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 . A method for activating a sirtuin deacetylase protein family member, comprising contacting the sirtuin deacetylase protein family member with an activating compound having a formula selected from the group consisting of formulas 1-25 and 30.  
     
     
         2 . The method of  claim 1 , wherein the compound is a polyphenol compound or analog or derivative thereof.  
     
     
         3 . The method of  claim 1 , wherein the plant compound is selected from the group consisting of flavones, stilbenes, flavanones, isoflavones, catechins, chalcones, tannins and anthocyanidins or analog or derivative thereof.  
     
     
         4 . The method of  claim 1 , wherein, if the compound is a naturally occurring compound, it is not in a form in which it is naturally occurring.  
     
     
         5 . The method of  claim 3 , wherein the compound is selected from the group consisting of resveratrol, butein, piceatannol, isoliquiritgenin, fisetin, luteolin, 3,6,3′,4′-tetrahydroxyflavone, quercetin, and analogs and derivatives thereof.  
     
     
         6 . The method of  claim 1 , wherein the sirtuin deacetylase protein family member is SIRT1.  
     
     
         7 . The method of  claim 1 , wherein the sirtuin deacetylase protein family member is in a cell, and the method comprises contacting the cell with the compound.  
     
     
         8 . The method of  claim 7 , wherein the cell is in vitro.  
     
     
         9 . The method of  claim 7 , wherein the cell is a cell of a subject.  
     
     
         10 . The method of  claim 7 , wherein the cell is in a subject and the method comprises administering the compound to the subject.  
     
     
         11 . The method of  claim 1 , further comprising determining the activity of the sirtuin deacetylase protein family member.  
     
     
         12 . The method of  claim 10 , further comprising determining the activity of the sirtuin deacetylase protein family member.  
     
     
         13 . The method of  claim 7 , wherein the cell is contacted with the compound at a concentration of 0.1-100 μM.  
     
     
         14 . The method of  claim 1 , further contacting the cell with an additional activating compound having a formula selected from the group consisting of formulas 1-25 and 30.  
     
     
         15 . The method of  claim 14 , comprising contacting the cell with a least three different activating compounds having a formula selected from the group consisting of formulas 1-25 and 30.  
     
     
         16 . A method for inhibiting the activity of a sirtuin protein family member, comprising contacting the sirtuin deacetylase protein family member with an inhibiting compound having a formula selected from the group consisting of formulas 26-29 and 31.  
     
     
         17 . A method for shortening the lifespan of a cell or rendering it resistant to stress, comprising contacting the cell with an inhibiting compound having a formula selected from the group consisting of formulas 26-29 and 31.  
     
     
         18 . A composition comprising two compounds each having a formula selected from the group of formulas 1-31.  
     
     
         19 . A method for identifying a compound that modulates SIRT1 in vivo, comprising (i) contacting a cell comprising a SIRT1 protein with a peptide of p53 comprising an acetylated residue 382 in the presence of an inhibitor of class I and class II HDAC under conditions appropriate for SIRT1 to deacetylate the peptide and (ii) determining the level of acetylation of the peptide, wherein a different level of acetylation of the peptide in the presence of the test compound relative to the absence of the test compound indicates that the test compound modulates SIRT1 in vivo.