Aging genetics and aging.
Journal: 2012/August - Aging and Disease
ISSN: 2152-5250
PUBMED: 22396873
The process of aging refers to the decay of an organism's structure and function, in which molecular and cellular modifications can have various effects at the individual level over the course of a lifetime. The accumulation of molecular errors that compromise adult stem cell functions occurs because of genetic and epigenetic interactions and depends on hereditary, environmental, and stochastic factors. Here we review the known genetic factors involved in aging.
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Aging Dis 2(3): 186-195

Aging Genetics and Aging

Cell aging: DNA damage and telomeres

A principal factor in aging is an exponential increase in incidence and mortality rates of cancer and non-cancerous diseases, as well progressive tissue degeneration and atrophy, caused by a decrease in adult or somatic stem cell function [4].

Cells are constantly exposed to a harmful environment throughout life. Increasing cell damage contributes to the dysfunction that characterizes the aging body. The best example of DNA damage as a cause of aging are the progeroid syndromes, which are caused by a deficiency in the mechanisms involved in DNA repair and whose symptoms begin early in life[5, 6].

Mutations in certain genes confer greater stress resistance and a reduced rate of damage accumulation, increasing longevity. For example, mutation in the gene that encodes the oxidative stress response protein p66, which prolongs life and protects from a variety of aging-associated diseases in mice, enhances resistance to apoptosis following oxidative stress in vitro-cultured cells [7].

Telomeres are DNA-protein complexes that cap the ends of linear DNA strands, stabilizing them and preventing chromosome instability [8]. A correlation has been proposed between telomere shortening and somatic stem cell decline during aging [9]. The enzyme telomerase adds specific DNA sequence repeats to the chromosome ends that are lost through cell division, thus restoring telomere length and delaying cell senescence, apoptosis, and death [10]. The repetitive DNA at chromosome ends shortens with age, as observed in fibroblasts, lymphocytes, and hematopoietic stem cells (HSC) [11]. Telomeres become critically short after repeated mitotic divisions without adequate telomerase activity, making cells susceptible to apoptosis, death and to a clear increase in mutation [12, 13].

Telomere shortening is associated with age-related diseases in humans [14], and patients with accelerated aging syndromes show a higher rate of telomere erosion and marked chromosome instability[9]. Consistent with this, telomere dynamics are important for HSC maintenance [15], telomere shortening impairs adult stem cell function [1618], and telomerase-deficient mice have short telomeres and age prematurely [9]; most strikingly, telomerase-overexpressing mice have longer telomeres and show delayed aging and cancer resistance [19]. The pathways that involve DNA sequence alterations in somatic stem cell aging are still unclear, but these findings raise the possibility that telomere length or deficiencies in DNA repair systems could be part of these routes.

Genetic factors in aging

Several genetic factors are implicated in aging. Specific gene combinations (genotypes) determine lifespan: remarkable changes in duration are observed as a result of alteration in a single gene, as in human progeroid syndromes [20]. Twin studies show the impact of hereditary factors in lifespan variation [21, 22], which concur with the wide range of genetic variants involved in aging and age-related diseases described in genome association studies in centenarians[23]. In addition, mutations in genomic and mitochondrial DNA are a consequence of reduced repair efficiency, and lead in part to deterioration of somatic stem cell function [4].

Examples of the importance of genetic factors in aging include genes that maintain organism structure and function throughout life, alleles that enhance reproductive capacity early in life but have negative effects later in life when their impact has escaped natural selective pressure, and constitutional mutations that are phenotypically relevant until late in life, when they have eluded selection and cannot be removed from the population [2426].

Two main classes have been described of lifespan-extension mutants in Caenorhabditis elegans. The first consists of genes with activity in the mitochondrial electron transport chain, such as clk-1 [27] and isp-1 [28], whose mutation moderately reduces oxidative phosphorylation capacity and prolongs life in worms [29]; these mutations established the first link between energy metabolism and longevity. The second mutant class is related to hormone mechanisms of the insulin/IGF-I signaling (IIS) pathway, such as daf-2 and age-1 mutants [30, 31], which extend lifespan in worms, flies and mice [32].

The clk-1 mutant lacks an enzyme implicated in the biosynthesis of ubiquinone (coenzyme Q), an electron acceptor in the respiratory electron transport chain. Mice with moderately reduced oxidative phosphorylation have improved glucose homeostasis and live longer [33, 34]. Mutation of isp-1, which encodes an iron sulfur protein in mitochondrial complex III, was the first evidence of lifespan extension caused by an impaired electron transport function [3537]. These findings suggest that reduced mitochondrial function could promote aging.

IIS is mediated by DAF-2, the insulin/IGF-I receptor. C. elegans daf-2 mutants with reduced DAF-2 activity remain young and live longer than wild-type worms [31]. The life-prolonging effect of the daf-2 mutant is suppressed by mutations in daf-16, which is negatively regulated by DAF-2 signaling. daf-16 encodes a FOXO transcription factor [38] that regulates genes involved in defensive activities such as cell stress response, antimicrobial activity, detoxification of xenobiotics and free radicals.

Suppression of the TOR pathway, which interacts with IIS, lengthens C. elegans lifetime [39]; following TOR activation, the insulin receptor signaling pathway downregulates expression of proteins in the sirtuin family and inhibits autophagic mechanisms involved in cell integrity, through removal of damaged mitochondria. Both pathways are essential for lifespan extension, as shown by longevity mutants of C. elegans [4042].

Sirtuins are protein deacetylases that modulate pathways implicated in the aging process [43]. Certain sirtuins regulate glucose and fat metabolism in mammals [44, 45] by enhancing mitochondrial biogenesis in liver and muscle through the transcriptional coactivator peroxisome proliferator-activator receptor-γ coactivator 1α (PGC-1α) [45]; they also govern cell survival by reducing p53 tumor suppressor activity [46, 47]. Resveratrol, a plant-derived polyphenol, increases the deacetylase activity of some sirtuins and increases yeast lifespan by nearly 70% [48]. Similarly, when treated with resveratrol, the short-lived fish Nothobranchius furzeri also showed a 60% increase in lifetime, accompanied by maintenance of motor and cognitive capacities [49]; resveratrol-treated middle-aged mice on a high-calorie diet showed a significant lifespan extension [50].

Specific genetic factors that determine length of life

Current understanding of biological aging implies that some aging-associated changes are programmed, whereas others are random and not predictable. Human senescence is a complex process involving genetic and environmental factors that affect most physiological pathways. The enormous variation in the average lifespan in different species suggests that maximum lifetime is determined by the species-specific genotype (Fig. 1). Identification of genes and mutations responsible for progeroid syndromes (age-related monogenic hereditary disorders) [20] will help to establish the function of a specific genotype in an individual’s lifespan.

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Object name is AD-2-3-186-Figure1.jpg

Representation of genetic factors′ influence in aging and lifespan. The environmental conditions (stress, pesticides), individual genotype (genomic and mitochondrial DNA) and stochastic factors can induce genetic and epigenetic alterations that cause a decline in somatic stem cell function that can be the origin of metabolic, degenerative diseases, cancer and aging in the individuals.

Progerias are a group of diseases characterized by a premature aging phenotype and are a model for studying aging-associated genetic changes. Patients with these conditions, including Cockayne syndrome, Fanconi anemia, Werner, Bloom, Rothmund-Thomson and Hutchinson-Gilford syndromes, xeroderma pigmentosum and ataxia-telangiectasia, develop features of accelerated aging caused by mutations in genes implicated in genetic stability (Table 1). The clinical characteristics of progerias can include premature senescence (gray hair, atherosclerosis, increased risk of cancer), skin changes (atrophy, ulcer, hyperkeratosis), metabolic disorders (diabetes, hyperlipidemia) and senile dementia. Also termed “segmental progerias”, these syndromes are often selective of certain features of physiological aging.

Table 1.

Genetic alterations associated to premature aging phenotypes

Cockayne SyndromeERCC6(CSA)
DNA repair
DNA repair
Werner Syndrome (WS)WRNDNA helicase
Bloom SyndromeBLMDNA helicase
Rothmund-Thomson SyndromeRECQL4DNA helicase
Hutchinson-Gilford SyndromeLMNAStructural Protein

Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutation at WRN, a member of the RecQ helicase family [51], involved in DNA repair systems and replication [5254]. WS patients develop normally until puberty; the first sign of disease is absence of the pubertal growth spurt and gonadal atrophy, which results in short stature of the affected adult. By the third decade of life, premature graying, loss of hair and skin atrophy become apparent; they also show accelerated development of all forms of arteriosclerosis, type 2 diabetes mellitus, regional loss of subcutaneous tissue, osteoporosis, ocular cataracts, and increased cancer susceptibility [55, 56]. Individuals with WS show reduced telomere length in fibroblasts, which cease to divide prematurely, as well as deficiency in DNA repair systems, leading to genomic mutations that increase cancer incidence [5661].

The Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease. As for other segmental aging syndromes, its clinical signs include precocious aging in early childhood with reduced life expectancy; patients do not usually reach adolescence [62]. This syndrome is a laminopathia caused by a single-base substitution (GGC>GGT) at position 1824 in exon 11 of the LMNA gene [63, 64]. LMNA encodes the nuclear lamin A protein, a constituent of the nuclear lamina, a structure that has an important role in nuclear stability [65, 66]. Truncated lamins caused nuclear anomalies compatible with the HGPS phenotype [6773]. Several animal models of progerias have confirmed the effect of a single genetic alteration on the mechanisms of aging. Mice with a mutation in the LMNA gene or deletion of the metalloprotease that processes prelamin A (Zmpste24) acquire a pathologic phenotype similar to HGPS syndrome [74, 75].

Bloom syndrome is a rare hereditary disease characterized by short stature, telangiectasia (tiny blood vessels dilated facial) facial photosensitivity (increased sensitivity to light), and increased susceptibility to tumors. Bloom syndrome is a rare disorder in most populations. It is more common in people of Central and Eastern European (Ashkenazi) Jewish background, among who 1 in 48,000 are affected. This syndrome is associated with mutations in the BLM gene, which encodes a protein family of DNA helicases (enzymes involved in DNA replication and transcription) [76]. These individuals have chromosomal instability by a high frequency of breaks and rearrangements with abnormal sister chromatid exchanges, increased sensitivity to ultraviolet radiation and alterations in DNA synthesis. Alterations have also been located on chromosome 15q26. The higher frequency in Ashkenazi Jewish population s is due to a founder effect; approximately 1% of them are heterozygous carriers of the LMAsh mutation (a six nucleotide deletion and a seven nucleotide insertion at position 2281 of the cDNA) [77].

Rothmund-Thomson syndrome (RTS) is inherited as an autosomal recessive disease and presenting early in life with clinical characteristics such as facial rash (poikiloderma), short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, premature aging and a predisposition to osteosarcoma [78]. This spectrum of clinical features is suggestive of genetic heterogeneity. It has been described in all ethnic groups with a very low prevalence.

Two subtypes of this disease have been found in the affected individuals, the type I RTS is characterised by poikiloderma and juvenile cataracts is negative for the RECQL4 mutation [78], while the type II RTS, is characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life, is caused by homozygous or compound heterozygous mutations in the RECQ4 helicase gene [78].

Progerias are excellent examples of the influence of genetic factors on the aging process, and understanding the mechanisms involved in these pathologies will contribute to the development of new treatments for these patients.

Linkage and association studies of genetic variants that affect longevity and aging

The observation that certain genetic factors act as modulators of the aging process has led to the development of studies in populations of centenarians, whose lifespan is approximately twice the mean predicted for the population at the time of their birth [21, 22]. The longevity of these individuals is often accompanied by increased resistance to diseases that lead to early death [79, 80]. In families whose members show exceptional longevity, in addition to other environmental factors, family habits (lifestyle, nutrition) were thought to influence survival, although data are limited on the contribution of these factors to greater resistance to disease [81].

Aging-associated polymorphisms in the IGF1R, PON1, APOC3 and PI3K genes [82] and the evolutionarily conserved extension in longevity through IIS[83, 84] are examples of the genetic factors involved in extreme longevity. The IIS equivalent in mammals is part of the somatotropic axis that regulates body growth. Somatic growth is mediated by growth hormone (GH), which is released by the hypophysis. Circulating GH activates the GH receptor (GHR); this in turn leads to secretion of IGF-1, which binds the IGF-1 receptor (IGF-1R) on target cells, triggering cell growth and survival [85]. The role of GH in aging became clear in Ghr knockout mice, which showed increased longevity [8688]. Specific polymorphisms associated with a decrease in plasma IGF-1 concentrations are frequently found in Ashkenazi Jewish centenarians [60, 89, 90], suggesting a role for GH and IGF-1 signaling downregulation in human longevity.

Willcox et al. [91] recently described three SNP (single nucleotide polymorphisms) in the FOXO3A gene, a homologue of the key IIS effector daf-16 in C. elegans, that were significantly associated with longevity and aging phenotypes in a population of long-lived Americans of Japanese ancestry; these associations were confirmed by Flaschbart et al. [92].

A large number of genome-wide case-control association studies have identified many genetic variants linked to age-related diseases. Examples include the genetic variation in APOE and PCDH11X, associated with Alzheimer’s disease (AD) [93, 94]. Individuals homozygous for the APOE ε2 allele have a longer lifespan than ε3 or ε4 carriers in Caucasian populations [95, 96], which could be linked to increased risk of coronary disease for these latter alleles [97]. Moreover, the ε4 allele appears to be associated with risk of developing the familiar and sporadic forms of AD, and ε4 carriers showed symptoms of the disease at younger ages [97, 98].

An adequate immune response seems to be related to increased lifespan; the alleles HLA-DR11 and haplotypes HLA-B8, DR3 have a protective effect in infections and are associated with longer life; studies in Sicilian male centenarians show an increase in the presence of the HLA DRB1*18 allele in these individuals [99].

Singh et al. [100] described the association with extended survival of three single nucleotide polymorphisms, HSPA1A (−110A>C), HSPA1B (1267A>G) and HSPA1L (2437T>C) of the three HSP70 genes. These authors found that HSPA1A-AA and HSPA1B-AA genotypes in a cohort Danish nonagenarian were significantly associated with poor survival in women and the female carriers of haplotype G-C-T survived longer than non-carriers.

Reactive oxygen species (ROS) are widely linked to aging, as part of the DNA damage mechanisms. Mutations in proteins that participate in free radical detoxification can also affect variation in aging and life span; the rs4880 and rs1050450 SNP in the MnSOD (manganese superoxide dismutase) and GPX1 (glutathione peroxidase 1) genes, respectively, are associated with age-related diseases [101]. Decreased mortality was also described in individuals bearing the MnSODrs4880C (MnSOD(CC/CT) or the GPX1rs 1050450T alleles (GPX1(TT/TC) in a nonagenarian Danish cohort [102].

Although analyses of these long-lived populations have allowed the identification of loci that could be associated with a better chance of living longer, additional studies are needed to confirm these associations.

Concluding remarks

Aging is a complex process that can be described as a group of cellular functions that participate in an integrated way in the process of senescence. The great variability in longevity between individuals of the same species suggests that the aging process is profoundly affected by processes that lead to the accumulation of errors that damage repair systems and compromise stem cell function. These changes can be caused through genetic and epigenetic mechanisms, which are influenced by genes, environmental and stochastic factors; the contribution of each of these factors remains to be determined by future studies.

Aging is characterized by a progressive decline in physical, mental, and reproductive capacity, as well as an increase in morbidity and mortality. Damage invariably accumulates with age and contributes to the cell dysfunction that characterizes this process, and is clearly influenced by genetic and environmental factors. The effects of the variety of factors involved in aging are the result of the balance between our defense and damage repair systems and the aggression to which we are subjected [103]. Defense and repair systems are highly enzyme dependent; the absence or malfunction of a gene necessary for production and activity of these enzymes can lead to accumulation of cell damage, as demonstrated by the progeria syndromes.

There is increasing evidence that, in addition to genetic factors, age-associated alteration of gene function might also depend on epigenetic factors. Examples of epigenetic alterations with age include global DNA hypomethylation and promoter hypermetylation. Thus, aging is not probably mediated by a single gene or main mechanism. The magnitude of the contribution of the pathways cited above to the onset and progression of aging and age-related diseases remains unclear. Many questions regarding epigenetic and its role in age related diseases still remain open, but may be able to explain many of the phenotypic changes related to the aging process. Further studies are needed to describe the pathways involved in age-related physiological alteration (hypertension, insulin resistance) and predisposition to age-related pathological changes (cancer, neurodegenerative disease). Exploration of these functional connections might provide options to help develop more efficient anti-aging strategies to ameliorate senescence-related diseases. Exploration of these functional connections might provide options to help develop more efficient anti-aging strategies to ameliorate senescence-related diseases.

Fundación ASTURCOR, Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Av. Julian Clavería s/n, 33006 Oviedo, Spain
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Cantoblanco, Madrid E-28049, Spain
Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Correspondence should be addressed to: Dr. Mario F. Fraga, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Cantoblanco, Madrid E-28049, Spain. Email: se.cisc.bnc@agarffm
Received 2011 Mar 4; Revised 2011 Apr 27; Accepted 2011 Apr 27.


The process of aging refers to the decay of an organism’s structure and function, in which molecular and cellular modifications can have various effects at the individual level over the course of a lifetime. The accumulation of molecular errors that compromise adult stem cell functions occurs because of genetic and epigenetic interactions and depends on hereditary, environmental, and stochastic factors. Here we review the known genetic factors involved in aging.

Keywords: Longevity, Environment, Genes, Progerias, DNA repair and telomeres

Aging affects physiological functions and can be defined as the accumulation of damage in molecules, cells and tissues over a lifetime; this often decreases an organism’s capacity to maintain homeostasis in stress conditions, and entails a greater risk for many diseases (cancer, cardiovascular and neurodegenerative disorders) and premature mortality[1, 2]. Identification of factors that regulate aging is limited by the complexity of the process and by the considerable heterogeneity among individuals and even among tissues within a body. At the cellular level, the most prominent event in an aging tissue is cell senescence, a consequence of exposure to intrinsic and extrinsic aging factors; it is characterized by gradual accumulation of DNA damage and epigenetic changes in DNA structure that affect correct gene expression and lead to altered cell function.

Aging is a multifactorial process that is determined by genetic and environmental factors. The genotype determines the variation in lifespan among species or individuals; this variation is more severely affected by the tendency to accumulate molecular errors that compromise adult stem cell function than by a specific genetic program[3]. Here, we review the best known genetic factors involved in aging.


We thank C. Mark for editorial assistance. SRR is funded by the Asturcor Foundation. VC received a Formación de Profesorado Universitario Spanish Research Programme Fellowship. Cancer Epigenetics unit at the IUOPA is funded by Spanish Ministry of Health grants PI061267 and PS09/02454, Spanish National Research Council (CSIC) grant 200820I172 and The Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología grant (FICYT-IB09-106). The Instituto Universitario de Oncología is supported by Obra Social Cajastur, Spain.



  • 1. Fraga MF, Esteller MEpigenetics and aging: the targets and the marks. Trends Genet. 2007;23:413–418.[PubMed][Google Scholar]
  • 2. Fraga MF, Agrelo R, Esteller MCross-talk between aging and cancer: the epigenetic language. Ann N Y Acad Sci. 2007;1100:60–74.[PubMed][Google Scholar]
  • 3. Kirkwood TB. Time of our lives. What controls the length of life? EMBO Rep. 2005;6:S4–8. Spec No:
  • 4. Sharpless NE, DePinho RAHow stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol. 2007;8:703–713.[PubMed][Google Scholar]
  • 5. Li B, Jog S, Candelario J, Reddy S, Comai LAltered nuclear functions in progeroid syndromes: a paradigm for aging research. Scientific World Journal. 2009;9:1449–1462.[Google Scholar]
  • 6. Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali MPolycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PLoS One. 2009;4:e5622.[Google Scholar]
  • 7. Trinei M, Berniakovich I, Beltrami E, Migliaccio E, Fassina A, Pelicci P, Giorgio MP66Shc signals to age. Aging (Albany NY) 2009;1:503–510.[Google Scholar]
  • 8. O’Sullivan RJ, Karlseder JTelomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11:171–181.[Google Scholar]
  • 9. Collado M, Blasco MA, Serrano MCellular senescence in cancer and aging. Cell. 2007;130:223–233.[PubMed][Google Scholar]
  • 10. Blackburn EH, Greider CW, Szostak JWTelomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med. 2006;12:1133–1138.[PubMed][Google Scholar]
  • 11. Greenwood MJ, Lansdorp PMTelomeres, telomerase, and hematopoietic stem cell biology. Arch Med Res. 2003;34:489–495.[PubMed][Google Scholar]
  • 12. Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K, Humphries SEAssociation of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis. 2010;209:42–50.[Google Scholar]
  • 13. von Zglinicki TOxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–344.[PubMed][Google Scholar]
  • 14. Canela A, Vera E, Klatt P, Blasco MAHigh-throughput telomere length quantification by FISH and its application to human population studies. Proc Natl Acad Sci U S A. 2007;104:5300–5305.[Google Scholar]
  • 15. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PGThe p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309–313.[PubMed][Google Scholar]
  • 16. Flores I, Cayuela ML, Blasco MAEffects of telomerase and telomere length on epidermal stem cell behavior. Science. 2005;309:1253–1256.[PubMed][Google Scholar]
  • 17. Rojas-Cartagena C, Appleyard CB, Santiago OI, Flores IExperimental intestinal endometriosis is characterized by increased levels of soluble TNFRSF1B and downregulation of Tnfrsf1a and Tnfrsf1b gene expression. Biol Reprod. 2005;73:1211–1218.[PubMed][Google Scholar]
  • 18. Rojas-Cartagena C, Flores I, Appleyard CBRole of tumor necrosis factor receptors in an animal model of acute colitis. Cytokine. 2005;32:85–93.[PubMed][Google Scholar]
  • 19. Tomas-Loba A, Flores I, Fernandez-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borras C, Matheu A, Klatt P, Flores JM, Vina J, Serrano M, Blasco MATelomerase reverse transcriptase delays aging in cancer-resistant mice. Cell. 2008;135:609–622.[PubMed][Google Scholar]
  • 20. Navarro CL, Cau P, Levy NMolecular bases of progeroid syndromes. Hum Mol Genet. 2006;15(Spec No 2):R151–161.[PubMed][Google Scholar]
  • 21. v BHJ, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen KGenetic influence on human lifespan and longevity. Hum Genet. 2006;119:312–321.[PubMed][Google Scholar]
  • 22. Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller MEpigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci U S A. 2006;103:8822–8827.[Google Scholar]
  • 23. Martin GM, Bergman A, Barzilai NGenetic determinants of human health span and life span: progress and new opportunities. PLoS Genet. 2007;3:e125.[Google Scholar]
  • 24. Bekris LM, Yu CE, Bird TD, Tsuang DWGenetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23:213–227.[Google Scholar]
  • 25. Kalaria RNVascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr Rev. 2010;68(Suppl 2):S74–87.[Google Scholar]
  • 26. Saliques S, Zeller M, Lorin J, Lorgis L, Teyssier JR, Cottin Y, Rochette L, Vergely CTelomere length and cardiovascular disease. Arch Cardiovasc Dis. 2010;103:454–459.[PubMed][Google Scholar]
  • 27. Lakowski B, Hekimi SDetermination of life-span in Caenorhabditis elegans by four clock genes. Science. 1996;272:1010–1013.[PubMed][Google Scholar]
  • 28. Feng J, Bussiere F, Hekimi SMitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell. 2001;1:633–644.[PubMed][Google Scholar]
  • 29. Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon CRates of behavior and aging specified by mitochondrial function during development. Science. 2002;298:2398–2401.[PubMed][Google Scholar]
  • 30. Johnson TECaenorhabditis elegans 2007: the premier model for the study of aging. Exp Gerontol. 2008;43:1–4.[Google Scholar]
  • 31. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464.[PubMed]
  • 32. Piper MD, Selman C, McElwee JJ, Partridge LSeparating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? J Intern Med. 2008;263:179–191.[PubMed][Google Scholar]
  • 33. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, Ebersberger I, Nakashima T, Sarao R, Neely G, Esterbauer H, Kozlov A, Kahn CR, Kroemer G, Rustin P, Burcelin R, Penninger JMTargeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell. 2007;131:476–491.[PubMed][Google Scholar]
  • 34. Dell’agnello C, Leo S, Agostino A, Szabadkai G, Tiveron C, Zulian A, Prelle A, Roubertoux P, Rizzuto R, Zeviani MIncreased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Hum Mol Genet. 2007;16:431–444.[PubMed][Google Scholar]
  • 35. Yang W, Hekimi STwo modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell. 2010;9:433–447.[PubMed][Google Scholar]
  • 36. Agrawal A, Tay J, Yang GE, Agrawal S, Gupta SAge-associated epigenetic modifications in human DNA increase its immunogenicity. Aging (Albany NY) 2010;2:93–100.[Google Scholar]
  • 37. Butler JA, Ventura N, Johnson TE, Rea SLLong-lived mitochondrial (Mit) mutants of Caenorhabditis elegans utilize a novel metabolism. FASEB J. 2010;24:4977–88.[Google Scholar]
  • 38. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997;389:994–999.[PubMed]
  • 39. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 2008;4:e24.
  • 40. Droge WOxidative aging and insulin receptor signaling. J Gerontol A Biol Sci Med Sci. 2005;60:1378–1385.[PubMed][Google Scholar]
  • 41. Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 2003;301:1387–1391.[PubMed]
  • 42. Anway MD, Cupp AS, Uzumcu M, Skinner MKEpigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005;308:1466–1469.[PubMed][Google Scholar]
  • 43. Hekimi S, Guarente LGenetics and the specificity of the aging process. Science. 2003;299:1351–1354.[PubMed][Google Scholar]
  • 44. Guarente L, Picard FCalorie restriction--the SIR2 connection. Cell. 2005;120:473–482.[PubMed][Google Scholar]
  • 45. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver PNutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–118.[PubMed][Google Scholar]
  • 46. Smith JHuman Sir2 and the ‘silencing’ of p53 activity. Trends Cell Biol. 2002;12:404–406.[PubMed][Google Scholar]
  • 47. Belinsky SA, Palmisano WA, Gilliland FD, Crooks LA, Divine KK, Winters SA, Grimes MJ, Harms HJ, Tellez CS, Smith TM, Moots PP, Lechner JF, Stidley CA, Crowell REAberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res. 2002;62:2370–2377.[PubMed][Google Scholar]
  • 48. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DASmall molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–196.[PubMed][Google Scholar]
  • 49. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino AResveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol. 2006;16:296–300.[PubMed][Google Scholar]
  • 50. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DAResveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342.[Google Scholar]
  • 51. Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GDPositional cloning of the Werner’s syndrome gene. Science. 1996;272:258–262.[PubMed][Google Scholar]
  • 52. Matsumoto T, Shimamoto A, Goto M, Furuichi YImpaired nuclear localization of defective DNA helicases in Werner’s syndrome. Nat Genet. 1997;16:335–336.[PubMed][Google Scholar]
  • 53. Chen L, Oshima JWerner Syndrome. J Biomed Biotechnol. 2002;2:46–54.[Google Scholar]
  • 54. Lebel M, Spillare EA, Harris CC, Leder PThe Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem. 1999;274:37795–37799.[PubMed][Google Scholar]
  • 55. Ledford HAgeing: Much ado about ageing. Nature. 2010;464:480–481.[PubMed][Google Scholar]
  • 56. Orren DKWerner syndrome: molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging. Front Biosci. 2006;11:2657–2671.[PubMed][Google Scholar]
  • 57. Perona R, Machado-Pinilla R, Manguan C, Carrillo JTelomerase deficiency and cancer susceptibility syndromes. Clin Transl Oncol. 2009;11:711–714.[PubMed][Google Scholar]
  • 58. Machwe A, Xiao L, Orren DKTRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA. Oncogene. 2004;23:149–156.[PubMed][Google Scholar]
  • 59. Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RG, Kipling DTelomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nat Genet. 2000;24:16–17.[PubMed][Google Scholar]
  • 60. Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto MRole of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells. Cancer Sci. 2008;99:843–848.[PubMed][Google Scholar]
  • 61. Pallardo FV, Lloret A, Lebel M, d’Ischia M, Cogger VC, Le Couteur DG, Gadaleta MN, Castello G, Pagano GMitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. Biogerontology. 2010;11:401–419.[PubMed][Google Scholar]
  • 62. Dominguez-Gerpe L, Araujo-Vilar DPrematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes. Curr Aging Sci. 2008;1:202–212.[PubMed][Google Scholar]
  • 63. Scharner J, Gnocchi VF, Ellis JA, Zammit PSGenotype-phenotype correlations in laminopathies: how does fate translate? Biochem Soc Trans. 2010;38:257–262.[PubMed][Google Scholar]
  • 64. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FSRecurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–298.[PubMed][Google Scholar]
  • 65. Rodriguez S, Eriksson MEvidence for the involvement of lamins in aging. Curr Aging Sci. 2010;3:81–89.[PubMed][Google Scholar]
  • 66. Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O’Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreno L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar EChanges in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20:170–179.[Google Scholar]
  • 67. Taimen P, Pfleghaar K, Shimi T, Moller D, Ben-Harush K, Erdos MR, Adam SA, Herrmann H, Medalia O, Collins FS, Goldman AE, Goldman RDA progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization. Proc Natl Acad Sci U S A. 2009;106:20788–93.[Google Scholar]
  • 68. Gonzalez-Suarez I, Redwood AB, Gonzalo SLoss of A-type lamins and genomic instability. Cell Cycle. 2009;8:3860–3865.[PubMed][Google Scholar]
  • 69. Gonzalez-Suarez I, Redwood AB, Perkins SM, Vermolen B, Lichtensztejin D, Grotsky DA, Morgado-Palacin L, Gapud EJ, Sleckman BP, Sullivan T, Sage J, Stewart CL, Mai S, Gonzalo SNovel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. 2009;28:2414–2427.[Google Scholar]
  • 70. Parnaik VK, Manju KLaminopathies: multiple disorders arising from defects in nuclear architecture. J Biosci. 2006;31:405–421.[PubMed][Google Scholar]
  • 71. Liu B, Zhou ZLamin A/C, laminopathies and premature ageing. Histol Histopathol. 2008;23:747–763.[PubMed][Google Scholar]
  • 72. Verstraeten VL, Broers JL, Ramaekers FC, van Steensel MAThe nuclear envelope, a key structure in cellular integrity and gene expression. Curr Med Chem. 2007;14:1231–1248.[PubMed][Google Scholar]
  • 73. Halton TL, Liu S, Manson JE, Hu FBLow-carbohydrate-diet score and risk of type 2 diabetes in women. Am J Clin Nutr. 2008;87:339–346.[Google Scholar]
  • 74. Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb MH, Young SG, Fong LGBlocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci U S A. 2005;102:10291–10296.[Google Scholar]
  • 75. Pendas AM, Zhou Z, Cadinanos J, Freije JM, Wang J, Hultenby K, Astudillo A, Wernerson A, Rodriguez F, Tryggvason K, Lopez-Otin CDefective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet. 2002;31:94–99.[PubMed][Google Scholar]
  • 76. Tikoo S, Sengupta STime to bloom. Genome Integr. 2010;1:14.[Google Scholar]
  • 77. Shahrabani-Gargir L, Shomrat R, Yaron Y, Orr-Urtreger A, Groden J, Legum CHigh frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin. Genet Test. 1998;2:293–296.[PubMed][Google Scholar]
  • 78. Larizza L, Roversi G, Volpi LRothmund-Thomson syndrome. Orphanet J Rare Dis. 2010;5:2.[Google Scholar]
  • 79. Salvioli S, Capri M, Bucci L, Lanni C, Racchi M, Uberti D, Memo M, Mari D, Govoni S, Franceschi CWhy do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother. 2009;58:1909–1917.[PubMed][Google Scholar]
  • 80. Pawelec GImmunity and ageing in man. Exp Gerontol. 2006;41:1239–1242.[PubMed][Google Scholar]
  • 81. Terry DF, Evans JC, Pencina MJ, Murabito JM, Vasan RS, Wolf PA, Kelly-Hayes M, Levy D, D’Agostino RB, Sr, Benjamin EJCharacteristics of Framingham offspring participants with long-lived parents. Arch Intern Med. 2007;167:438–444.[PubMed][Google Scholar]
  • 82. Atzmon G, Pollin TI, Crandall J, Tanner K, Schechter CB, Scherer PE, Rincon M, Siegel G, Katz M, Lipton RB, Shuldiner AR, Barzilai NAdiponectin levels and genotype: a potential regulator of life span in humans. J Gerontol A Biol Sci Med Sci. 2008;63:447–453.[Google Scholar]
  • 83. Henis-Korenblit S, Zhang P, Hansen M, McCormick M, Lee SJ, Cary M, Kenyon CInsulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 107:9730–9735.[Google Scholar]
  • 84. Kenyon CThe plasticity of aging: insights from long-lived mutants. Cell. 2005;120:449–460.[PubMed][Google Scholar]
  • 85. Carter CS, Ramsey MM, Sonntag WEA critical analysis of the role of growth hormone and IGF-1 in aging and lifespan. Trends Genet. 2002;18:295–301.[PubMed][Google Scholar]
  • 86. Bonkowski MS, Pamenter RW, Rocha JS, Masternak MM, Panici JA, Bartke ALong-lived growth hormone receptor knockout mice show a delay in age-related changes of body composition and bone characteristics. J Gerontol A Biol Sci Med Sci. 2006;61:562–567.[PubMed][Google Scholar]
  • 87. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc YIGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;421:182–187.[PubMed][Google Scholar]
  • 88. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o MSuppression of aging in mice by the hormone Klotho. Science. 2005;309:1829–1833.[Google Scholar]
  • 89. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen PFunctionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105:3438–3442.[Google Scholar]
  • 90. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv EAssociation of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell. 2009;8:460–472.[Google Scholar]
  • 91. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JDFOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008;105:13987–13992.[Google Scholar]
  • 92. Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel AAssociation of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A. 2009;106:2700–2705.[Google Scholar]
  • 93. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh JAssociation of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298:1300–1311.[PubMed][Google Scholar]
  • 94. Drenos F, Kirkwood TBSelection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E. PLoS One. 2010;5:e10022.[Google Scholar]
  • 95. Lewis BP, Burge CB, Bartel DPConserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.[PubMed][Google Scholar]
  • 96. Lewis SJ, Brunner EJMethodological problems in genetic association studies of longevity--the apolipoprotein E gene as an example. Int J Epidemiol. 2004;33:962–970.[PubMed][Google Scholar]
  • 97. Rosvall L, Rizzuto D, Wang HX, Winblad B, Graff C, Fratiglioni LAPOE-related mortality: effect of dementia, cardiovascular disease and gender. Neurobiol Aging. 2009;30:1545–1551.[PubMed][Google Scholar]
  • 98. Wolk DA, Dickerson BC, Weiner M, Aiello M, Aisen P, Albert MS, Alexander G, Anderson HS, Anderson K, Apostolova L, Arnold S, Ashford W, Assaly M, Asthana S, Bandy D, Bartha R, Bates V, Beckett L, Bell KL, Benincasa AL, Bergman H, Bernick C, Bernstein M, Black S, Blank K, Borrie M, Brand C, Brewer J, Brown AD, Burns JM, Cairns NJ, Caldwell C, Capote H, Carlsson CM, Carmichael O, Cellar JS, Celmins D, Chen K, Chertkow H, Chowdhury M, Clark D, Connor D, Correia S, Crawford K, Dale A, de Leon MJ, De Santi SM, Decarli C, Detoledo-Morrell L, Devous M, Diaz-Arrastia R, Dolen S, Donohue M, Doody RS, Doraiswamy PM, Duara R, Englert J, Farlow M, Feldman H, Felmlee J, Fleisher A, Fletcher E, Foroud TM, Foster N, Fox N, Frank R, Gamst A, Given CA, 2nd, Graff-Radford NR, Green RC, Griffith R, Grossman H, Hake AM, Hardy P, Harvey D, Heidebrink JL, Hendin BA, Herring S, Honig LS, Hosein C, Robin Hsiung GY, Hudson L, Ismail MS, Jack CR, Jr, Jacobson S, Jagust W, Jayam-Trouth A, Johnson K, Johnson H, Johnson N, Johnson KA, Johnson S, Kachaturian Z, Karlawish JH, Kataki M, Kaye J, Kertesz A, Killiany R, Kittur S, Koeppe RA, Korecka M, Kornak J, Kozauer N, Lah JJ, Laubinger MM, Lee VM, Lee TY, Lerner A, Levey AI, Longmire CF, Lopez OL, Lord JL, Lu PH, Macavoy MG, Malloy P, Marson D, Martin-Cook K, Martinez W, Marzloff G, Mathis C, Mc-Adams-Ortiz C, Mesulam M, Miller BL, Mintun MA, Mintzer J, Molchan S, Montine T, Morris J, Mulnard RA, Munic D, Nair A, Neu S, Nguyen D, Norbash A, Oakley M, Obisesan TO, Ogrocki P, Ott BR, Parfitt F, Pawluczyk S, Pearlson G, Petersen R, Petrella JR, Potkin S, Potter WZ, Preda A, Quinn J, Rainka M, Reeder S, Reiman EM, Rentz DM, Reynolds B, Richard J, Roberts P, Rogers J, Rosen A, Rosen HJ, Rusinek H, Sabbagh M, Sadowsky C, Salloway S, Santulli RB, Saykin AJ, Scharre DW, Schneider L, Schneider S, Schuff N, Shah RC, Shaw L, Shen L, Silverman DH, Simpson DM, Sink KM, Smith CD, Snyder PJ, Spann BM, Sperling RA, Spicer K, Stefanovic B, Stern Y, Stopa E, Tang C, Tariot P, Taylor-Reinwald L, Thai G, Thomas RG, Thompson P, Tinklenberg J, Toga AW, Tremont G, Trojanowki JQ, Trost D, Turner RS, van Dyck CH, Vanderswag H, Varon D, Villanueva-Meyer J, Villena T, Walter S, Wang P, Watkins F, Williamson JD, Wolk D, Wu CK, Zerrate M, Zimmerman EAApolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2010;107:10256–10261.[PubMed][Google Scholar]
  • 99. Listi F, Caruso C, Colonna-Romano G, Lio D, Nuzzo D, Candore GHLA and KIR frequencies in Sicilian Centenarians. Rejuvenation Res. 2010;13:314–318.[PubMed][Google Scholar]
  • 100. Singh R, Kolvraa S, Bross P, Christensen K, Bathum L, Gregersen N, Tan Q, Rattan SIAnti-inflammatory heat shock protein 70 genes are positively associated with human survival. Curr Pharm Des. 2010;16:796–801.[Google Scholar]
  • 101. Honda Y, Tanaka M, Honda SRedox regulation, gene expression and longevity. Geriatr Gerontol Int. 2010;10(Suppl 1):S59–69.[PubMed][Google Scholar]
  • 102. Soerensen M, Christensen K, Stevnsner T, Christiansen LThe Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old. Mech Ageing Dev. 2009;130:308–314.[Google Scholar]
  • 103. Adams JM, White MBiological ageing: a fundamental, biological link between socio-economic status and health? Eur J Public Health. 2004;14:331–334.[PubMed][Google Scholar]
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