Genes and Longevity: Lessons From Studies of Centenarians

Yashin, Anatoli I.; Benedictis, G. De; Vaupel, James W.; Tan, Qihua; Andreev, Kirill; Iachine, Ivan A.; Bonafè, Massimiliano; Valensin, Silvana; Luca, María De; Carotenuto, L.; Franceschi, Claudio

doi:10.1093/gerona/55.7.b319

Cited by 72 publications

(76 citation statements)

References 27 publications

(34 reference statements)

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“…The statistical method we are going to apply is based on a relative risk approach that has been recently proposed and described by Yashin et al (1998Yashin et al ( , 1999bYashin et al ( , 2000, Tan et al (2001b). We define the relative risk of one observed genotype r as the ratio of hazard of death for carriers, m (x , r), to that for the non-carriers or the baseline hazard, m 0 (x ).…”

Section: Methodsmentioning

confidence: 99%

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene)

Tan

Bellizzi

Rose

et al. 2002

Mechanisms of Ageing and Development

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A new method based on the recently developed relative risk approach is introduced, and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10, as defined according to the number of repeats) may contribute in reducing or increasing the hazard of death with different patterns of influences. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity. #

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Section: Methodsmentioning

confidence: 99%

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene)

Tan

Bellizzi

Rose

et al. 2002

Mechanisms of Ageing and Development

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“…Recent progress in the search for candidate aging genes in centenarian studies has been significantly helped by the availability of more sensitive statistical techniques [39,40]. For example, an allele-specific association with longevity was found for SOD2 [41] due to the increased sensitivity of the relative risk method [42,43] over the gene frequency method [41].…”

Section: Discussionmentioning

confidence: 99%

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

Bergman

Atzmon

et al. 2005

PLoS Comput Biol

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An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the ''oldest old'' Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows diseaserelated genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidatebuffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.

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“…In the frailty modeling, one assumes that the unobserved frailty z follows a gamma-distribution with mean 1 and variance σ 2 [42,43], so that the genotype specific survival functions in (2) become (4) σ 2 has been estimated when applying the above model to genotype data in marker-longevity association studies [38,44,45] but with large variations due to small sample sizes. A higher 2 σ is expected to bring about larger variation in the unobserved frailty and thus more uncertainty in individual survival, even if they carry the same genotype.…”

Section: The Parametric Approachmentioning

confidence: 99%

Multidisciplinary Approaches in Genetic Studies of Human Aging and Longevity

Tan¹,

Yashin²,

Christensen³

et al. 2004

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Abstract:The amount of research on human aging and longevity has been growing rapidly in recent years. Multidisciplinary approaches, which integrate classic population genetics methods with the principles of epidemiological and demographic investigation, are emerging as powerful tools for disentangling the complex gene network which modulates human lifespan. We try to summarize the different approaches and discuss the various aspects concerning their applications in studies of human aging and longevity. We also discuss the significance of the newly emerging DNA chip technology and its implications by highlighting new research topics. In fact, with the entering of the post-genomic era, hints given by observational studies, and thus founded on statistical evidence, can be exploited to cast light upon biological pathways crucial in aging and longevity.

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Genes and Longevity: Lessons From Studies of Centenarians

Cited by 72 publications

References 27 publications

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene)

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene)

Buffering Mechanisms in Aging: A systems approach towards uncovering the genetic component of aging

Multidisciplinary Approaches in Genetic Studies of Human Aging and Longevity

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