Compositions That Lower Cytosolic NADH Level to Mimic Calorie Restriction for Life Extension and Methods

Abstract

Embodiments herein relate to agents that mimic calorie restriction (CR) to extend life span, especially agents that lower the level of cytosolic NADH and increase the level of cytosolic NAD+ (relative to NADH) required to mimic calorie restriction that results in life span extension, at least in part by inhibition by NADH of SIR2, which is a key regulator of life span in both yeast and animals. NADH is a competitive inhibitor of SIR2, an NAD-requiring NAD-dependent histone deacetylase required for chromatin silencing and life-span extension. An overall reduction in NADH activates SIR2 and extends life span. The use of fluorescence measurements of NADH levels in a 96-well plate assay utilizing Baker's yeast ( Saccharomyces cerevisiae ) as a model to screen for agents and supplements that lower NADH levels is disclosed herein. A caloric restriction mimetic contains 1 part Mg2+ malate, 1 part turmeric and 98 parts dehydrated potato skins.

What is claimed is: 
     
         1 . A composition useful for extension of a healthy life comprising at least one agent in an amount sufficient to reduce cytosolic NADH to levels that mimic calorie restriction, wherein said composition comprises dried and milled Irish potato ( Solanum tuberosum ) skins, or dehydrated hot water extracts of whole Irish potatoes, or dehydrated Irish potato skins, or skins of sweet potato ( Ipomea batas ) or hulls of pigmented bean ( Phaseolus vulgarus ) seeds. 
     
     
         2 . The composition of  claim 1 , further comprising turmeric or curcumin. 
     
     
         3 . The composition of  claim 1  or  2  further comprising Mg 2+ -malate, sodium malate or malic acid. 
     
     
         4 . The composition of  claim 2  where the composition comprises a mixture of 1 part turmeric, 1 part Mg 2+  malate and 98 parts dried potato skins. 
     
     
         5 . The composition of  claim 4 , wherein the potato skins are freeze dried. 
     
     
         6 . The composition of  claim 2  wherein the ratio of turmeric and malate or malic acid to dehydrated potato skins is from 1:10 to 1:100 (weight/weight) and wherein the ratio of Mg 2 + malate to dehydrated potato skins is from 1:10 to 1:100 (weight/weight). 
     
     
         7 . The composition of  claim 2  further comprising oxaloacetic acid, Mg ++ -oxaloacetate or other pharmaceutically acceptable salts of oxaloacetic acid or a natural source enriched in oxaloacetic acid or its salts (e.g.  Coleus  ( Coleus  spp) or strawberry ( Frageria  spp.) leaves. 
     
     
         8 . The composition of  claim 1  where the potato skins are skins of Irish potatoes ( Solanum tuberosum ) or from pigmented dry beans ( Phaseolus vulgaris ). 
     
     
         9 . The composition of  claim 2  comprising dehydrated hot water extracts of whole potatoes or potato skins. 
     
     
         10 . The composition of  claim 4 , wherein Mg malate is replaced by sugar-free apple extracts or apple products. 
     
     
         11 . The composition of  claim 1 , wherein the composition further includes a pharmaceutically acceptable carrier. 
     
     
         12 . The composition of  claim 1 , wherein further comprising an additional agent and where the ingredients are provided as a pharmaceutically acceptable plant powder, plant extract or plant infusion. 
     
     
         13 . The composition of  claim 1  where one agent augments or is additive to the effects of another agent in reducing cytosolic NADH levels. 
     
     
         14 . The composition of  claim 1  where the agent is provided at a dose of about 400 to 1200 mg/day. 
     
     
         15 . The composition of  claim 1 , wherein the composition is orally administered. 
     
     
         16 . The composition of  claim 1 , wherein said compositions is formulated in a gel capsule, tablet, pill or any suitable oral dosage form. 
     
     
         17 . The composition of  claim 1 , wherein said composition is administered at a frequency necessary to maintain required constant levels of reduced NADH to serve as a calorie restriction mimic. 
     
     
         18 . The composition of  claim 1 , wherein said composition is a sustained release formulation. 
     
     
         19 . A method for identifying agents that mimic calorie restriction by lowering cytosolic NAHD levels, said method comprising the steps of:
 (a) providing live cells;   (b) treating the cells of step (a) with a test agent;   (c) measuring NADH level of the cells treated with the test agent in step (b);   (d) measuring NADH level in a parallel sample autofluorescence of the cells not treated with test agent;   (e) identifying a test agent as one which mimics calorie restriction when the NADH level is reduced in the cells treated with the test agent as compared to the parallel sample not treated with the test agent.   
     
     
         20 . The method of  claim 19 , wherein the NADH level is measured by measuring autofluorescence in the cells. 
     
     
         21 . The method of  claim 19 , wherein the cells are  Saccharomyces cerevisiae.    
     
     
         22 . The method of  claim 20 , wherein the cells are  Saccharomyces cerevisiae.    
     
     
         23 . The method of  claim 19 , wherein the cells are mammalian cells. 
     
     
         24 . The method of  claim 20 , wherein the cells are mammalian cells.