{
  "question": [
    "which genes are involved in aging",
    "what genes are involved in  the aging process",
    "Describe the genotypes related to Alzheimers and dementia which have commonalities with those for aging.",
    "Describe the genotypes related to Alzheimer's and dementia which have commonalities with those for aging.",
    "What genetic factors influence aging in humans? "
  ],
  "answer": [
    "Several genes are involved in aging, including BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, ZKSCAN1, DBH, TPO, LSS, GPER, HCRTR2, ATG2A, NEDD4L, PSMB1, UBXN4, USP6, EEF1A2, DBH, ITGB2, TUBB2C, WRN, ABCA7, AZGP1, CD36, DEGS2, LSS, PI4KA, SOAT2, APOE, LDLR, CDKN2B, RBM38, IGF1R, FOXO3, SNCA, CDKN2B, USP28, E2F2, BCL3, NAP1L4, GAB2, QKI, Lamp2, Fas, Ghr, Anxa2, Anxa3, Anxa4, and several S100 calcium binding proteins.",
    "Several genes are involved in the aging process. These include BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, ZKSCAN1, DBH, TPO, LSS, GPER, HCRTR2, ATG2A, NEDD4L, PSMB1, UBXN4, USP6, EEF1A2, DBH, ITGB2, TUBB2C, WRN, ABCA7, AZGP1, CD36, DEGS2, LSS, PI4KA, SOAT2, IGF-1, CYP19, NAP1L4, GAB2, QKI, APOE, LDLR, CDKN2B, RBM38, IGF1R, FOXO3, SNCA, USP28, E2F2, BCL3, mre11, rad50, Ku80, mus308, mus205, DNApol-eta, Trxr-1, GlnRS, isoQC, QC, Cct1, Cct4, Cct5, Cct6, Hsc70-4, Xbp1, NAT1, Rack1, Rheb, Lamp2, Fas, Ghr, Anxa2, Anxa3, Anxa4, SIR2, DAF-2/IGF1R, DAF-16/FOXO, AAK-2/AMPK, LET-363/mTOR, SIRT1/SIR2, p53, Werner's syndrome gene, iff-1, SIR2, TERT, ZBTB16, CA9, HEY2, Smarca4, Amarcb1, Hdac1, -5, -6, Dnmt3b, and genes in the insulin/ insulin-like growth factor (IGF12 )/growth hormone (GH) pathway.",
    "The genotypes related to Alzheimer's and dementia that have commonalities with those for aging include a locus on chromosome 17 associated with the age at onset of Alzheimer's. A specific variant in the CCL11 gene is likely responsible for this association. Additionally, the APOE gene is a strong genetic risk factor for late-onset Alzheimer's, which typically occurs in individuals aged 65 and older. Other genes associated with Alzheimer's include APP, PSEN1, and PSEN2 for early-onset Alzheimer's, and CR1, BIN1, CLU for late-onset Alzheimer's. These genetic factors are believed to interact with environmental components and contribute to the complex etiology of these aging-associated neurodegenerative diseases.",
    "The genotypes related to Alzheimer's and dementia that have commonalities with those for aging include a locus on chromosome 17 associated with the age at onset of Alzheimer's. A specific variant in CCL11 is probably responsible for this association. Other genes associated with Alzheimer's include APP, PSEN1, PSEN2, and APOE. These genes are also associated with early-onset and late-onset forms of Alzheimer's, which are more common in older individuals. The APOE gene, specifically the 4 allele, is a significant genetic risk factor for late-onset Alzheimer's. Genome-wide studies have also identified several genetic susceptibility factors for age-related macular degeneration (AMD), another aging-associated neurodegenerative disease.",
    "Several genetic factors influence aging in humans. These include genes such as the apolipoprotein E gene (APOE), the forkhead box O3A (FOXO3A) gene, and the exonuclease 1 (EXO1) gene. Other factors include the insulin-IGF1 signaling pathway, the growth hormone or insulinlike growth factor and insulin (GH, IGF, INS) axis, and the heatshock proteins and heat-shock factors. Additionally, genetic variants within genes involved in pathways associated with aging identified in animal models, such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipoprotein metabolism, the mTOR pathway, and the oxidative stress response may also influence survival to old age in humans."
  ],
  "contexts": [
    [
      "Following are examples of the identified genes and experimental or GWAS link between these genes and aging.On the list of the 25 top genes, NAP1L4 encodes a member of the nucleosome assembly protein (NAP) family, which interacts with both core and linker histones, and shuttles between the cytoplasm and nucleus, suggesting a role as histone chaperone.Histone protein levels decline during aging, and dramatically affect chromatin structure.Remarkably, the lifespan can be extended by manipulations that reverse the age-dependent changes to chromatin structure, indicating the pivotal role of chromatin structure in aging [32].In another example, gene expression of NAP1L4 increases with age in the skin tissue [33].Findings of GWAS link a number of the identified genes to age-related disorders, such as GAB2 and late onset Alzheimer's disease [86], and QKI and coronary heart disease/myocardial infarction [79].Interestingly, GWAS reports also link QKI to successful aging [87].Indicative biological pathways associated with the candidate aging genes",
      "Examples of biological candidate genes with pleiotropic functions, which are involved in aging in general and in musculoskeletal aging in particular, are numerous: (a) in addition to the IGF-1 and vitamin D genes, estrogen metabolism pathway genes, including estrogen receptors and aromatase (CYP19), are associated with fat-free mass (Walsh et al. 2005) and BMD (Shearman et al. 2004), prostate and breast cancer (Gallicchio et al. 2006), and cardiovascular disease risk (Shearman et al. 2003).",
      "In-depth analysis of the age-regulated genes revealed that multiple genes in the DNA damage response pathway were upregulated with age including those that function in non-homologous end-joining repair (mre11, rad50, Ku80 and mus308) and in translesion DNA synthesis (mus205 and DNApol-eta) [44][45][46].Genes that encoded enzymes with antioxidant properties, such as the thioredoxin reductase Trxr-1, and antioxidant genes involved in glutamate metabolism, such as GlnRS, isoQC and QC, were also upregulated with age [47][48][49][50].We also observed increased age-associated expression of chaperone genes (Cct1, Cct4, Cct5, Cct6, Hsc70-4) and the unfolded protein response transcription factor Xbp1, consistent with an induction of the unfolded protein response [51][52][53].Under stress conditions, there is a translational switch that favors production of stressrelated proteins while decreasing translation of other proteins [54].Paralogs of canonical translation factors such as NAT1 and Rack1, which were both upregulated, promote this switch to cap-independent translation [55,56].Notably, Rheb, which is downregulated with age, positively regulates ribosome production and capdependent translation by activating the mechanistic target of rapamycin (mTOR) kinase pathway [57].Thus, decreased Rheb levels during aging could decrease mTOR pathway activity, which extends lifespan and is protective against age-related pathology [58].Together, these data suggest that multiple genes are induced in aging photoreceptors to mitigate the effects of oxidative stress, protein misfolding and DNA damage.",
      "CellAge vs human orthologues of longevity-associated model organism genesTo understand how senescence is linked to the genetics of aging processes, we looked at the intersection of CellAge genes and the 869 genes in the human orthologues of model organisms' longevity-associated genes (LAGs) dataset, collected based on quantitative changes in lifespan [34].Like CellAge, where genes are classified based on whether their upregulation induces, inhibits, or has an unknown impact on CS, the longevity orthologues dataset also provides information on the effect of upregulation of its genes, namely whether it promotes (pro, 421) or inhibits (anti, 448) longevity (Additional file 1: Table S7; Additional file 2: Fig. S2).",
      "Analysis of prior research (Online Resource 5) shows that the revealed genes can be explicitly involved in other key biological processes in an organism whose role is known to be changing with aging.Specifically, ten genes (BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, and ZKSCAN1) regulate transcription which is believed to be disrupted when an organism is getting older (Roy et al. 2002).The DBH, TPO, and LSS genes are involved in synthesis of catecholamine, thyroid, and vitamin D hormones, respectively.The GPER binds estrogen and HCRTR2 binds orexin-A and orexin-B neuropeptid hormones.Hormonal deregulation with aging is considered to be one of the major components of senescent processes in an organism (Barzilai and Gabriely 2010).Five genes (ATG2A, NEDD4L, PSMB1, UBXN4, and USP6) are involved in degradation of proteins through ubiquitin-proteasome and the lysosomal/autophagic system.Dysfunction of this system leads to accumulation of damaged proteins in an organism that is associated with aging (Koga et al. 2011).Protein degradation through ubiquitin-mediated proteolysis plays an important role in cell-cycle regulation (Reed 2003).The PSMB1, SIK1, TRIP13, and TTN genes in the revealed set coordinate cell cycle.Cell cycle is linked with the aging-related processes in humans through a gradual increase in cell division errors in all tissues in an organism (Ly et al. 2000).Five genes (EEF1A2, DBH, ITGB2, TUBB2C, and WRN) take part in regulation of apoptosis which plays an important role in the aging process and tumorigenesis (Salvioli et al. 2008).Seven genes (ABCA7, AZGP1, CD36, DEGS2, LSS, PI4KA, and SOAT2) are involved in lipid metabolism which plays one of the key roles in human longevity and healthy aging (Barzilai et al. 2003).",
      "In addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27].",
      "Genes Whose Expression Decreased with Age.Of the 26 genes that decreased expression with age in control mice, 23% are involved in DNA replication and the cell cycle (Table 2).Most of these have a negative effect on cell growth and division.Among these, the product of phosphatase and tensin homolog (Pten) gene is a tumor suppressor that induces cell-cycle arrest through inhibition of the phosphoinositide 3-kinase pathway (28).B cell translocation gene 2 (Btg2) is a tumor suppressor that increases expression in response to DNA damage (29).The murine gene product of the amino-terminal enhancer of split (Aes) is a potent corepressor of gene expression and cellular proliferation (30).Calcium-binding protein A11 (S100a10) binds to and regulates the activity of annexin II, which is involved in the transduction of calcium-related mitogenic signals (31).Insulin-like growth factor (IGF) binding protein 1 (Igfbp1) plays an important role in the negative regulation of the IGF-1 system, a stimulator of mitogenesis (32).",
      "daf-16 dependent genesAmong the 52 genes that we have tested, 29 genes act almost completely in a daf-16 dependent manner, to regulate lifespan (Table 2).One of the genes identified was daf-2 (Y55D5A_391.b).This serves as a proof of principle that our screen is effective in identification of aging genes.",
      "Several of the genes we identify have previously been shown to influence lifespan in experiments on model organisms.For example, knockouts of the orthologs of APOE, LDLR, CDKN2B, and RBM38 in mice shortens their lifespan [24][25][26][27] , while knockout of IGF1R has the opposite effect 28 .Similarly, overexpression of the FOXO3 orthologue in Drosophila melanogaster 29 and the SNCA orthologue in Caenorhabditis elegans 30 have shown to extend their respective lifespans.Many of our genes are also enriched for pathways previously related to ageing in eukaryotic model organisms, including genomic stability, cellular senescence, and nutrient sensing 31 .For example, FOXO3 and IGF1R are well-known players modulating survival in response to dietary restriction 32 , but we also highlight genes involved in the response to DNA damage and apoptosis, such as CDKN2B, USP28, E2F2, and BCL3.In addition to hallmarks discovered in model organisms, our results suggest that haem metabolism may play a role in human ageing.This pathway includes genes involved in processing haem and differentiation of erythroblasts 33 .Although the enrichment is largely driven by genes linked to the LDLR locus, genes linked to other loci of interest (such as FOXO3, CDKN2B, LINC02513) are involved in similar biological pathways: myeloid differentiation, erythrocyte homeostasis, and chemical homeostasis.",
      "In recent years, some of the aging-related genes identified in worms have been shown to have mammalian homologs that modulate longevity and delay age-related diseases in mice, in particular as part of the insulin/ insulin-like growth factor (IGF12 )/growth hormone (GH) pathway (Bartke, 2005), and variants in these genes have even been associated with human longevity, such as the daf-2 homolog IGF1R (Suh et al., 2008).Therefore, there is great potential for human homologs of genes shown to modulate aging in model organisms to represent pharmaceutical targets with human applications.",
      "Hundreds of genes in several pathways act as regulators of ageing (1,32).However, analysis of DrugAge and other HAGR databases has revealed that the overlap between the targets of lifespan-extending drugs and known ageing related genes is modest (31).This indicates that most ageing-related pathways have yet to be targeted pharmacologically; DrugAge may aid in guiding further assays.This was recently demonstrated in one study where machine learning was used to predict whether a compound would increase lifespan in worms using data from Dru-gAge.The best model had 80% prediction accuracy and the top hit compounds could broadly be divided into compounds affecting mitochondria, inflammation, cancer, and gonadotropin-releasing hormone (33).",
      "Aging-related gene prediction and putative transcriptional mechanismsGeneFriends was used to identify genes related to aging.A seed list of genes known to be consistently overexpressed with age in mammals was used [18].In total, 1119 genes were co-expressed with the aging seed list at p <10 -6 ; Table 1 shows the top 25 genes.Many of these genes have been associated with age-related diseases.Several other genes that have been shown to play a role in aging such as lysosomal-associated membrane protein-2 Lamp2 [19] (p = 5.68 -30 ), Fas [20] (p = 2.70 -31 ) and growth hormone receptor Ghr [21] (p = 1.34 -19 ) also showed a significant co-expression.Anxa2, Anxa3 and Anxa4 also show a low p-value (p < 10 -25 ) as well as several S100 calcium binding proteins which have been shown to interact with annexins [22].Top 25genes co-expressed with aging related genes",
      "Fig. 7 Functional relationships of genes implicated in longevity.The genes in red/blue boxes represent genes with increased/decreased mRNA expression in ageing Drosophila (color figure online)",
      "The genome-wide RNAi study conducted by the Ruvkun lab, authored by Hamilton et al. [88], identified a total of 89 additional aging genes with disparate functions including cell structure, cell surface proteins, cell signaling, cellular metabolism, and protein turnover.Of the 66 genes with previously known functions, 17 corresponded to various aspects of carbon metabolism, including citric acid cycle enzymes and subunits of complexes I, IV, and V of the ETC.Researchers also speculated that protein translation might play a role in lifespan regulation, based on the identification of iff-1 (T05G5.10),a gene that has homology to the translation initiation factor eIF5A.Other hits from this screen included two genes containing PH domains known to interact with phosphatidylinositol lipids, multiple G protein-coupled receptors, protein processing and degradation genes such as proteases and ubiquitin ligases/hydrolases, and chromatin modifying factors.",
      "INTRODUCTIONAging has fascinated researchers since ancient times.The hugely complicated process that has been revealed may be interpreted from different aspects, such as the accumulation of oxidative damage, shortening of telomeres, the costs of reproduction, metabolic rates, cellular senescence, etc., and these have in turn given rise to diverse theories of aging [1].However, thanks to forward and reverse genetic technologies, researchers in the recent decades have established that despite its complexity, a single or a few key genes in a few key pathways can modulate the aging rate.The most important players would appear to be those in nutrient sensing pathways or stress response pathways, such as DAF-2/IGF1R and DAF-16/FOXO in the Insulin/IGF like signaling pathway, AAK-2/AMPK in another nutrient sensing pathway, JNK in the stress response pathway, LET-363/mTOR as an inhibitor of autophagy and activator of translation and SIRT1/SIR2 in genome stability maintenance, to name a few [2,3].In addition to genetic perturbations, dietary perturbations, such as diet restriction (DR) are known to significantly extend lifespan in most organisms examined from yeasts to primates, although different pathways may act under different DR conditions, and alternative DR strategies also effect C.elegans lifespan in different ways [3,4].The main pathways revealed under different DR regimens are summarized in Fig. (1).In this small, convoluted DR response network, DAF-16 and ceTOR/LET-363 *Address correspondence to this author at the Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China; Tel: 86-21-54920458; Fax: 86-21-54920451; E-mail: jdhan@picb.ac.cn  These authors contributed equally to this work.",
      "IntroductionAging affects nearly all organisms and is a major risk factor in most human diseases.Recent work has begun to uncover molecular mechanisms that specify lifespan and to identify alterations in cellular physiology that occur at the end of life (Tissenbaum and Guarente 2002).For example, oxidative damage caused by the generation of free radicals in the mitochondria has been found to hasten aging by causing an accumulation of damaged cellular components (Droge 2003).Telomere shortening may also play a role in aging by preventing DNA replication and cell division in later years (Hasty et al. 2003).Genetic studies have identified many genes that play a role in specifying lifespan.For example, mutations in yeast sir2 (chromatin regulator), worm daf-2 (insulin-like growth factor receptor), fly methuselah (tyrosine kinase receptor), mouse p53, and the human Werner's syndrome gene (DNA helicase) cause dramatic changes in lifespan (Guarente and Kenyon 2000).Several aging mechanisms alter longevity in multiple organisms.For example, mutations in the gene encoding insulin-like growth factor receptor alter lifespan in worms, flies, and mice, indicating that an endocrine signaling pathway has a conserved role in aging (Hekimi and Guarente 2003).Genetic studies have shown that aging can be slowed in mutants that are defective in a wide range of cellular processes (such as mitochondrial function, chromatin regulation, insulin signaling, transcriptional regulation, and genome stability).This indicates that aging is a complex process driven by diverse molecular pathways and biochemical events.As such, a powerful approach to study aging is to use systems biology, which allows a multitude of factors affecting aging to be analyzed in parallel.For example, DNA microarrays and gene expression chips have been used to perform a genome-wide analysis of changes in gene expres-sion in old age.Extensive studies in Caenorhabditis elegans and Drosophila melanogaster have identified hundreds of ageregulated genes (Hill et al. 2000;Zou et al. 2000;Lund et al. 2002;Pletcher et al. 2002;Murphy et al. 2003).Several studies have described age-regulated genes in the muscle and brain of mice (Lee et al. 1999(Lee et al. , 2000) ) and the retina and muscle of humans (Yoshida et al. 2002;Welle et al. 2003Welle et al. , 2004).These age-regulated genes may serve as markers of aging, enabling one to assess physiological age independently of chronological age.Analysis of the functions of these age-regulated genes has identified specific biochemical mechanisms that change toward the end of life.",
      "In addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27]."
    ],
    [
      "Following are examples of the identified genes and experimental or GWAS link between these genes and aging.On the list of the 25 top genes, NAP1L4 encodes a member of the nucleosome assembly protein (NAP) family, which interacts with both core and linker histones, and shuttles between the cytoplasm and nucleus, suggesting a role as histone chaperone.Histone protein levels decline during aging, and dramatically affect chromatin structure.Remarkably, the lifespan can be extended by manipulations that reverse the age-dependent changes to chromatin structure, indicating the pivotal role of chromatin structure in aging [32].In another example, gene expression of NAP1L4 increases with age in the skin tissue [33].Findings of GWAS link a number of the identified genes to age-related disorders, such as GAB2 and late onset Alzheimer's disease [86], and QKI and coronary heart disease/myocardial infarction [79].Interestingly, GWAS reports also link QKI to successful aging [87].",
      "Examples of biological candidate genes with pleiotropic functions, which are involved in aging in general and in musculoskeletal aging in particular, are numerous: (a) in addition to the IGF-1 and vitamin D genes, estrogen metabolism pathway genes, including estrogen receptors and aromatase (CYP19), are associated with fat-free mass (Walsh et al. 2005) and BMD (Shearman et al. 2004), prostate and breast cancer (Gallicchio et al. 2006), and cardiovascular disease risk (Shearman et al. 2003).",
      "In-depth analysis of the age-regulated genes revealed that multiple genes in the DNA damage response pathway were upregulated with age including those that function in non-homologous end-joining repair (mre11, rad50, Ku80 and mus308) and in translesion DNA synthesis (mus205 and DNApol-eta) [44][45][46].Genes that encoded enzymes with antioxidant properties, such as the thioredoxin reductase Trxr-1, and antioxidant genes involved in glutamate metabolism, such as GlnRS, isoQC and QC, were also upregulated with age [47][48][49][50].We also observed increased age-associated expression of chaperone genes (Cct1, Cct4, Cct5, Cct6, Hsc70-4) and the unfolded protein response transcription factor Xbp1, consistent with an induction of the unfolded protein response [51][52][53].Under stress conditions, there is a translational switch that favors production of stressrelated proteins while decreasing translation of other proteins [54].Paralogs of canonical translation factors such as NAT1 and Rack1, which were both upregulated, promote this switch to cap-independent translation [55,56].Notably, Rheb, which is downregulated with age, positively regulates ribosome production and capdependent translation by activating the mechanistic target of rapamycin (mTOR) kinase pathway [57].Thus, decreased Rheb levels during aging could decrease mTOR pathway activity, which extends lifespan and is protective against age-related pathology [58].Together, these data suggest that multiple genes are induced in aging photoreceptors to mitigate the effects of oxidative stress, protein misfolding and DNA damage.",
      "Results: We develop CellAge (http://genomics.senescence.info/cells),a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses.Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes.Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates.We also build cellular senescence protein-protein interaction and co-expression networks.Clusters in the networks are enriched for cell cycle and immunological processes.Network topological parameters also reveal novel potential cellular senescence regulators.Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence.Conclusions: Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.",
      "Genes involved intranscriptional silencing via chromatin remodeling (Smarca4 and Amarcb1) as well ashistone deacetylases (Hdac1, -5, and -6) and a DNA methyltransferace (Dnmt3b) weredownregulated in aged cells. They also showed that several chromosomal regionschanged with age in a coordinated manner resulting in an overall increase intranscriptional activity. They propose that chromatin dysregulation and epigeneticchanges drive the loss of cellular function and ultimately drive the aging process inHSCs.",
      "Analysis of prior research (Online Resource 5) shows that the revealed genes can be explicitly involved in other key biological processes in an organism whose role is known to be changing with aging.Specifically, ten genes (BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, and ZKSCAN1) regulate transcription which is believed to be disrupted when an organism is getting older (Roy et al. 2002).The DBH, TPO, and LSS genes are involved in synthesis of catecholamine, thyroid, and vitamin D hormones, respectively.The GPER binds estrogen and HCRTR2 binds orexin-A and orexin-B neuropeptid hormones.Hormonal deregulation with aging is considered to be one of the major components of senescent processes in an organism (Barzilai and Gabriely 2010).Five genes (ATG2A, NEDD4L, PSMB1, UBXN4, and USP6) are involved in degradation of proteins through ubiquitin-proteasome and the lysosomal/autophagic system.Dysfunction of this system leads to accumulation of damaged proteins in an organism that is associated with aging (Koga et al. 2011).Protein degradation through ubiquitin-mediated proteolysis plays an important role in cell-cycle regulation (Reed 2003).The PSMB1, SIK1, TRIP13, and TTN genes in the revealed set coordinate cell cycle.Cell cycle is linked with the aging-related processes in humans through a gradual increase in cell division errors in all tissues in an organism (Ly et al. 2000).Five genes (EEF1A2, DBH, ITGB2, TUBB2C, and WRN) take part in regulation of apoptosis which plays an important role in the aging process and tumorigenesis (Salvioli et al. 2008).Seven genes (ABCA7, AZGP1, CD36, DEGS2, LSS, PI4KA, and SOAT2) are involved in lipid metabolism which plays one of the key roles in human longevity and healthy aging (Barzilai et al. 2003).",
      "Genes that are age-regulated in all tissues would reveal genes involved in core mechanisms that underlie cellular ageing.Zahn et al. [63] discovered genetic pathways that show common age regulation in human kidney, brain and muscle.They used microarrays to analyse expression in 81 skeletal muscle samples from patients aged 16 -86 years and found 250 age-regulated muscle genes [63].Similar to the ageing expression profile for the kidney, the overall expression behaviour of this set of age-regulated muscle genes correlated with the physiological as well as chronological age of the muscle sample.Next, they compared their muscle-ageing results to previously published data on kidney and brain ageing of similarly large sample size [56,60].Although most of the age-related changes were tissue specific, they found evidence for common age regulation of six genetic pathways in all three tissues.Specifically, there is an overall increase in expression of the extracellular matrix genes, the ribosomal genes, the cell growth genes and the complement activation genes in all three tissues.Increased overall expression of the extracellular matrix and complement activation gene sets with advancing age may contribute to widespread fibrosis and inflammation in the elderly.There is an overall decrease in expression of the chloride transport genes and the electron transport genes in all three tissues.Decreased overall expression of electron transport chain genes with age might support the mitochondrial free-radical theory of ageing [67], as free-radical generation by mitochondria would preferentially damage the electron transport chain protein complexes.Decreased expression of the electron transport genes (encoded in the nucleus) might be caused by feedback regulation from damage to the electron transport chain protein complexes [63].However, it is also possible that increased oxidative damage occurs as a consequence of the decreased expression of the electron transport chain genes.In addition, an increasing number of studies in model organisms have critically challenged the mitochondrial free-radical theory of ageing [68].In addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27].",
      "Aging can be viewed as a lethal by-product of activities, such as reproduction and food intake, that are controlled by genes [1].Since most of these genes are evolutionarily conserved, distant species may share common pathways of aging [2].The insulin/insulin-like growth factor 1 (IGF1) signaling pathway could be one such common pathway, as it modulates aging in many species, including Caenorhabditis elegans, Drosophila, mice [3], and possibly humans [4].An elegant study carried out in C. elegans by applying microarray techniques showed that a member of the SIR2like protein family is regulated downstream of DAF-16, a FOXO-family transcription factor that affects the rate of aging in response to the insulin/IGF1 pathway [5].SIR2 proteins constitute an evolutionarily conserved family of NAD-dependent deacetylases called sirtuins [6][7][8].In model organisms the expression levels of SIR2 modulate life span [9][10][11].Since sirtuins are NAD + dependent these proteins through different routes may link energy metabolism, genome maintenance, and aging [11,12].Thus SIR2 genes may play a crucial role in conserved pathways of aging and longevity.",
      "Regarding cancer and aging, Serrano and Blasco (2007) suggested that an equilibrium between mechanisms diminishing cellular damage and mechanisms preventing excessive cellular proliferation is required between both processes [43].The authors argue that the p53 pathway may be seen as an anti-aging mechanism as it is a key defense mechanism against cellular damage protecting from both aging and cancer.One effect of aging at the cellular level is reduced telomerase activity and progressive shorter telomeres in somatic cells [45].Shortened telomeres are highly recombinogenic, leading to a genome-susceptible cancer development [46,47].Genomic instability driven by dysfunctional telomeres is also associated with the transition from benign to malignant tumors [48].Conversely, telomere dysfunction also acts to induce the p53 gene to suppress tumor development by initiating cell-cycle arrest, cellular senescence or, apoptosis.Our analysis has identified several genes involved in the regulation and activity of the p53 pathway as being affected by age.In skin, the telomerase reverse transcriptase (TERT) showed an age-related expression in association with a genetic variant (rs10866530).In addition p21, a gene directly regulated by p53 and also involved in telomere-driven aging, was shown to be differentially expressed with age [49].In brain, theZBTB16, CA9,and HEY2, genes associated to the p53 pathway directly or via SIRT1, all showed age-related expression.The activity of p53 has been shown to enhance the transcription of inhibitors of the insulin receptor pathway, preventing cell growth and division after stress signaling [50,51] and many genes from the insulin signaling pathway have been extensively associated with longevity in multiple studies and organisms.Our results suggest that the link between aging and cancer is evident in multiple tissues through differential expression of genes with age.",
      "Several of the genes we identify have previously been shown to influence lifespan in experiments on model organisms.For example, knockouts of the orthologs of APOE, LDLR, CDKN2B, and RBM38 in mice shortens their lifespan [24][25][26][27] , while knockout of IGF1R has the opposite effect 28 .Similarly, overexpression of the FOXO3 orthologue in Drosophila melanogaster 29 and the SNCA orthologue in Caenorhabditis elegans 30 have shown to extend their respective lifespans.Many of our genes are also enriched for pathways previously related to ageing in eukaryotic model organisms, including genomic stability, cellular senescence, and nutrient sensing 31 .For example, FOXO3 and IGF1R are well-known players modulating survival in response to dietary restriction 32 , but we also highlight genes involved in the response to DNA damage and apoptosis, such as CDKN2B, USP28, E2F2, and BCL3.In addition to hallmarks discovered in model organisms, our results suggest that haem metabolism may play a role in human ageing.This pathway includes genes involved in processing haem and differentiation of erythroblasts 33 .Although the enrichment is largely driven by genes linked to the LDLR locus, genes linked to other loci of interest (such as FOXO3, CDKN2B, LINC02513) are involved in similar biological pathways: myeloid differentiation, erythrocyte homeostasis, and chemical homeostasis.",
      "In recent years, some of the aging-related genes identified in worms have been shown to have mammalian homologs that modulate longevity and delay age-related diseases in mice, in particular as part of the insulin/ insulin-like growth factor (IGF12 )/growth hormone (GH) pathway (Bartke, 2005), and variants in these genes have even been associated with human longevity, such as the daf-2 homolog IGF1R (Suh et al., 2008).Therefore, there is great potential for human homologs of genes shown to modulate aging in model organisms to represent pharmaceutical targets with human applications.",
      "Aging-related gene prediction and putative transcriptional mechanismsGeneFriends was used to identify genes related to aging.A seed list of genes known to be consistently overexpressed with age in mammals was used [18].In total, 1119 genes were co-expressed with the aging seed list at p <10 -6 ; Table 1 shows the top 25 genes.Many of these genes have been associated with age-related diseases.Several other genes that have been shown to play a role in aging such as lysosomal-associated membrane protein-2 Lamp2 [19] (p = 5.68 -30 ), Fas [20] (p = 2.70 -31 ) and growth hormone receptor Ghr [21] (p = 1.34 -19 ) also showed a significant co-expression.Anxa2, Anxa3 and Anxa4 also show a low p-value (p < 10 -25 ) as well as several S100 calcium binding proteins which have been shown to interact with annexins [22].",
      "The genome-wide RNAi study conducted by the Ruvkun lab, authored by Hamilton et al. [88], identified a total of 89 additional aging genes with disparate functions including cell structure, cell surface proteins, cell signaling, cellular metabolism, and protein turnover.Of the 66 genes with previously known functions, 17 corresponded to various aspects of carbon metabolism, including citric acid cycle enzymes and subunits of complexes I, IV, and V of the ETC.Researchers also speculated that protein translation might play a role in lifespan regulation, based on the identification of iff-1 (T05G5.10),a gene that has homology to the translation initiation factor eIF5A.Other hits from this screen included two genes containing PH domains known to interact with phosphatidylinositol lipids, multiple G protein-coupled receptors, protein processing and degradation genes such as proteases and ubiquitin ligases/hydrolases, and chromatin modifying factors.",
      "INTRODUCTIONAging has fascinated researchers since ancient times.The hugely complicated process that has been revealed may be interpreted from different aspects, such as the accumulation of oxidative damage, shortening of telomeres, the costs of reproduction, metabolic rates, cellular senescence, etc., and these have in turn given rise to diverse theories of aging [1].However, thanks to forward and reverse genetic technologies, researchers in the recent decades have established that despite its complexity, a single or a few key genes in a few key pathways can modulate the aging rate.The most important players would appear to be those in nutrient sensing pathways or stress response pathways, such as DAF-2/IGF1R and DAF-16/FOXO in the Insulin/IGF like signaling pathway, AAK-2/AMPK in another nutrient sensing pathway, JNK in the stress response pathway, LET-363/mTOR as an inhibitor of autophagy and activator of translation and SIRT1/SIR2 in genome stability maintenance, to name a few [2,3].In addition to genetic perturbations, dietary perturbations, such as diet restriction (DR) are known to significantly extend lifespan in most organisms examined from yeasts to primates, although different pathways may act under different DR conditions, and alternative DR strategies also effect C.elegans lifespan in different ways [3,4].The main pathways revealed under different DR regimens are summarized in Fig. (1).In this small, convoluted DR response network, DAF-16 and ceTOR/LET-363 *Address correspondence to this author at the Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China; Tel: 86-21-54920458; Fax: 86-21-54920451; E-mail: jdhan@picb.ac.cn  These authors contributed equally to this work.",
      "IntroductionAging affects nearly all organisms and is a major risk factor in most human diseases.Recent work has begun to uncover molecular mechanisms that specify lifespan and to identify alterations in cellular physiology that occur at the end of life (Tissenbaum and Guarente 2002).For example, oxidative damage caused by the generation of free radicals in the mitochondria has been found to hasten aging by causing an accumulation of damaged cellular components (Droge 2003).Telomere shortening may also play a role in aging by preventing DNA replication and cell division in later years (Hasty et al. 2003).Genetic studies have identified many genes that play a role in specifying lifespan.For example, mutations in yeast sir2 (chromatin regulator), worm daf-2 (insulin-like growth factor receptor), fly methuselah (tyrosine kinase receptor), mouse p53, and the human Werner's syndrome gene (DNA helicase) cause dramatic changes in lifespan (Guarente and Kenyon 2000).Several aging mechanisms alter longevity in multiple organisms.For example, mutations in the gene encoding insulin-like growth factor receptor alter lifespan in worms, flies, and mice, indicating that an endocrine signaling pathway has a conserved role in aging (Hekimi and Guarente 2003).Genetic studies have shown that aging can be slowed in mutants that are defective in a wide range of cellular processes (such as mitochondrial function, chromatin regulation, insulin signaling, transcriptional regulation, and genome stability).This indicates that aging is a complex process driven by diverse molecular pathways and biochemical events.As such, a powerful approach to study aging is to use systems biology, which allows a multitude of factors affecting aging to be analyzed in parallel.For example, DNA microarrays and gene expression chips have been used to perform a genome-wide analysis of changes in gene expres-sion in old age.Extensive studies in Caenorhabditis elegans and Drosophila melanogaster have identified hundreds of ageregulated genes (Hill et al. 2000;Zou et al. 2000;Lund et al. 2002;Pletcher et al. 2002;Murphy et al. 2003).Several studies have described age-regulated genes in the muscle and brain of mice (Lee et al. 1999(Lee et al. , 2000) ) and the retina and muscle of humans (Yoshida et al. 2002;Welle et al. 2003Welle et al. , 2004).These age-regulated genes may serve as markers of aging, enabling one to assess physiological age independently of chronological age.Analysis of the functions of these age-regulated genes has identified specific biochemical mechanisms that change toward the end of life.",
      "Age-Regulated Genes Involved in Reproductive Capacity.Decline in reproductive capacity is an age-related phenotype, and the reproductive system seems to play an important role in longevity (22).For example, signals from germ cells can affect lifespan in C. elegans (23).In our study, we observed decreased RNA levels for several genes involved in reproduction (Fig. 3).These include two genes that encode members of the Acp family.The Acp from male flies stimulates female egg-laying and facilitates storage of sperm in the female genital tract (24).In addition, two ESTs showing age-regulated decrease of transcript levels represent different genes with homology to Arabidopsis MALE STERIL-  In Northern analysis, the ratios were calculated by dividing mRNA levels at 25-, 40-, and 50-day time points by those at 3-day time points after normalization with mRNA levels of the control gene rp49.Ratios in microarray analysis are provided from each of the duplicate experiments for comparison.ITY 2 (MS2; ref. 25), a gene involved in gametogenesis.Furthermore, an EST with homology to peanut, a member of the septin family (26), is down-regulated in older flies.This downregulation may reflect a decrease in spermatogenesis.",
      "Genes that are age-regulated in all tissues would reveal genes involved in core mechanisms that underlie cellular ageing.Zahn et al. [63] discovered genetic pathways that show common age regulation in human kidney, brain and muscle.They used microarrays to analyse expression in 81 skeletal muscle samples from patients aged 16 -86 years and found 250 age-regulated muscle genes [63].Similar to the ageing expression profile for the kidney, the overall expression behaviour of this set of age-regulated muscle genes correlated with the physiological as well as chronological age of the muscle sample.Next, they compared their muscle-ageing results to previously published data on kidney and brain ageing of similarly large sample size [56,60].Although most of the age-related changes were tissue specific, they found evidence for common age regulation of six genetic pathways in all three tissues.Specifically, there is an overall increase in expression of the extracellular matrix genes, the ribosomal genes, the cell growth genes and the complement activation genes in all three tissues.Increased overall expression of the extracellular matrix and complement activation gene sets with advancing age may contribute to widespread fibrosis and inflammation in the elderly.There is an overall decrease in expression of the chloride transport genes and the electron transport genes in all three tissues.Decreased overall expression of electron transport chain genes with age might support the mitochondrial free-radical theory of ageing [67], as free-radical generation by mitochondria would preferentially damage the electron transport chain protein complexes.Decreased expression of the electron transport genes (encoded in the nucleus) might be caused by feedback regulation from damage to the electron transport chain protein complexes [63].However, it is also possible that increased oxidative damage occurs as a consequence of the decreased expression of the electron transport chain genes.In addition, an increasing number of studies in model organisms have critically challenged the mitochondrial free-radical theory of ageing [68].In addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27]."
    ],
    [
      "We briefly comment on rare mutations that shorten life span through the early onset of diseases that are increasingly common during aging in the general population, e.g., familial forms of Alzheimer, breast cancer, coronary artery disease, type II diabetes, etc.The later onset forms of these diseases are associated with causes of death at later ages.A major question is what role the more common allelic variants of these same genes have in \"normal aging\".Although examination of this huge emerging topic goes beyond the present discussion, we may consider the example of Werner's syndrome, a rare autosomal recessive that causes adult onset progeria with a high incidence of cancer and atherosclerosis (70).The absence of Alzheimer-type dementia in Werner's syndrome illustrates the \"segmental\" nature of this and other progerias (70).Thus, heritable shortening of life span should not be considered as a simple acceleration of general aging processes.The Werner's lesion maps to a defective gene encoding a helicase and exonuclease, which also has several polymorphisms.In Japan, 1367Arg was associated with a lower risk of myocardial infarction (70), although it was not associated with longevity in Finland (14).In general, we know little of the genetic factors involved in frailty and morbidity at later ages, which are important to the geneenvironment interactions implied in the major longevity increase seen during the twentieth century.",
      "Indicative diseases associated with the candidate aging genes",
      "Dementia has an age-and sex-standardized prevalence of ~7.1% in Europeans 1 , with Alzheimer's disease (AD) being the most common form of dementia (50-70% of cases) 2 .AD is pathologically characterized by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain 3 .Most patients are diagnosed with AD after the age of 65, termed late-onset AD (LOAD), while only 1% of AD cases have an early onset (before the age of 65) 3 .On the basis of twin studies, the heritability of LOAD is estimated to be ~60-80% (refs. 4,5 ), suggesting that a large proportion of individual differences in LOAD risk is driven by genetics.The heritability of LOAD is spread across many genetic variants; however, Zhang et al. 6 suggested that LOAD is more of an oligogenic than a polygenic disorder due to the large effects of APOE variants.Zhang et al. 6 and Holland et al. 7 predicted there to be ~100-10,000 causal variants contributing to LOAD; however, only a fraction have been identified.Increasing the sample size of genome-wide association studies (GWAS) will improve the statistical power to identify the missing causal variants and may highlight additional disease mechanisms.In combination with increasing the number of samples, it is beneficial to use different approaches to identify rare and private variation to help identify additional causal variants and increase understanding of disease mechanisms; however, we deem this to be out of the scope of the current analysis.",
      "Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance.Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (e4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD.A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease.We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade.Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE.Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e.two-point lod score (TLS) !1.9 and/ or multipoint lod score (MLS) !2.2] in at least one of our analyses.Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance.Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (e4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD.A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease.We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade.Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE.Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e.two-point lod score (TLS) !1.9 and/ or multipoint lod score (MLS) !2.2] in at least one of our analyses.Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.",
      "IntroductionAlzheimer's disease (AD) is a complex disorder and is the most common form of dementia [1].After age, family history is the single greatest risk factor for AD.AD can be classified into early and late onset forms.Mutations in three genes: PSEN1/2 and APP are known to cause early onset AD in an autosomal dominant manner [2,3].The majority of AD cases, however, are late onset (LOAD) and the APOE e4 allele is the strongest known genetic risk factor.Many additional genetic polymorphisms have been identified, though with substantially lower risk estimates [1,4,5,6,7,8,9,10].LOAD appears to be inherited and/or sporadic and there is evidence of a maternal inheritance pattern [11].Current estimates suggest that more than 20% of inherited LOAD cases are maternally inherited [12].",
      "INTRODUCTIONMany common noninfectious diseases exhibit a more severe clinical presentation in older individuals.These diseases often exhibit complex etiology and can affect different tissues and cell types, with a wide spectrum of clinical outcomes.Prominent aging-associated neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD), all of which can severely compromise the quality of life and have serious repercussions on both the individual and society at large.These late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.Sequencing of the human genome, cataloging of millions of single nucleotide polymorphisms (SNPs) together with the development of a map of common haplotypes, and technological innovations in genotyping are among the major milestones that are facilitating exploration of the genetic basis of common diseases (1,7,50).In the field of AMD genetics, these advances have led to the identification of several genetic susceptibility factors and enabled us to start dissecting the relationship between environmental risk factors and the genetic constitution of each individual (66,118,148).As a result, new opportunities are emerging for improved understanding of disease pathogenesis that may lead to better management and treatment of AMD.Clinical aspects of AMD are discussed only briefly (for a more in-depth discussion, see Reference 79).Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.",
      "Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.Genetics of Alzheimer Disease: Early-Onset ADIn the early to mid-1990s, genetic studies of AD focused on extended families with high burden of disease (two or more cases among first-degree relatives), and used linkage analysis of highly polymorphic genetic markers called short tandem repeats (STRs, or microsattelites) in order to identify genomic regions co-transmitting with disease in affected family members.This strategy, followed by \"fine mapping\"-the positional cloning of candidate genes-was used to identify genes and genetic variants contributing to AD risk.The first three genes known to cause AD were identified among families with multiple early-onset cases (age-at-onset <60 years): APP, encoding amyloid precursor protein [Goate et al., 1991], and PS1 and PS2, encoding presenilins I and II respectively [Levy-Lahad et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995], each transmitting disease-causing variants in the predicted autosomal-dominant fashion.Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.",
      "The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (65 years) representing most cases of AD has yet to be explained by a purely genetic model.The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease.Numerous putative genetic risk alleles and genetic variants have been reported.Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations.Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders.There have already been success stories for diseases such as macular degeneration and diabetes mellitus.Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging.This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances.The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.Arch Neurol.2008;65(3): 329-334   Alzheimer disease (AD) is the most common cause of dementia and the most prevalent neurodegenerative disorder associated with aging. 1 Alzheimer disease is a heterogeneous disorder with a complex etiology owing to genetic and environmental influences as causal or risk modifiers.The neuropathologic hallmarks of disease are extracellular amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. 2 Only 10% of AD cases occurring before 60 years of age (early-onset AD) are due to rare, fully penetrant (autosomal dominant) mutations in 3 genes: A precursor protein (APP) on chromosome 21, 3 presenilin 1 (PSEN1) on chromosome 14, 4 and presenilin 2 (PSEN2) on chromosome 1. 5,6In contrast, most cases of AD are later in onset ( 65 years of age) (late-onset AD), are nonfamilial, and are likely the result of highly prevalent genetic variants with low penetrance. 7To date, the only genetic risk factor for lateonset AD remains the apolipoprotein E gene (APOE), specifically the 4 allele, which is moderately penetrant, accounting for up to 50% of cases. 8owever, a robust literature reports numerous putative genetic risk alleles and promising genetic variants.Recent reports from individual studies reveal significant associations with the sortilin-related receptor (SORL1 [NCBI Entrez gene 6653]) 9,10 and glycine-rich protein 2-associated binding protein 2 (GAB2 [NCBI Entrez gene 9846]) 11 on chromosome 11; death-associated protein kinase 1 (DAPK1 [NCBI Entrez gene 1612]), 12 ubiquilin 1 (UBQLN1 [NCBI Entrez gene 299798]), 13 and adenosine triphosphate-binding cassette transporter 1, subfamily A (ABCA1 [NCBI Entrez gene 19]), on chromosome 9 14 ; and low-density lipoprotein receptor-related protein 6 (LRP6 [NCBI Entrez gene 4040]) on chromosome 12. 15 All of these putative variants still lack replication in large representative populations but have relevance to neuropathologic mechanisms and pathways that may be associated with AD pathogenesis (   A large meta-analysis from the AlzGene database 16 17 All are associated with relevant biological mechanisms and pathways but await replication to further elucidate their utility as significant markers for AD.",
      "BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the elderly [1].Diagnosis of AD is based on the presence of neurofibrillary tangles and amyloid plaques [2], and symptoms typically include memory loss and impaired cognitive ability.Although the pathological hallmarks associated with dementia-related symptoms in AD appear largely similar between both the early-onset and late-onset forms of the disease, their underlying etiologies contrast [3].Whereas early-onset AD is a familial autosomal dominant disorder caused by rare, highly penetrant mutations in one of a small set of genes (APP, PSEN1, and PSEN2), the more common late-onset form of the disease (accounting for 90-95 % of cases) occurs sporadically, and risk is determined by complex underlying mechanisms [3][4][5][6].Estimates based on twin concordance rates suggest heritability of late-onset AD is as high as 70 %, implicating major roles for genetic as well as non-genetic factors [6].Indeed, through candidate gene studies, as well as more recent genome-wide association studies (GWASs) and whole-exome sequencing, both common and rare variants associated with the late-onset form of AD have been identified [7][8][9][10][11].Collectively, however, common GWAS variants account for only a modest proportion (~30 %) of the underlying variance in disease susceptibility [12].Several environmental factors are also thought to play a role [5,6], yet exactly how these contribute to risk, onset, and progression remains poorly defined.",
      "Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence.Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence.",
      "INTRODUCTIONAlzheimer's disease (AD) is a common debilitating disorder with a prevalence that rises steeply with age from below 1% at 65 years to as high as 40% after the age of 90 [Bachman et al., 1992].Genes are known to play a role in the development of AD.Twin studies show heritabilities of around 60% [Bergem et al., 1997;Gatz et al., 1997].Indeed, variation in four genes has already been shown to cause rare forms of early-onset AD [the Amyloid Precursor Protein Gene (APP); Goate et al., 1991; Presenilin 1 (PS1); Sherrington et al., 1995; Presenilin 2 (PS2); Levy Lahad et al., 1995, Rogaev et al., 1995] or increase the general risk of disease development [Apolipoprotein E (APOE), Corder et al., 1993].As well as increasing disease susceptibility, APOE e4 alleles are associated with reduced age at onset (AAO) and appear to show their strongest effect below 70 years [Farrer et al., 1997].There is also evidence from both twin [Pedersen et al., 2001] and family studies [Tunstall et al., 2000;Li et al., 2002] that AAO in AD is heritable.Daw et al. [2000] have estimated that in addition to APOE, there are at least four loci with similar effect sizes, which contribute to AAO in AD.",
      "IntroductionAlzheimer's disease (AD), a devastating neurodegenerative disease, is the most common form of dementia among the elderly.Genetically, AD is a complex and multifactorial disease with the possible involvement of multiple genes.The rare early-onset form of the disease usually follows an autosomal-dominant inheritance pattern and to date three genes have been identified: amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2).The common late-onset form of the disease is much more complex than the early-onset form and until recently the apolipoprotein E (APOE) gene was the only major genetic factor accounting for 20-29% of the risk for late-onset AD. 1,2 Recent large genome-wide association studies (GWAS) have identi-fied nine additional genes for late-onset AD, including CR1, BIN1, CLU (a.k.a.4][5][6][7] There is high heritability for AD risk (up to 80%), 8 but the total risk attributable to all confirmed loci is about 50%, indicating the presence of additional risk genes for late-onset AD.",
      "NE OF EVERY 5 PERSONS AGED 65 years is predicted to develop Alzheimer disease (AD) in their lifetime, and genetic variants may play an important part in the development of the disease. 1 The apparent substantial heritability of late-onset AD 2 is inadequately explained by genetic variation within the well-replicated genes (apolipoprotein E [APOE; RefSeq NG_007084], presenilin-1 [PSEN1; RefSeq NG_007386], presenilin-2 [PSEN2; RefSeq NG_007381], and amyloid beta precursor protein [APP;"
    ],
    [
      "We briefly comment on rare mutations that shorten life span through the early onset of diseases that are increasingly common during aging in the general population, e.g., familial forms of Alzheimer, breast cancer, coronary artery disease, type II diabetes, etc.The later onset forms of these diseases are associated with causes of death at later ages.A major question is what role the more common allelic variants of these same genes have in \"normal aging\".Although examination of this huge emerging topic goes beyond the present discussion, we may consider the example of Werner's syndrome, a rare autosomal recessive that causes adult onset progeria with a high incidence of cancer and atherosclerosis (70).The absence of Alzheimer-type dementia in Werner's syndrome illustrates the \"segmental\" nature of this and other progerias (70).Thus, heritable shortening of life span should not be considered as a simple acceleration of general aging processes.The Werner's lesion maps to a defective gene encoding a helicase and exonuclease, which also has several polymorphisms.In Japan, 1367Arg was associated with a lower risk of myocardial infarction (70), although it was not associated with longevity in Finland (14).In general, we know little of the genetic factors involved in frailty and morbidity at later ages, which are important to the geneenvironment interactions implied in the major longevity increase seen during the twentieth century.",
      "Indicative diseases associated with the candidate aging genes",
      "Dementia has an age-and sex-standardized prevalence of ~7.1% in Europeans 1 , with Alzheimer's disease (AD) being the most common form of dementia (50-70% of cases) 2 .AD is pathologically characterized by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain 3 .Most patients are diagnosed with AD after the age of 65, termed late-onset AD (LOAD), while only 1% of AD cases have an early onset (before the age of 65) 3 .On the basis of twin studies, the heritability of LOAD is estimated to be ~60-80% (refs. 4,5 ), suggesting that a large proportion of individual differences in LOAD risk is driven by genetics.The heritability of LOAD is spread across many genetic variants; however, Zhang et al. 6 suggested that LOAD is more of an oligogenic than a polygenic disorder due to the large effects of APOE variants.Zhang et al. 6 and Holland et al. 7 predicted there to be ~100-10,000 causal variants contributing to LOAD; however, only a fraction have been identified.Increasing the sample size of genome-wide association studies (GWAS) will improve the statistical power to identify the missing causal variants and may highlight additional disease mechanisms.In combination with increasing the number of samples, it is beneficial to use different approaches to identify rare and private variation to help identify additional causal variants and increase understanding of disease mechanisms; however, we deem this to be out of the scope of the current analysis.Dementia has an age-and sex-standardized prevalence of ~7.1% in Europeans 1 , with Alzheimer's disease (AD) being the most common form of dementia (50-70% of cases) 2 .AD is pathologically characterized by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain 3 .Most patients are diagnosed with AD after the age of 65, termed late-onset AD (LOAD), while only 1% of AD cases have an early onset (before the age of 65) 3 .On the basis of twin studies, the heritability of LOAD is estimated to be ~60-80% (refs. 4,5 ), suggesting that a large proportion of individual differences in LOAD risk is driven by genetics.The heritability of LOAD is spread across many genetic variants; however, Zhang et al. 6 suggested that LOAD is more of an oligogenic than a polygenic disorder due to the large effects of APOE variants.Zhang et al. 6 and Holland et al. 7 predicted there to be ~100-10,000 causal variants contributing to LOAD; however, only a fraction have been identified.Increasing the sample size of genome-wide association studies (GWAS) will improve the statistical power to identify the missing causal variants and may highlight additional disease mechanisms.In combination with increasing the number of samples, it is beneficial to use different approaches to identify rare and private variation to help identify additional causal variants and increase understanding of disease mechanisms; however, we deem this to be out of the scope of the current analysis.The largest previous GWAS of LOAD, identified 29 risk loci from 71,880 (46,613 proxy) cases and 383,378 (318,246 proxy) controls 8 .Our current study expands this to include 90,338 (46,613 proxy) cases and 1,036,225 (318,246 proxy) controls.The recruitment of LOAD cases can be difficult due to the late age of onset, so proxy cases can allow for the inclusion of younger individuals by estimating their risk of LOAD using parental status.Proxy cases and controls were defined on the basis of known parental LOAD status weighted by parental age (Supplementary Information).In the current study, we identified 38 loci, including seven loci that have not been reported previously.Functional follow-up analyses implicated tissues, cell types and genes of interest through tissue and cell type enrichment, colocalization and statistical fine-mapping.This study highlights microglia, immune cells and protein catabolism as relevant to LOAD, while identifying previously unidentified genes of potential interest. ResultsGenome-wide inferences.We performed meta-analysis on data from 13 cohorts, totaling 1,126,563 individuals (Supplementary",
      "Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance.Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (e4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD.A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease.We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade.Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE.Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e.two-point lod score (TLS) !1.9 and/ or multipoint lod score (MLS) !2.2] in at least one of our analyses.Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.",
      "IntroductionAlzheimer's disease (AD) is a complex disorder and is the most common form of dementia [1].After age, family history is the single greatest risk factor for AD.AD can be classified into early and late onset forms.Mutations in three genes: PSEN1/2 and APP are known to cause early onset AD in an autosomal dominant manner [2,3].The majority of AD cases, however, are late onset (LOAD) and the APOE e4 allele is the strongest known genetic risk factor.Many additional genetic polymorphisms have been identified, though with substantially lower risk estimates [1,4,5,6,7,8,9,10].LOAD appears to be inherited and/or sporadic and there is evidence of a maternal inheritance pattern [11].Current estimates suggest that more than 20% of inherited LOAD cases are maternally inherited [12].",
      "INTRODUCTIONMany common noninfectious diseases exhibit a more severe clinical presentation in older individuals.These diseases often exhibit complex etiology and can affect different tissues and cell types, with a wide spectrum of clinical outcomes.Prominent aging-associated neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD), all of which can severely compromise the quality of life and have serious repercussions on both the individual and society at large.These late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.Sequencing of the human genome, cataloging of millions of single nucleotide polymorphisms (SNPs) together with the development of a map of common haplotypes, and technological innovations in genotyping are among the major milestones that are facilitating exploration of the genetic basis of common diseases (1,7,50).In the field of AMD genetics, these advances have led to the identification of several genetic susceptibility factors and enabled us to start dissecting the relationship between environmental risk factors and the genetic constitution of each individual (66,118,148).As a result, new opportunities are emerging for improved understanding of disease pathogenesis that may lead to better management and treatment of AMD.Clinical aspects of AMD are discussed only briefly (for a more in-depth discussion, see Reference 79).Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.",
      "Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.Genetics of Alzheimer Disease: Early-Onset ADIn the early to mid-1990s, genetic studies of AD focused on extended families with high burden of disease (two or more cases among first-degree relatives), and used linkage analysis of highly polymorphic genetic markers called short tandem repeats (STRs, or microsattelites) in order to identify genomic regions co-transmitting with disease in affected family members.This strategy, followed by \"fine mapping\"-the positional cloning of candidate genes-was used to identify genes and genetic variants contributing to AD risk.The first three genes known to cause AD were identified among families with multiple early-onset cases (age-at-onset <60 years): APP, encoding amyloid precursor protein [Goate et al., 1991], and PS1 and PS2, encoding presenilins I and II respectively [Levy-Lahad et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995], each transmitting disease-causing variants in the predicted autosomal-dominant fashion.",
      "Arch Neurol.2008;65(3): 329-334   Alzheimer disease (AD) is the most common cause of dementia and the most prevalent neurodegenerative disorder associated with aging. 1 Alzheimer disease is a heterogeneous disorder with a complex etiology owing to genetic and environmental influences as causal or risk modifiers.The neuropathologic hallmarks of disease are extracellular amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. 2 Only 10% of AD cases occurring before 60 years of age (early-onset AD) are due to rare, fully penetrant (autosomal dominant) mutations in 3 genes: A precursor protein (APP) on chromosome 21, 3 presenilin 1 (PSEN1) on chromosome 14, 4 and presenilin 2 (PSEN2) on chromosome 1. 5,6In contrast, most cases of AD are later in onset ( 65 years of age) (late-onset AD), are nonfamilial, and are likely the result of highly prevalent genetic variants with low penetrance. 7To date, the only genetic risk factor for lateonset AD remains the apolipoprotein E gene (APOE), specifically the 4 allele, which is moderately penetrant, accounting for up to 50% of cases. 8owever, a robust literature reports numerous putative genetic risk alleles and promising genetic variants.Recent reports from individual studies reveal significant associations with the sortilin-related receptor (SORL1 [NCBI Entrez gene 6653]) 9,10 and glycine-rich protein 2-associated binding protein 2 (GAB2 [NCBI Entrez gene 9846]) 11 on chromosome 11; death-associated protein kinase 1 (DAPK1 [NCBI Entrez gene 1612]), 12 ubiquilin 1 (UBQLN1 [NCBI Entrez gene 299798]), 13 and adenosine triphosphate-binding cassette transporter 1, subfamily A (ABCA1 [NCBI Entrez gene 19]), on chromosome 9 14 ; and low-density lipoprotein receptor-related protein 6 (LRP6 [NCBI Entrez gene 4040]) on chromosome 12. 15 All of these putative variants still lack replication in large representative populations but have relevance to neuropathologic mechanisms and pathways that may be associated with AD pathogenesis (   A large meta-analysis from the AlzGene database 16 17 All are associated with relevant biological mechanisms and pathways but await replication to further elucidate their utility as significant markers for AD.The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (65 years) representing most cases of AD has yet to be explained by a purely genetic model.The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease.Numerous putative genetic risk alleles and genetic variants have been reported.Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations.Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders.There have already been success stories for diseases such as macular degeneration and diabetes mellitus.Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging.This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances.The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.",
      "BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the elderly [1].Diagnosis of AD is based on the presence of neurofibrillary tangles and amyloid plaques [2], and symptoms typically include memory loss and impaired cognitive ability.Although the pathological hallmarks associated with dementia-related symptoms in AD appear largely similar between both the early-onset and late-onset forms of the disease, their underlying etiologies contrast [3].Whereas early-onset AD is a familial autosomal dominant disorder caused by rare, highly penetrant mutations in one of a small set of genes (APP, PSEN1, and PSEN2), the more common late-onset form of the disease (accounting for 90-95 % of cases) occurs sporadically, and risk is determined by complex underlying mechanisms [3][4][5][6].Estimates based on twin concordance rates suggest heritability of late-onset AD is as high as 70 %, implicating major roles for genetic as well as non-genetic factors [6].Indeed, through candidate gene studies, as well as more recent genome-wide association studies (GWASs) and whole-exome sequencing, both common and rare variants associated with the late-onset form of AD have been identified [7][8][9][10][11].Collectively, however, common GWAS variants account for only a modest proportion (~30 %) of the underlying variance in disease susceptibility [12].Several environmental factors are also thought to play a role [5,6], yet exactly how these contribute to risk, onset, and progression remains poorly defined.",
      "Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence.Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence.",
      "INTRODUCTIONAlzheimer's disease (AD) is a common debilitating disorder with a prevalence that rises steeply with age from below 1% at 65 years to as high as 40% after the age of 90 [Bachman et al., 1992].Genes are known to play a role in the development of AD.Twin studies show heritabilities of around 60% [Bergem et al., 1997;Gatz et al., 1997].Indeed, variation in four genes has already been shown to cause rare forms of early-onset AD [the Amyloid Precursor Protein Gene (APP); Goate et al., 1991; Presenilin 1 (PS1); Sherrington et al., 1995; Presenilin 2 (PS2); Levy Lahad et al., 1995, Rogaev et al., 1995] or increase the general risk of disease development [Apolipoprotein E (APOE), Corder et al., 1993].As well as increasing disease susceptibility, APOE e4 alleles are associated with reduced age at onset (AAO) and appear to show their strongest effect below 70 years [Farrer et al., 1997].There is also evidence from both twin [Pedersen et al., 2001] and family studies [Tunstall et al., 2000;Li et al., 2002] that AAO in AD is heritable.Daw et al. [2000] have estimated that in addition to APOE, there are at least four loci with similar effect sizes, which contribute to AAO in AD.",
      "IntroductionAlzheimer's disease (AD), a devastating neurodegenerative disease, is the most common form of dementia among the elderly.Genetically, AD is a complex and multifactorial disease with the possible involvement of multiple genes.The rare early-onset form of the disease usually follows an autosomal-dominant inheritance pattern and to date three genes have been identified: amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2).The common late-onset form of the disease is much more complex than the early-onset form and until recently the apolipoprotein E (APOE) gene was the only major genetic factor accounting for 20-29% of the risk for late-onset AD. 1,2 Recent large genome-wide association studies (GWAS) have identi-fied nine additional genes for late-onset AD, including CR1, BIN1, CLU (a.k.a.4][5][6][7] There is high heritability for AD risk (up to 80%), 8 but the total risk attributable to all confirmed loci is about 50%, indicating the presence of additional risk genes for late-onset AD.",
      "NE OF EVERY 5 PERSONS AGED 65 years is predicted to develop Alzheimer disease (AD) in their lifetime, and genetic variants may play an important part in the development of the disease. 1 The apparent substantial heritability of late-onset AD 2 is inadequately explained by genetic variation within the well-replicated genes (apolipoprotein E [APOE; RefSeq NG_007084], presenilin-1 [PSEN1; RefSeq NG_007386], presenilin-2 [PSEN2; RefSeq NG_007381], and amyloid beta precursor protein [APP;"
    ],
    [
      "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
      "Recent developments on the genetics of aging can be seen as several streams of effort.In general, humans show a relatively modest (<50%) heritability of life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.",
      "Background: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.Methods: We performed a whole-genome sequencing in 19 centenarians to establish the genetic basis of human longevity.Results: Using SKAT analysis, we found 41 significantly correlated genes in centenarians as compared to control genomes.Pathway enrichment analysis of these genes showed that immune-related pathways were enriched, suggesting that immune pathways might be critically involved in aging.HLA typing was next performed based on the whole-genome sequencing data obtained.We discovered that several HLA subtypes were significantly overrepresented.Conclusions: Our study indicated a new mechanism of longevity, suggesting potential genetic variants for further study.Background: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.",
      "INTRODUCTIONHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining 20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging.",
      "Somatic mutations with the inherited gene variations of each individual cumulatively or synergistically influence the health span and life span [11].Very few genetic variants have been associated with human longevity, but those found include the transcription factor FOXO3 gene, the APOE/TOMM40 and the CDKN2B/ ANRIL loci, which are associated with Alzheimer's disease and cellular senescence [12][13][14].In fact, the heritability for human longevity has been estimated to be approximately 20-30%, according to studies of twins, suggesting that external factors such as diet, environment, physical activity and microbiomes are important factors that influence the health span [14][15][16].The increase in the rate of retrotranscription reflects genome deregulation, creating additional mutations, DNA damage, and other forms of genome instability.For instance, the expression of several families of retrotransposable elements increases with age, as observed in mouse skeletal muscle and human fibroblasts, particularly the long interspersed nuclear element-1 (L1 LINE) [17,18].Influence of Genetic Factors in Ageing and LifespanAgeing is defined as the decline of physiological functions in several tissues and organs inducing an increasing probability of death [17].The understanding of genetic factors involved in ageing has been limited due to the complexity of this process and the heterogeneity among individuals and even among tissues [18][19][20].Tissue cells adopt a senescent phenotype as a consequence of multiple intrinsic, extrinsic, and stochastic factors [21].The combination of these genetic factors is related to longevity and healthy ageing [22].Although this decline is somewhat predictable, some individuals show a much slower decline and get to live past the age of 100.Studies in these individuals showed polymorphisms in some genes which are associated with long life, such as APOE and FOXO3.However, these associations have not been consistent across different populations, suggesting that ageing is rather polygenic [23].",
      "On the other hand, the same evolutionary-motivated strategy suggesting to focus on more heterogeneous phenotypes (as opposite to more homogenous) can be highly beneficial for unraveling genetic predisposition to fundamental mechanisms of intrinsic biological aging and, consequently, to geriatric diseases.Indeed, aging is associated with systemic remodeling of an organism's functioning which increases chances of virtually all geriatric disorders (Franco et al. 2009;Franceschi et al. 2000;Martin et al. 2007;Cutler and Mattson 2006).Experiments with laboratory animals (Johnson 2006) and heritability estimates in humans (Christensen et al. 2006;Iachine et al. 1998) show that aging can be genetically regulated (Finch and Tanzi 1997;Martin et al. 2007;Vaupel 2010).Accordingly, yielding insights in genetic predisposition to aging-related processes in an organism could be a major breakthrough in preventing and/or ameliorating not one geriatric trait, but perhaps a major subset of such traits (Martin et al. 2007) that can greatly advance progress in solving the problem of extending healthy lifespan in humans.",
      "M OST genetic studies involved with aging have focused on identifying genes contributing to particular diseases.More recently, it has been recognized that it is also valuable to examine genetic factors related to diseasefree or healthy aging (1,2).Utilizing twins from the National Academy of Sciences-National Research Council (NAS-NRC) twin panel, we have demonstrated that healthy physical aging is under a significant degree of genetic influence, with a heritability over 50% (3).Our definition of healthy aging focused principally on freedom from cardiovascular disease, and has received considerable support in the more recent literature.Brand and colleagues (4) reported that parental age at death was a significant predictor of coronary heart disease death in the Framingham offspring study and concluded that familial similarities for age at death may be mediated through shared coronary heart disease risk factors.Frederiksen and colleagues (5) reported that increased parental life was associated with a reduction in odds ratio for their children to have diabetes, ischemic heart disease, heart failure, stroke, and hypertension.We have found that better midlife lipid levels and blood pressures were associated with increased parental longevity in the National Heart, Lung, and Blood Institute twin study (6).Centenarian siblings and offspring, besides having increased longevity, have been shown to have better health and better cardiovascular risk factor profiles (7)(8)(9)(10).",
      "IntroductionThe recent, remarkable extension of life expectancy is largely attributed to the postponement of mortality at old age (Vaupel, 1997(Vaupel, , 2010)).The years of life gained in the older population residing in developed nations are a success story of public health measures and improved health care.In addition to such external factors, longevity and healthy aging consistently show a modest heritability between 20% and 50% and aging-associated genetic research may provide further insights into the mechanisms of aging (Herskind et al., 1996;McGue et al., 1993;Reed and Dick, 2003).It has been postulated that genes involved in pathways associated with aging identified in animal models, such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipoprotein metabolism, the mTOR pathway, and the oxidative stress response may also influence survival to old or even exceptionally old age in humans (Christensen et al., 2006;Kenyon, 2010;Vellai et al., 2003).However, in humans, common variants within genes involved in these pathways have not been consistently associated with lifespan (Chris-tensen et al., 2006;Kenyon, 2010;Kuningas et al., 2008;Vijg and Suh, 2005).",
      "TranslationalA LTHOUGH there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1).Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively 'fit' life span must have an inherited genetic foundation.Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2).Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer's disease (AD) typically have onsets after the fourth decade of life; \"successful\" agers delay these onsets until relatively late in life (3).Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors.",
      "Many factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.",
      "The genetic basis of human longevity has so far been primarily investigated by association studies.Most results from these experiments have been difficult to confirm in independent samples, probably owing to the modest heritability, multifactorial nature, and heterogeneity of the phenotype (Christensen et al., 2006).To date, variation in only two genes has been identified, which has an effect on longevity in various populations: (i) the apolipoprotein E gene (APOE) (Scha chter et al., 1994;Christensen et al., 2006) and (ii) the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling (IIS) pathway (Willcox et al., 2008;Flachsbart et al., 2009).Given the apparent lack of susceptibility candidates, it is conceivable that other genetic factors influence the function or expression of genes relevant for human longevity.IntroductionHuman longevity is influenced by multiple genetic and environmental factors.Approximately 25-32% of the overall variation in adult lifespan is because of genetic variation that becomes particularly important for survival at advanced age (Hjelmborg et al., 2006).Epidemiological studies have revealed that long-lived individuals (LLI), that is, people surviving to the 95th percentile of the respective birth cohort-specific age distributions (Gudmundsson et al., 2000), frequently show a favorable ('healthy') course of the aging process, with the absence or a delayed onset of agerelated diseases (Hitt et al., 1999).Hence, the LLI offer the key to elucidate the molecular mechanisms underlying the 'healthy aging' phenotype (Perls, 2006).",
      "IntroductionApproximately 25-30% of the variation in adult lifespan is attributable to genetic factors that become more important with increasing age and exert their strongest effects in nonagenarians and centenarians (Go gele et al., 2010;Hjelmborg et al., 2006).As yet, however, only a few genetic variants have been found consistently to influence longevity.The first to be discovered was the e4 allele of the apolipoprotein E (APOE) gene, a mortality factor that predisposes to both Alzheimer's and cardiovascular diseases (Corder et al., 1993; Panza et al., 2004).APOE e4 is the only variant with a reportedly large adverse effect upon survival at advanced age (Scha chter et al., 1994), and this association has been replicated in several populations (Christensen et al., 2006).Variation in the human forkhead box O3A gene (FOXO3A), in contrast, has been found to be associated with the ability to live long, an effect corroborated by studies in Japanese, German, Italian, US-American, Jewish, Chinese and Danish populations (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010;Willcox et al., 2008).More recently, we have identified exonuclease 1 (EXO1) as a potential novel longevity gene (Nebel et al., 2009).All three genes were detected through candidate-gene approaches.",
      "GenAge: the aging gene database Philosophy and overview of resourcesIt is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalhes, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.",
      "I NCREASES in longevity of the general population world- wide are an unprecedented phenomenon with significant health and social impact.Although environmental factors have led to an increase in life span, there is ample evidence that genetic factors are involved in extreme longevity both in humans (1-7) and in other organisms (8).The protective genetic factors that lead to longevity are likely to involve fundamental processes of aging that may be different from those associated with early mortality or premature onset of age-related diseases in younger individuals.The mechanisms of aging in humans are far from understood, but available evidence suggests that several pathways-inflammation, oxidative stress and stress responses, cellular senescence, DNA damage and repair, and the growth hormone or insulinlike growth factor and insulin (GH, IGF, INS) axis-may play key roles (9)(10)(11)(12).Model organisms suggest that inhibiting the GH, IGF, or INS axis, which is involved in regulating cell proliferation, cell death, wound repair, and metabolism, may promote longevity by reducing oxidative stress and slowing the rate of cell replication and the accumulation of somatic-cell DNA mutations (13).There is also evidence for other important pathways such as the heatshock proteins and heat-shock factors that are highly conserved across species and play a role in prolongevity transcription pathways.Clinical and epidemiological investigations, including candidate gene studies, have suggested that inflammation pathways may affect life span and risk of age-related conditions such as cardiovascular disease (CVD) and its risk factors (14)(15)(16)(17)(18)(19).A combination of multiple genetic variants may be required for an individual to achieve exceptional longevity, which may account in part for its rarity.",
      "Studies of mono-and dizygous twins have revealed that the genetic contribution to the variation in human lifespan is about 25-30% [12,13], and is most prominent in families clustered for longevity [14,15].This genetic contribution is mainly apparent after the age of 60 years and seems to increase with age [13,16].Furthermore, human lifespan is a complex trait which is assumed to be determined by many genes with small individual effects [17], although the polygenic architecture still needs to be characterized [18,19].The diverse health features of long-lived families illustrate that different age-related diseases have common determinants and implicate that pathways can be identified that attenuate aging and delay age-related disease.From a genomic perspective, individuals from long-lived families are assumed to be characterized by a decreased prevalence of disease-promoting variants (referred to as disease-susceptibility alleles) and an increased prevalence of variants conferring maintenance of health and protection from disease, when compared to population controls.In the last 5 years, many diseasesusceptibility alleles have been identified (National Human Genome Research Institute (NHGRI) genome-wide association study (GWAS) Catalog; http://www.genome.gov/gwastudies/)[20].A first comparison between long-lived individuals, selected from both long-lived families (LLS) and the general population (Leiden 85-plus study), and young controls showed no difference in the distribution or frequency of disease-susceptibility alleles identified in cancer, coronary artery disease and type 2 diabetes [21].The search for lifespan regulating loci -contributing to longevity and population mortality -must therefore extend beyond a focus on disease-susceptibility alleles.We will first discuss the efforts to identify longevity loci by genetics approaches.Conclusions and prospectsOver the past two decades the human aging field has built up the necessary resources to study the biology of aging and longevity by establishing human populations with a diversity of designs.Meta-analyses integrating genetic and phenotypic datasets have successfully identified variants associated with a range of age-related traits and diseases.Despite these accomplishments, the number of novel leads contributing to human lifespan regulation is limited.Although positive regions of linkage and suggestive GWAS hits have been reported, the field has not yet identified the loci that explain the clustering of longevity in families and the variation in biological aging rate in the population.As for animal models, down-signaling of the IIS and mTOR pathway appeared to be relevant in humans.These findings are being followed up by molecular and physiological profiling using skin, fat and muscle tissue of long-lived family members and controls.Human studies now also include the response of nutrient sensing systems to the application of dietary and physical challenges."
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