Enhancing autophagy or increasing longevity by administration of urolithins or precursors thereof

Abstract

Disclosed are methods, compounds, and compositions useful for increasing autophagy and promoting longevity. The methods, compounds, and compositions relate to urolithins and urolithin precursors and use thereof. Certain urolithins are represented by Formula I, while certain urolithin precursors are represented by Formula IV. The urolithin may be urolithin A, urolithin B, urolithin C, or urolithin D. The urolithin precursor may be ellagic acid or an ellagitannin. The methods include in vivo, ex vivo, and in vitro uses of the compounds and compositions.

1 - 113 . (canceled) 
     
     
         114 . A composition, comprising L-carnitine or a pharmaceutically acceptable salt thereof, and a urolithin represented by Formula I or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of H and OR; and 
 R is independently for each occurrence H, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 
 
       
     
     
         115 . The composition of  claim 114 , wherein the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof. 
     
     
         116 . The composition of  claim 114 , wherein the urolithin is urolithin A. 
     
     
         117 . The composition of  claim 114 , wherein the urolithin is urolithin B. 
     
     
         118 . A method of improving or increasing autophagy in a vertebrate, comprising conjointly administering to a vertebrate in need thereof an effective amount of L-carnitine or a pharmaceutically acceptable salt thereof, and a urolithin represented by Formula I or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of H and OR; and 
 R is independently for each occurrence H, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 
 
       
     
     
         119 . The method of  claim 118 , wherein the vertebrate is a mammal. 
     
     
         120 . The method of  claim 118 , wherein the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof. 
     
     
         121 . The method of  claim 118 , wherein the urolithin is urolithin A. 
     
     
         122 . The method of  claim 118 , wherein the urolithin is urolithin B. 
     
     
         123 . The method of  claim 118 , wherein the autophagy is mitophagy. 
     
     
         124 . The method of  claim 118 , wherein the conjoint administration is oral. 
     
     
         125 . The method of  claim 119 , wherein the mammal is a human. 
     
     
         126 . The method of  claim 125 , wherein the human is healthy. 
     
     
         127 . The method of  claim 125 , wherein the human is elderly. 
     
     
         128 . The method of  claim 127 , wherein the human is healthy. 
     
     
         129 . The method of  claim 118 , wherein said conjoint administration is sequential. 
     
     
         130 . The method of  claim 118 , wherein said conjoint administration is simultaneous. 
     
     
         131 . A method of treating, preventing, or managing a disease selected from the group consisting of muscle degenerative disorder, sarcopenia, muscular dystrophy, cardiomyopathy, Ulrich myopathy, obesity, cardiovascular disease, atherosclerosis, a mitochondria-related disease associated with altered mitochondrial function or a reduced mitochondrial density; or disease related to a metabolic function, comprising:
 conjointly administering to a vertebrate in need thereof an effective amount of L-carnitine or a pharmaceutically acceptable salt thereof, and a urolithin represented by Formula I or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of H and OR; and 
 R is independently for each occurrence H, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 
 
     
     
         132 . The method of  claim 131 , wherein the vertebrate is a mammal. 
     
     
         133 . The method of  claim 131 , wherein the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof. 
     
     
         134 . The method of  claim 131 , wherein the urolithin is urolithin A. 
     
     
         135 . The method of  claim 131 , wherein the urolithin is urolithin B. 
     
     
         136 . The method of  claim 131 , wherein the muscular dystrophy is Duchenne muscular dystrophy. 
     
     
         137 . The method of  claim 141 , wherein the sarcopenia is sarcopenia of aging. 
     
     
         138 . The method of  claim 132 , wherein the mammal is a human. 
     
     
         139 . The method of  claim 138 , wherein the human is elderly. 
     
     
         140 . The method of  claim 131 , wherein the conjoint administration is oral. 
     
     
         141 . A method of preventing, treating, or managing a condition selected from the group consisting of frailty, muscular atrophy, muscle disuse atrophy, skeletal muscle atrophy or impaired muscle strength associated with aging, and skeletal muscle damage, a mitochondria-related condition associated with altered mitochondrial function or a reduced mitochondrial density, a condition related to a metabolic function; in protecting against muscle damage or injury; in protecting or maintaining cardiac muscle; in improving muscle function, muscle strength, muscle mass, muscle endurance, muscle recovery following exercise; in improving balance or coordination; in improving mitochondrial function; or in weight management, comprising:
 conjointly administering to a vertebrate in need thereof an effective amount of L-carnitine or a pharmaceutically acceptable salt thereof, and a urolithin represented by Formula I or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of H and OR; and 
 R is independently for each occurrence H, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 
 
     
     
         142 . The method of  claim 141 , wherein the vertebrate is a mammal. 
     
     
         143 . The method of  claim 141 , wherein the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof. 
     
     
         144 . The method of  claim 141 , wherein the urolithin is urolithin A. 
     
     
         145 . The method of  claim 141 , wherein the urolithin is urolithin B. 
     
     
         146 . The method of  claim 141 , wherein the metabolic function is metabolic stress. 
     
     
         147 . The method of  claim 141 , wherein the metabolic function is metabolic stress. 
     
     
         148 . The method of  claim 142 , wherein the mammal is a human. 
     
     
         149 . The method of  claim 148 , wherein the human is elderly. 
     
     
         150 . The method of  claim 141 , wherein the conjoint administration is oral.