Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment

Abstract

A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. The processes identified by the strategy suggest a new hypothesis of brain aging in which initially decreased neuronal activity and/or oxidative metabolism trigger separate but parallel genomic cascades in neurons and glia. In neurons, the cascade results in elevations in calcium signaling and reductions of immediate early gene signaling, biosynthesis, synaptogenesis and neurite remodeling. In contrast, glia undergo increased lipid metabolism and mediate a cycle of demyelination and remyelination that induces antigen presentation, inflammation, oxidative stress and extracellular restructuring. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against age-related cognitive decline, Alzheimer's Disease and Parkinson's Disease.

1 . A method for identifying a biomarker for brain aging, wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, comprising the steps of: 
 (a) obtaining a set of polynucleotides obtained from a set of brain samples, wherein the members of the set of brain samples were obtained from members of a set of mammals, wherein the set of mammals contains more than two members and wherein the set of mammals comprises young, mid-aged and aged members;    (b) identifying the identity and amount of the members of the set of polynucleotides present in the brain samples;    (c) deleting from the set of polynucleotides; 
 (1) quality control oligonucleotides;  
 (2) polynucleotides in which the difference between the young and the aged members did not comprise at least 75% of the maximum normalized difference among the members; and  
   (d) testing by a conventional statistical test for a significant effect of aging across the young, mid-aged and aged members;    wherein the polynucleotides, and polypeptide encoded by said polynucleotides, that are both significantly altered in an age-dependent fashion across age are identified as biomarkers for brain aging.    
   
   
       2 . The identification method of  claim 1 , further comprising the step of: 
 (e) correlating the identity and amount of the members of the set of polynucleotides present in the brain samples with cognitive performance in a behavioral test, using a conventional statistical correlation test;    wherein the polynucleotides, and polypeptide encoded by said polynucleotides, that are both significantly altered in an age-dependent fashion as well as significantly correlated with cognitive performance across age are identified as biomarkers for brain aging.    
   
   
       3 . The identification method of  claim 1 , wherein the biomarker for brain aging is a biomarker for an age-related neurodegenerative condition.  
   
   
       4 . The identification method of  claim 3 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       5 . The identification method of  claim 1 , wherein the brain sample is a hippocampal sample.  
   
   
       6 . The identification method of  claim 1 , wherein the mammal is selected from the group consisting of rat, mouse and human.  
   
   
       7 . The identification method of  claim 1 , wherein the biomarker for brain aging is an expressed sequence tag (EST).  
   
   
       8 . The identification method of  claim 1 , further comprising, in the deletion step (c), the step of: 
 (3) deleting, from the set of polynucleotides, polynucleotides for expressed sequence tags (ESTs) which have not been associated with known genes.    
   
   
       9 . The identification method of  claim 1 , further comprising, in the deletion step (c), the step of: 
 (3) deleting, from the set of polynucleotides, polynucleotides that are not expressed sequence tags (ESTs).    
   
   
       10 . The identification method of  claim 1 , wherein the conventional statistical test in step (d) is ANOVA or student's t test.  
   
   
       11 . The identification method of  claim 1 , wherein the testing in step (d) is testing by 1-way ANOVA for a significant effect of aging p<0.05.  
   
   
       12 . The identification method of  claim 1 , wherein the behavioral tests of step (e) specifically test for cognitive deficits related to the region of the brain from which the brain sample has been obtained in step (a).  
   
   
       13 . The identification method of  claim 1 , wherein the identification of the identity and amount of the members of the set of polynucleotides present in the brain samples in step (b) is by microarray analysis.  
   
   
       14 . The identification method of  claim 1 , wherein the significant effect in step (d) is p<0.025.  
   
   
       15 . The identification method of  claim 1 , wherein the significant effect in step (d) is p<0.01.  
   
   
       16 . The identification method of  claim 1 , wherein the significant effect in step (d) is p<0.001.  
   
   
       17 . The identification method of  claim 1 , wherein the behavioral test in step (e) is selected from the group consisting of the Morris spatial water maze (SWM) and the object memory task (OMT).  
   
   
       18 . The identification method of  claim 1 , wherein the behavioral tests in step (e) are selected from the group consisting of tests for Alzheimer's disease and tests for Parkinson's disease.  
   
   
       19 . The identification method of  claim 1 , wherein the correlation of the identity and amount of the members of the set of polynucleotides present in the brain samples with cognitive performance in behavioral tests is a Pearson or Spearman correlation of expression with behavior.  
   
   
       20 . The identification method of  claim 19 , wherein the correlation is p<0.025.  
   
   
       21 . The identification method of  claim 19 , wherein the correlation is p<0.01.  
   
   
       22 . The identification method of  claim 19 , wherein the correlation is p<0.001.  
   
   
       23 . A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polynucleotides: 
 (a) wherein the set of biomarkers comprises at least two members;    (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical test, with p<0.05;    (c) wherein the brain expression patterns of the members of the set are correlated across age groups with cognitive performance in behavioral tests, using a conventional statistical correlation test with a correlation of p<0.05 between brain expression and cognitive performance; and    (d) wherein the cognitive performance in behavioral tests significantly altered with aging as determined by a conventional statistical test.    
   
   
       24 . The set of biomarkers of  claim 23 , wherein the biomarkers further correlate with a behavioral measure of functional impairment.  
   
   
       25 . The set of biomarkers of  claim 23 , wherein the behavioral measure of functional impairment is a test for an age-related neurodegenerative condition.  
   
   
       26 . The set of biomarkers of  claim 25 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       27 . The set of biomarkers of  claim 23 , wherein the mammal is selected from the group consisting of rat, mouse and human.  
   
   
       28 . The set of biomarkers of  claim 23 , wherein the conventional statistical method in step (b) is ANOVA or student's t-test.  
   
   
       29 . The set of biomarkers of  claim 23 , wherein the correlation in step (c) is tested by a correlation test selected from the group consisting of Pearson's correlation test and Spearman's correlation test.  
   
   
       30 . The set of biomarkers of  claim 23 , wherein the age groups in step (c) comprises young, mid-aged and aged.  
   
   
       31 . The set of biomarkers of  claim 23 , wherein the conventional statistical test in step (d) is ANOVA or student's t-test.  
   
   
       32 . The set of biomarkers of  claim 23 , wherein at least one member of the set of biomarkers is a polynucleotide, or a polypeptide encoded by said polynucleotide, selected from the group consisting of L03294 (Lpl, lipoprotein lipase) (SEQ ID NO:37); M18416 (Egr1, Early growth response 1 (Krox-24)) (SEQ ID NO:8); S68245 (Ca4, carbonic anhydrase 4) (SEQ ID NO:38); M64780 (Agm, Agrin) (SEQ ID NO:1); M27207 (Col1a1, Procollagen-type I (alpha 1)) (SEQ ID NO:32); X16554 (Prps1, Phosphoribosyl pyrophosphate synthetase 1) (SEQ ID NO:51); M92433 (NGFI-C, Zinc-finger transcription factor (early response gene)) (SEQ ID NO:9); AA859975 (LOC64201, 2-oxoglutarate carrier) (SEQ ID NO:39); L08595 (Nuclear receptor subfamily 4, group A, member 2) (SEQ ID NO:10); M24542 (RISP, Rieske iron-sulfur protein) (SEQ ID NO:40); AI030089 (Nopp130, nucleolar phosphoprotein p130) (SEQ ID NO:11); AF104362 (Omd, Osteomodulin (osteoadherin)) (SEQ ID NO:33); L46873 (Slc15a1, Oligopeptide transporter) (SEQ ID NO:47; AI176689 (MAPKK 6, mitogen-activated protein kinase kinase 6) (SEQ ID NO:19); U66470 (rCGR11, Cell growth regulator) (SEQ ID NO:52); AF016387 (RXRG, retinoid X-receptor gamma) (SEQ ID NO:12); M18467 (Got2, glutamate oxaloacetate transaminase 2) (SEQ ID NO:41); X54793 (Hsp60, heat shock protein 60) (SEQ ID NO:62); X64401 (Cyp3a3, Cytochrome P450-subfamily IIIA (polypeptide 3)) (SEQ ID NO:42); M37584 (H2afz, H2A histone family (member Z)) (SEQ ID NO:53); L21192 (GAP-43, membrane attached signal protein 2 (brain)) (SEQ ID NO:2); AA875047 (TCPZ, T-complex protein 1 (zeta subunit)) (SEQ ID NO:63); U90610 (Cxcr4, CXC chemokine receptor) (SEQ ID NO:54); AF003904 (CRH-binding protein) (SEQ ID NO:27); U83880 (GPDH-M, glycerol-3-phosphate dehydrogenase, mitochondrial) (SEQ ID NO:43); X89703 (TPCR19, Testis Polymerase Chain Reaction product 19) (SEQ ID NO:20); D63886 (MMP16, matrix metalloproteinase 16) (SEQ ID NO:34); J05499 (GLS, glutaminase (mitochondrial)) (SEQ ID NO:44); D21799 (Psmb2, Proteasome subunit (beta type 2)) (SEQ ID NO:64); AA800794 (HT2A, zinc-finger protein) (SEQ ID NO:13); U90887 (Arg2, arginase type II) (SEQ ID NO:45); S82649 (Narp, neuronal activity-regulated pentraxin) (SEQ ID NO:3); M74223 (VGF, neurosecretory protein) (SEQ ID NO:4); AA874794 (Bex3, brain expressed X-linked 3) (SEQ ID NO:55); M15191 (Tac1, Tachykinin) (SEQ ID NO:28); AA892506 (coronin, actin binding protein 1A) (SEQ ID NO:56); L04485 (MAPPK1, mitogen-activated protein kinase kinase 1) (SEQ ID NO:21); AA799641 (S 164, Contains a PWI domain associated with RNA splicing) (SEQ ID NO:14); AA817892 (Gnb2, Guanine nucleotide binding protein (beta 2 subunit)) (SEQ ID NO:22); AA893939 (DSS1, deleted in split hand/split foot protein 1) (SEQ ID NO:57); AF000901 (P58/P45, Nucleoporin p58) (SEQ ID NO:23); AF087037 (Btg3, B-cell translocation gene 3) (SEQ ID NO:58); AB000280 (PHT1, peptide/histidine transporter) (SEQ ID NO:48); M87854 (Beta-ARK-1, beta adrenergic receptor kinase 1) (SEQ ID NO:24); U06099 (Prdx2, Peroxiredoxin 2) (SEQ ID NO:59); AF058795 (Gb2, GABA-B receptor) (SEQ ID NO:25; AA800517 (VAP1, vesicle associated protein) (SEQ ID NO:26); U63740 (Fez1, Protein kinase C-binding protein Zeta1) (SEQ ID NO:5); U53922 (Hsj2, DnaJ-like protein (RDJ1)) (SEQ ID NO:65); U78102 (Egr2, Early growth response 2) (SEQ ID NO 5); U44948 (SmLIM, smooth muscle cell LIM protein) (SEQ ID NO:16); U87627 (MCT3, putative monocarboxylate transporter) (SEQ ID NO:49); AB020504 (PMF31, highly homologus to mouse F-box-WD40 repeat protein 6) (SEQ ID NO:67); M21354 (Col3a1, collagen type III alpha-1) (SEQ ID NO:35); AA893664 (Temo, sertoli cell marker (KIAA0077 protein fragment)) (SEQ ID NO:68); AB010437 (CDH8, Cadherin-8) (SEQ ID NO:36); M22756 (Ndufv2, mitochondrial NADH dehydrogenase (24 kDa)) (SEQ ID NO:46); AA799389 (Rab3B, ras-related protein) (SEQ ID NO:50); AI172476 (Tieg-1, TGF-beta-inducible early growth response protein 1) (SEQ ID NO:60); AF091563 (Olfactory receptor) (SEQ ID NO:29); M64376 (Olfactory protein) (SEQ ID NO:30); J04488 (Ptgds, Prostaglandin D synthase) (SEQ ID NO:69); X71127 (c1qb, complement component 1-q (beta polypeptide)) (SEQ ID NO:70); J03752 (Microsomal GST-1, glutathione S-transferase) (SEQ ID NO:71); J03481 (Qdpr, Dihydropteridine reductase) (SEQ ID NO:115); L40362 (MHC class I RT1.C-type protein) (SEQ ID NO:72); M94918 (Hbb, beta hemoglobin) (SEQ ID NO:125); M55534 (Cryab, alpha crystallin polypeptide 2) (SEQ ID NO:105); U17919 (Aif1, allograft inflammatory factor 1) (SEQ ID NO:73); M15562 (MHC class II RT1.u-D-alpha chain) (SEQ ID NO:74); AA799645 (Phospholemman, FXYD domain-containing ion transport regulator 1) (SEQ ID NO:130); X13044 (Cd74, CD74 antigen) (SEQ ID NO:75); M24324 (RTS, MHC class I RT1 (RTS) (u haplotype)) (SEQ ID NO:76); U31866 (Nclone10) (SEQ ID NO:126); M32062 (Fcgr3, Fc IgG receptor III (low affinity)) (SEQ ID NO:77); AF095741 (Mg87) (SEQ ID NO:151); L03201 (Ctss, cathepsin S) (SEQ ID NO:131); M27905 (Rpl21, Ribosomal proteinL21) (SEQ ID NO:132); D38380 (Tf, Transferrin) (SEQ ID NO:127); AA893493 (RPL26, Ribosomal protein L26) (SEQ ID NO:133); AJ222813 (118, interleukin 18) (SEQ ID NO:78); E13541 (Cspg5, chondroitin sulfate proteoglycan 5) (SEQ ID NO:102); X54096 (Lcat, Lecithin-cholesterol acyltransferase) (SEQ ID NO:110); L40364 (RT1Aw2, RT1 class Ib) (SEQ ID NO:79); D28111 (MOBP, myelin-associated oligodendrocytic basic protein) (SEQ ID NO:106); M32016 (Lamp2, lysosomal-associated membrane protein 2) (SEQ ID NO:142); X13167 (NF1-A, nuclear factor 1 A) (SEQ ID NO:89); U26356 (S100A1, S100 protein (alpha chain)) (SEQ ID NO:95); AI231213 (Kangai 1, suppression of tumorigenicity 6) (SEQ ID NO:80); AI170268 (Ptgfr, Prostaglandin F receptor) (SEQ ID NO:81); X62952 (Vim, vimentin) (SEQ ID NO:119); AI014169 (Vdup1, vitamin D-upregulated) (SEQ ID NO:152); AA850219 (Anx3, Annexin A3) (SEQ ID NO:96); D84477 (Rhoa, ras-related homolog A2) (SEQ ID NO:97); X52477 (C3, Complement component 3) (SEQ ID NO:82); X52619 (Rpl28, Ribosomal protein L28) (SEQ ID NO:134); X06554 (S-MAG, myelin-associated glycoprotein C-term) (SEQ ID NO:107); Z50144 (Kat2, kynurenine aminotransferase II) (SEQ ID NO:116); X14181 (RPL18A, Ribosomal protein L18a) (SEQ ID NO:135); AA892333 (Tuba1, alpha-tubulin) (SEQ ID NO:120); U67082 (KZF-1, Kruppel associated box (KRAB) zinc finger 1) (SEQ ID NO:90); U11760 (Vcp, valosin-containing protein) (SEQ ID NO:121); AF048828 (VDAC1, voltage-dependent anion channel 1) (SEQ ID NO:98); M31076 (TNF-alpha, Transforming growth factor (alpha)) (SEQ ID NO:136); S83279 (HSDIV, 17-beta-hydroxysteroid dehydrogenase type IV) (SEQ ID NO:111); AI102103 (Pik4cb, Phosphatidylinositol 4-kinase) (SEQ ID NO:99); X56325 (Hba1, alpha 1 hemoglobin) (SEQ ID NO:128); X73371 (FCGR2, Low affinity immunoglobulin gamma Fc receptor II) (SEQ ID NO:83); X78848 (Gsta1, Glutathione-S-transferase (alpha type)) (SEQ ID NO:84); U92564 (Roaz, Olf-1/EBF associated Zn finger protein) (SEQ ID NO:91); AI171462 (Cd24, CD24 antigen) (SEQ ID NO:137); X83231 (PAIHC3, Pre-alpha-inhibitor, heavy chain 3) (SEQ ID NO:103); AF097593 (Ca4, cadherin 2-type 1 (neuronal)) (SEQ ID NO:104); X68283 (Rpl29, Ribosomal protein L29) (SEQ ID NO:138); S55427 (Pmp, peripheral myelin protein) (SEQ ID NO:108); AA818025 (Cd59, CD59 antigen) (SEQ ID NO:85); E01534 (Rps15, Ribosomal protein S15) (SEQ ID NO:143); U37138 (Sts, Steroid sulfatase) (SEQ ID NO:112); X55572 (Apod, Apolipoprotein D) (SEQ ID NO:113); AI028975 (AP-1, adaptor protein complex (beta 1)) (SEQ ID NO:144); L16995 (ADD1, adipocyte determination/differentiation-dependent factor 1) (SEQ ID NO:92); U07971 (Transamidinase, Glycine amidinotransferase, mitochondrial) (SEQ ID NO:117); L07736 (Cpt1a, Carnitine palmitoyltransferase 1 alpha (liver)) (SEQ ID NO:114); AI237535 (LitaF, LPS-induced TNF-alpha factor) (SEQ ID NO:93); AI175486 (Rps7, Ribosomal protein S7) (SEQ ID NO:145); U32498 (RSEC8, rat homolog of yeast sec8) (SEQ ID NO:122); X53504 (RPL12, Ribosomal protein L12) (SEQ ID NO:139); AF023621 (Sort1, sortilin) (SEQ ID NO:146); AF083269 (P41-Arc, actin-related protein complex 1b) (SEQ ID NO:123); AA891810 (GST, Glutathione S-transferase) (SEQ ID NO:86); M77694 (Fah, fumarylacetoacetate hydrolase) (SEQ ID NO:118); M22357 (MAG, myelin-associated glycoprotein) (SEQ ID NO:109); AI230712 (Pace4, Subtilisin-like endoprotease) (SEQ ID NO:147); AF008439 (NRAMP2, Natural resistance-associated macrophage protein 2) (SEQ ID NO:129); U77829 (Gas-5, growth arrest homolog) (SEQ ID NO:140); U92081 (Gp38, Glycoprotein 38) (SEQ ID NO:87); AA891445 (Skd3, suppressor of K +  transport defect 3) (SEQ ID NO:148); AI177161 (Nfe212, NF-E2-related factor 2) (SEQ ID NO:94); AF031430 (Stx7, Syntaxin 7) (SEQ ID NO:149); L35921 (Ggamma, GTP-binding protein (gamma subunit)) (SEQ ID NO:100); X62322 (Gm, Granulin) (SEQ ID NO:88); AF028784 (GFAP, glial fibrillary acidic protein) (SEQ ID NO:124); AI234146 (Csrp1, Cysteine rich protein 1) (SEQ ID NO:141) and mammalian homologues thereof.  
   
   
       33 . The set of biomarkers of  claim 23 , wherein at least one member of the set of biomarkers is an expressed sequence tag (EST).  
   
   
       34 . The set of biomarkers of  claim 23 , for use in the measurement of age-dependent cognitive decline.  
   
   
       35 . The set of biomarkers of  claim 34 , wherein the age-dependent cognitive decline is an age-related neurodegenerative condition.  
   
   
       36 . The set of biomarkers of  claim 35 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       37 . The set of biomarkers of  claim 23 , for use in the measurement of degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline.  
   
   
       38 . A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polypeptides: 
 (a) wherein the set of biomarkers comprises at least two members;    (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as measured by a conventional statistical method at a significance level of p<0.01.    
   
   
       39 . The set of biomarkers of  claim 38 , wherein the mammal is selected from the group consisting of rat, mouse and human.  
   
   
       40 . The set of biomarkers of  claim 38 , wherein the conventional statistical method is ANOVA or student's t-test.  
   
   
       41 . The set of biomarkers of  claim 38 , wherein at least one member of the set of biomarkers is a polynucleotide, or a polypeptide encoded by said polynucleotide, selected from the group consisting of AA891651 (rc_AA891651 EST195454 cDNA) (SEQ ID NO:173); AI070108 (rc_AI070108 UI-R-Y0-lu-a-09-0-UI.s1 cDNA) (SEQ ID NO:170); AI176689 (mitogen-activated protein kinase kinase 6) (SEQ ID NO:19); AI012051 (rc_AI012051 EST206502 cDNA) (SEQ ID NO:191); AI233365 (rc_AI233365 EST230053 cDNA) (SEQ ID NO:157); AA892532 (rc_AA892532 EST196335 cDNA) (SEQ ID NO:154); AA893185 (rc_AA893185 EST196988 cDNA) (SEQ ID NO:399); AA964320 (rc_AA964320 UI-R-C0-gu-e-09-0-UI.s1 cDNA) (SEQ ID NO:177); AA963449 (rc_AA963449 UI-R-E1-gj-e-08-0-UI.s1 cDNA) (SEQ ID NO:153); AA859632 (rc_AA859632 UI-R-E0-bs-h-08-0-UI.s1 cDNA) (SEQ ID NO:172); AI169265 (Atp6s1) (SEQ ID NO:219); AA850781 (rc_AA850781 EST193549 cDNA) (SEQ ID NO:181); AJ222813 (interleukin 18) (SEQ ID NO:78); D38380 (Transferrin) (SEQ ID NO:127); J03481 (dihydropteridine reductase) (SEQ ID NO:115); M24542 (Rieske iron-sulfur protein) (SEQ ID NO:40); L03294 (Lipoprotein lipase) (SEQ ID NO:37); L19998 (sulfotransferase family 1A, phenol-preferring, member 1) (SEQ ID NO:321); U53922 (DnaJ-like protein (RDJ1)) (SEQ ID NO:65); X54793 (liver heat shock protein (hsp60)) (SEQ ID NO:62); X62952 (vimentin) (SEQ ID NO:119); M55534 (Crystallin, alpha polypeptide 2) (SEQ ID NO:105); J03752 (microsomal glutathione S-transferase 1) (SEQ ID NO:71); X64401 (Cytochrome P450, subfamily 111A, polypeptide 3) (SEQ ID NO:42); X78848 (Gsta1) (SEQ ID NO:84); AF016387 (retinoid X receptor gamma) (SEQ ID NO:12); AF031430 (syntaxin 7) (SEQ ID NO:149); AF051561 (solute carrier family 12, member 2) (SEQ ID NO:322); AF076183 (cytosolic sorting protein PACS-1a (PACS-1)) (SEQ ID NO:231); AF095576 (adaptor protein with pleckstrin homology and src homology 2 domains) (SEQ ID NO:18); AF095741 (MG87) (SEQ ID NO:151); AF097593 (cadherin 2, type 1, N-cadherin (neuronal)) (SEQ ID NO:104); AF104362 (osteoadherin) (SEQ ID NO:33); D10699 (ubiquitin carboxy-terminal hydrolase L1) (SEQ ID NO:234); D28111 (myelin-associated oligodendrocytic basic protein) (SEQ ID NO:106); D37951 (MIBP1 (c-myc intron binding protein 1)) (SEQ ID NO:230); D84477 (RhoA) (SEQ ID NO:97); L13202 (RATHFH2 HNF-3/fork-head homolog-2 (HFH-2)) (SEQ ID NO:220); L26292 (Kruppel-like factor 4 (gut)) (SEQ ID NO:218); L46873 (solute carrier family 15 (oligopeptide transporter), member 1) (SEQ ID NO:47); M13100 (RATLIN3A long interspersed repetitive DNA sequence LINE3 (L1Rn)) (SEQ ID NO:435); M27207 (procollagen, type I, alpha 1) (SEQ ID NO:32); M92433 (Zinc-finger transcription factor NGFI-C (early response gene)) (SEQ ID NO:9); M94918 (Hemoglobin, beta) (SEQ ID NO:125); M94919 (Hemoglobin, beta) (SEQ ID NO:452); S55427 (Peripheral myelin protein) (SEQ ID NO:108); S68245 (carbonic anhydrase 4) (SEQ ID NO:38); S82649 (Narp=neuronal activity-regulated pentraxin); U10894 (allograft inflammatory factor 1) (SEQ ID NO:453); U26356 (RNSHUNA1 S100A1 gene) (SEQ ID NO:95); U75397 (RNKROX2 Krox-24) (SEQ ID NO:454); U75405 (procollagen, type I, alpha 1) (SEQ ID NO:217); U77829 (RNU77829 gas-5 growth arrest homolog non-translated sequence) (SEQ ID NO:140); U92081 (glycoprotein 38) (SEQ ID NO:87); X06554 (RNMAGSR myelin-associated glycoprotein (S-MAG) C-term) (SEQ ID NO:107); X13167 (Nuclear Factor IA) (SEQ ID NO:89); X14181 (RRRPL18A ribosomal protein L18a) (SEQ ID NO:135); X56325 (Hemoglobin, alpha 1) (SEQ ID NO:128); X60351 (Crystallin, alpha polypeptide 2) (SEQ ID NO:455); E13541 (chondroitin sulfate proteoglycan 5) (SEQ ID NO:102); M22357 (1B236/myelin-associated glycoprotein (MAG)) (SEQ ID NO:109); M24026 (RT1 class Ib gene) (SEQ ID NO:456); M24324 (MHC class I RT1 (RTS) (u haplotype)) (SEQ ID NO:76); J04488 (Prostaglandin D synthase) (SEQ ID NO:69); M15191 (Tachykinin (substance P, neurokinin A, neuropeptide K, neuropeptide gamma)) (SEQ ID NO:28); M74223 (VGF) (SEQ ID NO:4); U17254 (immediate early gene transcription factor NGFI-B) (SEQ ID NOS:225 & 257); U08259 (Glutamate receptor, ionotropic, N-methyl D-aspartate 2C) (SEQ ID NO:323); U19866 (activity regulated cytoskeletal-associated protein) (SEQ ID NO:7); L40364 (RT1 class Ib gene) (SEQ ID NO:79); U17919 (allograft inflammatory factor 1) (SEQ ID NO:73); U78102 (early growth response 2) (SEQ ID NO:15); U67082 (KRAB-zinc finger protein KZF-1) (SEQ ID NO:90); U77777 (interleukin 18) (SEQ ID NO:319); D78018 (Nuclear Factor IA) (SEQ ID NO:457); U92564 (Olf-1/EBF associated Zn finger protein Roaz) (SEQ ID NO:91); AF008439 (Solute carrier family 11 member 2 (natural resistance-associated macrophage protein 2)) (SEQ ID NO:129); AB003726 (RuvB-like protein 1) (SEQ ID NO:6); M83561 (Glutamate receptor, ionotropic, kainate 1) (SEQ ID NO:101); AI639151 (mixed-tissue library cDNA clone rx02802 3) (SEQ ID NO:438); AI639247 (mixed-tissue library cDNA clone rx03939 3) (SEQ ID NO:160); AI639381 (mixed-tissue library cDNA clone rx01495 3) (SEQ ID NO:196); AI639532 (mixed-tissue library cDNA clone rx01030 3) (SEQ ID NO:189); AA799645 (FXYD domain-containing ion transport regulator 1) (SEQ ID NO:130); AA900516 (Pdi2) (SEQ ID NO:150); AI014169 (Vdup1) (SEQ ID NO:152); AI030089 (Nopp140) (SEQ ID NO:1); AI102299 (Bid3) (SEQ ID NO:320); AA818025 (CD59 antigen) (SEQ ID NO:85); AI170268 (Prostaglandin F receptor) (SEQ ID NO:81); AI171462 (CD24 antigen) (SEQ ID NO:137); AI171966 (ESTs, Highly similar to SPS2 MOUSE SELENIDE, WATER DIKINASE 2 [ M. musculus ]) (SEQ ID NO:437); AI176456 (ESTs, Weakly similar to ABP2_HUMAN ENDOTHELIAL ACTIN-BINDING PROTEIN [ H. sapiens ]) (SEQ ID NO:182); AI177161 (NF-E2-related factor 2) (SEQ ID NO:94); AI179576 (Hemoglobin, beta) (SEQ ID NO:458); AI230712 (Subtilisin-like endoprotease) (SEQ ID NO:147); AI230914 (farnesyltransferase beta subunit) (SEQ ID NO:229); AI231213 (kangai 1 (suppression of tumorigenicity 6), prostate) (SEQ ID NO:80); AI237731 (Lipoprotein lipase) (SEQ ID NO:459); M83745 (Protein convertase subtilisin/kexin, type I) (SEQ ID NO:226); M27905 (ribosomal protein L21) (SEQ ID NO:132); M32016 (Lysosomal-associated membrane protein 2) (SEQ ID NO:142); M11071 (RT1 class Ib gene) (SEQ ID NO:460); M15562 (MHC class II RT1.u-D-alpha chain) (SEQ ID NO:74); M15880 (Neuropeptide Y) (SEQ ID NO:31); L08595 (nuclear receptor subfamily 4, group A, member 2) (SEQ ID NO:10); M18416 (Early growth response 1) (SEQ ID NO:8); L40362 (MHC class I RT1.C-type protein) (SEQ ID NO:72); Z50144 (kynurenine/alpha-aminoadipate aminotransferase) (SEQ ID NO:116); X71127 (complement component 1, q subcomponent, beta polypeptide) (SEQ ID NO:70); U44948 (smooth muscle cell LIM protein (SmLIM)) (SEQ ID NO:16); AA850219 (Annexin A3) (SEQ ID NO:96); X73371 (FCGR2) (SEQ ID NO:83); X57281 (Glycine receptor alpha 2 subunit (glycine receptor, neonatal)) (SEQ ID NO:235); X83231 (pre-alpha-inhibitor) (SEQ ID NO:103); X52477 (Complement component 3) (SEQ ID NO:82); X16554 (phosphoribosyl pyrophosphate synthetase 1) (SEQ ID NO:51); X78605 ((Sprague Dawley) rab4b ras-homologous GTPase) (SEQ ID NO:66); X82445 (nuclear distribution gene C homolog ( Aspergillus )) (SEQ ID NO:232); X52619 (ribosomal protein L28) (SEQ ID NO:134); X68283 (ribosomal protein L29) (SEQ ID NO:138); X13044 (CD74 antigen (invariant polpypeptide of major histocompatibility class II antigen-associated)) (SEQ ID NO:75); X54096 (Lecithin-cholesterol acyltransferase) (SEQ ID NO:110); U31866 (Nclone10) (SEQ ID NO:126); U72620 (Lot1) (SEQ ID NO:224); U66470 (rCGR11) (SEQ ID NO:52); M31018 (RT1 class Ib gene) (SEQ ID NO:461); U90887 (arginase type II) (SEQ ID NO:45); M18467 (Glutamate oxaloacetate transaminase 2, mitochondrial (aspartate aminotransferase 2)) (SEQ ID NO:41); M64780 (Agrin) (SEQ ID NO:1); U87627 (putative monocarboxylate transporter (MCT3)) (SEQ ID NO:49); AF019974 (Chromogranin B, parathyroid secretory protein) (SEQ ID NO:223); L03201 (cathepsin S) (SEQ ID NO:131); AB008538 (HB2) (SEQ ID NO:324); D89340 (dipeptidylpeptidase III) (SEQ ID NO:222); M77694 (fumarylacetoacetate hydrolase) (SEQ ID NO:118); M32062 (Fc-gamma receptor) (SEQ ID NO:77); L21192 (brain abundant, membrane attached signal protein 2) (SEQ ID NO:2); M37584 (H2afz) (SEQ ID NO:53); AA858588 (ESTs, Weakly similar to ODP2 RAT DIHYDROLIPOAMIDE ACETYLTRANSFERASE COMPONENT OF PYRUVATE DEHYDROGENASE COMPLEX [ R. norvegicus ]) (SEQ ID NO:184); AA858617 (rc_AA858617 UI-R-E0-bq-b-06-0-UI.s1 cDNA) (SEQ ID NO:161); AA859562 (rc_AA859562 UI-R-E0-by-b-03-0-UI.s1 cDNA) (SEQ ID NO:403); AA859626 (rc_AA859626 UI-R-E0-bs-h-02-0-UI.s1 cDNA) (SEQ ID NO:155); AA859690 (rc_AA859690 UI-R-E0-bx-e-11-0-UI.s1 cDNA) (SEQ ID NO:396); AA859777 (rc_AA859777 UI-R-E0-bu-e-10-0-UI.s1 cDNA) (SEQ ID NO:188); AA859975 (LOC64201) (SEQ ID NO:39); AA860030 (UI-R-E0-bz-e-07-0-UI.s2 cDNA) (SEQ ID NO:404); AA866291 (rc_AA866291 UI-R-A0-ac-e-12-0-UI.s3 cDNA) (SEQ ID NO:164); AA866409 (rc_AA866409 UI-R-E0-ch-a-03-0-UI.s1 cDNA) (SEQ ID NO:171); AA866411 (NDN) (SEQ ID NO:61); AA874794 (Bex3) (SEQ ID NO:55); AA874887 (rc_AA874887 UI-R-E0-ci-g-10-0-UI.s1 cDNA) (SEQ ID NO:180); AA875004 (rc_AA875004 UI-R-E0-cb-b-07-0-UI.s1 cDNA) (SEQ ID NO:397); AA875037 (rc_AA875037 UI-R-E0-cb-a-03-0-UI.s1 cDNA) (SEQ ID NO:439); AA875047 (TCPZ) (SEQ ID NO:63); AA875059 (rc_AA875059 UI-R-E0-cb-f-04-0-UI.s1 cDNA) (SEQ ID NO:190); AA875129 (rc_AA875129 UI-R-E0-bu-e-01-0-UI.s2 cDNA) (SEQ ID NO:401); H31418 (rc_H31418 EST105434 cDNA) (SEQ ID NO:183); H31665 (rc_H31665 EST105952 cDNA) (SEQ ID NO:158); H32977 (rc_H32977 EST108553 cDNA) (SEQ ID NO:179); H33725 (associated molecule with the SH3 domain of STAM) (SEQ ID NO:228); AA891037 (rc_AA891037 EST194840 cDNA) (SEQ ID NO:398); AA891445 (Skd3) (SEQ ID NO:148); AA891690 (ESTs, Weakly similar to SERC_HUMAN PHOSPHOSERINE AMINOTRANSFERASE [ H. sapiens ]) (SEQ ID NO:440); AA891717 (USF1) (SEQ ID NO:17); AA891734 (rc_AA891734 EST195537 cDNA) (SEQ ID NO:436); AA891785 (rc_AA891785 EST195588 cDNA) (SEQ ID NO:185); AA891810 (ESTs, Highly similar to GTK1 RAT GLUTATHIONE S-TRANSFERASE, MITOCHONDRIAL [ R. norvegicus ]) (SEQ ID NO:86); AA891965 (rc_AA891965 EST195768 cDNA) (SEQ ID NO:175); AA892333 (Tuba1) (SEQ ID NO:120); AA892353 (ESTs, Moderately similar to JC5823 NADH dehydrogenase [ H. sapiens ]) (SEQ ID NO:159); AA892511 (rc_AA892511 EST196314 cDNA) (SEQ ID NO:400); AA892986 (rc_AA892986 EST196789 cDNA) (SEQ ID NO:434); AA893032 (ESTs, Moderately similar to CALX RAT CALNEXIN PRECURSOR [ R. norvegicus ]) (SEQ ID NO:174); AA893082 (rc_AA893082 EST196885 cDNA) (SEQ ID NO:433); AA893493 (RPL26) (SEQ ID NO:133); AA893607 (rc_AA893607 EST197410 cDNA) (SEQ ID NO:195); AA893708 (KIAA0560) (SEQ ID NO:227); AA893743 (rc_AA893743 EST197546 cDNA) (SEQ ID NO:156); AA894104 (rc_AA894104 EST197907 cDNA) (SEQ ID NO:165); AA799449 (EST, Weakly similar to UBP4 MOUSE UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 4 [ M. musculus ]) (SEQ ID NO:187); AA799779 (acyl-CoA:dihydroxyacetonephosphate acyltransferase) (SEQ ID NO:221); AA799803 (ESTs, Weakly similar to K1CU RAT KERATIN, TYPE I CYTOSKELETAL 21 [ R. norvegicus ]) (SEQ ID NO:186); AA799854 (rc_AA799854 EST189351 cDNA) (SEQ ID NO:193); AA799996 (rc_AA799996 EST189493 cDNA) (SEQ ID NO:166); AA800693 (rc_AA800693 EST190190 cDNA) (SEQ ID NO:402); AA800708 (ESTs, Weakly similar to S28312 hypothetical protein F02A9.4- Caenorhabditis elegans [C. elegans ]) (SEQ ID NO-176); AA800794 (HT2A) (SEQ ID NO:13); AA800948 (Tuba4) (SEQ ID NO:233); and mammalian homologues thereof.  
   
   
       42 . The set of biomarkers of  claim 38 , wherein at least one member of the set of biomarkers is an expressed sequence tag (EST).  
   
   
       43 . The set of biomarkers of  claim 38 , for use in the measurement of age-dependent cognitive decline.  
   
   
       44 . The set of biomarkers of  claim 43 , wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition.  
   
   
       45 . The set of biomarkers of  claim 44 , wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       46 . The set of biomarkers of  claim 38 , for use in the measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline.  
   
   
       47 . The use of an expressed sequence tag (EST) in an assay for aging in a mammal, wherein the EST is selected from the group consisting of AA963449 (UI-R-E1-gj-e-08-0-UI.s1 cDNA) (SEQ ID NO:153); AA892532 (EST196335 cDNA) (SEQ ID NO:154); AA859626 (UI-R-E0-bs-h-02-0-UI.s1 cDNA) (SEQ ID NO:155); AA893743 (EST197546 cDNA) (SEQ ID NO:156); AI233365 (EST230053 cDNA) (SEQ ID NO:157); H31665 (EST105952 cDNA) (SEQ ID NO:158); AA892353 (ESTs, Moderately similar to JC5823 NADH dehydrogenase) (SEQ ID NO:159); AI639247 (mixed-tissue library cDNA clone rx03939 3) (SEQ ID NO:160); AA858617 (UI-R-E0-bq-b-06-0-UI.s1 cDNA) (SEQ ID NO:161); AI639429 (mixed-tissue library cDNA clone rx00973 3) (SEQ ID NO:162); AA858620 (UI-R-E0-bq-b-09-0-UI.s1 cDNA) (SEQ ID NO:163); AA866291 (UI-R-A0-ac-e-12-0-UI.s3 cDNA) (SEQ ID NO:164); AA894104 (EST197907 cDNA) (SEQ ID NO:165); AA799996 (EST189493 cDNA) (SEQ ID NO:166); AA892805 (EST196608 cDNA) (SEQ ID NO:167); AI639019 (mixed-tissue library cDNA clone rx01107 3) (SEQ ID NO:168); AA799538 (EST189035 cDNA) (SEQ ID NO:169); AI070108 (UI-R-Y0-lu-a-09-0-UI.s1 cDNA) (SEQ ID NO:170); AA866409 (UI-R-E0-ch-a-03-0-UI.s1 cDNA) (SEQ ID NO:171); AA859632 (UI-R-E0-bs-h-08-0-UI.s1 cDNA) (SEQ ID NO:172); AA891651 (EST195454 cDNA) (SEQ ID NO:173); AA893032 (ESTs, Moderately similar to CALX calnexin precursor) (SEQ ID NO:174); AA891965 (EST195768 cDNA) (SEQ ID NO:175); AA800708 (ESTs, Weakly similar to S28312 hypothetical protein F02A9.4); AA964320 (UI-R-C0-gu-e-09-0-UI.s1 cDNA) (SEQ ID NO:177); AA893173 (EST196976 cDNA) (SEQ ID NO:178); H32977 (EST108553 cDNA) (SEQ ID NO:179); AA874887 (UI-R-E0-ci-g-10-0-UI.s1 cDNA) (SEQ ID NO:180); AA850781 (EST193549 cDNA) (SEQ ID NO:181); AI176456 (ESTs, Weakly similar to endothelial actin-binding protein); H31418 (EST105434 cDNA) (SEQ ID NO:183); AA858588 (ESTs, Weakly similar to ODP2 dihydrolipoamide acetyl transferase) (SEQ ID NO:184); AA891785 (EST195588 cDNA) (SEQ ID NO:185); AA799803 (ESTs, Weakly similar to K1CU cytoskeletal keratin (type 1)) (SEQ ID NO:186); AA799449 (EST, Weakly similar to UBP4 ubiquitin carboxyl-terminal hydrolase 4) (SEQ ID NO:187); AA859777 (UI-R-E0-bu-e-10-0-UI.s1 cDNA) (SEQ ID NO:188); AI639532 (mixed-tissue library cDNA clone rx01030 3) (SEQ ID NO:189); AA875059 (UI-R-E0-cb-f-04-0-UI.s1 cDNA) (SEQ ID NO:190); AI012051 (EST206502 cDNA) (SEQ ID NO:191); AA800549 (EST190046 cDNA) (SEQ ID NO:192); AA799854 (EST189351 cDNA) (SEQ ID NO:193); AA892520 (EST196323 cDNA) (SEQ ID NO:194) and mammalian homologues thereof.  
   
   
       48 . The use of  claim 47 , wherein the assay for aging is a measurement of age-dependent cognitive decline.  
   
   
       49 . The use of  claim 48 , wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition.  
   
   
       50 . The use of  claim 49 , wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       51 . The use of  claim 47 , wherein the assay for aging is a measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline.  
   
   
       52 . A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polynucleotides: 
 (a) wherein the set of biomarkers comprises at least two members; and    (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical method, with p<0.05.    
   
   
       53 . The set of biomarkers of  claim 52 , wherein the set contains at least one member selected from the group consisting of AA685974 (EST108806 cDNA) (SEQ ID NO:414); AA799396 (EST188893 cDNA); AA799479 (ESTs, Highly similar to NADH-ubiquinone oxidoreduct.) (SEQ ID NO:295); AA799481 (EST188978 cDNA) (SEQ ID NO:411); AA799529 (EST189026 cDNA) (SEQ ID NO:382); AA799599 (EST189096 cDNA) (SEQ ID NO:380); AA799636 (EST189133 cDNA) (SEQ ID NO:392); AA799680 (EST189177 cDNA) (SEQ ID NO:390); AA799724 (ESTs, Highly similar to DNA-directed RNA polymerase I) (SEQ ID NO:199); AA799773 (EST189270 cDNA) (SEQ ID NO:450); AA799779 (acyl-CoA:dihydroxyacetonephosphate acyltransferase) (SEQ ID NO:221); AA799858 (EST189355 cDNA) (SEQ ID NO:422); AA800026 (EST189523 cDNA) (SEQ ID NO:423); AA800318 (EST189815 cDNA) (SEQ ID NO:432); AA800622 (EST190119 cDNA) (SEQ ID NO:385); AA800693 (EST190190 cDNA) (SEQ ID NO:402); AA800948 (Tuba4) (SEQ ID NO:233); AA801286 (Inositol (myo)-1(or 4)-monophosphatase 1) (SEQ ID NO:265); AA817887 (profilin) (SEQ ID NO:291); AA818025 (CD59 antigen) (SEQ ID NO:85); AA818240 (Nuclear pore complex protein) (SEQ ID NO:312); AA818487 (cyclophilin B) (SEQ ID NO:294); AA819500 (ESTs, Highly similar to AC12_HUMAN 37 kD subunit) (SEQ ID NO:283); AA819708 (Cox7a3) (SEQ ID NO:247); AA848831 (lysophosphatidic acid G-protein-coupled receptor, 2) (SEQ ID NO:328); AA852046 (EST194815 cDNA) (SEQ ID NO:444); AA859545 (ESTs, Weakly similar to hypothetical protein C09H6.3) (SEQ ID NO:425); AA859562 (UI-R-E0-by-b-03-0-UI.s1 cDNA) (SEQ ID NO:403); AA859643 (UI-R-E0-bs-a-08-0-UI.s1 cDNA) (SEQ ID NO:412); AA859645 (attractin) (SEQ ID NO:346); AA859690 (UI-R-E0-bx-e-11-0-UI.s1 cDNA) (SEQ ID NO:396); AA859848 (UI-R-E0-cc-h-10-0-UI.s1 cDNA) (SEQ ID NO:426); AA859954 (Vacuole Membrane Protein 1) (SEQ ID NO:271); AA859980 (T-complex 1) (SEQ ID NO:278); AA860030 (UI-R-E0-bz-e-07-0-UI.s2 cDNA) (SEQ ID NO:404); AA866257 (ESTs) (SEQ ID NO:248); AA866299 (UI-R-A0-ac-f-12-0-UI.s3 cDNA) (SEQ ID NO:449); AA866432 (UI-R-E0-ch-e-06-0-UI.s1 cDNA) (SEQ ID NO:441); AA866477 (UI-R-E0-br-h-03-0-UI.s1 cDNA) (SEQ ID NO:418); AA874830 (UI-R-E0-cg-f-04-0-UI.s1 cDNA) (SEQ ID NO:378); AA874874 (ESTs, Highly similar to alcohol dehydrogenase class III) (SEQ ID NO:258); AA874969 (ESTs, Highly similar to c-Jun leucine zipper interactive) (SEQ ID NO:263); AA874995 (UI-R-E0-cf-d-08-0-UI.s1 cDNA) (SEQ ID NO:393); AA875004 (UI-R-E0-cb-b-07-0-UI.s1 cDNA) (SEQ ID NO:397); AA875019 (UI-R-E0-cb-f-08-0-UI.s1 cDNA) (SEQ ID NO:417); AA875032 (UI-R-E0-cb-h-09-0-UI.s1 cDNA) (SEQ ID NO:379); AA875037 (UI-R-E0-cb-a-03-0-UI.s1 cDNA) (SEQ ID NO:439); AA875129 (UI-R-E0-bu-e-01-0-UI.s2 cDNA) (SEQ ID NO:401); AA875257 (UI-R-E0-cq-d-12-0-UI.s1 cDNA) (SEQ ID NO:413); AA891037 (EST194840 cDNA) (SEQ ID NO:398); AA891041 (un B proto-oncogene) (SEQ ID NO:290); AA891221 (EST195024 cDNA) (SEQ ID NO:387); AA891476 (EST195279 cDNA) (SEQ ID NO:415); AA891537 (EST195340 cDNA) (SEQ ID NO:389); AA891690 (ESTs, Weakly similar to p-serine aminotransferase) (SEQ ID NO:440); AA891727 (EST195530 cDNA) (SEQ ID NO:405); AA891734 (EST195537 cDNA) (SEQ ID NO:436); AA891774 (EST195577 cDNA) (SEQ ID NO:447); AA891810 (EST195613 cDNA) (SEQ ID NO:86); AA891880 (Loc65042) (SEQ ID NO:243); AA891916 (membrane interacting protein of RGS16) (SEQ ID NO:209); AA891944 (EST195747 cDNA) (SEQ ID NO:451); AA891950 (EST195753 cDNA) (SEQ ID NO:416); AA892146 (EST195949 cDNA) (SEQ ID NO:443); AA892298 (EST196101 cDNA) (SEQ ID NO:394); AA892414 (EST196217 cDNA) (SEQ ID NO:409); AA892511 (EST196314 cDNA) (SEQ ID NO:400); AA892520 (EST196323 cDNA) (SEQ ID NO:194); AA892538 (EST196341 cDNA) (SEQ ID NO:395); AA892637 (EST196440 cDNA) (SEQ ID NO:424); AA892775 (Lysozyme) (SEQ ID NO:354); AA892796 (EST196599 cDNA) (SEQ ID NO:406); AA892813 (EST196616 cDNA) (SEQ ID NO:381); AA892986 (EST196789 cDNA) (SEQ ID NO:434); AA893082 (EST196885 cDNA) (SEQ ID NO:433); AA893185 (EST196988 cDNA) (SEQ ID NO:399); AA893199 (EST197002 cDNA) (SEQ ID NO:391); AA893224 (EST197027 cDNA) (SEQ ID NO:428); AA893320 (EST197123 cDNA) (SEQ ID NO:388); AA893584 (EST197387 cDNA) (SEQ ID NO:383); AA893690 (EST197493 cDNA) (SEQ ID NO:386); AA893708 (KIAA0560) (SEQ ID NO:227); AA893717 (EST197520 cDNA) (SEQ ID NO:408); AA893743 (EST197546 cDNA) (SEQ ID NO:156); AA893788 (ESTs, Highly similar to chromobox protein homolog 5) (SEQ ID NO:299); AA893946 (EST197749 cDNA) (SEQ ID NO:429); AA894305 (EST198108 cDNA) (SEQ ID NO:384); AA924925 (ER transmembrane protein Dri 42) (SEQ ID NO:372); AA942685 (cytosolic cysteine dioxygenase 1) (SEQ ID NO:249); AA955306 (ras-related protein rab10) (SEQ ID NO:365); AA955388 (Na + K +  transporting ATPase 2, beta polypeptide 2) (SEQ ID NO:307); AA957132 (N-acetylglucosaminyltransferase I) (SEQ ID NO:375); AB000778 (Phoshpolipase D gene 1) (SEQ ID NO:357); AB006451 (Tim23) (SEQ ID NO:253); AB008538 (HB2) (SEQ ID NO:324); AB016532 (period homolog 2 ( Drosophila )) (SEQ ID NO:259); AF000899 (p58/p45, nucleolin) (SEQ ID NO:286); AF007554 (Mucin1) (SEQ ID NO:266); AF007758 (synuclein, alpha) (SEQ ID NO:260); AF007890 (resection-induced TPI (rs11)) (SEQ ID NO:262); AF008554 (implantation-associated protein (IAG2)) (SEQ ID NO:331); AF013144 (MAP-kinase phosphatase (cpg21)) (SEQ ID NO:281); AF016269 (kallikrein 6 (neurosin, zyme)) (SEQ ID NO:301); AF016296 (neuropilin) (SEQ ID NO:325); AF019974 (Chromogranin B, parathyroid secretory protein) (SEQ ID NO:223); AF020046 (integrin alpha E1, epithelial-associated) (SEQ ID NO:284); AF021935 (Ser-Thr protein kinase) (SEQ ID NO:302); AF023087 (Early growth response 1) (SEQ ID NO:269); AF030050 (replication factor C) (SEQ ID NO:327); AF030088 (RuvB-like protein 1) (SEQ ID NO:280); AF040954 (putative protein phosphatase 1 nuclear targeting subunit) (SEQ ID NO:213); AF051561 (solute carrier family 12, member 2) (SEQ ID NO:322); AF055477 (L-type voltage-dependent Ca 2+  channel (?1D subunit)) (SEQ ID NO:207); AF074608 (MHC class I antigen (RT1.EC2) gene) (SEQ ID NO:340); AF076183 (cytosolic sorting protein PACS-1a (PACS-1)) (SEQ ID NO:231); AF095927 (protein phosphatase 2C) (SEQ ID NO:246); AI010110 (SH3-domain GRB2-like 1) (SEQ ID NO:273); AI012589 (glutathione S-transferase, pi 2) (SEQ ID NO:356); AI013627 (defender against cell death 1) (SEQ ID NO:208); AI013861 (3-hydroxyisobutyrate dehydrogenase) (SEQ ID NO:342); AI045249 (heat shock 70 kD protein 8) (SEQ ID NO:245); AI102031 (myc box dependent interacting protein 1) (SEQ ID NO:370); AI102299 (Bid3) (SEQ ID NO:320); AI102839 (cerebellar Ca-binding protein, spot 35 protein) (SEQ ID NO:203); AI102868 (EST212157 cDNA) (SEQ ID NO:420); AI104388 (heat shock 27 kD protein 1) (SEQ ID NO:296); AI136891 (zinc finger protein 36, C3H type-like 1) (SEQ ID NO:275); AI168942 (branched chain keto acid dehydrogenase E1) (SEQ ID NO:268); AI169265 (Atp6s1) (SEQ ID NO:219); AI171966 (ESTs, Highly similar to selenide, water dikinase 2) (SEQ ID NO:437); AI175973 (ESTs, Highly similar to NADH dehydrogenase) (SEQ ID NO:198); AI176491 (EST220076 cDNA) (SEQ ID NO:410); AI176595 (Cathepsin L) (SEQ ID NO:351); AI176621 (iron-responsive element-binding protein) (SEQ ID NO:272); AI 77404 (EST221024 cDNA) (SEQ ID NO:431); AI178204 (EST221869 cDNA) (SEQ ID NO:421); AI178921 (Insulin degrading enzyme) (SEQ ID NO:215); AI228548 (ESTs, Highly similar to DKFZp586G0322.1) (SEQ ID NO:316); AI230247 (selenoprotein P, plasma, 1) (SEQ ID NO:300); AI230778 (ESTs, Highly similar to protein-tyrosine sulfotrans. 2) (SEQ ID NO:277); AI230914 (farnesyltransferase beta subunit) (SEQ ID NO:229); AI231807 (ferritin light chain 1) (SEQ ID NO:332); AI232268 (LDL receptor-related protein associated protein 1) (SEQ ID NO:244); AI235344 (geranylgeranyltransferase type I (GGTase-I)) (SEQ ID NO:304); AI237007 (ESTs, Highly similar to flavoprot.-ubiquin. Oxidoreduct.) (SEQ ID NO:376); AI638971 (mixed-tissue library cDNA clone rx04989 3) (SEQ ID NO:446); AI638997 (mixed-tissue library cDNA clone rx05048 3) (SEQ ID NO:430); AI639151 (mixed-tissue library cDNA clone rx02802 3) (SEQ ID NO:438); AI639209 (mixed-tissue library cDNA clone rx00680 3) (SEQ ID NO:419); AI639257 (mixed-tissue library cDNA clone rx01119 3) (SEQ ID NO:448); AI639477 (mixed-tissue library cDNA clone rx02351 3) (SEQ ID NO:407); D00569 (2,4-dienoyl CoA reductase 1, mitochondrial) (SEQ ID NO:311); D10262 (choline kinase) (SEQ ID NO:214); D10699 (ubiquitin carboxy-terminal hydrolase L1) (SEQ ID NO:234); D10854 (aldehyde reductase) (SEQ ID NO:285); D10874 (lysosomal vacuolar proton pump (16 kDa)) (SEQ ID NO:211); D16478 (mitochondrial long-chain enoyl-CoA hydratase) (SEQ ID NO:250); D17309 (delta 4-3-ketosteroid-5-beta-reductase) (SEQ ID NO:364); D28110 (myelin-associated oligodendrocytic basic protein) (SEQ ID NO:309); D28557 (cold shock domain protein A) (SEQ ID NO:313); D29766 (v-crk-associated tyrosine kinase substrate) (SEQ ID NO:202); D37951 (MIBP1 (c-myc intron binding protein 1)) (SEQ ID NO:230); D45247 (proteasome subunit RCX) (SEQ ID NO:212); D45249 (protease (prosome, macropain) 28 subunit, alpha) (SEQ ID NO:338); D78308 (calreticulin) (SEQ ID NO:293); D83948 (adult liver S1-1 protein) (SEQ ID NO:298); D88586 (eosinophil cationic protein) (SEQ ID NO:251); D89340 (dipeptidylpeptidase III) (SEQ ID NO:222); D89730 (Fibulin 3, fibulin-like extracellular matrix protein 1) (SEQ ID NO:344); D90211 (Lysosomal-associated membrane protein 2) (SEQ ID NO:345); E03229 (cytosolic cysteine dioxygenase 1) (SEQ ID NO:252); H33086 (EST108750 cDNA) (SEQ ID NO:427); H33725 (associated molecule with the SH3 domain of STAM) (SEQ ID NO:228); J02752 (acyl-coA oxidase) (SEQ ID NO:368); J02773 (heart fatty acid binding protein) (SEQ ID NO:289); J05022 (peptidylarginine deiminase) (SEQ ID NO:362); J05031 (Isovaleryl Coenzyme A dehydrogenase) (SEQ ID NO:288); J05132 (UDP-glucuronosyltransferase) (SEQ ID NO:330); K02248 (Somatostatin) (SEQ ID NO:270); L00191 (Fibronectin 1) (SEQ ID NO:350); L13202 (RATHFH2 HNF-3/fork-head homolog-2 (HFH-2)) (SEQ ID NO:220); L19998 (sulfotransferase family 1A, phenol-preferring, member 1) (SEQ ID NO:321); L24896 (glutathione peroxidase 4) (SEQ ID NO:318); L25605 (Dynamin 2) (SEQ ID NO:349); L26292 (Kruppel-like factor 4 (gut)) (SEQ ID NO:218); L29573 (neurotransmitter transporter, noradrenalin) (SEQ ID NO:216); L42855 (transcription elongation factor B (SIII) polypeptide 2) (SEQ ID NO:274); M10068 (NADPH-cytochrome P-450 oxidoreductase) (SEQ ID NO:254); M13100 (long interspersed repetitive DNA sequence LINE3) (SEQ ID NO:435); M19936 (Prosaposin-sphingolipid hydrolase activator) (SEQ ID NO:366); M23601 (Monoamine oxidase B) (SEQ ID NO:361); M24104 (synaptobrevin 2) (SEQ ID NO:303); M24104 (Vesicle-associated membrane protein (synaptobrevin 2)) (SEQ ID NO:303); M24852 (Neuron specific protein PEP-19 (Purkinje cell protein 4)) (SEQ ID NO:239); M31174 (thyroid hormone receptor alpha) (SEQ ID NO:264); M36453 (Inhibin, alpha) (SEQ ID NO:206); M55015 (nucleolin) (SEQ ID NO:348); M57276 (Leukocyte antigen (Ox-44)) (SEQ ID NO:367); M58404 (thymosin, beta 10) (SEQ ID NO:282); M80550 (adenylyl cyclase) (SEQ ID NO:204); M83745 (Protein convertase subtilisin/kexin, type I) (SEQ ID NO:226); M89646 (ribosomal protein S24) (SEQ ID NO:371); M91234 (VL30 element) (SEQ ID NO:329); M93273 (somatostatin receptor subtype 2) (SEQ ID NO:197); M93669 (Secretogranin II) (SEQ ID NO:256); M99485 (Myelin oligodendrocyte glycoprotein) (SEQ ID NO:360); S53527 (S100 calcium-binding protein, beta (neural)) (SEQ ID NO:343); S61868 (Ryudocan/syndecan 4) (SEQ ID NO:334); S72594 (tissue inhibitor of metalloproteinase 2) (SEQ ID NO:333); S77492 (Bone morphogenetic protein 3) (SEQ ID NO:276); S77858 (non-muscle myosin alkali light chain) (SEQ ID NO:287); U04738 (Somatostatin receptor subtype 4) (SEQ ID NO:261); U07619 (Coagulation factor III (thromboplastin, tissue factor)) (SEQ ID NO:377); U08259 (Glutamate receptor, N-methyl D-aspartate 2C) (SEQ ID NO:323); U10357 (pyruvate dehydrogenase kinase 2 subunit p45 (PDK2)) (SEQ ID NO:310); U14950 (tumor suppressor homolog (synapse associ. protein)) (SEQ ID NO:306); (immediate early gene transcription factor NGFI-B) (SEQ ID NO:225); U18771 (Ras-related protein Rab-26) (SEQ ID NO:205); U27518 (UDP-glucuronosyltransferase) (SEQ ID NO:279); U28938 (receptor-type protein tyrosine phosphatase D30) (SEQ ID NO:242); U38379 (Gamma-glutamyl hydrolase) (SEQ ID NO:292); U38801 (DNA polymerase beta) (SEQ ID NO:257); U67080 (r-MyT13) (SEQ ID NO:341); U67136 (A kinase (PRKA) anchor protein 5) (SEQ ID NO:336); U67137 (guanylate kinase associated protein) (SEQ ID NO:339); U72620 (Lot1) (SEQ ID NO:224); U75405 (procollagen, type I, alpha 1) (SEQ ID NO:217); U75917 (clathrin-associated protein 17) (SEQ ID NO:240); U77777 (interleukin 18) (SEQ ID NO:319); U78517 (cAMP-regulated guanine nucleotide exchange factor II) (SEQ ID NO:369); U89905 (alpha-methylacyl-CoA racemase) (SEQ ID NO:238); V01244 (Prolactin) (SEQ ID NO:317); X02904 (glutathione S-transferase P subunit) (SEQ ID NO:355); X05472 (2.4 kb repeat DNA right terminal region) (SEQ ID NO:442); X06769 (FBJ v-fos oncogene homolog) (SEQ ID NO:200); X06916 (S100 calcium-binding protein A4) (SEQ ID NO:335); X13905 (ras-related rab1B protein) (SEQ ID NO:315); X14323 (Fc receptor, IgG, alpha chain transporter) (SEQ ID NO:352); X16933 (RNA binding protein p45AUF1) (SEQ ID NO:373); X53427 (glycogen synthase kinase 3 alpha (EC 2.7.1.37)) (SEQ ID NO:241); X53504 (ribosomal protein L12) (SEQ ID NO:139); X54467 (cathepsin D) (SEQ ID NO:314); X55153 (ribosomal protein P2) (SEQ ID NO:347); X57281 (Glycine receptor alpha 2 subunit) (SEQ ID NO:235); X58294 (carbonic anhydrase 2) (SEQ ID NO:359); X59737 (ubiquitous mitochondrial creatine kinase) (SEQ ID NO:297); X60212 (ASI homolog of bacterial ribosomal subunit protein L22) (SEQ ID NO:305); X62950 (pBUS30 with repetitive elements) (SEQ ID NO:326); X67805 (Synaptonemal complex protein 1) (SEQ ID NO:210); X72757 (cox VIa gene (liver)) (SEQ ID NO:374); X74226 (LL5 protein) (SEQ ID NO:353); X76489 (CD9 cell surface glycoprotein) (SEQ ID NO:308); X76985 (latexin) (SEQ ID NO:236); X82445 (nuclear distribution gene C homolog ( Aspergillus )) (SEQ ID NO:232); X84039 (lumican) (SEQ ID NO:237); X89696 (TPCR06 protein) (SEQ ID NO:201); X97443 (integral membrane protein Tmp21-I (p23)) (SEQ ID NO:358); X98399 (solute carrier family 14, member 1) (SEQ ID NO:267); Y17295 (thiol-specific antioxidant protein (1-Cys peroxiredoxin)) (SEQ ID NO:337); Z48225 (protein synthesis initiation factor eIF-2B delta subunit) (SEQ ID NO:255); Z49858 (plasmolipin) (SEQ ID NO:363) and mammalian homologues.  
   
   
       54 . The set of biomarkers of  claim 52 , wherein at least one member of the set of biomarkers is an expressed sequence tag (EST).  
   
   
       55 . The set of biomarkers of  claim 52 , for use in the measurement of age-dependent cognitive decline.  
   
   
       56 . The set of biomarkers of  claim 55 , wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition.  
   
   
       57 . The set of biomarkers of  claim 56 , wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       58 . The set of biomarkers of  claim 52 , for use in the measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline.  
   
   
       59 . The use of a biomarker for brain aging in the treatment of cognitive decline in aging in a mammal, 
 (a) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: 
 (1) a biomarker selected from the set of biomarkers of  claim 23;   
 (2) a biomarker selected from the set of biomarkers of  claim 38;   
 (3) a biomarker selected from the set of expressed sequence tags (EST) of  claim 47;  and  
 (4) a biomarker identified by the method of  claim 1;  and  
   (b) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide.    
   
   
       60 . The use of  claim 59 , wherein at least one member of the set of biomarkers is an expressed sequence tag (EST).  
   
   
       61 . The use of  claim 59 , wherein the cognitive decline in aging is an age-related neurodegenerative condition.  
   
   
       62 . The use of  claim 61 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       63 . The use of a biomarker for brain aging, in identification of a medicament for the treatment of cognitive decline in aging in a mammal, 
 (a) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: 
 (1) a biomarker selected from the set of biomarkers of  claim 23;   
 (2) a biomarker selected from the set of biomarkers of  claim 38;   
 (3) a biomarker selected from the set of expressed sequence tags (EST) of  claim 47;  and  
 (4) a biomarker identified by the method of  claim 1;  and  
   (b) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide.    
   
   
       64 . The use of  claim 63  wherein at least one member of the set of biomarkers is an expressed sequence tag (EST).  
   
   
       65 . The use of  claim 63 , wherein the cognitive decline in aging is an age-related neurodegenerative condition.  
   
   
       66 . The use of  claim 65 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.  
   
   
       67 . A medicament, device or procedure for the treatment of cognitive decline in aging in a mammal, 
 (a) wherein the medicament is identified by the use of a biomarker,    (b) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: 
 (1) a biomarker selected from the set of biomarkers of  claim 23;   
 (2) a biomarker selected from the set of biomarkers of  claim 38;   
 (3) a biomarker selected from the set of expressed sequence tags (EST) of  claim 47;  and  
 (4) a biomarker identified by the method of  claim 1;  and  
   (c) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide.    
   
   
       68 . The medicament, device or procedure of  claim 67 , wherein the cognitive decline in aging an age-related neurodegenerative condition.  
   
   
       69 . The medicament, device or procedure of  claim 67 , wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease.