Biomarkers Related To Metabolic Age and Methods Using The Same

Abstract

Biomarkers relating to metabolic age are provided, as well as methods for using such biomarkers as biomarkers for determining metabolic age. In addition, methods for modulating the metabolic age of a subject are also provided. Also provided are suites of small molecule entities as biomarkers for metabolic age.

1 - 25 . (canceled) 
     
     
         26 . A method of determining whether the metabolic age of an adult subject is older than the chronological age of the subject, comprising:
 providing a blood or blood plasma sample collected from the subject;   detecting levels of five or more biomarkers for age in the sample, wherein the five or more biomarkers for age are selected from the group consisting of 4-guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, dehydroepiandrosterone-sulfate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, alpha-L-sorbopyranose, aspartate, benzoic acid, beta-hydroxypyruvic acid, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, dulcitol, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, L-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, thyroxine, tyramine, uridine, xanthine, and combinations thereof; wherein said detecting is carried out using liquid chromatography/mass spectrometry;   wherein an increased level of 4-guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, aspartate, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, 1-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, tyramine, uridine, or xanthine in comparison to an age reference level for such biomarker indicates that the metabolic age of the subject is older than the chronological age of the subject, and   wherein a decreased level of dehydroepiandrosterone-sulfate, alpha-L-sorbopyranose, benzoic acid, beta-hydroxypyruvate, dulcitol, gamma-glu-leu, or thyroxine in comparison to an age reference level for such biomarker indicates that the metabolic age of the subject is older than the chronological age of the subject.   
     
     
         27 . The method of  claim 26 , wherein the levels of the five or more biomarkers in the sample are compared to a biochemical age index to determine whether the metabolic age of the subject is older than the chronological age of the subject. 
     
     
         28 . The method of  claim 26 , wherein the reference levels are tailored to a population selected from the group consisting of gender, race and combinations thereof. 
     
     
         29 . The method of  claim 26 , wherein said subject is a male subject and the biomarkers are selected from five or more biomarkers selected from the group consisting of 4-Guanidinobutanoic acid, leucine, glutamic acid, dehydroepiandrosterone-sulfate, isocitrate, malic acid, 5-oxoproline, cis/trans-aconitic acid, phenylalanine, uridine, isoleucine, valine, lysine, ornithine, lactate, serine, glycine, alanine, allantoin, caffeine, choline, DL-phenyllactic acid, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, octadecanoic acid, pantothenic acid, paraxanthine, proline, succinate, sucrose, threonine, thyroxine, and combinations thereof. 
     
     
         30 . The method of  claim 26 , wherein said subject is a female subject and the biomarkers are selected from five or more biomarkers selected from the group consisting of 4-Guanidinobutanoic acid, leucine, glutamic acid, dehydroepiandrosterone-sulfate, isocitrate, malic acid, 5-oxoproline, cis/trans-aconitic acid, phenylalanine, uridine, isoleucine, valine, lysine, ornithine, lactate, serine, glycine, alanine, allantoin, caffeine, choline, DL-phenyllactic acid, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, octadecanoic acid, pantothenic acid, paraxanthine, proline, succinate, sucrose, threonine, thyroxine, and combinations thereof. 
     
     
         31 . The method of  claim 27 , wherein the biochemical age index is generated using regression analysis and using the detected levels of 4-Guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, dehydroepiandrosterone-sulfate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, alpha-L-sorbopyranose, aspartate, benzoic acid, beta-hydroxypyruvic acid, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, dulcitol, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, L-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, thyroxine, tyramine, uridine, and xanthine. 
     
     
         32 . The method of  claim 26 , wherein one of the five or more biomarkers is dehydroepiandrosterone-sulfate. 
     
     
         33 . The method of  claim 26 , wherein one of the five or more biomarkers is inositol. 
     
     
         34 . The method of  claim 26 , wherein one of the five or more biomarkers is lactate. 
     
     
         35 . A method of determining whether the metabolic age of an adult subject is younger than the chronological age of the subject, comprising:
 providing a blood or blood plasma sample collected from the subject;   detecting levels of five or more biomarkers for age in the sample, wherein the five or more biomarkers for age are selected from the group consisting of 4-guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, dehydroepiandrosterone-sulfate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, alpha-L-sorbopyranose, aspartate, benzoic acid, beta-hydroxypyruvic acid, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, dulcitol, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, L-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, thyroxine, tyramine, uridine, xanthine, and combinations thereof; wherein said detecting is carried out using liquid chromatography/mass spectrometry;   wherein a decreased level of 4-guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, aspartate, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, 1-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, tyramine, uridine, or xanthine in comparison to an age reference level for such biomarker indicates that the metabolic age of the subject is younger than the chronological age of the subject, and   wherein an increased level of dehydroepiandrosterone-sulfate, alpha-L-sorbopyranose, benzoic acid, beta-hydroxypyruvate, dulcitol, gamma-glu-leu, or thyroxine in comparison to an age reference level for such biomarker indicates that the metabolic age of the subject is younger than the chronological age of the subject.   
     
     
         36 . The method of  claim 35 , wherein the levels of the five or more biomarkers in the sample are compared to a biochemical age index to determine whether the metabolic age of the subject is younger than the chronological age of the subject. 
     
     
         37 . The method of  claim 35 , wherein the reference levels are tailored to a population selected from the group consisting of gender, race and combinations thereof. 
     
     
         38 . The method of  claim 35 , wherein said subject is a male subject and the biomarkers are selected from five or more biomarkers selected from the group consisting of 4-Guanidinobutanoic acid, leucine, glutamic acid, dehydroepiandrosterone-sulfate, isocitrate, malic acid, 5-oxoproline, cis/trans-aconitic acid, phenylalanine, uridine, isoleucine, valine, lysine, ornithine, lactate, serine, glycine, alanine, allantoin, caffeine, choline, DL-phenyllactic acid, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, octadecanoic acid, pantothenic acid, paraxanthine, proline, succinate, sucrose, threonine, thyroxine, and combinations thereof. 
     
     
         39 . The method of  claim 35 , wherein said subject is a female subject and the biomarkers are selected from five or more biomarkers selected from the group consisting of 4-Guanidinobutanoic acid, leucine, glutamic acid, dehydroepiandrosterone-sulfate, isocitrate, malic acid, 5-oxoproline, cis/trans-aconitic acid, phenylalanine, uridine, isoleucine, valine, lysine, ornithine, lactate, serine, glycine, alanine, allantoin, caffeine, choline, DL-phenyllactic acid, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, octadecanoic acid, pantothenic acid, paraxanthine, proline, succinate, sucrose, threonine, thyroxine, and combinations thereof. 
     
     
         40 . The method of  claim 36 , wherein the biochemical age index is generated using regression analysis and using the detected levels of 4-Guanidinobutanoic acid, leucine, isoleucine, valine, lysine, glutamic acid, ornithine, alpha-keto-glutarate, lactate, dehydroepiandrosterone-sulfate, isocitrate, malic acid, serine, glycine, 2-amino-butyrate, 3-methyl-L-histidine/1-methyl-L-histidine, 5-oxoproline, alanine, allantoin, alpha-L-sorbopyranose, aspartate, benzoic acid, beta-hydroxypyruvic acid, caffeine, choline, cis/trans-aconitic acid, DL-phenyllactic acid, dulcitol, gamma-glu-leu, glutamine, hippuric acid, histamine, histidine, hypoxanthine, iminodiacetic acid, inosine, inositol, L-alpha-glycerophosphorylcholine, L-arabitol, linoleic acid, L-kynurenine, meso-erythritol, niacinamide, normetanephrine, octadecanoic acid, pantothenic acid, paraxanthine, phenylalanine, p-hydroxyphenyllactic acid, proline, pyrophosphate, saccharopine, succinate, sucrose, threonine, thyroxine, tyramine, uridine, and xanthine. 
     
     
         41 . The method of  claim 35 , wherein one of the five or more biomarkers is dehydroepiandrosterone-sulfate. 
     
     
         42 . The method of  claim 35 , wherein one of the five or more biomarkers is inositol. 
     
     
         43 . The method of  claim 35 , wherein one of the five or more biomarkers is lactate.