Table 5 Cognitive Ageing Candidate Genes (expressed in the brain).

antioxidant defence genes

BACE1

beta-site APP-cleaving enzyme 1. Responsible for the proteolytic processing of the amyloid precursor protein (APP).

CAT

catalase. Protects cells from the toxic effects of hydrogen peroxide. Contains functional promoter polymorphism [69].

CBS

cystathionine-beta-synthase.

CCS

copper chaperone for SOD. Delivers Cu/Zn to SOD1

CDKN1B

cyclin-dependent kinase inhibitor 1B (p27, Kip1). Involved in G1 arrest.

CP

ceruloplasmin. Ceruloplasmin is a blue, copper-binding (6–7 atoms per molecule) glycoprotein found in plasma. Four possible functions are ferroxidase activity, amine oxidase activity, copper transport and homeostasis, and superoxide dismutase activity.

FOXO3A

forkhead transcription factor (homologue of C elegans daf-16). May trigger apoptosis.

FTH1

ferritin, heavy polypeptide 1. Ferritin is an intracellular molecule that stores iron in a soluble, nontoxic, readily available form.

FTL

ferritin light polypeptide.

FXN

frataxin. Defects in FXN are the cause of Friedreich's ataxia. Probably involved in iron homeostasis.

GCLC

glutamate-cysteine ligase, catalytic subunit. The first rate-limiting enzyme in glutathione biosynthesis.

GGT1

gamma-glutamyltransferase 1. Initiates extracellular gluthatione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracelular GSH level.

GLRX

glutaredoxin (thioltransferase). GLRX has a glutathione-disulfide oxidoreductase activity in the presence of NADPH and glutathione reductase. Reduces low molecular weight disulfides and proteins.

GLRX2

glutaredoxin 2 (mitochondrial). Catalyses the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins. Implicated in the protection of mitochondria from ROS.

GPX1

glutathione peroxidase 1 (cytosolic). GPX catalyzes the reduction of hydrogen peroxide, organic hydroperoxide, and lipid peroxides by reduced glutathione and functions in the protection of cells against oxidative damage. Selinium in the form of selenocysteine is part of its catalytic site. GPX1 protects the hemoglobin in erythrocytes from oxidative breakdown. Can be targetted to mitochondria

GPX3

glutathione peroxidase 3 (plasma).

GPX4

glutathione peroxidase 4 (membrane associated phospholipid hydroperoxide GPX). Could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. Essential for embryonic development. Can be targetted to the mitochondria.

GSR

glutathione reductase. Maintains high levels of reduced glutathione in the cytosol.

GSS

glutathione synthetase. The second rate-limiting enzyme in glutathione biosynthesis.

GSTA1

glutathione S-transferase A1. GSTs are a family of phase II enzymes that utilize glutathione in reactions contributing to the transformation of a wide range of exogenous and endogenous compounds, including carcinogens, therapeutic drugs, and products of oxidative stress.

GSTA2

glutathione S-transferase A2.

GSTA3

glutathione S-transferase A3.

GSTA4

glutathione S-transferase A4.

GSTA5

glutathione S-transferase A5.

GSTK1

glutathione S-transferase kappa 1.

GSTM1

glutathione S-transferase M1.

GSTM3

glutathione S-transferase M3 (brain).

GSTM4

glutathione S-transferase M4.

GSTM5

glutathione S-transferase M5.

GSTO1

glutathione S-transferase omega 1. GSTO1 exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities. May have a significant housekeeping function, such as protection from oxidative stress.

GSTO2

glutathione S-transferase omega 2.

GSTP1

glutathione S-transferase pi.

GSTT1

glutathione S-transferase theta 1.

GSTT2

glutathione S-transferase theta 2.

GSTZ1

glutathione transferase zeta 1 (maleylacetoacetate isomerase).

LTF

lactotransferrin.

MPO

myeloperoxidase. Part of the host defence system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.

MSRA

methionine sulfoxide reductase A. Has an important function as a repair enzyme for proteins that have been inactivated by oxidation. Catalyzes the reversible oxidation-reduction of methionine sulfoxide in proteins to methionine.

MSRB

methionine sulfoxide reductase B.

NOS1

nitric oxide synthase 1 (neuronal) (mtNOS). Produces nitric oxide (NO) a free radical messenger molecule. NO regulates mitochondrial respiration.

NOS2A

nitric oxide synthase 2A (inducible, hepatocytes).

NOS2B

nitric oxide synthase 2B.

NOS2C

nitric oxide synthase 2C.

NOS3

nitric oxide synthase 3 (endothelial cell). Polymorphism associated with mild cognitive impairment [67].

PON2

paraoxonase 2. Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and a number of aromatic carboxylic acid esters (By similarity). Has antioxidant activity. Is not associated with high density lipoprotein. Prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL, and inhibits the ability of MM-LDL to induce monocyte chemotaxis.

PRDX1

peroxiredoxin 1. PRDX (a thioredoxin peroxidase) reduces hydrogen peroxide and alkyl hydroperoxide to water and alcohol respectively. Involved in redox regulation of the cell. Reduces peroxides with reducing equivalents provided through the thioredoxin system but not from glutaredoxin. May play an important role in eliminating peroxides generated during metabolism. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2).

PRDX2

peroxiredoxin 2.

PRDX3

peroxiredoxin 3 (mitochondrial).

PRDX4

peroxiredoxin 4.

PRDX5

peroxiredoxin 5 (mitochondrial, peroxisomal and cytoplasmic).

PRDX6

peroxiredoxin 6. PRDX6 mutant mice are susceptible to oxidative stress.

SEPP1

selenoprotein P, plasma, 1. Might be responsible for some of the extracellular antioxidant defence properties of selenium or might be involved in the transport of selenium. May supply selenium to tissues such as brain and testis.

SIRT1

sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae) controls the cellular response to stress by regulating the FOXO family. SIRT1 and FOXO3 form a complex in cells in response to oxidative stress.

SLC25A27

solute carrier family 25, member 27. (UCP4)

SOD1

superoxide dismutase 1 (cytoplasmic). SOD catalyses the formation of hydrogen peroxide and oxygen from superoxide, and thus protects against superoxide-induced damage.

SOD2

superoxide dismutase 2 (mitochondria)

SOD3

superoxide dismutase 3 (extracellular)

TF

transferrin. Transferrins are iron binding transport proteins which can bind two atoms of ferric iron in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation.

TXN

thioredoxin. Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions.

TXN2

thioredoxin 2 (mitochondrial). A mitochondrial protein-disulphide oxidoreductase essential for control of cell survival during mammalian embryonic development.

TXNRD1

thioredoxin reductase 1.

TXNRD2

thioredoxin reductase 2 (mitochondrial). Maintains thioredoxin in a reduced state. Implicated in the defences against oxidative stress.

TXNRD3

thioredoxin reductase 3.

UCP2

uncoupling protein 2 (mitochondrial, proton carrier). UCP are mitochondrial transporter proteins that create proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation from ATP synthesis. As a result, energy is dissipated in the form of heat.

Vitagenes (longevity assurance processes-chaperones)

HMOX1

heme oxygenase (decycling) 1(HSP32) (stress induced). Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin (an antioxidant) by biliverdin reductase.

HMOX2

heme oxygenase (decycling) 2 (constitutive).

HSPA1A

heat shock 70 kDa protein 1A. Member of the HSP70 family. HSP70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. The HSP70s in mitochondria and the endoplasmic reticulum play an additional role by providing a driving force for protein translocation. They are involved in signal transduction pathways in cooperation with HSP90. They participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage.

HSPA1B

heat shock 70 kDa protein 1B.

HSPA1L

heat shock 70 kDa protein 1-like.

HSPA2

heat shock 70 kDa protein 2.

HSPA4

heat shock 70 kDa protein 4.

HSPA5

heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa).

HSPA6

heat shock 70 kDa protein 6 (HSP70B').

HSPA8

heat shock 70 kDa protein 8. Polymorphism associated with mild mental impairement [70].

HSPA9B

heat shock 70 kDa protein 9B (mortalin-2). Implicated in the control of cell proliferation and cellular aging. May also act as a chaperone.

HSPA12A

heat shock 70 kDa protein 12A.

HSPA12B

heat shock 70 kD protein 12B.

HSPA14

heat shock 70 kDa protein 14.

genes associated with cognitive function

AR

androgen receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. CAG repeat polymorphism is associated with cognitive function in older men [71].

CHRM2

cholinergic muscarinic 2 receptor. The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Polymorphism associated with IQ [60].

CTSD

cathepsin D (lysosomal aspartyl protease). Acid protease active in intracellular protein breakdown. Polymorphism associated with AD [61] and general intelligence in a healthy older population [62].

VEGF

vascular endothelial growth factor. Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. VEGF links hippocampal activity with neurogenesis, learning and memory [72].

genes associated with AD

AGER

advanced glycosylation end product-specific receptor (RAGE). Mediates interactions of advanced glycosylation end products (AGE). Increased expression in AD [73].

APP

amyloid beta (A4) precursor protein. Polymorphisms associated with AD (reviewed in [34]).

HTR2A

5-hydroxytryptamine (serotonin) receptor 2A. This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. Polymorphisms associated with episodic memory [63,74] and neuropsychiatric symptoms in AD [64].

IDE

insulin degrading enzyme. May play a role in the cellular processing of insulin. May be involved in intercellular peptide signaling. Polymorphism associated with AD [65].

IL1B

interleukin 1, beta. Produced by activated macrophages. IL-1 proteins are involved in the inflammatory response, being identified as endogenous pyrogens, and are reported to stimulate the release of prostaglandin and collagenase from synovial cells. Polymorphism associated with AD [66].

PLAU

plasminogen activator, urokinase. Polymorphisms associated with AD [68].

stress response genes altered in aged mouse brain [28].

APOD

apolipoprotein D. APOD occurs in the macromolecular complex with lecithin-cholesterol acyltransferase. It is probably involved in the transport and binding of bilin. Appears to be able to transport a variety of ligands in a number of different contexts.

CRYAB

alpha B2 crystallin. May contribute to the transparency and refractive index of the lens.

CSNK1D

casein-kinase 1 delta. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling.

CTNNB1

catenin (cadherin-associated protein), beta 1, 88 kDa. Involved in the regulation of cell adhesion and in signal transduction through the Wnt pathway.

CTSD

cathepsin D. Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer's disease.

CTSH

cathespin H. Important for the overall degradation of proteins in lysosomes.

CTSS

cathespin S. Thiol protease. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N.

CTSZ

cathepsin Z. Exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity.

DDIT3

gadd153 DNA-damage inducible transcript 3. Inhibits the DNA-binding activity of C/EBP and LAP by forming heterodimers that cannot bind DNA.

DNAJB1

DnaJ (Hsp40) homolog, subfamily B, member 1. Interacts with HSP70 and can stimulate its ATPase activity. Stimulates the association between HSC70 and HIP.

DNAJB2

DnaJ (Hsp40) homolog, subfamily B, member 2.

FOSB

FBJ murine osteosarcoma viral oncogene homolog B. FosB interacts with Jun proteins enhancing their DNA binding activity.

GFAP

glial fibrillary acidic protein. A class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.

JUNB

jun B proto-oncogene. Transcription factor involved in regulating gene activity following the primary growth factor response. Binds to the DNA sequence 5'-TGA [CG]TCA-3'.

NDRG1

N-myc downstream regulated gene 1. Cycophilin C associated protein. May have a growth inhibitory role.

NR2C2

nuclear receptor subfamily 2, group C, member 2. Orphan nuclear receptor. May regulate gene expression during the late phase of spermatogenesis.

SAA2

serum amyloid A2.

UCHL1

ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase). Ubiquitin-protein hydrolase is involved both in the processing of ubiquitin precursors and of ubiquinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin.

VIM

vimentin. Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells.

Mitochondria complex 1

NDUFA1

NDUFA2

NDUFA3

NDUFA4

NDUFA5

NDUFA6

NDUFA7

NDUFA8

NDUFA9

NDUFA10

NDUFAB1

NDUFB1

NDUFB2

NDUFB3

NDUFB4

NDUFB5

NDUFB6

NDUFB7

NDUFB8

NDUFB9

NDUFB10

NDUFC1

NDUFC2

NDUFS1

NDUFS2

NDUFS3

NDUFS4

NDUFS5

NDUFS6

NDUFS7

NDUFS8

NDUFV1

NDUFV2

NDUFV3