Genetic Signatures of Exceptional Longevity in Humans

Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Science (Impact Factor: 33.61). 07/2010; 2010. DOI: 10.1126/science.1190532
Source: PubMed


Healthy aging is thought to reflect the combined influence of environmental factors (lifestyle choices) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity (EL) in 1055 centenarians and 1267 controls. Using these data, we built a genetic model that includes 150 single-nucleotide polymorphisms (SNPs) and found that it could predict EL with 77% accuracy in an independent set of centenarians and controls. Further in silico analysis revealed that 90% of centenarians can be grouped into 19 clusters characterized by different combinations of SNP genotypes-or genetic signatures-of varying predictive value. The different signatures, which attest to the genetic complexity of EL, correlated with differences in the prevalence and age of onset of age-associated diseases (e.g., dementia, hypertension, and cardiovascular disease) and may help dissect this complex phenotype into subphenotypes of healthy aging.

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    • "In the literature, the few approaches to multivariate SNP analysis on a genome-wide scale mainly rely on two methodological frameworks: penalized logistic regression [10-12] and Bayesian analysis [13]. In the first case, SNPs are modelled as discrete variables from the finite domain {0,1,2} (where 0 usually encodes the homozygous pair of minor alleles, 1 the heterozygous pair and 2 the homozygous pair of major alleles) and a log-additive model of genetic effect on the disease is assumed. "
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    ABSTRACT: Multifactorial diseases arise from complex patterns of interaction between a set of genetic traits and the environment. To fully capture the genetic biomarkers that jointly explain the heritability component of a disease, thus, all SNPs from a genome-wide association study should be analyzed simultaneously. In this paper, we present Bag of Naïve Bayes (BoNB), an algorithm for genetic biomarker selection and subjects classification from the simultaneous analysis of genome-wide SNP data. BoNB is based on the Naïve Bayes classification framework, enriched by three main features: bootstrap aggregating of an ensemble of Naïve Bayes classifiers, a novel strategy for ranking and selecting the attributes used by each classifier in the ensemble and a permutation-based procedure for selecting significant biomarkers, based on their marginal utility in the classification process. BoNB is tested on the Wellcome Trust Case-Control study on Type 1 Diabetes and its performance is compared with the ones of both a standard Naïve Bayes algorithm and HyperLASSO, a penalized logistic regression algorithm from the state-of-the-art in simultaneous genome-wide data analysis. The significantly higher classification accuracy obtained by BoNB, together with the significance of the biomarkers identified from the Type 1 Diabetes dataset, prove the effectiveness of BoNB as an algorithm for both classification and biomarker selection from genome-wide SNP data. Source code of the BoNB algorithm is released under the GNU General Public Licence and is available at
    BMC Bioinformatics 09/2012; 13 Suppl 14(Suppl 14):S2. DOI:10.1186/1471-2105-13-S14-S2 · 2.58 Impact Factor
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    • "The second condition necessary and/or sufficient for exceptional longevity is the presence of factors that uniquely protect against common serious diseases [26]. Association studies have identified several genetic characteristics associated with longevity [27]–[29]. "
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    ABSTRACT: Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.
    PLoS ONE 07/2012; 7(7):e41572. DOI:10.1371/journal.pone.0041572 · 3.23 Impact Factor
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    • "Healthy centenarians are ‘expert survivors’ with important lessons to share, in particular regarding the most modifiable lifestyle factor: the diet. However, it is necessary to emphasize that several lines of evidence suggest that the genetic contribution to a healthy life span in populations with exceptional longevity may be greater than that seen in the general population [14,15]. A recent study on a cohort of 477 Ashkenazi Jewish centenarians with exceptional longevity reported that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle [16]. "
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    ABSTRACT: Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.
    Immunity & Ageing 04/2012; 9(1):9. DOI:10.1186/1742-4933-9-9 · 3.54 Impact Factor
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