Therapeutic intervention to MIMIC the effect of caloric restriction

Abstract

Methods are provided for promoting longevity and decreasing the incidence of aging associated pathologies (e.g., cancer) by the administration of one or more of the following LFFA: linoleic, oleic and palmitic acid. Secondary LFFA derived from this set, as well as their CoA derivatives and synthetic analogs, are effective also in promoting longevity and delaying the onset of age associated disorders. In addition, interventions including LFFA and CoA LFFA formulations are described which protect the organism from acute physical stress, tissue damage and hypoxia (either due to trauma or secondary to surgical procedures.

1 - 10 . (canceled) 
   
   
       11 . A method of enhancing tolerance of hypoxia comprising:
 (a) selecting a mammal, and   (b) administering to said mammal a long chain free fatty acid, its CoA adduct, non-hydrolyzable CoA analogs, derivatives which have greater half-lives, or combinations thereof in an amount sufficient to achieve a systemic level which serves to provide said mammal with a signal equivalent to that experienced during caloric restriction,   whereby hypoxia tolerance is enhanced due to reduction in oxygen consumption.   
   
   
       12 . The method of  claim 11 , wherein the long chain free fatty acid is palmitic acid, oleic acid, or linoleic acid. 
   
   
       13 . The method of  claim 11 , wherein the CoA adduct is palmitoyl CoA, oleoyl CoA, or linoleoyl CoA. 
   
   
       14 . The method of  claim 11 , wherein said mammal:
 (a) is suffering from a condition selected from the group consisting of angina, cerebrovascular, myocardial, or peripheral vascular insults, pulmonary embolism, and heart failure;   (b) is in situations involving high altitude, undersea, or outerspace operations;   (c) is a surgical candidate; or   (d) is an athlete.   
   
   
       15 . The method of  claim 14 , wherein the mammal is suffering from local or systemic hypoxia due to atherosclerotic artery disease or cerebral ischemia. 
   
   
       16 . The method of  claim 14 , wherein said mammal is a surgical candidate and the administering occurs prior to surgery by an acute course of therapy. 
   
   
       17 . The method of  claim 14 , wherein said mammal is a surgical candidate and the administering occurs during surgery concomitantly with methods for extracorporeal circulation. 
   
   
       18 . The method of  claim 11 , wherein the mammal is a human. 
   
   
       19 . A method improving the health of a mammal comprising:
 (a) selecting a mammal, and   (b) administering to said mammal a long chain free fatty acid, its CoA adduct, non-hydrolyzable CoA analogs, derivatives which have greater half-lives, or combinations thereof in an amount sufficient to achieve a systemic level which serves to provide said mammal with a signal equivalent to that experienced during caloric restriction, and
 wherein said sufficient amount is determined by monitoring the inhibition of thyroid hormone receptor binding in vivo, inhibition of the Na/K ATPase and Ca ATPase in vivo, conservation of energy fuels, reduction in oxygen consumption, a decrease in core body temperature in said mammal, or activation of protective genes in vivo. 
   
   
   
       20 . The method of  claim 19 , wherein the long chain free fatty acid is palmitic acid, oleic acid, or linoleic acid. 
   
   
       21 . The method of  claim 19 , wherein the CoA adduct is palmitoyl CoA, oleoyl CoA, or linoleoyl CoA. 
   
   
       22 . The method of  claim 19 , wherein said protective genes are p53, SOD, α-2-globulin, or HSP-70. 
   
   
       23 . The method of  claim 19 , wherein the mammal is a human. 
   
   
       24 . A method decreasing angiogenesis a mammal comprising:
 (a) selecting a mammal, and   (b) administering to said mammal a long chain free fatty acid, its CoA adduct, non-hydrolyzable CoA analogs, derivatives which have greater half-lives, or combinations thereof in an amount sufficient to achieve a systemic level which serves to provide said mammal with a signal equivalent to that experienced during caloric restriction,   whereby angiogenesis is decreased.   
   
   
       25 . The method of  claim 24 , wherein the long chain free fatty acid is palmitic acid, oleic acid, or linoleic acid. 
   
   
       26 . The method of  claim 24 , wherein the CoA adduct is palmitoyl CoA, oleoyl CoA, or linoleoyl CoA. 
   
   
       27 . The method of  claim 24 , wherein the mammal is a human.