Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways

Kojima, Toshio; Kamei, Hidehiko; Aizu, Tomoyuki; Arai, Yasumichi; Takayama, M.; Nakazawa, S; Ebihara, Yoshinori; Inagaki, Hiroki; Masui, Yukie; Gondo, Yasuyuki; Sakaki, Yoshiyuki; Hirose, Nobuyoshi

doi:10.1016/j.exger.2004.05.007

Cited by 97 publications

(71 citation statements)

References 13 publications

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“…There has been some prior work linking genes in the IIS pathway to human longevity (36,37) including an interesting recent report by Suh et al (38), which links functionally significant IGF-1 receptor mutations to exceptional longevity, but we have not found any published reports of association between FOXO genes and human longevity. Prior studies have found links between FOXO genes and other aging phenotypes, including 4-year survival and stroke risk (39) as well as premature menopause (40).…”

mentioning

confidence: 40%

FOXO3A genotype is strongly associated with human longevity

Willcox

Donlon²,

He³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

854

690

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Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/ IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P ‫؍‬ 0.00009; adjusted P ‫؍‬ 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.gene ͉ insulin ͉ healthy aging ͉ disease ͉ disability

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mentioning

confidence: 40%

FOXO3A genotype is strongly associated with human longevity

Willcox

Donlon²,

He³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

854

690

View full text Add to dashboard Cite

show abstract

“…These authors found substantial gender differences in the independent effects and showed that the positive effects of FOXO3A and negative effects of FOXO1A largely compensate each other, although FOXO3A has a stronger impact (Zeng et al ., 2010). Others have also revealed the importance of genetic variations in the IIS pathway in long‐lived individuals from Italian, Japanese, Ashkenazi Jewish, or Dutch ethnicity (Arai et al ., 2001; Bonafe et al ., 2003; Kojima et al ., 2004; Kuningas et al ., 2007; Suh et al ., 2008; Pawlikowska et al ., 2009). A meta‐analysis comprising 11 independent case–control studies and 5241 cases from different ethnic groups revealed five FOXO3A polymorphisms as associated with longevity: rs2802292, rs2764264, rs13217795, rs1935949, and rs2802288 (Bao et al ., 2014).…”

Section: Population Studiesmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…In addition, these mice do not develop diabetes or glucose intolerance and, importantly, live 18% longer than wild-type control mice (Bluher et al, 2002;. Studies of centenarians have shown that greatly enhanced insulin sensitivity is strongly correlated with longevity in this unique population 2001;Kojima et al, 2004;van Heemst et al, 2005).…”

Section: Growth Hormone/insulin-like Growth Factor 1/insulinmentioning

confidence: 97%

Hormonal regulation of longevity in mammals

Brown‐Borg

2007

Ageing Research Reviews

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Multiple biological and environmental factors impact the life span of an organism. The endocrine system is a highly integrated physiological system in mammals that regulates metabolism, growth, reproduction, and response to stress, among other functions. As such, this pervasive entity has a major influence on aging and longevity. The growth hormone, insulin-like growth factor-1 and insulin pathways have been at the forefront of hormonal control of aging research in the last few years. Other hormones, including those from the thyroid and reproductive system have also been studied in terms of life span regulation. The relevance of these hormones to human longevity remains to be established, however the evidence from other species including yeast, nematodes, and flies suggest that evolutionarily well-conserved mechanisms are at play and the endocrine system is a key determinant.

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Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways

Cited by 97 publications

References 13 publications

FOXO3A genotype is strongly associated with human longevity

FOXO3A genotype is strongly associated with human longevity

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Hormonal regulation of longevity in mammals

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