Genetic factors associated with longevity: A review of recent findings

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Contents lists available at ScienceDirect

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Review

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Genetic factors associated with longevity: A review of recent findings

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Aladdin H. Shadyab a,b,∗ , Andrea Z. LaCroix c

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San Diego State University/University of California, San Diego Joint-Doctoral Program in Public Health (Epidemiology), USA Graduate School of Public Health, San Diego State University, Hardy Tower Room 119, 5500 Campanile Drive, San Diego, CA, 92182-4162, USA c Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA b

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a r t i c l e

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a b s t r a c t

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Article history: Received 13 August 2014 Received in revised form 20 October 2014 Accepted 27 October 2014 Available online xxx

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Keywords: Exceptional longevity Gene Genome Longevity Aging Lifespan

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Contents

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Given the rising rate of survival into advanced old age in the United States, achieving longevity and healthy aging is becoming increasingly important. Besides maintaining healthy lifestyle behaviors, positive aging outcomes may also be heritable, with estimates ranging from 20% to 35%. In this qualitative review, we summarize recent findings on genetic factors linked to longevity across different populations and study designs. Recent studies not only confirm the association of APOE with longevity in different populations, but also implicate several other pathways that may influence longevity including nitric oxide production, inflammation, immunity, and DNA damage response and repair. Recent evidence also suggests that mitochondrial DNA may play an important role in attaining longevity. Despite these implicated pathways, longevity may be a polygenic trait influenced by a complex interplay of multiple genes. Future genetic studies on aging would benefit from larger samples of long-lived individuals, birth-cohort matched controls, inclusion of different aging phenotypes (e.g., aging free of morbidities), and analysis of gender differences. © 2014 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. APOE and FOX03A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Additional genes associated with longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genome-wide association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. The role of mitochondrial DNA in aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Oxidative stress and longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Longevity as a polygenic trait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Study design issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Life expectancy and the rate of survival into old age have risen dramatically throughout the past century in the United States. Between 2000 and 2010, the population aged ≥65 years grew at

∗ Corresponding author at: Graduate School of Public Health, San Diego State University, Hardy Tower Room 119, 5500 Campanile Drive, San Diego, CA, 921824162, USA. Tel.: +1 858 245 1485. E-mail addresses: [email protected], [email protected] (A.H. Shadyab), [email protected] (A.Z. LaCroix).

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a faster rate than the total US population (Werner, 2010). In addition, the likelihood of surviving to advanced old age has increased, with the US population aged 85–94 years experiencing the fastest rate of growth among the older population (Werner, 2010). Achieving longevity and healthy aging, which can be defined in a variety of ways, is thus gaining prominence in the popular press and is of increasing concern to older adults and their families, from a public health perspective. “Healthy aging” and “successful aging” are usually defined as survival to a specific advanced age (e.g., ≥85 years old) and free of chronic diseases such as coronary heart disease, stroke, cancer, and

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Please cite this article in press as: Shadyab, A.H., LaCroix, A.Z., Genetic factors associated with longevity: A review of recent findings. Ageing Res. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2014.10.005

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diabetes (Bell et al., 2014; Newman and Murabito, 2013; Willcox et al., 2006). Definitions of these phenotypes may also include good physical and cognitive functioning (Britton et al., 2008; Willcox et al., 2006). The age threshold used to define longevity varies by study but is typically ≥85 years old; “exceptional longevity” may be considered age ≥95 years old (Rajpathak et al., 2011). While these positive aging outcomes may be due to a variety of factors including maintaining healthy lifestyle behaviors such as avoidance of smoking and engaging in physical activity (Bell et al., 2014; Newman and Murabito, 2013), longevity may also have a genetic basis, with heritability estimates of 20–35% (Herskind et al., 1996; Newman and Murabito, 2013). However, studies on genetic factors associated with longevity have yielded inconsistent results, and not all findings have been replicated. This mini-review will discuss recent findings shedding light on the genetic basis of longevity.

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2. Discussion

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2.1. APOE and FOX03A

Table 1 presents findings from recent studies on genetic factors associated with longevity. In prior candidate gene association 71 studies, only variants of two genes, APOE and FOX03A, have 72 been consistently associated with longevity (Brooks-Wilson, 2013; 73 Flachsbart et al., 2009; Jacobsen et al., 2010; Schächter et al., 1994; 74 Willcox et al., 2008). Apolipoprotein E (APOE) is a major carrier of 75 cholesterol and supports lipid transport and injury repair in the 76 brain. The APOE gene has three common polymorphic alleles (␧2, 77 ␧3, and ␧4), leading to six possible genotypes (Liu et al., 2013). The 78 ␧4 allele is associated with Alzheimer’s disease (AD) risk, whereas 79 the ␧2 allele may protect against AD (Farrer et al., 1997); both alleles 80 have been associated with cardiovascular disease (CVD) risk (Lahoz 81 et al., 2001). The associations with CVD and AD may be related to 82 the involvement of these isoforms in inflammation, elevated lipid 83 levels, and oxidative stress (Brooks-Wilson, 2013; Liu et al., 2013; 84 Jofre-Monseny et al., 2008). 85 Although not a consistent finding, some studies have observed 86 that APOE2 occurs at a higher frequency in the elderly and cente87 narians, suggesting an association with longevity (Schächter et al., 88 1994; Seripa et al., 2006); on the other hand, APOE4 may be 89 less common in these groups and associated with early mortality 90 91Q3 (Jacobsen et al., 2014). Interestingly, single nucleotide polymorphisms (SNPs) near the APOE locus are the only variants to have 92 attained genome-wide significance in genome-wide association 93 studies (GWAS) of longevity (Deelen et al., 2011; Nebel et al., 2011; 94 Sebastiani et al., 2012b). 95 A recent case-control study comparing allele and genotype fre96 quencies of centenarians to disease-free younger controls from 97 Spain, Italy, and Japan found that the ␧4 allele reduced the odds 98 of achieving longevity by 45–65% (Garatachea et al., 2014). How99 ever, the ␧2 allele was associated with an increased likelihood of 100 longevity in the Italian and Japanese cohorts. Interestingly, all of 101 the Italian centenarians were free of cognitive impairment and 102 major age-related diseases, suggesting an association of ␧2 with 103 successful aging. 104 A large genome-wide linkage scan among nonagenarian sib105 ling pairs of European ancestry found that chromosomal region 106 19q13.11–q13.32 showed linkage with longevity (Beekman et al., 107 2013); subsequent association analyses using GWAS data found 108 that APOE4 and APOE2 alleles explain linkage at this region. Another 109 linkage study comparing offspring of long-lived individuals to 110 spouse controls observed a 25% reduction in the likelihood of carry111 ing the ␧4 allele among offspring (Schupf et al., 2013). Furthermore, 112 a GWAS meta-analysis identified the TOMM40/APOE/APOC1 locus 113 70

as being significantly associated with reaching ≥90 years of age (Deelen et al., 2014). Regarding the association of rare APOE variants with longevity, a recent study comparing men and women without a history of chronic diseases to younger controls found that the frequency of rare variants was not higher in cases compared to controls (Tindale et al., 2014). However, this study was limited by a small sample size. The effect of rare variants on longevity may be important, as common variants may not fully explain the heritability of longevity (Sebastiani et al., 2012a). Further studies are needed to elucidate the role of rare APOE variants on longevity and healthy aging. The forkhead box 03A (FOX03A) gene has been associated with longevity in multiple candidate gene association studies in diverse groups including German, Italian, and Chinese centenarians (Anselmi et al., 2009; Flachsbart et al., 2009; Li et al., 2009). This gene is involved in the insulin/insulin-like growth factor 1 signaling pathway, which has previously been shown to extend lifespan in animal models and is evolutionarily conserved (Bonafè et al., 2003; Holzenberger et al., 2003); recent studies have shown that other genes involved in this pathway are not associated with healthy aging or longevity (Morris et al., 2014). The precise mechanism by which FOX03A influences longevity may be due to its effects on oxidative stress, insulin sensitivity, and cell-cycle progression (Newman and Murabito, 2013). A recent GWAS meta-analysis observed only a modest association of FOX03A with survival to ≥90 years of age (Deelen et al., 2014). Further, in a genome-wide linkage analysis among nonagenarians, linkage to FOX03A and another forkhead box gene, FOX01, was not detected (Beekman et al., 2013). The lack of an association observed in these studies may be due to small sample sizes of exceptionally long-lived individuals, as the association of FOX03A with longevity is stronger in persons aged ≥95 years and especially in centenarians (Flachsbart et al., 2009; Willcox et al., 2008). 2.2. Additional genes associated with longevity Other genetic factors associated with longevity reveal insights into additional biological pathways that may modulate the aging process. Variants in the cholesteryl ester transfer protein (CETP) gene, which is involved in the regulation of high-density lipoprotein levels, were previously suggested as markers of exceptional longevity and healthy aging in Ashkenazi Jews and JapaneseAmerican men, respectively (Barzilai et al., 2003; Koropatnick et al., Q4 2008). However, in a recent case-control study among Han Chinese long-lived individuals, none of the four SNPs in the promoter region of the CETP gene was associated with longevity (Yang et al., 2014). Additionally, a meta-analysis of eight studies did not observe an association between CETP polymorphisms and longevity (Li et al., 2014). A study in Chinese centenarians and nonagenarians and younger controls identified significant genotype differences in the GNB3 and eNOS genes, whose variants have been implicated in hypertension and vascular function via nitric oxide (NO) generation, respectively ( Nijati et al., 2013). Another study found that variants of two Q5 NO synthase genes, NOS1 and NOS2, decrease the probability of attaining longevity, suggesting that NO production and signaling may be involved in aging (Montesanto et al., 2013). Genes implicated in inflammatory pathways may be associated with longevity, as was demonstrated in a case-control study in which a homozygous genotype of the RAGE gene was more frequently found in male long-lived subjects (Falcone et al., 2013). A study in German long-lived cases and younger controls observed that cases were less likely to be deficient in complement C4 long genes, suggesting a potential role of immunity in lifespan (Flachsbart et al., 2014). Finally, a study in Danish individuals observed that genetic variation in nine sub-processes of DNA damage response and repair,

Please cite this article in press as: Shadyab, A.H., LaCroix, A.Z., Genetic factors associated with longevity: A review of recent findings. Ageing Res. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2014.10.005

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Table 1 Recent findings on genetic factors associated with longevity. First author

Study design

Sample characteristics

Aging phenotype

Gene(s)

Comments

Garatachea

Candidate gene association study

Age ≥100 yrs

APOE

␧4 allele negatively associated with longevity in all three cohorts in sex-adjusted analyses (OR: 0.55, 95% CI: 0.33–0.94; OR: 0.41, 95% CI: 0.18–0.99; OR: 0.35, 95% CI: 0.26–0.57 in Spanish, Italian, and Japanese cohorts, respectively)␧2 allele positively associated with longevity in Italians (OR: 2.14, 95% CI: 1.18, 3.45) and Japanese (OR: 1.81, 95% CI: 1.25–2.63)

Beekman

Linkage study in sibling pairs and candidate gene association study in subgroup from Genetics of Healthy Aging Study

Spanish cohort: 175 centenarians (100–111 yrs, 82% female); 1081 healthy controls (20–85 yrs, 58% female)Italian cohort: 79 healthy centenarians (100–104 yrs, 51% female); 597 healthy controls (27–81 yrs, 53% female)Japanese cohort: 742 centenarians (100–116 yrs, 84% female); 499 healthy controls (23–59 yrs, 71% female) 2118 nonagenarian sibling pairs (mean age 93 yrs; 30% male) from 11 European countries in linkage analysis1228 unrelated nonagenarians and 1907 geographically matched controls in association analysis

Age ≥90 yrs

APOE, FOX03A, FOX1

Schupf

Candidate gene association study from the Long Life Family Study

2307 offspring (mean age = 61 yrs; 58% female) of long-lived persons and 764 spouse controls (mean age = 61 yrs; 47% female)

Familial longevity (offspring of long-lived person)

APOE, TOMM40

Deelen

GWAS meta-analysis with replication

7729 cases (≥85 yrs) and 16,121 controls (<65 yrs) from 14 studies in seven European countries for meta-analysis; replication with 13,060 cases and 61,156 controls. Subset analysis in 5406 cases ≥90 yrs and 15,112 controls <65 yrs

Age ≥90 yrs

TOMM40/APOE/APOC1, FOX03A

Tindale

Candidate gene association study

Nested case-control study from Honolulu Heart Program/Honolulu Asia Aging Study

Age ≥85 yrs with no self-reported history of cancer, CVD, diabetes, major pulmonary disease, or Alzheimer’s disease Case: surviving beyond the upper 1% of the US 1910 birth cohort-specific survival; ≥95 yrsControl: died near mean for 1910 cohort-specific survival (77 yrs)

APOE

Morris

Yang

Candidate gene association study

Li

Meta-analysis

376 cases aged 85–108 yrs (68% female) and 376 controls aged 41–54 yrs (61% female) all of European ancestry 213 cases (of whom 176 had died [mean age at death = 98 yrs] and 37 were still alive [mean age = 99 yrs]) and 402 dead controls (mean age at death = 79 yrs). All American men of Japanese ancestry 380 cases (mean age 95 yrs; 54% female) and 283 controls (mean age 53 yrs; 54% female) of Han Chinese descent Eight studies with 4199 participants

Four regions associated with familial longevity, including 19q13.11–q13.32. APOE ␧2 and ␧4 alleles explained linkage at this region. Linkage at 14q11.2, 17q12–q22, and 19p13.3–p13.11 not explained by common variantsNo evidence for linkage to FOX03A or FOX1. FOX01 not associated with female longevity ␧2 allele of APOE more frequent (OR 1.5 [95% CI 1.1–1.9]), ␧4 allele (OR 0.75 [95% CI 0.6–0.9]) of APOE and G allele of TOMM40 (OR 0.70 [95% CI 0.6–0.9]) less frequent in offspring than controls in adjusted models rs4420638 on chromosome 19q13.32 (TOMM40/APOE/APOC1 locus) associated with longevity (OR 0.72, p = 3.4 × 10−36 ). No gender effect observedrs2149954 (T) (novel locus) on chromosome 5q33.3 associated with surviving to ≥90 yrs (OR 1.10, p = 1.74 × 10−8 )FOX03A moderately associated with survival to ≥90 yrs (p = 1.35 × 10−4 ) 17 rare variants only in cases, and 11 in controls; four in both groups. No excess of rare APOE variants in cases. seven nonsynonymous rare variants overall No SNP significantly associated with longevity

Nijati

Candidate gene association study

100 nonagenarians (39% female), 65 centenarians (29% female), 112 controls (53% female) aged 65–70 yrs who died of natural causes with no relations surviving to >70 yrs in most recent two generations. All from Xinjiang, China

ATF4, CBL, CDKN2B, EXO1, JUN (insulin signaling pathway genes)

Age ≥90 yrs

CETP

No SNP in the promoter region of the CETP gene associated with longevity

Age ≥90 yrs

CETP

Age ≥90 yrs, age ≥100 yrs

GNB3 C825 T and eNOS polymorphisms

No difference in 1405V (rs5882) polymorphism or Taq1B (rs708272) polymorphism between longevity and control groups Significant differences in frequencies of genotypes and alleles of GNB3 825C/T between groups. Genotype CC more common in controls. Significant genotypic differences for eNOS, with genotype TT higher in controls

Please cite this article in press as: Shadyab, A.H., LaCroix, A.Z., Genetic factors associated with longevity: A review of recent findings. Ageing Res. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2014.10.005

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Study design

Sample characteristics

Aging phenotype

Gene(s)

Comments

Montesanto

Candidate gene association study

763 subjects aged 19–107 yrs (55% female) from Calabria, Italy. 321 cases and 442 controls

Age ≥91 yrs (women) and ≥88 yrs men

NOS1, NOS2, NOS3

Falcone

Candidate gene association study

Age ≥90 yrs

RAGE

Flachsbart

Candidate gene association study

119 cases (mean age 93 yrs, range 90–106; 76% female), 135 controls (mean age 62 yrs, range 18–80; 59% female). All Italian 700 cases (94–110 yrs), 900 controls (19–75 yrs). All German

Age ≥90 yrs

C4

Debrabant

Candidate gene association study

1089 cases (92–94 yrs; 71% female) from Danish 1905 Cohort Study. 736 controls (46–55 yrs; 50% female) from Study of Middle-Aged Danish Twins

Age ≥90 yrs

Lee

Family-based GWAS and linkage study from Long-Life Family Study

4289 subjects (1418 probands, 2871 offspring; mean age 70.1 yrs, range 24–110 yrs; 55% female). Subjects from Boston, New York, Pennsylvania, & Denmark

Leukocyte telomere length

592 SNPs from 77 genes in nine sub-processes of DNA damage response and repair (e.g., base and nucleotide excision repair, mismatch repair, double-strand break repair, etc.) DKK2, PAPSS1, TERC, MYNN, OBFC1

NOS1 rs1879417 associated with longevity. NOS3 rs10277237 associated with functional activity measured by index of activities of daily living In promoter region of RAGE gene, AA genotype more common in male cases than male controls. AT more common in middle-aged males No significant differences in number of C4A, C4B, or C4S genes between cases and controls. Deficiency in long C4 genes more frequently identified in controls than cases Test of all SNPs associated with longevity (p = 9.9 × 10−5 ). No specific sub-process significantly associated with longevity

Raule

Candidate gene association study from Genetics of Healthy Aging Study

2086 cases and 2153 controls matched on sex and geographic origin. All of European descent

Age ≥90

Mitochondrial DNA

Gentschew

Candidate gene association study

Age ≥95 yrs

SOD1, SOD2, SOD3

Ganna

Prospective

Time to death

707 SNPs

Those in highest quartile of genetic score had 10% increased hazard of death than those in first quartile, or 10.8 months shorter median survivalGenetic score associated with age at death in those who died between 80–89 yrs

Sebastiani

Meta-analysis

1612 cases (mean age 99 yrs, range 95–109 yrs; 75% female) and 1104 control subjects (mean age 67 yrs, range 60–75 yrs) matched on ancestry, gender, geographical origin. All German 9076 participants from the Swedish TwinGene study (mean baseline age 65.1 yrs; mean age at death 77.9 yrs; 53% female); 5976 from Rotterdam I Study (mean baseline age 69.4 yrs; mean age at death 83.5 yrs; 59% female) Elixir Pharmaceutical Longevity Study, Japanese Centenarian Study, Long-Life Family Study, New England Centenarian Study, Southern Italian Centenarian Study

Age ≥95 yrs

281 SNPs

128 SNPs significant with 6% false discovery rate, including genes associated with Alzheimer’s disease (TOMM40/APOE; LMNA; WRN) and coronary artery disease (SOD2; XDH; GIP)

Strongest GWAS signal in a set of five SNPs in 4q25 (near DKK2 and PAPSS1 genes) associated with telomere length17q23.3 and 10q11.21 had linkage with telomere length (candidate gene at these loci included CEP95 and SMURF2 and HNRNPF and PRKG1, respectively)TERC, MYNN, OBFC1 associated with telomere length Nonsynonymous mutations within complex I (p = 0.03), III (p = 0.04), and V (p < 0.001) associated with longevity. No association of longevity with synonymous mutations or rRNA or tRNA genesTwo or more mutations in complex I/III or I/V higher in controls (p < 0.05) No association between tested SNPs and longevity in overall sample, in centenarians, or in gender-specific analyses

CVD, cardiovascular disease; CI, confidence interval; OR, odds ratio; rRNA, ribosomal RNA; SNP, single nucleotide polymorphism; tRNA, transfer RNA; yrs, years.

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which are central to genetic stability, was (as an entire pathway) significantly associated with longevity (Debrabant et al., 2014).

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2.3. Genome-wide association studies

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Prior GWAS have failed to show significant associations of genetic variants (besides those in or near APOE) with longevity (Deelen et al., 2011; Nebel et al., 2011; Sebastiani et al., 2012b). This may be due to the complex nature of longevity and healthy aging phenotypes, which may be influenced by a multitude of factors including genes and the environment (e.g., lifestyle behaviors); insufficient sample sizes of long-lived individuals; and modest effects of variants on longevity that cannot be detected at the genome-wide level. A previous meta-analysis of GWAS from four prospective studies comparing Caucasians surviving to age 90 years or older and controls who died between the ages of 55 and 80 years found that none of the SNP-longevity associations reached the pre-specified level of significance of p < 5 × 10−8 (Newman et al., 2010). However, in a recent meta-analysis of 14 studies among European cohorts, a novel locus, rs2149954 on chromosome 5q33.3, was significantly associated with survival to ≥90 years of age (Deelen et al., 2014); an association with rs4420638 on chromosome 19q13.32, the TOMM40/APOE/APOC1 locus, was also found. Carriers of the minor allele of rs2149954 had a lower risk of all-cause, CVD, and non-CVD mortality. However, examination of publically available GWAS data to search for associations of this novel locus with glucose or fat metabolism did not reveal any pathways that may explain the association with longevity. Longer leukocyte telomere length (LTL) has been associated with increased years of healthy life and may be considered a biomarker of healthy aging (Njajou et al., 2008). A family-based GWAS and linkage analysis of a cohort of healthy, exceptionally long-lived individuals and their offspring identified several genes that may contribute to variation in LTL (Lee et al., 2014). The strongest signal occurred at five SNPs located on chromosome 4q25 between the DKK2 and PAPSS genes. DKK2 may be involved with embryonic development, while mutations in PAPSS are associated with hereditary pancreatitis. However, neither gene has been previously linked to aging or common diseases, and their potential role in longevity remains to be elucidated.

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2.4. The role of mitochondrial DNA in aging

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mtDNA with the nuclear genome explains this paradox is an area of future investigation (De Benedictis et al., 2000; Rose et al., 2001).

2.5. Oxidative stress and longevity The oxidative stress response may play an important role in aging (Dato et al., 2013). Oxidative stress results from an imbalance between the generation of oxidant molecules and the endogenous antioxidant defense response acting against it. Increased generation of ROS with age overwhelms the antioxidant response and imposes a frail state upon the elderly individual, consequently increasing the risk of infection, age-related diseases, disability, and death (Dato et al., 2013; Finkel and Holbrook, 2000). However, maintaining moderate levels of oxidative stress via a mechanism involving downstream ROS signaling may improve the antioxidant stress response and promote longevity in a concept termed mitohormesis (Ristow and Zarse, 2010). Genetic factors may be involved in the oxidative stress response, an evolutionarily conserved pathway. The superoxidase dismutases (SODs) are a class of antioxidant molecules that protect cells from free radicals and have been previously studied in relation to age-related diseases and longevity. A prior longitudinal study in 1650 participants from the Danish 1905 Cohort identified a SNP (rs4880) in the SOD2 gene as being associated with variation in human lifespan, with individuals carrying the C allele having reduced mortality compared to individuals who do not carry this allele (Soerensen et al., 2009). However, in a recent case-control study among Germans of exceptional age, 19 SNPs (including rs4880) from three SOD genes (SOD1, SOD2, SOD3) were not significantly associated with longevity (Gentschew et al., 2013). These inconsistent findings may be attributed to differences in study design (i.e., retrospective vs. prospective), age ranges of the populations under study, and population-specific effects. Since genetic variants may exert small to moderate effects on human longevity, additional prospective investigations with large sample sizes are needed to elucidate the role of genetic variation in superoxidase mutases in human longevity.

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The role of mitochondrial DNA (mtDNA) variability in human longevity was covered in a recent review (Sevini et al., 2014). Mitochondria are central to energy production via oxidative phosphorylation (OXPHOS) and are also involved in the regulation of cellular metabolism and apoptosis. Furthermore, mitochondria produce and regulate reactive oxygen species (ROS), which have been identified as a cause of aging resulting from DNA damage (Finkel and Holbrook, 2000; Sevini et al., 2014). A recent study found that nonsynonymous mtDNA mutations at OXPHOS complexes I, III, and V are associated with longevity and have population-specific effects (Raule et al., 2014). For example, mutations in complex I were more frequent in the nonagenarian group than the control group in Finns, but the opposite pattern was observed in Danes and southern Europeans. In the overall cohort, the co-occurrence of mutations in both complexes I and III or I and V was more frequent in controls than nonagenarians. An additional finding was that the frequency of mtDNA mutations associated with degenerative diseases was more common in nonagenarians than controls, including a mutation in the mitochondria tRNA(gln) gene previously associated with AD, which was twice as likely to be found in nonagenarians. Whether the interaction of

Longevity may represent a complex, polygenic trait that is influenced by the interactions of multiple genetic variants. This hypothesis was recently tested in a study among two longitudinal cohorts from Sweden and the Netherlands, in which a genetic risk score composed of >700 SNPs related to common traits (e.g., blood pressure) and diseases (e.g., diabetes), was tested for its association with variation in human lifespan (Ganna et al., 2013). The genetic risk score was significantly associated with time-to-death, with stronger associations in older individuals (i.e., 80–89 years) but not extreme ages at death. These findings lie in contrast to those of a prior study which found that a genetic model consisting of 281 SNPs has increased sensitivity in distinguishing cases from controls at the oldest ages (85% sensitivity at age >105 years), consistent with the hypothesis that the genetic contribution of longevity is more important at extreme ages (Sebastiani et al., 2012b). In a recent meta-analysis among five case-control studies, 128 of these 281 SNPs were found to be significantly associated with exceptional longevity; these included SNPs associated with AD and coronary heart disease (Sebastiani et al., 2013). Taken together, the findings from these studies suggest that interactions, rather than individual effects, of genetic variants may be more important in extending human lifespan.

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2.7. Study design issues Studies on genetic factors associated with longevity use a variety of study designs (Table 1) with the candidate gene association study, the most commonly used design. However, these studies are limited by the selection of an appropriate control group, which is usually a group of younger and living individuals. A control group matched on birth cohort to the cases would render a stronger study design, as it would control for differences in environmental factors and life experiences (Newman and Murabito, 2013). A prospective design with genetic data on individuals in midlife with followup into old age would also circumvent the challenges inherent in case-control designs and would allow prediction of genetic factors contributing to diverse aging phenotypes, which to date has not been done. Recent studies on genetic factors and longevity have predominantly defined this aging phenotype as attaining 90 years of age or above. However, limited studies have evaluated healthy aging. While attaining longevity is important, reaching old age with intact physical and cognitive function and free of chronic diseases is more important from a public health perspective. It may also be worthwhile for future studies to evaluate the genetic basis of aging separately in males and females, which is especially important given the longer lifespan of females. 3. Conclusions Recent studies elucidating the genetic basis of longevity have revealed important insights and provided support for several biological pathways that may contribute to the aging process, including NO production, DNA damage response and repair, and oxidative phosphorylation. However, to date, only variants of APOE and FOXO3A have been consistently associated with longevity in GWAS and linkage and candidate gene association studies. While genetic variants of genes such as APOE may be important in achieving longevity, it is also possible that longevity is a polygenic trait influenced by joint effects of multiple genetic variants. Further studies in diverse populations are currently needed to confirm and extend these findings. These studies would greatly benefit from the following elements: (1) large sample sizes of exceptionally longlived individuals; (2) controls matched to cases on birth cohort; (3) characterization of rare variants of genes that may be associated with longevity; (4) inclusion of different aging phenotypes; and (5) analysis of gender differences. Uncited reference Njajou et al., 2009. References Anselmi, C.V., Malovini, A., Roncarati, R., Novelli, V., Villa, F., Condorelli, G., Bellazzi, R., Puca, A.A., 2009. Association of the FOXO3A locus with extreme longevity in a Southern Italian centenarian study. Rejuvenation Res. 12, 95–104. Barzilai, N., Atzmon, G., Schechter, C., Schaefer, E.J., Cupples, A.L., Lipton, R., Cheng, S., Shuldiner, A.R., 2003. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J. Am. Med. Assoc. 290, 2030–2040. Beekman, M., Blanché, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., Flachsbart, F., Christiansen, L., De Craen, A.J., Kirkwood, T.B., Rea, I.M., Poulain, M., Robine, J.M., Valensin, S., Stazi, M.A., Passarino, G., Deiana, L., Gonos, E.S., Paternoster, L., Sørensen, T.I., Tan, Q., Helmer, Q., van den Akker, E.B., Deelen, J., Martella, F., Cordell, H.J., Ayers, K.L., Vaupel, J.W., Törnwall, O., Johnson, T.E., Schreiber, S., Lathrop, M., Skytthe, A., Westendorp, R.G., Christensen, K., Gampe, J., Nebel, A., Houwing-Duistermaat, J.J., Slagboom, P.E., Pranceschi, C., GEHA consortium, 2013. Genome-wide linkage analysis for human longevity: genetics of Healthy Ageing Study. Ageing Cell 12, 184–193. Bell, C.L., Chen, R., Masaki, K., Yee, P., He, Q., Grove, J., Donlon, T., Curb, J.D., Willcox, D.C., Poon, L.W., Willcox, B.J., 2014. Late-life factors associated with healthy aging in older men. J. Am. Geriatr. Soc. 62, 880–888.

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