Methods and compositions for extending the life span and increasing the stress resistance of cells and organisms

Abstract

The invention provides methods and compositions for modulating the life span of eukaryotic and prokaryotic cells and for protecting cells against certain stresses, e.g., heatshock. One method comprises modulating the flux of the NAD+ salvage pathway in the cell, e.g., by modulating the level or activity of one or more proteins selected from the group consisting of NPT1, PNC1, NMA1 and NMA2. Another method comprises modulating the level of nicotinamide in the cell.

1 . A method for increasing the life span of a cell or its resistance to stress, comprising contacting the cell with a compound of formula A: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents independently for each occurrence H, acetyl, benzoyl, acyl, phosphate, sulfate, (alkyoxy)methyl, triarylmethyl, (trialkyl)silyl, (dialkyl)(aryl)silyl, (alkyl)(diaryl)silyl, or (triaryl)silyl; and 
 X represents O or S, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the compound is nicotinamide riboside. 
     
     
         3 .- 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the life span of the cell is extended by at least about 40%. 
     
     
         10 . The method of  claim 1 , wherein the cell is in vitro. 
     
     
         11 . The method of  claim 1 , wherein the cell is a eukaryotic cell. 
     
     
         12 . The method of  claim 11 , wherein the cell is a mammalian cell. 
     
     
         13 . The method of  claim 1 , wherein the cell is a yeast cell. 
     
     
         14 . The method of  claim 1 , wherein stress is a heatshock; osmotic stress; a DNA damaging agent; inadequate salt level; inadequate nitrogen levels; inadequate nutrient level; radiation or exposure to a toxic compound. 
     
     
         15 .- 21 . (canceled) 
     
     
         22 . A method for treating or preventing a disorder that is associated with cell death or aging in a subject, comprising administering to a subject in need thereof a compound of formula A: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents independently for each occurrence H, acetyl, benzoyl, acyl, phosphate, sulfate, (alkyoxy)methyl, triarylmethyl, (trialkyl)silyl, (dialkyl)(aryl)silyl, (alkyl)(diaryl)silyl, or (triaryl)silyl; and 
 X represents O or S, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . (canceled) 
     
     
         24 . A method for protecting a subject from a stress condition, comprising administering to the subject a compound of formula A: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents independently for each occurrence H, acetyl, benzoyl, acyl, phosphate, sulfate, (alkyoxy)methyl, triarylmethyl, (trialkyl)silyl, (dialkyl)(aryl)silyl, (alkyl)(diaryl)silyl, or (triaryl)silyl; and 
 X represents O or S, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         25 . The method of  claim 24 , wherein the stress condition consists of exposure to radiation or a toxic compound. 
     
     
         26 .- 27 . (canceled) 
     
     
         28 . The method of  claim 22 , wherein the compound is nicotinamide riboside. 
     
     
         29 . The method of  claim 24 , wherein the compound is nicotinamide riboside. 
     
     
         30 . The method of  claim 22 , wherein the subject is a human subject. 
     
     
         31 . The method of  claim 22 , wherein the disorder that is associated with cell death or aging is selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Huntington's disease and muscular dystrophy. 
     
     
         32 . The method of  claim 24 , wherein the subject is a human subject. 
     
     
         33 . The method of  claim 12 , wherein the cell is a human cell.