Novel anti-aging agents and methods to identify them

Abstract

The present invention discloses novel mechanisms in the aging process and describes novel methods for high-throughput screening to identify, detect, and purify agents to be used for improving mitochondrial function, maintaining the cell cycle-arrested state in senescent and post mitotic cells, and thus preventing or treating age-related diseases or disorders associated with accelerated mitochondrial function loss, telomere dysfunction, and/or deterioration of the growth-arrested state. The present invention also discloses a number of compounds or compositions identified from this method. The present invention further provides the use of low doses of rapamycin or its analogs as a mimic of caloric restriction in preventing age-related diseases or disorders.

1 - 45 . (canceled) 
     
     
         46 . A method of preventing or treating an age-related disease or disorder, the method comprising administering to a subject in need thereof a composition comprising a low dose of a target of rapamycin (TOR) inhibitor, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the low dose of target of rapamycin (TOR) inhibitor is capable of preventing cell aging by extending the G0-phase in a cell and does not inhibit protein translation and/or cell growth at G1 phase of cell cycle. 
     
     
         47 . The method of  claim 46 , wherein the low dose of target-of-rapamycin (TOR) inhibitor: (a) extends replication potential, (b) maintains senescence or cell cycle-arrested state in post-mitotic cells, and/or (c) prevents deterioration of mitochondria or cell death following senescence deterioration. 
     
     
         48 . The method of  claim 46 , wherein the age-related disease or disorder is associated with mitochondrial function loss, telomere dysfunction, senescence deterioration and age-dependent cell loss, mitochondrial deterioration, and/or cell cycle-arrested state in post-mitotic cells. 
     
     
         49 . The method of  claim 46 , wherein the age-related disease or disorder is an abnormal proliferative disease, a degenerative disease, or a function-decreasing disorder. 
     
     
         50 . The method of  claim 46 , wherein the age-related disease or disorder is selected from the group consisting of tumorigenesis and malignant cancer development, neurodegenerating disease, myocardial infarction (heart attack), heart failure, atherosclerosis, hypertension, osteoarthritis, osteoporosis, sarcopenia, loss of bone marrow, cataract, multiple sclerosis, Sjogren, Rheumatoid arthritis, degraded immune function, diabetes, Idiopathic pulmonary fibrosis, and age-related macular degeneration, cerebellar infarction, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, and disorders caused by the decline in testosterone, estrogen, growth hormone, IGF-I, or energy production. 
     
     
         51 . The method of  claim 50 , wherein the TOR inhibitor is rapamycin or an analog selected from the group consisting of Deforolimus, AP-23675, AP-23841, Zotarolimus, CCI779/Temsirolimus, RAD-001/Everolimus, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxy-rapamycin, 2-desmethyl-rapamycin, and 42-O-(2-hydroxy)ethyl-rapamycin. 
     
     
         52 . The method of  claim 51 , wherein the low dose of rapamycin or analog thereof is below about 10%, below about 8%, below about 6%, below about 4%, below about 2%, below about 1%, below about 0.1%, below about 0.01%, or below about 0.001% of an approved therapeutic dose of rapamycin or analog thereof, respectively. 
     
     
         53 . The method of  claim 51 , wherein the low dose of rapamycin is in the range of about 0.01 μg/day to about 50 μg/day. 
     
     
         54 . The method of  claim 52 , wherein the method further comprises administering to the subject a composition comprising a second agent selected from the group consisting of an antioxidant, an antihypertensive agent, a lipid-lowering agent, an anti-stroke agent, an anti-cancer agent, and a different anti-aging agent. 
     
     
         55 . The method of  claim 54 , wherein the second agent is selected from the group consisting of AICAR, low dose of rapamycin or analogs thereof, EGCG, grape seed extract, bilberry extract, selenite, genistein, diallyl trisulfide, benzyl isothiocyanate, phenyl isothiocyanate, phenethyl isothiocyanate, resveratrol, lycopene, and allyl isothiocyanate. 
     
     
         56 . The method of  claim 54 , wherein the second agent is an antioxidant selected from vitamin C, vitamin E, beta carotene and other carotenoids, selenium, lipoic acid, lycopine, lutein, zeaxanthin, coenzyme Q10, glutathione, N-acetyl cysteine, melatonin, genistein, estrodiol, tea extract, and grape seed extract. 
     
     
         57 . The method of  claim 50 , wherein the TOR inhibitor is a low dose of rapamycin or an analog thereof, and wherein the age-related disease or disorder is tumorigenesis or malignant progression of a cancer, Parkinson's disease, stroke, cerebellar infarction, myocardial infarction, or neurodegenerating disease. 
     
     
         58 . The method of  claim 57 , wherein the low dose of rapamycin or analog thereof is below about 10%, below about 8%, below about 6%, below about 4%, below about 2%, below about 1%, below about 0.1%, below about 0.01%, or below about 0.001% of an approved therapeutic dose of rapamycin or analog thereof, respectively. 
     
     
         59 . The method of  claim 57 , wherein the low dose of rapamycin is in the range of about 0.01 μg/day to about 50 μg/day. 
     
     
         60 . The method of  claim 57 , wherein the method further comprises administering to the subject a composition comprising a second agent selected from the group consisting of an antioxidant, an antihypertensive agent, a lipid-lowering agent, an anti-stroke agent, an anti-cancer agent, and another anti-aging agent. 
     
     
         61 . The method of  claim 60 , wherein the second agent is an antioxidant selected from the group consisting of vitamin C, vitamin E, beta carotene and other carotenoids, selenium, lipoic acid, lycopene, lutein, zeaxanthin, coenzyme Q10, glutathione, N-acetyl cysteine, melatonin, genistein, estrodiol, tea extract, and grape seed extract. 
     
     
         62 . The method of  claim 59 , wherein the method further comprises administering to the subject a composition comprising a second agent selected from the group consisting of an antioxidant, an antihypertensive agent, a lipid-lowering agent, an anti-stroke agent, an anti-cancer agent, and another anti-aging agent. 
     
     
         63 . The method of  claim 62 , wherein the second agent is an antioxidant selected from the group consisting of vitamin C, vitamin E, beta carotene and other carotenoids, selenium, lipoic acid, lycopene, lutein, zeaxanthin, coenzyme Q10, glutathione, N-acetyl cysteine, melatonin, genistein, estrodiol, tea extract, and grape seed extract. 
     
     
         64 . The method of  claim 59 , wherein the age-related disease or disorder is stroke, cerebellar infarction, myocardial infarction, or a neurodegenerating disease.