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1.  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
2.  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
3.  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.
4.  Biogenetic Mechanisms Predisposing to Complex Phenotypes in Parents May Function Differently in Their Children 
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.
PMCID: PMC3674715  PMID: 23213029
Heritability; Longevity regulation; Aging; Disease; Genetics of healthspan
5.  Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol 
Frontiers in Genetics  2014;5:159.
The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
PMCID: PMC4042684  PMID: 24917880
NALP1; lipids; genomewide association study; aging; familial longevity; family-based study
6.  AKT1 fails to replicate as a longevity-associated gene in Danish and German nonagenarians and centenarians 
In addition to APOE and FOXO3, AKT1 has recently been suggested as a third consistent longevity gene, with variants in AKT1 found to be associated with human lifespan in two previous studies. Here, we evaluated AKT1 as a longevity-associated gene across populations by attempting to replicate the previously identified variant rs3803304 as well as by analyzing six additional AKT1 single-nucleotide polymorphisms, thus capturing more of the common variation in the gene. The study population was 2996 long-lived individuals (nonagenarians and centenarians) and 1840 younger controls of Danish and German ancestry. None of the seven SNPs tested were significantly associated with longevity in either a case–control or a longitudinal setting, although a supportive nominal indication of a disadvantageous effect of rs3803304 was found in a restricted group of Danish centenarian men. Overall, our results do not support AKT1 as a universal longevity-associated gene.
PMCID: PMC3641374  PMID: 22929028
human longevity; AKT1; association
7.  Apolipoprotein E and Familial Longevity 
Neurobiology of aging  2012;34(4):1287-1291.
Exceptional longevity is associated with substantial heritability. The ε4 allele in Apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently.
Offspring from long lived families and spouse controls were recruited at three sites in the US and in Denmark. We used Generalized Estimating Equations to compare the likelihood of carrying risk alleles in offspring (n=2,307) and spouse controls (n=764), adjusting for age, sex, level of education and family membership.
The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (OR=0.75, p =.005 and OR=0.70, p = .002) and the likelihood of carrying an APOE ε2 allele was higher (OR= 1.5, p = .007) among family members in the offspring generation than among their spouse controls.
Our findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity.
PMCID: PMC3545094  PMID: 23040522
Exceptional longevity; familial longevity; offspring; APOE; TOMM40
8.  Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity 
Age  2012;35(2):487-500.
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 (R2 = 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.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9373-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3592963  PMID: 22234866
Human longevity; Candidate gene association study; Case–control data; Longitudinal data
9.  Analyzing age-specific genetic effects on human extreme age survival in cohort-based longitudinal studies 
The analysis of age-specific genetic effects on human survival over extreme ages is confronted with a deceleration pattern in mortality that deviates from traditional survival models and sparse genetic data available. As human late life is a distinct phase of life history, exploring the genetic effects on extreme age survival can be of special interest to evolutionary biology and health science. We introduce a non-parametric survival analysis approach that combines population survival information with individual genotype data in assessing the genetic effects in cohort-based longitudinal studies. Our approach is characterized by non-parametric analysis of late age survival to capture the observed pattern of mortality deceleration and frailty modeling to account for individual heterogeneity in unobserved frailty. The method is applied to ApoE genotype data in the Danish 1905 birth cohort to estimate effect of the e4 allele. Our results revealed an age-specific relative risk of the allele that increases nonlinearly with age and non-proportional patterns in hazard of death for carriers and non-carriers of the allele, suggesting that the e4 mutation preserves its deleterious effect that progressively affect human survival even at extreme ages.
PMCID: PMC3598313  PMID: 22892531
genetic effect; extreme age survival; cohort design; population data; frailty modeling
10.  The Male-Female Health-Survival Paradox and Sex Differences in Cohort Life Expectancy in Utah, Denmark and Sweden 1850-1910 
Annals of epidemiology  2013;23(4):10.1016/j.annepidem.2013.02.001.
In Utah, prevalence of unhealthy male risk behaviours are lower than in most other male populations while women experience higher mortality risk due to higher fertility rates. Therefore, we hypothesize that the Utah sex differential in mortality would be small and less than in Sweden and Denmark.
Life tables from Utah, Denmark and Sweden, were used to calculate cohort life expectancies for men and women born 1850-1910.
The sex difference in cohort life expectancy was similar or larger in Utah when compared to Denmark and Sweden. The change over time in the sex differences in cohort life expectancy was approximately two years smaller for active Mormons in Utah than for other groups suggesting lifestyle as an important component for the overall change seen in cohort life expectancy. Sex differences in cohort life expectancy at age 50 were similar for individuals actively affiliated with the Church of Jesus Christ of Latter-day Saints and for Denmark and Sweden.
The hypothesis that a smaller sex difference in cohort life expectancies in Utah would be detected in relation to Denmark and Sweden was not supported. In Utah the male-female differences in life expectancy remain substantial pointing towards biological mechanisms, or other unmeasured risk factors.
PMCID: PMC3651922  PMID: 23453386
Life expectancy; lifestyle; religion; immigrants
11.  Genome-wide linkage analysis for human longevity: Genetics of Healthy Ageing Study 
Aging cell  2013;12(2):184-193.
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 fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (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 1,228 unrelated nonagenarian and 1,907 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. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
PMCID: PMC3725963  PMID: 23286790
Human familial longevity; genome-wide linkage analysis; APOE gene; association analysis; nonagenarian sibling pairs
12.  Association of Leukocyte Telomere Length with Fatigue in Nondisabled Older Adults 
Journal of Aging Research  2014;2014:403253.
Introduction. Fatigue is often present in older adults with no identified underlying cause. The accruing burden of oxidative stress and inflammation might be underlying factors of fatigue. We therefore hypothesized that leukocyte telomere length (LTL) is relatively short in older adults who experience fatigue. Materials and Methods. We assessed 439 older nondisabled Danish twins. LTL was measured using Southern blots of terminal restriction fragments. Fatigue was measured by the Mob-T Scale based on questions on whether the respondents felt fatigued after performing six mobility items. Results. LTL was significantly associated with fatigue (P = 0.023), showing an increase of 0.038 kb/fatigue score unit. Aging-related diseases and mental health did not explain the association, while lifestyle factors slightly attenuated the estimates. Conclusion. Our results support an association between LTL and fatigue. Further studies are required to confirm this finding and the link of LTL with oxidative stress/inflammation over the life course.
PMCID: PMC3945148  PMID: 24693429
13.  Indoor mobility-related fatigue and muscle strength in nonagenarians: a prospective longitudinal study 
Background and aims
Mobility-related fatigue is an important indicator of functional decline in old age, however, very little is known about fatigue in the oldest old population segment. The aim of this study was to examine the association between indoor mobility-related fatigue and muscle strength decline in nonagenarians.
The study is based on a prospective longitudinal study of all Danes born in 1905 and assessed in 1998, 2000 and 2003, and includes 92- to 93-year-old persons who were independent of help in basic indoor mobility at baseline (n = 1,353). Fatigue was assessed at baseline and defined as a subjective feeling of fatigue when transferring or walking indoors. The outcome measure, maximum grip strength, was measured at each measurement point.
Grip strength declined throughout the study in participants with and without fatigue, but those reporting fatigue had significantly (P < .001) lower muscle strength during the entire study period. Longitudinal analyses indicated slightly slower decline in muscle strength among participants with fatigue compared to those without; however, observed selective dropout of participants with fatigue and poor performance at baseline needs to be considered when interpreting the results. Accordingly, participants without fatigue had significantly higher chances of being alive and having muscle strength above gender-specific median at first (RR 1.32, 95 % CI 1.07–1.58), second (RR 1.51, 1.06–1.96) and third (RR 1.39, 1.01–1.97) measurement points.
Indoor mobility-related fatigue in advanced later life should not merely be considered as an unpleasant symptom, but rather an indicator of physical impairment, and consequently declined physiological reserve.
PMCID: PMC3916839  PMID: 24297217
Aging; Nonagenarians; Fatigue; Muscle strength
14.  Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan 
PLoS Genetics  2014;10(1):e1004141.
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.
Author Summary
Discovering genetic origins of healthspan and lifespan could lead to breakthroughs in increasing the years of healthy and long life. In this paper we characterize the association of the e4 allele of the well-studied ApoE gene with lifespan in two generations of participants of large longitudinal studies, the Framingham Heart Study and the Long Life Family Study, and investigate the role of major human diseases such as cardiovascular disease, cancer, and neurodegenerative disorders in this association. This wide range of systemic analyses is possible given the large sample with directly genotyped ApoE polymorphism available from these studies (N = 9841, with 2557 deaths). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in these populations. However, the strongly adverse effect of the e4 allele is not observed for all women, but only for those 70 to 95 years old. Cardiovascular disease, cancer, and neurodegenerative disorders do not mediate the association of the e4 allele with lifespan. However, cancer, but not cardiovascular and neurodegenerative diseases, non-additively enhances this effect resulting in 4.2 years of difference in mean lifespan for the e4 allele carriers compared to the non-carriers.
PMCID: PMC3907310  PMID: 24497847
15.  Genome wide association and linkage analyses identified three loci—4q25, 17q23.2, and 10q11.21—associated with variation in leukocyte telomere length: the Long Life Family Study 
Frontiers in Genetics  2014;4:310.
Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes—TERC, MYNN, and OBFC1—were significantly associated with leukocyte telomere length at pempirical < 0.05.
PMCID: PMC3894567  PMID: 24478790
telomere length; aging; familial longevity; genome wide association and linkage; family-based study; novel genes
16.  Twins for epigenetic studies of human aging and development 
Ageing research reviews  2012;12(1):182-187.
Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on the epigenetic processes remains limited. Twins are of special interest for genetic studies due to their genetic similarity and rearing-environment sharing. The classical twin design has made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose toextend the classical twin design to studythe aging–related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process.
PMCID: PMC3509237  PMID: 22750314
twins; aging; epigenetics; environments; genomics
17.  Optimism and survival: does an optimistic outlook predict better survival at advanced ages? A twelve-year follow-up of Danish nonagenarians 
Aging clinical and experimental research  2013;25(5):10.1007/s40520-013-0122-x.
Background and aims
Studies examining predictors of survival among the oldest-old have primarily focused on objective measures, such as physical function and health status. Only a few studies have examined the effect of personality traits on survival, such as optimism. The aim of this study was to examine whether an optimistic outlook predicts survival among the oldest-old.
The Danish 1905 Cohort Survey is a nationwide, longitudinal survey comprising all individuals born in Denmark in 1905. At baseline in 1998, a total of 2,262 persons aged 92 or 93 agreed to participate in the intake survey. The baseline in-person interview consisted of a comprehensive questionnaire including physical functioning and health, and a question about whether the respondent had an optimistic, neutral or pessimistic outlook on his or her own future.
During the follow-up period of 12 years (1998–2010) there were 2,239 deaths (99 %) in the 1905 Cohort Survey. Univariable analyses revealed that optimistic women and men were at lower risk of death compared to their neutral counterparts [HR 0.82, 95 % CI (0.73–0.93) and 0.81, 95 % CI (0.66–0.99), respectively]. When confounding factors such as baseline physical and cognitive functioning and disease were taken into account the association between optimism and survival weakened in both sexes, but the general pattern persisted. Optimistic women were still at lower risk of death compared to neutral women [HR 0.85, 95 % CI (0.74–0.97)]. The risk of death was also decreased for optimistic men compared to their neutral counterparts, but the effect was non-significant [HR 0.91, 95 % CI (0.73–1.13)].
An optimistic outlook appears to be a significant predictor of survival among the oldest-old women. It may also be a significant predictor for men but the sample size is small.
PMCID: PMC3844795  PMID: 24014276
Predictors of mortality; Survival; Optimism; Oldest-old
18.  CLU Genetic Variants and Cognitive Decline among Elderly and Oldest Old 
PLoS ONE  2013;8(11):e79105.
The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study CLU genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73–83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and analysed using random effects models and vital status. The rs11136000 T allele was associated with better baseline cognitive performance both in the LSADT (effect on intercept: 0.41 95% CI [−0.04; 0.87]) and the 1905 birth cohort (effect on intercept: 0.28 95% CI [0.01; 0.55]), although it did not reach significance in the LSADT cohort. However, the rs11136000 T allele was significantly associated with a steeper decline (effect on slope: −0.06 95% CI [−0.11; −0.01]) in the LSADT cohort, but not in the 1905 birth cohort. Haplotype analyses revealed that carriers of the common rs11136000, rs1532278 and rs9331888 TTC haplotype (36%) in the CLU gene performed cognitively better than non-carriers in the 1905 birth cohort (effect on intercept: 0.50 95% CI [0.12; 0.91]) and carriers of a rare TCC haplotype (1%) performed worse on the cognitive composite score (effect on intercept: −1.51 95% CI [−2.92; −0.06]). The association between the TTC haplotype and better cognitive composite score was higher among those surviving past the age of 98 (p = 0.014), and among these the TTC haplotype was borderline associated with a steep decline (effect on slope: −0.13 95% CI [−0.27; 0.00]). In summery CLU genetic variants associate with cognition in two cohorts, but the genetic effect of CLU seems to regress toward the mean when aging.
PMCID: PMC3828341  PMID: 24244428
19.  Are familial factors underlying the association between socioeconomic position and prescription medicine? A register-based study on Danish twins 
BMJ Open  2013;3(11):e003292.
Although well established, the association between socioeconomic position and health and health behaviour is not clearly understood, and it has been speculated that familial factors, for example, dispositional factors or exposures in the rearing environment, may be underlying the association. The objective was to compare prescription fillings within twin pairs who are partly or fully genetically identical and share childhood exposures.
Twin cohort study.
Data from the Danish Twin Registry were linked to registers in Statistics Denmark and the Danish Registry of Medicinal Product statistics. A total of 8582 monozygotic (MZ) and 15 788 dizygotic same sex (DZSS) twins were included.
Outcome measures
Number of prescription fillings during follow-up (1995–2005) was analysed according to education and income. Results of unpaired and intrapair analyses were compared.
An inverse social gradient in filling of prescriptions for all-purpose and system-specific drugs was observed in the unpaired analyses. In the intrapair analyses, associations were attenuated some in DZSS and more in MZ twins. Filling of drugs targeting the nervous system was still strongly associated with income in the intrapair analyses.
Familial factors seem to account for part of the observed social inequality in filling of prescription medicine.
PMCID: PMC3831100  PMID: 24227869
Epidemiology; Genetics; Social Medicine
20.  Physical and cognitive functioning of people older than 90 years: a comparison of two Danish cohorts born 10 years apart 
Lancet  2013;382(9903):10.1016/S0140-6736(13)60777-1.
A rapidly increasing proportion of people in high-income countries are surviving into their tenth decade. Concern is widespread that the basis for this development is the survival of frail and disabled elderly people into very old age. To investigate this issue, we compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart.
People in the first cohort were born in 1905 and assessed at age 93 years (n=2262); those in the second cohort were born in 1915 and assessed at age 95 years (n=1584). All cohort members were eligible irrespective of type of residence. Both cohorts were assessed by surveys that used the same design and assessment instrument, and had almost identical response rates (63%). Cognitive functioning was assessed by mini-mental state examination and a composite of five cognitive tests that are sensitive to age-related changes. Physical functioning was assessed by an activities of daily living score and by physical performance tests (grip strength, chair stand, and gait speed).
The chance of surviving from birth to age 93 years was 28% higher in the 1915 cohort than in the 1905 cohort (6·50% vs 5·06%), and the chance of reaching 95 years was 32% higher in 1915 cohort (3·93% vs 2·98%). The 1915 cohort scored significantly better on the mini-mental state examination than did the 1905 cohort (22·8 [SD 5·6] vs 21·4 [6·0]; p<0·0001), with a substantially higher proportion of participants obtaining maximum scores (28–30 points; 277 [23%] vs 235 [13%]; p<0·0001). Similarly, the cognitive composite score was significantly better in the 1915 than in the 1905 cohort (0·49 [SD 3·6] vs 0·01 [SD 3·6]; p=0·0003). The cohorts did not differ consistently in the physical performance tests, but the 1915 cohort had significantly better activities of daily living scores than did the 1905 cohort (2·0 [SD 0·8] vs 1·8 [0·7]; p<0·0001).
Despite being 2 years older at assessment, the 1915 cohort scored significantly better than the 1905 cohort on both the cognitive tests and the activities of daily living score, which suggests that more people are living to older ages with better overall functioning.
Danish National Research Foundation; US National Institutes of Health—National Institute on Aging; Danish Agency for Science, Technology and Innovation; VELUX Foundation.
PMCID: PMC3818336  PMID: 23849796
21.  Type and Extent of Somatic Morbidity before and after the Diagnosis of Hypothyroidism. A Nationwide Register Study 
PLoS ONE  2013;8(9):e75789.
Hypothyroidism has been linked with an increased risk of other morbidities, such as cardiovascular diseases and diabetes mellitus. However, the temporal relationship between these diseases and the diagnosis of hypothyroidism is not well illuminated. Such information may provide insight into causal relationships between hypothyroidism and other morbidities.
To investigate the type and extent of somatic morbidity before and after a diagnosis of hypothyroidism.
Observational cohort study. From official Danish health registers, 2822 hypothyroid singletons were identified and matched 1:4 with non-hypothyroid controls and observed over a mean period of 6 years. Frequency of different morbidities was obtained by person-to-person linking in the registers. Logistic and Cox regression models were used to assess the risk of morbidity before and after the diagnosis of hypothyroidism, respectively.
Prior to the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (odds ratio (OR) 1.37; 95% confidence interval (CI): 1.19–1.58), lung diseases (OR 1.25; 95% CI: 1.13–1.39), diabetes mellitus (OR 1.92; 95% CI: 1.61–2.29), as well as malignant diseases (OR 1.24; 95% CI: 1.06–1.45). Following the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (hazard ratio (HR) 1.36; 95% CI: 1.15–1.60); lung diseases (HR 1.51; 95% CI: 1.30–1.75); and diabetes mellitus (HR 1.40; 95% CI: 1.11–1.77).
Prior to the diagnosis of hypothyroidism there is an excess risk of being diagnosed with cardiovascular diseases, lung diseases, diabetes mellitus, and malignant diseases. Following the diagnosis of hypothyroidism we demonstrate an increased frequency of cardiovascular diseases, lung diseases, and diabetes mellitus.
PMCID: PMC3774647  PMID: 24066186
22.  Candidate gene linkage approach to Identify DNA variants that predispose to preterm birth 
Pediatric research  2012;73(2):135-141.
To identify genetic variants contributing to preterm birth using a linkage candidate gene approach.
We studied 99 single nucleotide polymorphisms for 33 genes in 257 families with preterm births segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.
Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (p=0.0012) and CYP2E1 (p=0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (p=0.003), IGFBP3 (p=0.006), DHCR7 (p=0.009), and TRAF2 (p=0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.
These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of preterm birth.
PMCID: PMC3740714  PMID: 23168575
23.  Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs 
Aging Cell  2012;11(4):694-703.
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk for most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18 to 89 years old, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, inter-individual variation in locus specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2 fold larger at ABCA1 (p = 0.010) to 1.6 fold larger at INS (p = 3.7 * 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8 % increase in discordance each decade at CRH (p = 8.9 * 10−06) to a 16 % increase each decade at LEP (p = 2.0 * 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10 year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally due to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during ageing.
PMCID: PMC3399918  PMID: 22621408
Epigenetics; Aging; MZ twin design; Full adult lifespan; DNA methylation; Stochastic variation
24.  Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor 
Neurology  2012;79(3):243-248.
Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET.
Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET.
We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10−5, odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10−3, OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10−10, OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087.
We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.
PMCID: PMC3398434  PMID: 22764253
25.  IGEMS: The Consortium on Interplay of Genes and Environment across Multiple Studies 
The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.
PMCID: PMC3699700  PMID: 23186995
twins; gene-environment interaction; aging; longitudinal

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