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1.  Sex Differences in Biological Markers of Health in the Study of Stress, Aging and Health in Russia 
PLoS ONE  2015;10(6):e0131691.
The apparent contradiction that women live longer but have worse health than men, the so called male-female health-survival paradox, is very pronounced in Russia. The present study investigates whether men in Moscow are healthier than women at the level of biomarkers, and whether the associations between biomarkers and subjective health have sex-specific patterns.
Previously collected data in the study of Stress, Aging, and Health in Russia (SAHR, n = 1800) were used to examine sex differences in biomarkers and their associations with physical functioning and self-rated health.
The present study found mixed directions and magnitudes for sex differences in biomarkers. Women were significantly disadvantaged with regard to obesity and waist circumference, whereas men had a tendency toward higher prevalence of electrocardiographic abnormalities. No sex differences were indicated in the prevalence of immunological biomarkers, and mixed patterns were found for lipid profiles. Many biomarkers were associated with physical functioning and general health. Obesity and waist circumference were related to lower physical functioning among females only, while major Q-wave abnormalities with high probabilities of myocardial infarction and atrial fibrillation or atrial flutter were associated with physical functioning and self-rated health among males only.
No clear patterns of sex differences in prevalence of high-risk levels of biomarkers suggest that the male-female health-survival paradox is weaker at the level of health biomarkers. We found some evidence that certain biomarkers reflecting pathophysiological changes in the organism that do not possess acute health risks, but over many years may lead to physical disability, are associated with physical functioning and self-rated health in women, whereas others reflecting more serious life-threatening pathophysiological changes are associated with physical functioning and self-rated health in men.
PMCID: PMC4484801  PMID: 26121035
2.  The nature of behavioural correlates of healthy ageing: a twin study of lifestyle in mid to late life 
Background With the greying of the industrialized world has come increased interest in identifying the modifiable lifestyle factors that promote healthy and successful ageing. Whereas many of the behavioural correlates of late-life morbidity and mortality have been identified, relatively little is known about the origins of individual differences in these factors.
Methods A sample of 12 714 twins, including both members of 3806 pairs of known zygosity, ascertained through the Danish Twin Registry and aged 40 to 80 years, completed a self-report assessment of six lifestyle factors associated with ageing: smoking, drinking, diet and physical, social and intellectual activities. Standard biometric methods were used to analyse the twin data and determine the extent to which individual differences in each of the lifestyle factors are heritable.
Results For each of the six lifestyle factors, the estimate of heritability ranged from 32% (95% CI: 19–42%) for the diet scale to 69% (62–72%) for the smoking measure. Biometric estimates of the contribution of the twins’ common rearing environment were uniformly small (≤6%). There was little evidence that standardized biometric estimates varied by gender or age.
Conclusions Individuals likely construct lifestyles in part to complement and reinforce underlying genetically influenced dispositions and talents. The heritable nature of lifestyle factors implies that the behavioural and genetic contributors to ageing processes are not necessarily conceptually distinct but rather reflect the complexity of gene-environment interplay in ageing.
PMCID: PMC4052129  PMID: 24711605
lifestyle and ageing; twin study; heritability; successful ageing
4.  Academic performance of opposite-sex and same-sex twins in adolescence: A Danish national cohort study 
Hormones and behavior  2015;69:123-131.
Testosterone is an important hormone in the sexual differentiation of the brain, contributing to differences in cognitive abilities between males and females. For instance, studies in clinical populations such as females with congenital adrenal hyperplasia (CAH) who are exposed to high levels of androgens in utero support arguments for prenatal testosterone effects on characteristics such as visuospatial cognition and behaviour. The comparison of opposite-sex (OS) and same-sex (SS) twin pairs can be used to help establish the role of prenatal testosterone. However, although some twin studies confirm a masculinizing effect of a male co-twin regarding for instance perception and cognition it remains unclear whether intra-uterine hormone transfer exists in humans. Our aim was to test the potential influences of testosterone on academic performance in OS twins. We compared ninth-grade test scores and teacher ratings of OS (n = 1812) and SS (n = 4054) twins as well as of twins and singletons (n = 13,900) in mathematics, physics/chemistry, Danish, and English. We found that males had significantly higher test scores in mathematics than females (.06–.15 SD), whereas females performed better in Danish (.33–.49 SD), English (.20 SD), and neatness (.45–.64 SD). However, we did not find that OS females performed better in mathematics than SS and singleton females, nor did they perform worse either in Danish or English. Scores for OS and SS males were similar in all topics. In conclusion, this study did not provide evidence for a masculinization of female twins with male co-twins with regard to academic performance in adolescence.
PMCID: PMC4444512  PMID: 25655669
Twins; Sex-difference; Testosterone; Behavior; Academic performance; Mathematics; School engagement
5.  Genetic Influences on Political Ideologies: Twin Analyses of 19 Measures of Political Ideologies from Five Democracies and Genome-Wide Findings from Three Populations 
Behavior genetics  2014;44(3):282-294.
Almost forty years ago, evidence from large studies of adult twins and their relatives suggested that between 30-60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase “Left-Right”. We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one’s genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits.
PMCID: PMC4038932  PMID: 24569950
Ideology; Politics; GWAS; Attitudes; Authoritarianism
6.  Physical and mental decline and yet rather happy? A study of Danes aged 45 and older 
Aging & mental health  2014;19(5):400-408.
Little is known about whether the feeling of happiness follows the age-related decline in physical and mental functioning. The objective of this study was to analyze differences with age in physical and mental functions and in the feeling of happiness among Danes aged 45 years and older.
Three Danish population-based surveys including 11,307 participants aged 45+ years, of whom 2411 were in the age group of 90+, were conducted in the period 1995–2001. The participation rate in the three surveys was between 63% and 82% and the same design and the same instrument were used. Self-reported mobility, a cognitive composite score, and a depression symptomatology score including a question about happiness were assessed. T-score metric was used to compare across domains and age groups.
Overall, successively older age groups performed worse than the youngest age group (45–49 years), and the estimated linear decline was greater after age 70 than before age 70. For example, when comparing the oldest age group (90+ years) with the youngest, the T-score differences were found to be the largest for the mobility score (men: 40.2, women: 41.4), followed by the cognitive function (men: 22.0, women: 24.9), and the total depression symptomatology score (men: 15.5, women: 17.4). Conversely, the T-score difference in happiness was small (men: 5.6, women: 6.0).
Despite markedly poorer physical and mental functions with increasing age, in this Danish sample age did not seem to affect happiness to a similarly notable extent, although, in this study, cohort and age effects cannot be disentangled.
PMCID: PMC4356733  PMID: 25117759
happiness; cognitive composite score; depression symptomatology; mobility; aging
7.  The heritability of leucocyte telomere length dynamics 
Journal of Medical Genetics  2015;52(5):297-302.
Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition.
We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19–64 years at baseline).
Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects.
This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity.
PMCID: PMC4413805  PMID: 25770094
8.  Musculoskeletal pain and physical functioning in the oldest old 
Little is known about the impact of pain on physical functioning among the oldest-old subjects. In this study, we first examined the associations between number of painful sites and measures of physical functioning reflecting different stages of the disablement process (physical impairment, functional limitation and disability) among nonagenarians aged 92 to 93 years. Second, we described the effect of painful sites on disability during a two year follow-up period.
This study is based on baseline (n=1177) and 2-year follow-up (n=709) data of the nationwide Danish 1905 cohort study. Musculoskeletal pain was assessed as reported pain in back, hips or knees when moving or resting. Physical performance measures included maximum grip strength and habitual walking speed. Disability in performing activities of daily living, was defined as need for assistive device or personal help in transferring, dressing, washing, using toilet and/or walking indoors.
At baseline, the number of painful sites was significantly associated with measured grip strength and walking speed as well as self-reported disability in a step-wise manner; the more sites with pain the poorer the physical functioning. The follow-up analyses showed corresponding but slightly weaker stepwise associations between baseline pain and disability level at follow-up, and indicated that although on the whole, single or multisite pain did not predict the onset of disability, multisite pain increased the risk of developing severe disability.
The findings of this study suggest that musculoskeletal pain in nonagenarians is highly prevalent and associated with poor physical performance and disability.
PMCID: PMC3933514  PMID: 24039015
Pain; Muscle strength; Mobility limitation; Disability; Nonagenarians
9.  Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS) 
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark.
A total of 4,088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8,231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing.
Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p < 5e–8). Of 25 suggestive (5e–8 < p < 1e–5) loci, one known (G6PC2 rs560887, replication p = 5e–5) and one novel (OR10R3P/SPTA1- rs12041363, replication p = 1e–17) loci were replicated (p < 0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1.
The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
PMCID: PMC3965585  PMID: 24405752
Genome-wide association study; Non-enzymatic glycation; Glucose, insulin resistance and diabetes; Premature aging processes
10.  Heritability of and Mortality Prediction With a Longevity Phenotype: The Healthy Aging Index 
Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI’s association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component–based family analysis using a polygenic model.
Cardiovascular Health Study participants with unhealthier index scores (7–10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0–2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
PMCID: PMC3968826  PMID: 23913930
Epidemiology; Genetics; Longevity; Successful aging.
11.  Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly 
JAMA neurology  2014;71(12):1514-1519.
There aregenetic influences on memory ability as we age. but no specific genes have been identified.
To use a cognitive endophenotype. exceptional episodic memory(EEM) performance. derived from nondemented offspring from the Long Life FamilyStudy(LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts
A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis
Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA
Heritability estimates indicated a significant genetic component for E EM (h2 = 0.21; SE = 0.09) Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64) Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ 05) Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SN Ps rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P= .009 and P = .013. respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele. SNP rs6902875 became statistically significant (meta-analysis. P = 6.7 × 10−5) Haplotypeanalysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs48975 74) revealed that the A-A-Chap lotype was significantly associated with episodic memory performance (P = 2.4 × 10−5). This genomic region harbors monooxygenase dopamine β-hydroxylase-1ike 1gene (MOXD1). implicated in the biosynthesis of norepinephrine. which is prominently involved in cognitive functions.
The results provide strong evidence for potential candidate genes related to EE Mon 6q24 Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.
PMCID: PMC4355405  PMID: 25317765
12.  DCAF4, a novel gene associated with leucocyte telomere length 
Journal of Medical Genetics  2015;52(3):157-162.
Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24.
We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
PMCID: PMC4345921  PMID: 25624462
Complex traits; Telomere; cancer: skin; melanoma
13.  A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol 
Genome-wide association analysis on monozygotic twin pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high density lipoprotein (HDL) cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (p = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1 261) which showed a moderate association for the variant (p = .002, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (p = 4.03 × 10−8).
PMCID: PMC4333218  PMID: 23031429
twins; association; lipids; apolipoproteins; interaction
14.  Association study of FOXO3ASNPs and aging phenotypes in Danish oldest-old individuals 
Aging Cell  2014;14(1):60-66.
FOXO3Avariation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3Avariation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3Atagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92–93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3Avariation with ADL (P = 0.044) and bone fracture (P = 0.006). The single-SNP statistics behind the gene-based analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P = 0.054), while ADL did not (P = 0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n = 1279, age 94–100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed.
PMCID: PMC4326903  PMID: 25470651
aging phenotypes; association study; Forkhead box O3; oldest-old; SNPs
15.  Epigenetic signature of birth weight discordance in adult twins 
BMC Genomics  2014;15(1):1062.
A low birth weight has been extensively related to poor adult health outcomes. Birth weight can be seen as a proxy for environmental conditions during prenatal development. Identical twin pairs discordant for birth weight provide an extraordinary model for investigating the association between birth weight and adult life health while controlling for not only genetics but also postnatal rearing environment. We performed an epigenome-wide profiling on blood samples from 150 pairs of adult monozygotic twins discordant for birth weight to look for molecular evidence of epigenetic signatures in association with birth weight discordance.
Our association analysis revealed no CpG site with genome-wide statistical significance (FDR < 0.05) for either qualitative (larger or smaller) or quantitative discordance in birth weight. Even with selected samples of extremely birth weight discordant twin pairs, no significant site was found except for 3 CpGs that displayed age-dependent intra-pair differential methylation with FDRs 0.014 (cg26856578, p = 3.42e-08), 0.0256 (cg15122603, p = 1.25e-07) and 0.0258 (cg16636641, p = 2.05e-07). Among the three sites, intra-pair differential methylation increased with age for cg26856578 but decreased with age for cg15122603 and cg16636641. There was no genome-wide statistical significance for sex-dependent effects on intra-pair differential methylation in either the whole samples or the extremely discordant twins.
Genome-wide DNA methylation profiling did not reveal epigenetic signatures of birth weight discordance although some sites displayed age-dependent intra-pair differential methylation in the extremely discordant twin pairs.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1062) contains supplementary material, which is available to authorized users.
PMCID: PMC4302120  PMID: 25476734
Identical twins; Birth weight discordance; DNA methylation
16.  Religiousness and Religious Coping in a Secular Society: The Gender Perspective 
Journal of religion and health  2014;53(5):1329-1341.
Women are found to be more religious than men and more likely to use religious coping. Only few studies have explored religious gender differences in more secular societies. This population-based study comprised 3,000 Danish men and women (response rate 45 %) between 20 and 40 years of age. Information about demographics, religiousness and religious coping was obtained through a web-based questionnaire. We organized religiousness in the three dimensions: Cognition, Practice and Importance, and we assessed religious coping using the brief RCOPE questionnaire. We found substantial gender differences in both religiousness and religious coping. Nearly, 60 % of the women believed in some sort of spirit or in God compared to 40 % of the men. Generally, both men and women scored low on the RCOPE scale. However, for respondents reporting high levels of religiousness, the proportion of men who scored high in the RCOPE exceeded the proportion of women in using positive and especially negative coping strategies. Also, in a secular society, women are found to be more religious than men, but in a subset of the most religious respondents, men were more inclined to use religious coping. Further studies on religious coping in secular societies are required.
PMCID: PMC4226847  PMID: 23625173
Religion; Religious coping; Gender; Secular society
17.  Best lung function equations for the very elderly selected by survival analysis 
The European respiratory journal  2014;43(5):1338-1346.
We evaluated which equations best predicted the lung function of a cohort of nonagenarians based on which best accounted for subsequent survival.
In 1998, we measured lung function, grip strength and dementia score (Mini Mental State Examination (MMSE)) in a population-based sample of 2262 Danes born in 1905. Mortality was registered to 2011 when only five (0.2%) subjects were alive. In half the cohort, we recorded forced expiratory volume in 1 s (FEV1).
Complete data were available in 592 subjects with results expressed as standardised residuals (SR) using various prediction equations. Cox proportional hazard regression found lower FEV1SR was a predictor of mortality having controlled for MMSE, grip strength and sex. The US National Health and Nutrition Examination Survey (NHANES) III (1999) equations gave a better spread of median survival by FEV1SR quartile: 3.94, 3.65, 3.51 and 2.61 years with a hazard ratio for death of 1, 1.16, 1.32 and 1.60 respectively, compared with equations derived with the inclusion of elderly subjects.
We conclude that extrapolating from NHANES III equations to predict lung function in nonagenarians gave better survival predictions from spirometry than when employing equations derived using very elderly subjects with possible selection bias. These findings can help inform how future lung function equations for the elderly are derived.
PMCID: PMC4226937  PMID: 24488567
18.  Risk of Metabolic Syndrome and Diabetes Among Young Twins and Singletons in Guinea-Bissau 
Diabetes Care  2013;36(11):3549-3556.
Twins in Africa may be at increased risk of metabolic disorders due to strained conditions in utero, including high exposure to infections. We studied metabolic syndrome (MS) and diabetes mellitus (DM) among young twins and singletons in Guinea-Bissau.
The study was cross-sectional and occurred from October 2009 until August 2011 at the Bandim Health Project, a demographic surveillance site in the capital Bissau. Twins and singleton controls between 5 and 32 years were visited at home. Fasting blood samples for metabolic measurements were collected. Zygosity was established genetically for a subset. DM was defined as HbA1c ≥6.5% (48 mmol/mol) and MS by the International Diabetes Federation criteria.
HbA1c was available for 574 twins and 463 singletons. Mean age was 15.3 years versus 15.8 years, respectively. Eighteen percent of twins were monozygotic. There were no DM cases among twins but one among singletons. A total of 1.4% (8 of 574) of twins had elevated HbA1c (6.0–6.4%, 42–46 mmol/mol) compared with 2.4% (11 of 463) of singletons (P = 0.28). Mean HbA1c was 5.3% (34 mmol/mol) for both groups. MS data were available for 364 twins and 360 singletons. The MS prevalence was 3.0% (11 of 364) among twins and 3.6% (13 of 360) among singletons (P = 0.66). The prevalence of fasting blood glucose (F-glucose) ≥5.6 mmol/L was 34.9% (127 of 364) for twins versus 24.7% (89 of 360) for singletons (P = 0.003). Median homeostasis model assessment–insulin resistance did not differ (P = 0.34).
The MS and DM prevalences among young individuals in Guinea-Bissau were low. Twins did not have a higher MS and DM burden than singletons, though elevated F-glucose was more common among twins.
PMCID: PMC3816924  PMID: 23949562
19.  Power Estimation for Gene-Longevity Association Analysis Using Concordant Twins 
Statistical power is one of the major concerns in genetic association studies. Related individuals such as twins are valuable samples for genetic studies because of their genetic relatedness. Phenotype similarity in twin pairs provides evidence of genetic control over the phenotype variation in a population. The genetic association study on human longevity, a complex trait that is under control of both genetic and environmental factors, has been confronted by the small sample sizes of longevity subjects which limit statistical power. Twin pairs concordant for longevity have increased probability for carrying beneficial genes and thus are useful samples for gene-longevity association analysis. We conducted a computer simulation to estimate the power of association study using longevity concordant twin pairs. We observed remarkable power increases in using singletons from longevity concordant twin pairs as cases in comparison with cases of sporadic proband. A similar power would require doubled sample sizes for fraternal twins than for identical twins who are concordant for longevity suggesting that longevity concordant identical twins are more efficient samples than fraternal twins. We also observed an approximate of 2- to 3-fold increase in sample sizes needed for longevity cutoff at age 90 as compared with that at age 95. Overall, our results showed high value of twins in genetic association studies on human longevity.
PMCID: PMC4181900  PMID: 25309757
20.  Reduced Prevalence of Cognitive impairment in families with exceptional longevity 
JAMA neurology  2013;70(7):867-874.
To determine if families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer’s disease (AD).
Cross-sectional analysis.
Multi-site study in NY, MA, PA, and Denmark.
1870 individuals (1510 family members and 360 spouse controls) recruited through the Long Life Family Study (LLFS).
Main Outcome Measures
Prevalence of cognitive impairment based on a diagnostic algorithm validated using the National Alzheimer’s Coordinating Center dataset.
The cognitive algorithm classified 546 (38.5%) individuals as having cognitive impairment consistent with AD. LLFS probands had a slightly but not statistically significant reduced risk of cognitive impairment compared with spouse controls (121/232 for probandsvs 45/103 for spouse controls: OR = 0.70; 95% CI (0.4–1.4)), whereas LLFS sons and daughters had a clearly reduced risk of cognitive impairment (11/213 for sons and daughters vs 28/216 for spouse controls: OR = 0.40; 95% CI (0.2–0.9)). Restriction to nieces and nephews in the offspring generation attenuated this effect (37/328 for nieces and nephews vs 28/216 for spouse controls OR = 0.70; 95% CI (0.4–1.4).
Rates of cognitive impairment characteristic of AD were relatively high. In the proband generation, rates were comparable across family members and spouse controls whereas sons and daughters of probands had significantly lower rates than spouse controls. Results suggest a delayed onset of cognitive impairment in families with exceptional longevity, but assessment of age-specific incidence rates is required to confirm this hypothesis.
PMCID: PMC4151346  PMID: 23649824
21.  A novel permutation test for case-only analysis identifies epistatic effects on human longevity in the FOXO gene family 
Aging cell  2013;12(4):690-694.
Genetic interactions or epistasis could make a substantial contribution to variation in human complex traits including longevity. However, detecting epistatic interactions in high dimensional datasets is difficult due to various reasons including multiple testing of correlated tests. We introduce a novel permutation strategy to the case-only analysis of gene by gene interaction using multiple SNPs. The method is applied to genes coding for Forkhead box O transcription factors which recently have been associated with human longevity across different populations hypothesizing that epistatic interaction in the regulation and expression of the FOXO gene family could contribute to the human longevity phenotype. Genotype data was collected from 1088 individuals from the Danish 1905 birth cohort aged over 92/93 years with 12 SNPs in the FOXO1a and 15 SNPs in the FOXO3a genes. Our analysis detected a joint effect between rs9486902 in FOXO3a and rs2701858 in FOXO1a that highly significantly contributes to human longevity (OR=3.23, 95% CI: 2.93–3.53) which is consistent in both males and females. Our results were compared with published studies and importance of our novel method and findings discussed.
PMCID: PMC3714332  PMID: 23607278
case-only analysis; epistatic effect; permutation; longevity; FOXO genes
22.  Sex difference in leukocyte telomere length is ablated in opposite-sex co-twins 
Background: In eutherian mammals and in humans, the female fetus may be masculinized while sharing the intra-uterine environment with a male fetus. Telomere length (TL), as expressed in leukocytes, is heritable and is longer in women than in men. The main determinant of leukocyte TL (LTL) is LTL at birth. However, LTL is modified by age-dependent attrition.
Methods: We studied LTL dynamics (LTL and its attrition) in adult same-sex (monozygotic, n = 268; dizygotic, n = 308) twins and opposite-sex (n = 144) twins. LTL was measured by Southern blots of the terminal restriction fragments.
Results: We observed that in same-sex (both monozygotic and dizygotic) twins, as reported in singletons, LTL was longer in females than in males [estimate ± standard error (SE):163 ± 63 bp, P < 0.01]. However, in opposite-sex twins, female LTL was indistinguishable from that of males (−31 ± 52 bp, P = 0.6), whereas male LTL was not affected. Findings were similar when the comparison was restricted to opposite-sex and same-sex dizygotic twins (females relative to males: same-sex: 188 ± 90 bp, P < 0.05; other-sex: −32 ± 64 bp, P = 0.6).
Conclusions: These findings are compatible with masculinization of the female fetus in opposite-sex twins. They suggest that the sex difference in LTL, seen in the general population, is largely determined in utero, perhaps by the intrauterine hormonal environment. Further studies in newborn twins are warranted to test this thesis.
PMCID: PMC4276058  PMID: 25056338
Telomeres; twins; sex; women; men
23.  Changes in hospitalisation and surgical procedures among the oldest-old: a follow-up study of the entire Danish 1895 and 1905 cohorts from ages 85 to 99 years 
Age and Ageing  2013;42(4):476-481.
Objective: to examine whether the Danish 1905 cohort members had more active hospital treatment than the 1895 cohort members from ages 85 to 99 years and whether it results in higher in-hospital and post-operative mortality.
Methods: in the present register-based follow-up study the complete Danish birth cohorts born in 1895 (n = 12,326) and 1905 (n = 15,477) alive and residing in Denmark at the age of 85 were followed from ages 85 to 99 years with regard to hospitalisations and all-cause and cause-specific surgical procedures, as well as in-hospital and post-operative mortality.
Results: the 1905 cohort members had more frequent hospital admissions and operations, but they had a shorter length of hospital stay than the 1895 cohort at all ages from 85 to 99 years. The increase in primary prosthetic replacements of hip joint was observed even within the 1895 cohort: no patients were operated at ages 85–89 years versus 2.2–3.6% at ages 95–99 years. Despite increased hospitalisation and operation rates, there was no increase in post-operative and in-hospital mortality rates in the 1905 cohort. These patterns were similar among men and women.
Conclusions: the observed patterns are compatible with more active treatment of the recent cohorts of old-aged persons and reduced age inequalities in the Danish healthcare system. No increase in post-operative mortality suggests that the selection of older patients eligible for a surgical treatment is likely to be based on the health status of old-aged persons and the safety of surgical procedures rather than chronological age.
PMCID: PMC3693434  PMID: 23531440
cohort comparison; hospitalisation; surgical procedure; old age; post-operative mortality; in-hospital mortality; register study; Denmark; older people
24.  Regulation of the Pituitary-Thyroid Axis in Adulthood Is Not Related to Birth Weight: Evidence from Extremely Birth Weight–Discordant Monozygotic Danish Twin Pairs 
Thyroid  2013;23(7):785-790.
Low birth weight has been linked with changes in thyroid function in adulthood, but it is unknown whether fetal programming or underlying genetic and environmental factors explains the association. We hypothesized that birth weight influences the pituitary-thyroid set point in adults.
A total of 152 birth weight–discordant monozygotic twin pairs with a median age of 57 years (interquartile range: 33–63) were ascertained from the Danish Twin Registry in 2010. Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and triiodothyronine (T3) levels were measured. Birth weights were retrieved from midwife records (individuals born before 1973) and the Danish Birth Record Registry (all other participants)
Birth weight was inversely associated with serum levels of FT4 (β=−0.48 pmol/[L·kg], p=0.014) and serum T3 (β=−0.09 nmol/[L·kg], p=0.010), but not serum TSH after adjustment for age, sex, and current use of tobacco products, when the twins were investigated as singletons. Serum levels of TSH and T3 were similar in within twin-pair analyses, while serum FT4 was higher in twins with the lowest birth weight (median difference 0.3 mIU/L). When the analyses were repeated in twin pairs (n=46 pairs) characterized by extreme difference in birth weight (>0.5 kg), serum TSH, T3, and FT4 levels were similar in twins with high and low birth weight. The proportion of individuals with serum TSH level >4 mIU/L or <0.3 mIU/L was identical in both groups.
No overall evidence of an association between birth weight and adult pituitary-thyroid axis set point, after control for genetic and environmental factors, could be demonstrated.
PMCID: PMC3704111  PMID: 23308389
25.  Age Validation in the Long Life Family Study Through a Linkage to Early-Life Census Records 
Studies of health and longevity require accurate age reporting. Age misreporting among older adults in the United States is common.
Participants in the Long Life Family Study (LLFS) were matched to early-life census records. Age recorded in the census was used to evaluate age reporting in the LLFS. The study population was 99% non-Hispanic white.
About 88% of the participants were matched to 1910, 1920, or 1930 U.S. censuses. Match success depended on the participant’s education, place of birth, and the number of censuses available to be searched. Age at the time of the interview based on the reported date of birth and early-life census age were consistent for about 89% of the participants, and age consistency within 1 year was found for about 99% of the participants.
It is possible to match a high fraction of older study participants to their early-life census records when detailed information is available on participants’ family of origin. Such record linkage can provide an important source of information for evaluating age reporting among the oldest old participants. Our results are consistent with recent studies suggesting that age reporting among older whites in the United States appears to be quite good.
PMCID: PMC3674734  PMID: 23704206
Age validation; Census; Centenarian; Longevity; Oldest old participants.

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