Browsing by Subject "Longevity"

Now showing 1 - 20 of 50
  • Thumbnail Image
    ItemOpen Access
    A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.
    (J Gerontol A Biol Sci Med Sci, 2010-05) Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L; Garcia, Melissa E; Slagboom, P Eline; Christensen, Kaare; Arnold, Alice M; Aspelund, Thor; Aulchenko, Yurii S; Benjamin, Emelia J; Christiansen, Lene; D'Agostino, Ralph B; Fitzpatrick, Annette L; Franceschini, Nora; Glazer, Nicole L; Gudnason, Vilmundur; Hofman, Albert; Kaplan, Robert; Karasik, David; Kelly-Hayes, Margaret; Kiel, Douglas P; Launer, Lenore J; Marciante, Kristin D; Massaro, Joseph M; Miljkovic, Iva; Nalls, Michael A; Hernandez, Dena; Psaty, Bruce M; Rivadeneira, Fernando; Rotter, Jerome; Seshadri, Sudha; Smith, Albert V; Taylor, Kent D; Tiemeier, Henning; Uh, Hae-Won; Uitterlinden, André G; Vaupel, James W; Walston, Jeremy; Westendorp, Rudi GJ; Harris, Tamara B; Lumley, Thomas; van Duijn, Cornelia M; Murabito, Joanne M
    BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
  • Thumbnail Image
    ItemOpen Access
    Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.
    (PLoS Genet, 2014-01) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Christensen, Kaare; Schupf, Nicole; Province, Michael A; Yashin, Anatoli I
    Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.
  • Thumbnail Image
    ItemOpen Access
    An age-structured extension to the vectorial capacity model.
    (PLoS One, 2012) Novoseltsev, Vasiliy N; Michalski, Anatoli I; Novoseltseva, Janna A; Yashin, Anatoliy I; Carey, James R; Ellis, Alicia M
    BACKGROUND: Vectorial capacity and the basic reproductive number (R(0)) have been instrumental in structuring thinking about vector-borne pathogen transmission and how best to prevent the diseases they cause. One of the more important simplifying assumptions of these models is age-independent vector mortality. A growing body of evidence indicates that insect vectors exhibit age-dependent mortality, which can have strong and varied affects on pathogen transmission dynamics and strategies for disease prevention. METHODOLOGY/PRINCIPAL FINDINGS: Based on survival analysis we derived new equations for vectorial capacity and R(0) that are valid for any pattern of age-dependent (or age-independent) vector mortality and explore the behavior of the models across various mortality patterns. The framework we present (1) lays the groundwork for an extension and refinement of the vectorial capacity paradigm by introducing an age-structured extension to the model, (2) encourages further research on the actuarial dynamics of vectors in particular and the relationship of vector mortality to pathogen transmission in general, and (3) provides a detailed quantitative basis for understanding the relative impact of reductions in vector longevity compared to other vector-borne disease prevention strategies. CONCLUSIONS/SIGNIFICANCE: Accounting for age-dependent vector mortality in estimates of vectorial capacity and R(0) was most important when (1) vector densities are relatively low and the pattern of mortality can determine whether pathogen transmission will persist; i.e., determines whether R(0) is above or below 1, (2) vector population growth rate is relatively low and there are complex interactions between birth and death that differ fundamentally from birth-death relationships with age-independent mortality, and (3) the vector exhibits complex patterns of age-dependent mortality and R(0) ∼ 1. A limiting factor in the construction and evaluation of new age-dependent mortality models is the paucity of data characterizing vector mortality patterns, particularly for free ranging vectors in the field.
  • Thumbnail Image
    ItemOpen Access
    Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.
    (Mech Ageing Dev, 2010-05) Kulminski, Alexander M; Culminskaya, Irina; Ukraintseva, Svetlana V; Arbeev, Konstantin G; Land, Kenneth C; Yashin, Anatoli I
    The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln(27) allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.
  • Thumbnail Image
    ItemOpen Access
    Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children.
    (J Gerontol A Biol Sci Med Sci, 2013-07) Kulminski, Alexander M; Arbeev, Konstantin G; Christensen, Kaare; Stallard, Eric; Miljkovic, Iva; Barmada, Michael; Yashin, Anatoliy I
    This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.
  • Thumbnail Image
    ItemOpen Access
    Birth cohort differences in the prevalence of longevity-associated variants in APOE and FOXO3A in Danish long-lived individuals.
    (Exp Gerontol, 2014-09) Nygaard, Marianne; Lindahl-Jacobsen, Rune; Soerensen, Mette; Mengel-From, Jonas; Andersen-Ranberg, Karen; Jeune, Bernard; Vaupel, James W; Tan, Qihua; Christiansen, Lene; Christensen, Kaare
    Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915. Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele (P=0.026) or for the FOXO3A rs7762395 minor allele (P=0.048). For the APOE ε4 allele, the significance is further strengthened when restricting to women (P=0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100years. Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.
  • Thumbnail Image
    ItemOpen Access
    C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms.
    (PLoS One, 2010-07-26) TeKippe, Michael; Aballay, Alejandro
    Reproduction extracts a cost in resources that organisms are then unable to utilize to deal with a multitude of environmental stressors. In the nematode C. elegans, development of the germline shortens the lifespan of the animal and increases its susceptibility to microbial pathogens. Prior studies have demonstrated germline-deficient nematodes to have increased resistance to gram negative bacteria. We show that germline-deficient strains display increased resistance across a broad range of pathogens including gram positive and gram negative bacteria, and the fungal pathogen Cryptococcus neoformans. Furthermore, we show that the FOXO transcription factor DAF-16, which regulates longevity and immunity in C. elegans, appears to be crucial for maintaining longevity in both wild-type and germline-deficient backgrounds. Our studies indicate that germline-deficient mutants glp-1 and glp-4 respond to pathogen infection using common and different mechanisms that involve the activation of DAF-16.
  • Thumbnail Image
    ItemOpen Access
    Cancer and longevity--is there a trade-off? A study of cooccurrence in Danish twin pairs born 1900-1918.
    (J Gerontol A Biol Sci Med Sci, 2012-05) Christensen, Kaare; Pedersen, Jacob K; Hjelmborg, Jacob VB; Vaupel, James W; Stevnsner, Tinna; Holm, Niels V; Skytthe, Axel
    BACKGROUND: Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin. METHODS: A total of 4,354 twin pairs born 1900-1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943-2008 through the Danish Cancer Registry. RESULTS: The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and, 2,524 cancers were diagnosed. A negative association between age at death of a twin and cancer incidence in the cotwin was found in the overall analyses as well as in the subanalysis stratified on sex, zygosity, and random selection of one twin from each twin pair. CONCLUSIONS: This study did not find evidence of a cancer-longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity.
  • Thumbnail Image
    ItemOpen Access
    Cumulative early life adversity predicts longevity in wild baboons.
    (Nat Commun, 2016-04-19) Tung, J; Archie, EA; Altmann, J; Alberts, SC
    In humans and other animals, harsh circumstances in early life predict morbidity and mortality in adulthood. Multiple adverse conditions are thought to be especially toxic, but this hypothesis has rarely been tested in a prospective, longitudinal framework, especially in long-lived mammals. Here we use prospective data on 196 wild female baboons to show that cumulative early adversity predicts natural adult lifespan. Females who experience ≥3 sources of early adversity die a median of 10 years earlier than females who experience ≤1 adverse circumstances (median lifespan is 18.5 years). Females who experience the most adversity are also socially isolated in adulthood, suggesting that social processes partially explain the link between early adversity and adult survival. Our results provide powerful evidence for the developmental origins of health and disease and indicate that close ties between early adversity and survival arise even in the absence of health habit and health care-related explanations.
  • Thumbnail Image
    ItemOpen Access
    Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.
    (Exp Gerontol, 2011-11) Skytthe, A; Valensin, S; Jeune, B; Cevenini, E; Balard, F; Beekman, M; Bezrukov, V; Blanche, H; Bolund, L; Broczek, K; Carru, C; Christensen, K; Christiansen, L; Collerton, JC; Cotichini, R; de Craen, AJM; Dato, S; Davies, K; De Benedictis, G; Deiana, L; Flachsbart, F; Gampe, J; Gilbault, C; Gonos, ES; Haimes, E; Hervonen, A; Hurme, MA; Janiszewska, D; Jylhä, M; Kirkwood, TBL; Kristensen, P; Laiho, P; Leon, A; Marchisio, A; Masciulli, R; Nebel, A; Passarino, G; Pelicci, G; Peltonen, L; Perola, M; Poulain, M; Rea, IM; Remacle, J; Robine, JM; Schreiber, S; Scurti, M; Sevini, F; Sikora, E; Skouteri, A; Slagboom, PE; Spazzafumo, L; Stazi, MA; Toccaceli, V; Toussaint, O; Törnwall, O; Vaupel, JW; Voutetakis, K; Franceschi, C; GEHA consortium
    In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.
  • Thumbnail Image
    ItemOpen Access
    Diversity of ageing across the tree of life.
    (Nature, 2014-01-09) Jones, Owen R; Scheuerlein, Alexander; Salguero-Gómez, Roberto; Camarda, Carlo Giovanni; Schaible, Ralf; Casper, Brenda B; Dahlgren, Johan P; Ehrlén, Johan; García, María B; Menges, Eric S; Quintana-Ascencio, Pedro F; Caswell, Hal; Baudisch, Annette; Vaupel, James W
    Evolution drives, and is driven by, demography. A genotype moulds its phenotype's age patterns of mortality and fertility in an environment; these two patterns in turn determine the genotype's fitness in that environment. Hence, to understand the evolution of ageing, age patterns of mortality and reproduction need to be compared for species across the tree of life. However, few studies have done so and only for a limited range of taxa. Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga. Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species, including increasing, constant, decreasing, humped and bowed trajectories for both long- and short-lived species. This diversity challenges theoreticians to develop broader perspectives on the evolution of ageing and empiricists to study the demography of more species.
  • Thumbnail Image
    ItemOpen Access
    Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits.
    (Mech Ageing Dev, 2011-04) Kulminski, Alexander M; Arbeev, Konstantin G; Christensen, Kaare; Mayeux, Richard; Newman, Anne B; Province, Michael A; Hadley, Evan C; Rossi, Winifred; Perls, Thomas T; Elo, Irma T; Yashin, Anatoli I
    We used an approach of cumulative deficits to evaluate the rate of aging in 4954 participants of the Long-Life Family Study (LLFS) recruited in the U.S. (Boston, New York, and Pittsburgh) and Denmark. We used an array of 85 health-related deficits covering major health dimensions including depression, cognition, morbidity, physical performance, and disability to construct several deficit indices (DIs) with overlapping and complementary sets of deficits to test robustness of the estimates. Our study shows that the DIs robustly characterize accelerated rates of aging irrespective of specific of deficits. When a wider spectrum of health dimensions is considered these rates are better approximated by quadratic law. Exponential rates are more characteristic for more severe health dimensions. The aging rates are the same for males and females. Individuals who contracted major diseases and those who were free of them exhibited the same aging rates as characterized by the DI constructed using mild deficits. Unlike health, disability can qualitatively alter the aging patterns of the LLFS participants. We report on systemic differences in health among the LLFS centenarians residing in New York and Boston. This study highlights importance of aggregated approaches to better understand systemic mechanisms of health deterioration in long-living individuals.
  • Thumbnail Image
    ItemOpen Access
    Effects of FOXO genotypes on longevity: a biodemographic analysis.
    (J Gerontol A Biol Sci Med Sci, 2010-12) Zeng, Y; Cheng, L; Chen, H; Cao, H; Hauser, ER; Liu, Y; Xiao, Z; Tan, Q; Tian, XL; Vaupel, JW
    Based on data from 760 centenarians and 1060 middle-age controls (all Han Chinese), this article contributes biodemographic insights and syntheses concerning the magnitude of effects of the FOXO genotypes on longevity. We also estimate independent and joint effects of the genotypes of FOXO1A and FOXO3A genes on long-term survival, considering carrying or not-carrying the minor allele of the single-nucleotide polymorphism of another relevant gene. We found substantial gender differences in the independent effects; positive effects of FOXO3A and negative effects of FOXO1A largely compensate each other if one carries both, although FOXO3A has a stronger impact. Ten-year follow-up cohort analysis shows that at very advanced ages 92-110, adjusted for various confounders, positive effects of FOXO3A on survival remain statistically significant, but no significant effects of FOXO1A alone; G × G interactions between FOXO1A-209 and FOXO3A-310 or FOXO3A-292 decrease survival likelihood by 32%-36% (p < .05); G × E interactions between FOXO1A-209 and regular exercise increase survival likelihood by 31%-32% (p < .05).
  • Thumbnail Image
    ItemOpen Access
    ESTIMATES OF FACTORS DIRECTLY RELATED TO FINE ROOT LONGEVITY USING A HIERARCHICAL BAYESIAN MODEL
    (2008-08-29T18:30:31Z) Zhang, SiYao
    Fine root longevity, measured using minirhizotrons, range from days to years (Hendrick & Pregitzer, 1992; Eissenstat et al., 2000). Although there are several hypotheses that relate to root tissue lifespan (Ryser, 1996), very few long-term studies have examined the factors that may be directly related to survivorship of individual roots. It is known that atmospheric CO2, which is the major greenhouse gas, directly affects plant photosynthesis and water use. As an important plant tissue that acquires water and nutrients, fine roots may limit the forest productivity by limiting plant absorptive capacity under the enriched atmospheric CO2 concentration. Moreover, the turnover time of fine roots, which are the major component of carbon input to the soil carbon pool, may respond to this enriched CO2 effect and thus have impact on belowground carbon balance. Free air CO2 enrichment (FACE) facilities enable research on the effects of elevated atmospheric CO2 concentrations over extended periods of time at ecosystem scale. By using a hierarchical Bayesian model with covariance variable estimates, we were able to identify this CO2 effect as well as several other covariates that correlate with fine root persistence. According to our result, enriched CO2 did not have an immediate effect on fine-root longevity; rather, it increased longevity with time over the 8.2-year study period. Furthermore, fine root longevity increased with soil depth, yet the effects of CO2-enrichment on longevity decreased with increasing depth. Coarser roots and roots grown in plots with higher N-mineralization rate had longer life spans. Nitrogen fertilization enhanced fine-root lifespan only in CO2-enriched plots.
  • Thumbnail Image
    ItemOpen Access
    Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data.
    (Biogerontology, 2011-04) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander M; Yashin, Anatoliy I
    Small sample size of genetic data is often a limiting factor for desirable accuracy of estimated genetic effects on age-specific risks and survival. Longitudinal non-genetic data containing information on survival or disease onsets of study participants for whom the genetic data were not collected may provide an additional "reserve" for increasing the accuracy of respective estimates. We present a novel method for joint analyses of "genetic" (covering individuals for whom both genetic information and mortality/morbidity data are available) and "non-genetic" (covering individuals for whom only mortality/morbidity data were collected) subsamples of longitudinal data. Our simulation studies show substantial increase in the accuracy of estimates in such joint analyses compared to analyses based on genetic subsample alone. Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.
  • Thumbnail Image
    ItemOpen Access
    Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity.
    (Age (Dordr), 2013-04) Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Suchiman, H Eka D; Jacobsen, Rune; McGue, Matt; Stevnsner, Tinna; Bohr, Vilhelm A; de Craen, Anton JM; Westendorp, Rudi GJ; Schreiber, Stefan; Slagboom, P Eline; Nebel, Almut; Vaupel, James W; Christensen, Kaare; Christiansen, Lene
    In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.
  • Thumbnail Image
    ItemOpen Access
    Gender-dependent association of body mass index and waist circumference with disability in the Chinese oldest old.
    (Obesity (Silver Spring), 2014-08) Yin, Zhaoxue; Shi, Xiaoming; Kraus, Virginia B; Brasher, Melanie Sereny; Chen, Huashuai; Liu, Yuzhi; Lv, Yuebin; Zeng, Yi
    OBJECTIVES: To explore associations of BMI and waist circumference (WC) with disability among the Chinese oldest old. METHODS: The 5,495 oldest old in the sixth wave of Chinese Longitudinal Healthy Longevity Study conducted in 2011 were included in this study. Disability was assessed by activities of daily living (ADL); height and weight for BMI and WC were measured; information including socio-demographics, lifestyles, and health status was collected. RESULTS: Generalized additive models analysis showed that the association of BMI/WC with ADL disability was nonlinear. Among the males, logistic regression results supported a "J" shape association between ADL disability with BMI/WC-the highest tertile group in BMI or WC was significantly associated with an increased risk of ADL disability: odds ratio 1.78 (95% confidence interval (CI): 1.26-2.52) for BMI and 2.01 (95% CI: 1.44-2.82) for WC. Among females, an inverse "J" shape association was found, only the lowest tertile group before the cutoff point had an increased risk of ADL disability: odds ratio 1.42 (95%CI: 1.02-1.97) for BMI and 1.47 (95% CI:1.06-2.04) for WC. CONCLUSIONS: Associations of BMI and WC with ADL disability are significant even in the oldest old, but differ between the genders.
  • Thumbnail Image
    ItemOpen Access
    Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.
    (Ann Gerontol Geriatr Res, 2017-06-02) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana V
    BACKGROUND: Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose. PROBLEM: For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations. DATA AND METHODS: We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification. RESULTS: The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation. CONCLUSION: The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.
  • Thumbnail Image
    ItemOpen Access
    Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
    (Aging Cell, 2013-04) Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Friederike; Christiansen, Lene; De Craen, Anton JM; Kirkwood, Tom BL; Rea, Irene Maeve; Poulain, Michel; Robine, Jean-Marie; Valensin, Silvana; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S; Paternoster, Lavinia; Sørensen, Thorkild IA; Tan, Qihua; Helmer, Quinta; van den Akker, Erik B; Deelen, Joris; Martella, Francesca; Cordell, Heather J; Ayers, Kristin L; Vaupel, James W; Törnwall, Outi; Johnson, Thomas E; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi GJ; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J; Slagboom, Pieternella Eline; Franceschi, Claudio; GEHA consortium
    Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
  • Thumbnail Image
    ItemOpen Access
    Health and function of participants in the Long Life Family Study: A comparison with other cohorts.
    (Aging (Albany NY), 2011-01) Newman, Anne B; Glynn, Nancy W; Taylor, Christopher A; Sebastiani, Paola; Perls, Thomas T; Mayeux, Richard; Christensen, Kaare; Zmuda, Joseph M; Barral, Sandra; Lee, Joseph H; Simonsick, Eleanor M; Walston, Jeremy D; Yashin, Anatoli I; Hadley, Evan
    Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.