Compositions for manipulating the lifespan and stress response of cells and organisms

Abstract

Provided herein are methods and compositions for modulating the activity of sirtuin deacetylase protein family members; p53 activity; apoptosis; lifespan and sensitivity to stress of cells and organisms. Exemplary methods comprise contacting a cell with an activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin; or an inhibitory compound, such as a sphingolipid, e.g., sphingosine.

1 .- 39 . (canceled) 
     
     
         40 . A method of modulating the activity of p53 in a cell, comprising contacting the cell with a compound that modulates SIRT1, thereby modulating the activity of p53 in the cell. 
     
     
         41 . The method of  claim 40 , wherein the cell is contacted with a SIRT1 activator compound that activates SIRT1 and thereby inhibits p53 activity in the cell. 
     
     
         42 . The method of  claim 41 , wherein the contacted cell is protected against apoptosis. 
     
     
         43 . The method of  claim 41 , wherein the compound is a non-naturally occurring SIRT1 activator that binds SIRT1, reduces the K m  of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1. 
     
     
         44 . The method of  claim 41 , wherein the cell is contacted with a SIRT1 activator at a concentration of less that about 0.5 μM. 
     
     
         45 . The method of  claim 40 , wherein the cell is contacted with a SIRT1 inhibitor compound that inhibits SIRT1, thereby stimulating the activity of p53 in the cell. 
     
     
         46 . The method of  claim 45 , wherein the SIRT1 inhibitor is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         47 . The method of claim  1 , wherein the cell is contacted with a SIRT1 activator at a concentration of at least about 50 μM. 
     
     
         48 . The method of any of  claims 45 - 47 , wherein apoptosis is induced in the contacted cell. 
     
     
         49 . The method of  claim 48 , wherein the contacted cell is a cancer cell. 
     
     
         50 . A method of extending the lifespan of an organism, comprising administering a non-naturally occurring compound that activates SIRT1 in the organism. 
     
     
         51 . The method of  claim 50 , wherein the compound is a non-naturally occurring SIRT1 activator that binds SIRT1, reduces the K m  of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1. 
     
     
         52 . The method of  claim 50 , wherein the organism is a plant. 
     
     
         53 . The method of  claim 50 , wherein the organism is a fish or bird. 
     
     
         54 . The method of  claim 50 , wherein the organism is  Saccharomyces cerevisiae, Caenorhabditis elegans  or  Drosophila melanogaster.    
     
     
         55 . A method of extending the lifespan of a eukaryotic cell, comprising contacting the cell with a non-naturally occurring compound that activates SIRT1 in the cell, thereby extending the lifespan of the eukaryotic cell. 
     
     
         56 . The method of  claim 55 , wherein the lifespan of the treated eukaryotic cell is extended by at least 20% compared to the lifespan of an identical untreated cell. 
     
     
         57 . The method of  claim 56 , wherein the lifespan of the treated eukaryotic cell is extended by at least 30%. 
     
     
         58 . The method of  claim 57 , wherein the lifespan of the treated eukaryotic cell is extended by at least 40%. 
     
     
         59 . The method of  claim 58 , wherein the lifespan of the treated eukaryotic cell is extended by at least 50%. 
     
     
         60 . The method of  claim 55 , wherein the eukaryotic cell is a human cell. 
     
     
         61 . The method of  claim 55 , wherein the eukaryotic cells is selected from the group consisting of a non-human primate cell, a bovine cell, an ovine cell, an equine cell, a porcine cell, a sheep cell, a bird cell, a canine cell, a feline cell and a rodent cell. 
     
     
         62 . The method of  claim 55 , wherein the compound is a non-naturally occurring SIRT1 activator that binds SIRT1, reduces the K m  of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1. 
     
     
         63 . The method of  claim 55 , wherein the eukaryotic cell is in a subject and wherein the method comprises administering the non-naturally occurring compound to the subject. 
     
     
         64 . A method of treating an aging-related disease in a subject, comprising administering to the subject a non-naturally occurring compound that activates SIRT1 in the organism. 
     
     
         65 . The method of  claim 64 , wherein the compound is a non-naturally occurring SIRT1 activator that binds SIRT1, reduces the K m  of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1. 
     
     
         66 . The method of  claim 64 , wherein the subject is a human subject. 
     
     
         67 . The method of  claim 64 , wherein the aging-related disease is stroke, cardiovascular disease, arthritis, high blood pressure, or Alzheimer's disease. 
     
     
         68 . A method of reducing the lifespan of a eukaryotic cell or rendering the eukaryotic cell more sensitive to cell death, comprising contacting the cell with a compound that binds SIRT1 in the cell and decreases the deacetylase activity of SIRT1. 
     
     
         69 . The method of  claim 68 , further comprising contacting the cell with a second compound that binds SIRT1 in the cell and decreases the deacetylase activity of SIRT1. 
     
     
         70 . A method of treating a disease or condition related to abnormal cell growth in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound that binds SIRT1 in the cell and decreases the deacetylase activity of SIRT1. 
     
     
         71 . The method of  claim 70 , wherein the disease or condition is cancer. 
     
     
         72 . The method of  claim 71 , further comprising administering to the subject a chemotherapeutic agent. 
     
     
         73 . A method for mimicking the effects of calorie restriction in a eukaryotic cell, comprising contacting the cell with a non-naturally occurring compound that binds SIRT1 in the cell and increases the deacetylase activity of SIRT1, wherein the compound reduces the K m  of SIRT1 for its substrate. 
     
     
         74 . The method of  claim 73 , wherein mimicking the effects of calorie restriction comprises increasing the replicative lifespan of the cell. 
     
     
         75 . The method of  claim 73 , wherein mimicking the effects of calorie restriction comprises increasing the cell's resistance to stress. 
     
     
         76 . The method of  claim 73 , wherein the eukaryotic cell is a human cell. 
     
     
         77 . The method of  claim 73 , wherein the eukaryotic cells is selected from the group consisting of a non-human primate cell, a bovine cell, an ovine cell, an equine cell, a porcine cell, a sheep cell, a bird cell, a canine cell, a feline cell and a rodent cell. 
     
     
         78 . The method of  claim 73 , wherein the eukaryotic cell is in a subject and wherein the method comprises administering the non-naturally occurring compound to the subject. 
     
     
         79 . The method of  claim 78 , wherein the non-naturally occurring compound is administered orally.