partially or completely.

[0003] Certain factors, if present, can increase the risk of developing BPH including aging, family history, diabetes, heart diseases, erectile dysfunction and obesity. BPH is rarely diagnosed in men prior to the age of 40, but the risk of onset increases from the age of 40 on and may be as high as 90% in men that are 80 years of age or older. In severe cases of BPH, there is a complete blockage of urine flow that may require surgical intervention or catheter insertion to drain the bladder. Incomplete voiding of the bladder as a result of BPH increases the risk of developing urinary tract infections; bladder stones that can cause bladder infection, irritation and hematuria; and damage to the muscular wall of the bladder. The kidneys may also be damaged by the inability to effectively urinate or from bladder or urinary tract infections that reach the kidneys. However, BPH is not considered a precursor to prostate cancer, nor is it believed to increase the risk of developing prostate cancer. [0004] While several different treatments for BPH are available, including surgery, medications, and minimally invasive procedures to reduce the size of the prostate, some of these treatments may be contraindicated depending on the severity of the disease, other health conditions and side effects associated with the treatments. Medications that are commonly used to treat BPH include 5-alpha reductase inhibitors, alpha-adrenergic blockers, phosphodiesterase-5 inhibitors or combinations thereof; however, symptom improvement is experienced by only about 30-60% of men and it is not currently possible to predict which patients will benefit from these therapies. Some of these therapies are required to be continued indefinitely and can have adverse effects including sexual dysfunction, physical changes including gynecomastia, muscle weakness and orthostatic hypotension, and psychological effects including depression, anxiety, and suicidal thoughts. New treatment approaches are needed.

BRIEF DESCRIPTION

[0005] Disclosed herein are pharmaceutical compositions for the treatment of benign prostatic hypertrophy comprising an effective amount of one or more mTOR inhibitors and optionally an effective amount of one or more thyroid hormones.

[0006] In other aspects, disclosed herein are methods for administering pharmaceutical compositions for the treatment of benign prostatic hypertrophy comprising administering an effective amount of a pharmaceutical composition of one or more mTOR inhibitors and optionally an effective amount of one or more thyroid hormones.

DETAILED DESCRIPTION

[0007] In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. “Optional” or “optionally” means that the subsequently described event or a circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0008] Approximating language, as used herein throughout the specification and claims, may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about,” “approximately,” and “substantially,” are not to be limited to the precise value specified. In at least some instances, the approximating language may correspond to the precision of an instrument for measuring the value. Here and throughout the specification and claims, range limitations may be combined and/or interchanged; such ranges are identified and include all the sub-ranges contained therein unless context or language indicates otherwise.

[0009] As used herein, the term "patient" refers to a warm-blooded animal such as a mammal which is the subject of a medical treatment for a medical condition that causes at least one symptom. It is understood that at least humans, dogs, cats, and horses are within the scope of the meaning of the term. In some aspects, the patient is human. Generally, as used herein, the term "patient" means a human or an animal for which the compositions of the disclosure may be administered.

[0010] As used herein, the terms "treat", "treating", and "treatment" include inhibiting the pathological condition, disorder, or disease, e.g., arresting or reducing the development of the pathological condition, disorder, or disease or its clinical symptoms; or relieving the pathological condition, disorder, or disease, e.g., causing regression of the pathological condition, disorder, or disease or its clinical symptoms. These terms encompass also therapy and cure. Treatment means any manner in which the symptoms of a pathological condition, disorder, or disease are ameliorated or otherwise beneficially altered.

[0011] As used herein, the terms “benign prostatic hypertrophy (BPH)” and “benign prostatic hyperplasia” are used interchangeably and refer to the same disease in which the cells of the prostate tissue overgrow to a point where the prostate is beyond a normal size and causes pressure against the urethra and/or the bladder. This growth is benign and is not thought to be a precursor nor increase the risk of developing prostate cancer. BPH often results in urinary symptoms including impeded flow of urine and/or semen, frequent and/or urgent need to urinate, nocturia, inability to urinate, and/or incomplete voiding of the bladder.

[0012] As used herein, the term “mTOR complex 1 (mTORCl)” refers to a protein complex comprising mTOR, regulatory-associated protein of mTOR (RAPTOR), mammalian lethal with SEC 13 protein 8 (mLST8), proline-rich AKT substrate of 40 kDa (PRAS40) and DEP domain-containing protein 6 (DEPTOR) that has been described to function as a nutrient/energy/redox sensor; regulator of cellular growth, proliferation, and motility; and controller of protein synthesis with roles in inflammation, autophagy and cell survival.

[0013] As used herein, the term “mTOR complex 2 (mTORC2)” refers to a protein complex comprising mTOR, mLST8, DEPTOR, rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSINl), and protein observed with rictor 1 and 2 (PROTORI/2) that has been described to function as an activator of insulin receptors and insulin-like growth hormone factor 1 receptors; and regulator of cell proliferation, cell migration and cytoskeletal remodeling with roles in signaling the production of cytokines, inflammation and cell survival.

[0014] As used herein, the term “mTOR inhibitor” refers to a composition that either directly or indirectly inhibits one or more functions of mTOR, mTORCl, mTORC2 and combinations thereof. Examples of suitable mTOR inhibitors include omega-3 fatty acid derivatives, biguanide antihyperglycemic agents, flavonoids, macrolides, and other agents that effectively inhibit one or more mTOR protein complex functions.

[0015] As used herein, the term “thyroid hormone” refers to a composition that is either equivalent to, a derivative of, or affects the same functions as triiodothyronine (T3). Examples of suitable thyroid hormones include liothyronine, a T3 thyroid hormone composition.

[0016] Without being bound by theory, it is believed that the pathology of BPH involves a benign overgrowth of the prostate tissue to an extent that the prostate applies pressure to the urethra and/or the bladder and may cause one or more associated symptoms including impeded flow of urine, frequent and/or urgent need to urinate, nocturia, inability to urinate, and incomplete voiding of the bladder. The development of BPH is believed to be generally related to age with increased risk of experiencing the disease and its symptoms associated with family history, diabetes, heart diseases, erectile dysfunction and obesity. BPH can be a significant factor in the development of bladder, urinary tract and kidney diseases.

[0017] BPH is believed to be most common in men that are 80 years of age or older (about 50-90% or more), and less common at younger ages (about 33-50% by age 60 and relatively rare below age 40). In some cases, genetic factors have been shown to increase the risk of developing BPH up to six-fold. In severe cases of BPH, there is a complete blockage of urine flow that may require surgical intervention or catheter insertion to drain the bladder. In most cases of BPH, incomplete voiding of the bladder is believed to result in increased risk of developing urinary tract infections; bladder stones; bladder infections, bladder irritation, hematuria; and damage to the muscular wall of the bladder. The kidneys may also be damaged by the inability to effectively urinate or from bladder or urinary tract infections that reach the kidneys. However, BPH is not believed to be a precursor to prostate cancer, nor is it believed to increase the risk of developing prostate cancer.

[0018] While several different treatments for BPH are available, including surgery, medications, and minimally invasive procedures to reduce the size of the prostate, some of these treatments may be contraindicated depending on the severity of the disease, other health conditions and side effects associated with the treatments. Mild cases of BPH may only call for active surveillance with recommendations for specific changes in diet and exercise. Whereas, moderate to severe cases of BPH generally involve treatment of some kind. Many options are currently available for treatment of BPH that have varying levels of success and potential side effects.

[0019] Medications are often prescribed to treat BPH prior to considering surgical options. Some of the pharmaceutical options include 5-alpha reductase inhibitors, alpha-adrenergic blockers, phosphodiesterase-5 inhibitors, or any combination thereof. Certain phytotherapies (herbal supplements, e.g. saw palmeho) have also been touted for their ability to treat BPH, but these therapies are not generally recommended by doctors and have been proven to be ineffective in several studies. 5-alpha reductase inhibitors have proven to have some beneficial effect in only about two-thirds of patients and are believed to act by blocking the production of the male hormone, dihydrotestosterone (DHT), which has been associated with activating prostate cell growth. However, 5-alpha reductase inhibitors are required to be continued indefinitely and the side effects can include impotence and gynecomastia as well as other sexual, physical, and psychological symptoms that may persist even after discontinuing therapy. Alpha-adrenergic blockers, which are believed to act by relaxing smooth muscle tissue in blood vessels and the prostate, have also proven to benefit only about two-thirds of patients with BPH. These agents also have side effects including orthostatic hypotension, fatigue, headaches, and ejaculatory dysfunction. Phosphodiesterase-5 inhibitors are also believed to act by relaxing smooth muscle of the prostate and bladder; however, despite exhibiting some beneficial effects of reducing urinary frequency and urgency, urinary flow was not shown to be significantly improved. Currently it is not possible to predict which patients will benefit from these medication therapies, and adverse effects can include sexual dysfunction, physical changes including gynecomastia, muscle weakness and orthostatic hypotension, and psychological effects including depression, anxiety, and suicidal thoughts.

[0020] Minimally invasive procedures are often used after medicinal treatment has failed to be effective, and more invasive surgeries are considered when other methods have failed, or in the more severe cases of BPH. Minimally invasive procedures are not believed to reduce the risk that the patient will require subsequent surgery or additional medication, and these procedures may have side effects including hematuria, burning sensation when urinating, need to urinate more frequently, urinary tract infections, retrograde ejaculation, and erectile dysfunction. Examples of minimally invasive procedures include prostatic urethral lift, water vapor thermal therapy, transurethral microwave therapy, and catheterization. More invasive surgery in more severe cases of BPH include transurethral incision of the prostate, photoselective vaporization, transurethral resection of the prostate, holmium laser enucleation of prostate, thulium laser enucleation of the prostate, transurethral vaporization of the prostate and transurethral water-jet ablation. Possible side effects of more invasive therapies include urinary tract infections, urinary incontinence, dry orgasm, retrograde ejaculation, and erectile dysfunction.

[0021] Without being bound by theory, some studies have indicated that omega-6 fatty acids stimulate the growth of prostatic cells, while omega-3 fatty acids provide an inhibitory effect on prostate cell growth. Some of the changes believed to occur involve an increase in omega- 6 to omega-3 fatty acids that can interfere with the normal presentation and function of certain membrane-bound receptors including cell bound enzymes, calcium channels, sodium channels, potassium channels and other signaling proteins. As a result, the membrane bound proteins can become less responsive to stimuli including hormones, cell signaling proteins and cell signaling substances, which may in part be due to oxidative stress over time leading to changes in mTOR complex gene regulation and degradation of the omega-3 to omega-6 fatty acid ratio in cellular membranes.

[0022] Without being bound by theory, is it also believed that inflammation and improper immune response is associated with and can be contributing factors for predisposition to the development of BPH. It is believed that an inflammatory environment is created that is promoted by inflammatory cytokines and other chemicals, some of which are released from cell membranes as a result of an imbalance of the ratio of omega-3 to omega-6 fatty acids and some of which are released from senescent cells that accumulate over time associated with aging. It is also believed that these pro-tumorigenic immune responses and inflammation are factors in inducing the growth of the prostate tissue.

[0023] Without being bound by theory, it is also believed that mTORCl and mTORC2 control multiple diffuse aspects of cellular metabolism, cellular integrity, cellular death, immune response and inflammation. It is believed that the mTORCl and mTORC2 activity is enhanced and driven upwards by cytokine release including those released as a result of higher than optimal ratios of omega-6 to omega-3 fatty acids in the cell membrane and that mTORCl and mTORC2 complex functions may be down regulated by the use of mTOR inhibitors. Examples of suitable mTOR inhibitors may include omega-3 fatty acid derivatives, biguanide antihyperglycemic agents, flavonoids, macrolides, and other agents that effectively inhibit mTOR protein complexes.

[0024] It is further believed that part of the maintenance of the cell membrane may involve maintaining an optimal ratio of omega-3 to omega-6 fatty acids, which results in an anti inflammatory effect. It is believed that increasing the ratio of omega-3 to omega-6 fatty acids will lead to a decrease or an inhibition of cytokine production. Examples of omega-3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are generally derived from diet. It is believed that EPA is superior to DHA for inhibition of inflammation and maintaining cell integrity. It is believed that omega-6 fatty acids (e.g. arachidonic acids) are precursors to the formation of cytokines. It is believed that omega-3 fatty acids may help to decrease cytokine production, for example, from the action of eicosanoid molecules. Accordingly, a decrease of omega-3 fatty acids, in relation to omega-6, may facilitate an inflammatory response caused by cytokines.

[0025] Without being bound by theory, it is believed that therapies including omega-3 fatty acids may downshift cellular signaling by decreasing cytokine formation. This may increase the maintenance of cellular adhesion and normal membrane anatomy with better sodium, potassium and calcium channel function and better response to stimuli from hormones, cell signaling proteins and other cell signaling substances such as nitric oxide. Therapies including omega-3 fatty acids may also facilitate the maintenance of membranes of mitochondria and other intracellular structures.

[0026] It is further believed that control over mTOR-associated protein complexes may also be of importance in the treatment of BPH. It is believed that mTOR-associated protein complexes may respond to stimuli that alter cellular metabolism and growth. The mTOR- associated protein complexes may be involved in many diseases and almost all tissues of the body, including the prostate. It is believed that the dysregulation of mTORCl and mTORC2 may be an underlying cause of disease over one’s lifetime. It is also believed that overactivity of these protein complexes may lead to BPH.

[0027] Without being bound by theory, it is believed that biguanide antihyperglycemic agents act through inhibition of the mTORC2 complex to modulate cell functions including metabolism, proliferation, migration, and survival as well as reduce oxidative stress and inflammation. It is further believed that biguanide antihyperglycemic agents inhibit the mTORC2 complex by mechanisms including the reduction of the downstream effects of the AKT protein that is a component of the PBK/AKT/mTOR pathway. The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle and is necessary to promote growth and proliferation over differentiation of adult stem cells. However, in BPH, this pathway is overactive, thus reducing apoptosis and allowing cell hypertrophy and proliferation. It is further believed that biguanide antihyperglycemic agents may be effective in treating BPH by reducing the downstream effect of the AKT protein in the PBK/AKT/mTOR pathway.

[0028] Without being bound by theory, it is believed that certain flavonoids act as senolytic agents by reducing mTOR complex activity, increasing the activity of sirtuins, and increasing the activity of AMP-activated protein kinase (AMPK). These actions are believed to play a role in cellular energy homeostasis and promotion of apoptosis in senescent cells that are resistant to signaling proteins and accumulate as we age during the aging process. It is further believed that the accumulation of senescent cells results from a weakened immune system related to aging, and these cells provide a source of chronic inflammation through the release of inflammatory chemicals and may lead to an increased risk of BPH. It is also believed that the mechanistic actions of certain flavonoids used in combination with a biguanide antihyperglycemic agent can exhibit synergistic effects for promoting apoptosis in senescent cells while promoting homeostasis in normal cells. It is further believed that when certain flavonoids are combined with certain galactomannans, the absorption of the certain flavonoids can be increased by as much as 25-fold.

[0029] Without being bound by theory, it is believed that compositions that include one or more mTOR inhibitors may be effective at treating BPH by decreasing inflammation, enhancing cell membrane stability and function, and promoting apoptosis in senescent cells. It is also believed that compositions comprised of one or more mTOR inhibitors may be more effective if the composition is comprised of at least two or more mTOR inhibitors.

[0030] Thyroid hormones, including e.g. liothyronine (a T3 thyroid hormone), are believed to assist in controlling metabolism by utilizing oxygen and calories for conversion into energy in the mitochondria through the formation of ATP. Thyroid hormones are believed to be necessary for energy production in all organs, especially in muscle, brain, heart, and other tissues. Increased levels of thyroid hormones are believed to affect increased levels of cellular metabolism. Various tests are available to determine thyroid hormone levels, e.g. by measuring the amount of thyroid hormone levels in the blood. Thyroid hormones are believed to enhance cell survival and the metabolism of fats, proteins, and carbohydrates. It is further believed that treatment comprising one or more thyroid hormones in combination with a flavonoid, such as fisetin may act synergistically to increase metabolism and promote the senolytic effects of fisetin.

[0031] Thyroid hormones are believed to affect nearly every cell of the body through receptors in the nucleus of the cell. Thyroid hormones bind to DNA-binding nuclear hormone receptors, cause conformational changes in the receptors, and activate transcription of the thyroid hormone sensitive genes by either initiating expression or upregulation. Also, functions of the PI3K/AKT pathway are believed to include regulation of cell adhesion, cell cycle progression, cell survival and signaling. Precursors to the thyroid hormones, referred to as T4 or thyroxine, are believed to stimulate the PI3/AKT pathway in the cytoplasm, whereas T3 does not. T3 also has a shorter half-life than T4, so T3 is recommended for the treatment of hepatic steatosis over T4.

[0032] Without being bound by theory, it is believed that rapamycin is primarily an mTORl inhibitor at lower doses and for short treatment cycles, whereas high levels and very prolonged treatment cycles can also inhibit mTOR2 by blocking mTOR2 production by the cell. Rapamycin treatment is normally administered continuously either orally or intravenously, which frequently causes side effects of insulin resistance and hyperglycemia, and causes immune deficiency. Also, long-term treatment with rapamycin may decrease antigen processing and inhibit T-cell proliferation leading to suppression of the immune system. Rapamycin is also believed to decrease the phosphorylation of the ribosomal s6 kinase, S6K1, which is believed to result in active decreases in protein synthesis and cell mortality. [0033] It is believed that treatment regimens that included rapamycin could be effective and safe if rapamycin is dosed at low-levels either intermittently or in conjunction with other mTOR inhibitors and/or additional medications that decrease or down regulate the PI3K-AKT pathway. It is further believed that using a biguanide antihyperglycemic agent, such as metformin, in these treatment regimens will allow for down regulation of both mTORl and mTOR2 safely without causing significant side effects of high-dose rapamycin. In addition to acting as an inhibitor of mTOR2, metformin also decreases glycolysis and is effective in controlling blood glucose levels. The addition of a flavonoid, such as fisetin, is believed to provide the added benefit of promoting apoptosis or cell death of senolytic cells effectuated at least partly through its inhibition of the mTOR pathway. The effects of fisetin may be further improved with the addition of a T3 thyroid hormone. It is believed that synergy of activity for inhibition of the PI3K-AKT pathway can be achieved with the combination of rapamycin, metformin, and fisetin while providing a low risk of side effects. The treatment regimens could further benefit from the addition of an omega-3 fatty acid derivative, which is believed to downregulate mTOR2, decrease cytokine formation, strengthen cell membranes and structures, and decrease phosphorylation of phosphatides. Additionally, the addition of a T3 thyroid hormone is believed to enhance the effectiveness of the therapy regimen. These combination therapies are believed to have minimal side effects, may be administered continuously over long periods of time, and result in an effective decrease in PI3K-AKT activity.

[0034] In various embodiments, the composition of the disclosure includes a composition for the treatment of BPH that includes an effective amount of one or more mTOR inhibitors and optionally an effective amount of one or more thyroid hormones. In various embodiments, suitable mTOR inhibitors may include omega-3 fatty acid derivatives, biguanide antihyperglycemic agents, flavonoids, macrolides, and other agents that effectively inhibit mTOR protein complexes. In various embodiments, suitable thyroid hormones may include a T3 hormone, such as liothyronine.

[0035] Preferentially, at least one of the components of the composition will decrease pro- tumorigenic inflammation associated with cancer and primary cancer treatments.

[0036] Preferentially, at least one of the components of the composition will decrease the rate of normal cell death or will increase the life span of normal cells including those involved in immune response systems. [0037] Preferentially, at least one of the components of the composition will enhance cellular membrane integrity and function and/or induce apoptosis in cancer and/or senescent cells. Preferentially, the compositions of the disclosure include a flavonoid, such as fisetin, at doses that are high enough to cause senescent cells to die and results in an overall decrease in inflammation in the patient.

[0038] Preferentially, the compositions of the disclosure include at least an effective amount of a biguanide antihyperglycemic agent in combination with an effective amount of an omega- 3 fatty acid derivative.

[0039] Preferentially, other than promoting euthyroid in patients, the compositions of the disclosure include a thyroid hormone concurrent with high doses of a flavonoid, such as fisetin.

[0040] In various embodiments, the composition may include an effective amount of an omega-3 fatty acid derivative. Suitable omega-3 fatty acid derivatives may include icosapent ethyl. In various embodiments, the composition of the disclosure may include an effective amount of at least about 0.5 g of icosapent ethyl, or between about 0.5 g to about 10.0 g, or 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,

2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,

4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,

6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,

9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 g, or any range between any two of these amounts including about 0.5 g to about 10.0 g, or about 1.0 g to about 7.0 g, or about 2.0 g to about 8.0 g. In some preferred forms, the amount of icosapent ethyl is sufficient to maintain an optimum level of icosapent ethyl in the blood of a subject receiving an administration of the composition.

[0041] In various embodiments, the composition of the disclosure may include an effective amount of a biguanide antihyperglycemic agent. Suitable biguanide antihyperglycemic agents include metformin. In various embodiments, the composition may include an effective amount of at least about 50 mg of biguanide antihyperglycemic agent, or between about 50 mg to about 4000 mg, or 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050,

2075, 2100, 2125, 2150, 2175, 2200, 2225, 2250, 2275, 2300, 2325, 2350, 2375, 2400, 2425,

2450, 2475, 2500, 2525, 2550, 2575, 2600, 2625, 2650, 2675, 2700, 2725, 2750, 2775, 2800,

2825, 2850, 2875, 2900, 2925, 2950, 2975, 3000, 3025, 3050, 3075, 3100, 3125, 3150, 3175,

3200, 3225, 3250, 3275, 3300, 3325, 3350, 3375, 3400, 3425, 3450, 3475, 3500, 3525, 3550,

3575, 3600, 3625, 3650, 3675, 3700, 3725, 3750, 3775, 3800, 3825, 3850, 3875, 3900, 3925,

3950, 3975, or 4000 mg or any range between any two of these amounts including about 250 mg to about 4000 mg, about 250 mg to about 500 mg, about 250 mg to about 750 mg, 250 mg to about 1000 mg, about 250 mg to about 1250 mg, about 250 mg to about 1500 mg, or between about 500 mg to about 3000 mg.

[0042] In various embodiments, the composition may include an effective amount of a flavonoid. Suitable flavonoid agents include fisetin and fisetin derivatives. In various embodiments, the composition may include an effective amount of at least about 10 mg/kg of patient body weight of a flavonoid, or between about 10 mg/kg to about 100 mg/kg of patient body weight, or 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of patient body weight or any range between any two of these amounts including about 10 mg/kg to about 20 mg/kg, about 15 mg/kg to about 25 mg/kg, about 20 mg/kg to about 30 mg/kg, about 25 mg/kg to about 50 mg/kg, or about 20 mg/kg to about 100 mg/kg. In some preferred forms, the amount of fisetin is sufficient to maintain an optimum level of fisetin in the blood of a subject receiving an administration of the composition. In some embodiments, such optimum level may be achieved by combining the fisetin with a galactomannan to enhance the absorption of the flavonoid.

[0043] In various embodiments, the composition may include an effective amount of a flavonoid. Suitable flavonoid agents include fisetin and fisetin derivatives. In various embodiments, the composition may include an effective amount at least about 50 mg of a flavonoid, or between about 50 mg to about 750 mg, or 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190,

195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285,

290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380,

385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475,

480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570,

575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, or 750 mg or any range between any two of these amounts including about 50 mg to about 500 mg, about 100 mg to about 750 mg, about 250 mg to about 500 mg, about 250 mg to about 750 mg, about 500 mg to about 750 mg, or about 100 mg to about 500 mg. In some preferred forms, the amount of fisetin is sufficient to maintain an optimum level of fisetin in the blood of a subject receiving an administration of the composition. In some embodiments, such optimum level may be achieved by combining the fisetin with a galactomannan to enhance the absorption of the flavonoid.

[0044] In various embodiments, the compositions may include an effective amount of a macrolide. Suitable macrolides include rapamycin. In various embodiments, the compositions may include an effective amount of a macrolide of at least about 0.1 mg of a macrolide, or between about 0.1 mg to about 10 mg, or 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2,

1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,

3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,

5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,

7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,

9.7, 9.8, 9.9, or 10.0 mg or any range between any two of these amounts including about 2.0 mg to about 6.0 mg, about 1.0 mg to about 10.0 mg, about 2.0 mg to about 4.0 mg, about 2.5 mg to about 5.0 mg, about 2.5 mg to about 7.5 mg, or about 1.0 mg to about 5.0 mg of a macrolide. In some preferred forms, the amount of rapamycin is administered as a loading dose followed by a lower daily dose. In some preferred forms, the amount of rapamycin is sufficient to maintain an optimum level of rapamycin in the blood of a subject receiving an administration of the composition; such optimum level may be determined as a preferred optimum trough level as measured in nanograms per ml of blood. In some preferred forms, the administration of rapamycin is provided intermittently at low levels.

[0045] In various embodiments, the compositions may include an effective amount of a thyroid hormone. Suitable thyroid hormones include the T3 liothyronine. In various embodiments, the compositions of the disclosure may include an effective amount of at least about 1 pg of liothyronine, or between about 1 pg to about 250 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9,

10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,

60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,

127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,

146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164,

165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183,

184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,

203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,

222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240,

241, 242, 243, 244, 245, 246, 247, 248, 249, 250 pg, or any range between any two of these amounts including about 5 pg to about 150 pg, or about 10 pg to about 100 pg, or about 10 pg to about 25 pg, or about 25 pg to about 150 pg, or about 25 pg to about 250 pg. In some preferred forms, the amount of liothyronine is sufficient to maintain an optimum level of liothyronine in the blood of a subject receiving an administration of the composition.

[0046] In various embodiments, the compositions may include an effective amount of a combination of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones. In various embodiments, the compositions may include an effective amount of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones and an effective amount of a flavonoid. In various embodiments, the compositions may include an effective amount of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones and an effective amount of a high dose of a flavonoid, which is associated with a senolytic effect.

[0047] In various embodiments, the composition of the disclosure may further contain additional pharmaceutically acceptable carriers. The pharmaceutical compositions may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, in a form suitable for parenteral injection as a sterile solution, suspension, or in a form of an emulsion for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical compositions may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical compositions may include conventional pharmaceutical carriers or excipients. In addition, the compositions may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. [0048] In various embodiments, the composition may be administered to a patient through any suitable route of administration effective in delivering an amount of active agent or active agents to a patient. Suitable routes of administration include oral, parenteral, enteral, and rectal or the like.

[0049] In some forms, the composition will comprise each of the ingredients in a single administration form, such as a pill, tablet, capsule, oral solution, injection solution, infusion solution, or any of the forms described herein. In other forms, the composition will comprise a kit comprising each of the individual ingredients, together with instructions for administering each ingredient. In some forms of the kit, certain ingredients will already be combined such that two, three, or more of the components or ingredients of the composition are in a single administration form as described herein.

[0050] Various embodiments of the disclosure further relate to methods for the treatment of BPH comprising the administration of a composition of an effective amount of one or more mTOR inhibitors and optionally an effective amount of one or more thyroid hormones. In various embodiments, suitable mTOR inhibitors may include omega-3 fatty acid derivatives, biguanide antihyperglycemic agents, flavonoids, macrolides, and other agents that effectively inhibit mTOR protein complexes. In various embodiments, suitable thyroid hormones may include a T3 hormone, such as liothyronine.

[0051] In various embodiments, the methods may include administering an effective amount of an omega-3 fatty acid derivative. Suitable omega-3 fatty acid derivatives may include icosapent ethyl. In various embodiments, the methods may include administering an effective amount of at least about 0.5 g of icosapent ethyl, or between about 0.5 g to about 10.0 g, or 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,

2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,

4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,

6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,

9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 g, or any range between any two of these amounts including about 0.5 g to about 10.0 g, or about 1.0 g to about 7.0 g, or about 2.0 g to about 8.0 g once, twice, or three or more times daily. In some preferred forms, the amount of icosapent ethyl is sufficient to maintain an optimum level of icosapent ethyl in the blood of a subject receiving an administration of the composition. [0052] In various embodiments, the method may include administering an effective amount of a biguanide antihyperglycemic agent. Suitable biguanide antihyperglycemic agents include metformin. In various embodiments, the methods may include administering an effective amount of at least about 50 mg of biguanide antihyperglycemic agent, or between about 50 mg to about 4000 mg, or 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2075, 2100, 2125, 2150, 2175, 2200, 2225, 2250, 2275, 2300, 2325, 2350, 2375, 2400, 2425, 2450, 2475, 2500, 2525, 2550, 2575, 2600, 2625, 2650, 2675, 2700, 2725, 2750, 2775, 2800, 2825, 2850, 2875, 2900, 2925, 2950, 2975, 3000, 3025, 3050, 3075, 3100, 3125, 3150, 3175, 3200, 3225, 3250, 3275, 3300, 3325, 3350, 3375, 3400, 3425, 3450, 3475, 3500, 3525, 3550, 3575, 3600, 3625, 3650, 3675, 3700, 3725, 3750, 3775, 3800, 3825, 3850, 3875, 3900, 3925, 3950, 3975, or 4000 mg or any range between any two of these amounts including about 250 mg to about 4000 mg, about 250 mg to about 500 mg, about 250 mg to about 750 mg, 250 mg to about 1000 mg, about 250 mg to about 1250 mg, about 250 mg to about 1500 mg, or between about 500 mg to about 3000 mg once, twice, or three or more times daily.

[0053] In various embodiments, the method may include administering an effective amount of a flavonoid. Suitable flavonoid agents include fisetin and fisetin derivatives. In various embodiments, the methods may include administering an effective amount of at least about 10 mg/kg of patient body weight of a flavonoid, or between about 10 mg/kg to about 100 mg/kg of patient body weight, or 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of patient body weight or any range between any two of these amounts including about 10 mg/kg to about 20 mg/kg, about 15 mg/kg to about 25 mg/kg, about 20 mg/kg to about 30 mg/kg, about 25 mg/kg to about 50 mg/kg, or about 20 mg/kg to about 100 mg/kg once, twice, or three or more times daily, weekly, monthly, trimonthly or intermittently with periods between administration when no flavonoid is administered. In some preferred methods, the flavonoid may be administered each day for two days on a weekly, monthly or trimonthly basis. In some preferred methods, the flavonoid may be administered each day for two days twice monthly for six months followed by administration one day per month. In some preferred methods, the flavonoid may be administered once every two weeks on a monthly basis for six to twelve months followed by administration once every month. In some preferred methods, the amount of fisetin is sufficient to maintain an optimum level of fisetin in the blood of a subject receiving an administration of the composition; such optimum level may be achieved by combining the fisetin with a galactomannan to enhance the absorption of the flavonoid. In various embodiments, a higher dose of fisetin may be associated with a senolytic effect. In various embodiments, a lower dose of fisetin may be associated with an antioxidant effect.

[0054] In various embodiments, the method may include administering an effective amount of a flavonoid that is administered on a daily basis. Suitable flavonoid agents include fisetin and fisetin derivatives. In various embodiments, the methods may include administering an effective amount of at least about 50 mg of a flavonoid, or between about 50 mg to about 750 mg, or 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240,

245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335,

340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430,

435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525,

530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620,

625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715,

720, 725, 730, 735, 740, 745, or 750 mg or any range between any two of these amounts including about 50 mg to about 500 mg, about 100 mg to about 750 mg, about 250 mg to about 500 mg, about 250 mg to about 750 mg, about 500 mg to about 750 mg, or about 100 mg to about 500 mg once, twice, or three or more times daily. In some preferred methods, the flavonoid may be administered each day for two days on a weekly, monthly or trimonthly basis. In some preferred methods, the flavonoid may be administered each day for two days twice monthly for six months followed by administration one day per month. In some preferred methods, the flavonoid may be administered once every two weeks on a monthly basis for six to twelve months followed by administration once every month. In some preferred methods, the amount of fisetin is sufficient to maintain an optimum level of fisetin in the blood of a subject receiving an administration of the composition; such optimum level may be achieved by combining the fisetin with a galactomannan to enhance the absorption of the flavonoid. In various embodiments, a higher dose of fisetin may be associated with a senolytic effect. In various embodiments, a lower dose of fisetin may be associated with an antioxidant effect.

[0055] In various embodiments, the methods may include administering an effective amount of a macrolide. Suitable macrolides include rapamycin. In various embodiments, the methods may include administering an effective amount of a macrolide of at least about 0.1 mg of a macrolide, or between about 0.1 mg to about 10 mg, or 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,

3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,

5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,

7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,

9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 mg or any range between any two of these amounts including about 2.0 mg to about 6.0 mg, about 1.0 mg to about 10.0 mg, about 2.0 mg to about 4.0 mg, about 2.5 mg to about 5.0 mg, about 2.5 mg to about 7.5 mg, or about 1.0 mg to about 5.0 mg of a macrolide. In some preferred forms, the amount of rapamycin is administered as a loading dose followed by a lower daily dose. In some preferred forms, the amount of rapamycin is sufficient to maintain an optimum level of rapamycin in the blood of a subject receiving an administration of the composition; such optimum level may be determined as a preferred optimum trough level as measured in nanograms per ml of blood. In some preferred forms, the administration of rapamycin is provided intermittently at low levels.

[0056] In various embodiments, the methods may include administering an effective amount of an omega-3 fatty acid derivative in a dosing regimen with an effective amount of a biguanide antihyperglycemic agent.

[0057] In various embodiments, the methods may include administering an effective amount of an omega-3 fatty acid derivative in a dosing regimen with an effective amount of a flavonoid.

[0058] In various embodiments, the methods may include administering an effective amount of a biguanide antihyperglycemic agent in a dosing regimen with an effective amount of a flavonoid.

[0059] In various embodiments, the methods may include administering an effective amount of an omega-3 fatty acid derivative in a dosing regimen with an effective amount of a biguanide antihyperglycemic agent and an effective amount of a flavonoid.

[0060] In various embodiments, the methods may include administering an effective amount of a thyroid hormone. Suitable thyroid hormones include the T3 liothyronine. In various embodiments, the methods of the disclosure may include administering an effective amount of at least about 1 pg of liothyronine, or between about 1 pg to about 250 pg, or 1, 2, 3, 4, 5, 6, 7,

8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,

84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125,

126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144,

145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,

164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182,

183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,

202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,

221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,

240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250 mg, or any range between any two of these amounts including about 5 pg to about 150 pg, or about 10 pg to about 100 pg, or about 10 pg to about 25 pg, or about 25 pg to about 150 pg, or about 25 pg to about 250 pg either weekly, bimonthly, or monthly; however, thyroid hormones should not be given daily and administration should not exceed three days per week. In some preferred methods, the administration of thyroid hormones is dependent upon the clinical response and tolerance of the patient and may continue long-term including many years. In some preferred methods, the amount of liothyronine administered is sufficient to maintain an optimum level of liothyronine in the blood of a subject receiving an administration of the composition.

[0061] In various embodiments, the methods may include diagnosing thyroid functions in each patient prior to administration of an effective amount of a thyroid hormone. In various embodiments, the methods for patients requiring thyroid hormone replacement in order to establish normal thyroid functions may preferentially be administered a T3 thyroid hormone. In various embodiments, patients with normal thyroid functions may be administered a low dose of a T3 thyroid hormone (e.g. 5 to 10 pg of liothyronine) combined with a high dose of a flavonoid. In various embodiments, the methods may include administering a combination of a low dose of a T3 thyroid hormone and a high dose of a flavonoid that effectively elicits a synergistic effect of increasing fat metabolism and promoting cellular senescence. In various embodiments, other than promoting euthyroid in patients, the methods include administering a thyroid hormone concurrent with high doses of a flavonoid, such as fisetin.

[0062] In various embodiments, the methods may include administering an effective amount of a combination of thyroid hormones. Suitable thyroid hormones that may be included in the combination include the T3 liothyronine. In various embodiments, the methods may include administering an effective amount of a combination of one or more thyroid hormones with an effective amount of a flavonoid. In various embodiments, the methods may include administering an effective amount of one or more thyroid hormones and an effective amount of a high dose of a flavonoid, which is associated with a senolytic effect unless the patient is hypo thyroid on the days of the week the thyroid hormone is administered. In various embodiments, the methods may include administering a combination of an effective amount of one or more thyroid hormones with either an effective amount of a flavonoid or a high dose of a flavonoid, wherein only some of the compositions that include an effective amount of a flavonoid also include an effective amount of one or more thyroid hormones. For example, an effective amount of one or more thyroid hormones may be included only in one of two weekly compositions administered that includes an effective amount of a flavonoid or a high dose of a flavonoid, which composition could be either the first or second weekly composition administered that includes a flavonoid or high dose flavonoid.

[0063] In various embodiments, the methods may include administering an effective amount of a combination of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones. In various embodiments, the methods may include administering an effective amount of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones and an effective amount of a flavonoid. In various embodiments, the methods may include administering an effective amount of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones and an effective amount of a high dose of a flavonoid, which is associated with a senolytic effect. In various embodiments, the methods may include administering a combination of an effective amount of one or more mTOR inhibitors with an effective amount of one or more thyroid hormones and either an effective amount of a flavonoid or a high dose of a flavonoid, wherein only some of the compositions that include an effective amount of a flavonoid also include an effective amount of one or more thyroid hormones. For example, an effective amount of one or more thyroid hormones may be included only in one of two weekly compositions administered that includes an effective amount of a flavonoid or a high dose of a flavonoid, which composition could be either the first or second weekly composition administered that includes a flavonoid or high dose flavonoid. In various embodiments, the one or more thyroid hormones should be administered for short durations (for example, two days a week, bimonthly, or monthly) during any periods of a dosing regimen that include a high dose of a flavonoid. [0064] In some preferred forms, the methods include administering a macrolide, such as rapamycin; in combination with a biguanide antihyperglycemic agent, such as metformin; in combination with an omega-3 fatty acid derivative, such as icosapent ethyl; in combination with a flavonoid, such as fisetin; and in combination with a T3 thyroid hormone, such as liothyronine. In some preferred forms, the methods include administering a macrolide, such as rapamycin, dosed weekly to achieve blood levels below specified levels measured at specified times following administration; in combination with a biguanide antihyperglycemic agent, such as metformin, dosed twice daily; in combination with an omega-3 fatty acid derivative, such as icosapent ethyl, dosed twice daily; in combination with a flavonoid, such as fisetin, dosed daily; in combination with a T3 thyroid hormone, such as liothyronine, dosed either for two days in a row per week or dosed on separated days for no more than 3 days per week. In some preferred forms, the methods include administering a macrolide, such as rapamycin, dosed weekly to achieve blood levels below about 12 nanograms per ml of blood measured at about 60 hours plus or minus 3 hours following administration; in combination with a biguanide antihyperglycemic agent, such as metformin, dosed twice daily at about 500 mg to about 2000 mg; in combination with an omega-3 fatty acid derivative, such as icosapent ethyl, dosed twice daily at about 2.0 g to about 4.0 g; in combination with a flavonoid, such as fisetin, dosed daily at about 20.0 mg/kg patient body weight (which dose may be achieved by starting at a daily dose of about 200 mg and stepping up to the daily dose of about 20.0 mg/kg); in combination with a T3 thyroid hormone, such as liothyronine, dosed either for two days in a row per week or dosed on separated days for no more than 3 days per week at about 5.0 pg to about 10.0 pg. In some preferred forms, the methods include administering a composition that does not include a macrolide, such as rapamycin, when it is not clinically necessary. In some preferred forms, the macrolide is administered intermittently, as directed by a physician. In some forms, the macrolide is administered daily or twice daily as set forth above for a period of 1, 2, 3, 4,

5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35,

40, 45, 50, 55, 60, or more days in a row wherein it is then not administered for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, or more days in a row. Once the period of non-administration is complete, the macrolide is again administered as set forth herein before another period of non administration. This process can be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, or more times. [0065] In various embodiments, the methods may include administering the effective amount of the compositions of the disclosure that may further contain at least one additional pharmaceutically acceptable carriers, excipients, other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0066] In various embodiments, the methods may include administering the effective amount of the compositions to a patient through any suitable route of administration effective in delivering an amount of active agent or active agents to a patient. Suitable routes of administration include oral, intravascular, intramuscular, subcutaneous, parenteral, enteral, and rectal or the like.

[0067] In various embodiments, the methods may include administering the effective amount of the compositions comprised of each of the ingredient in a single administration form, such as a pill, tablet, capsule, oral solution, injection solution, infusion solution, or any of the forms described herein. In various embodiments, the methods may include administering the effective amount of the compositions from a kit comprising each of the individual ingredients, together with instructions for administering each ingredient. In some forms of the kit, certain ingredients will already be combined such that one, two, three, four, or more of the components or ingredients of the composition are in a single administration form as described herein.

[0068] Example

[0069] Treatment with Icosapent Ethyl, Metformin, and Fisetin

[0070] Normal total PSA levels are considered to be at or below 4.0 ng/ml. A patient experiencing elevated total PSA levels of about 5.3 ng/ml on average during about a 4 year period was treated with the following regimen: Vescepa® (icosapent ethyl) dosed at 2 grams twice daily, metformin dosed twice daily at 750 mg each morning and 500 mg each evening, and fisetin dosed two times weekly at 1,400 mg on Monday and Tuesday of each week. The treatment regimen was conducted for 1 month at which time total PSA levels were tested and found to return to a normal level of 3.89 ng/ml, representing about a 27% decrease in total PSA level. [0071] This writen description uses examples to disclose the subj ect mater herein, including the best mode, and also to enable any person skilled in the art to practice the subject mater disclosed herein, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.