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The quest for genetic determinants of human longevity: challenges and insights

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TLDR
Large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress in human studies of longevity.
Abstract
Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

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Citations
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Journal ArticleDOI

Biodemography of human ageing.

TL;DR: Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival — and healthy survival — to even greater ages.
Journal ArticleDOI

FOXO3A genotype is strongly associated with human longevity

TL;DR: Long-lived men 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.
Journal ArticleDOI

Association of FOXO3A variation with human longevity confirmed in German centenarians

TL;DR: This study investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provided evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age, and confirmed the initial discovery in the Japanese sample.
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Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

TL;DR: The mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals, and compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.
References
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Journal ArticleDOI

Modest implication of interleukin-6 promoter polymorphisms in longevity.

TL;DR: A modest, but significant, increase in the frequency of interleukin-6 -174GG homozygotes with age is found suggesting that this genotype is advantageous for longevity.
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Association of mutations in the hemochromatosis gene with shorter life expectancy.

TL;DR: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy.
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Longevity and carrying the C282Y mutation for haemochromatosis on the HFE gene: case control study of 492 French centenarians

TL;DR: Genotypes that increase the concentrations of iron for transport and storage may be associated with an increased risk for common diseases, such as cancers and cardiovascular diseases, and for inflammatory and infectious conditions.
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The allele (A)-110 in the promoter region of the HSP70-1 gene is unfavorable to longevity in women

TL;DR: Investigating whether the gene pool relevant to the (A/C)-110 polymorphism in the promoter region of the HSP70-1 gene changes as the population ages and survival selection occurs showed that the ( A)-110 allele is unfavorable to longevity in females.
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