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1.
Eur J Neurol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571318

RESUMO

BACKGROUND AND PURPOSE: The effect of cognitive resources on the risk of dementia following traumatic brain injury (TBI) has been scarcely investigated. The aim of this study was to examine the influence of cognitive ability and education in young adulthood on the association between TBI and dementia in men. METHOD: A cohort of 658,447 Danish men, born 1939-1959, who had been cognitively assessed at conscription were followed in the Danish National Patient Registry and the National Prescription Registry from 1977 through 2016 for incident TBI and dementia. The association between TBI and dementia was analysed using Cox proportional regression. RESULTS: During follow-up, 29,781(4.5%) men experienced TBI and 10 971(1.7%) developed dementia. TBI was associated with higher risk of subsequent dementia after adjustment for cognitive ability, education and psychiatric comorbidity. The risk estimate was higher for early-onset dementia (hazard ratio (HR)=5.49 (4.97-6.06)) than for dementia diagnosed after age 60 years (HR= 2.85 (2.63-3.10). The association was slightly stronger in men with the highest cognitive scores or education than among those at lower levels CONCLUSION: Young adult cognitive ability did not explain a relatively strong association between TBI and dementia, and we found no evidence that cognitive ability or education were protective.

2.
Scand J Clin Lab Invest ; : 1-6, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31581851

RESUMO

The number of very old individuals in the population is rapidly increasing. Previous studies have indicated that many factors known to be strongly associated with survival among middle-aged and elderly show no association among the oldest old. Resting heart rate (RHR) is associated with increased risk of death in the general population as well as in patients with various types of heart disease. The association between RHR and mortality in the very old is the subject of this report. The study population was identified in The Nationwide Danish 1905 Cohort Study (n = 1086) and comprised 854 subjects with a median age of 95.2 years (range 94.7-95.9), in whom RHR was measured by radial pulse palpation. Participants were followed until death through the civil registration system, and remaining lifespan after RHR measure was used as outcome. Participants were divided into six groups according to RHR (≤50, 51-60, 61-70, 71-80, 81-90 and ≥91) with the largest group used as the reference group (61-70 beats per minute (bpm)). Survival analyses using Cox' proportional hazards models were performed to study the association between RHR and mortality. Median RHR was 68 bpm in males (IQR 62-76) and 70 bpm (IQR 64-78) in females. After stratifying both sexes into six groups according to RHR, we found no significant difference in remaining lifespan between groups in either males or females. No significantly increased risk was demonstrated in groups with higher RHR. In very old people, elevated RHR is not associated with increased mortality.

3.
Twin Res Hum Genet ; : 1-9, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31544734

RESUMO

The Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.

4.
Aging (Albany NY) ; 11(16): 5876-5894, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31461406

RESUMO

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

5.
Nat Commun ; 10(1): 3669, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

6.
Geroscience ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332674

RESUMO

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.

7.
Twin Res Hum Genet ; : 1-7, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31317858

RESUMO

Sub-Saharan Africa has the highest natural twinning rate in the world. Unfortunately, due to lack of adequate care during pregnancy, labor and postnatally, twin mortality in Sub-Saharan Africa also remains very high. Thus, it has been estimated that one in five twins dies during the childhood years. In spite of this, surprisingly few twin studies have been conducted in the region, making additional epidemiological data much needed. In 2009, we established one of the first twin registries in Sub-Saharan Africa at the Bandim Health Project in Guinea-Bissau. The registry had two main objectives. First, we wanted to describe the twinning rate and mortality patterns among newborn twins, including mortality risk factors and hospitalization patterns. Such studies can help the local clinicians improve twin health by identifying the most vulnerable children. Second, and in light of the rapidly increasing diabetes rates in Africa, we wanted to use the registry to particularly focus on metabolic disorders. Twins are often born with low birth weight, which according to the 'thrifty phenotype hypothesis' could predispose them to metabolic disorders later in life. Yet, no such 'fetal programming' data have previously been available from African twins despite the fact that nutritional patterns and influences from other factors (e.g., infections) could be markedly different here compared to high-income settings. In this article, we summarize the findings and current status of the Guinea-Bissau twin registry.

8.
Int J Public Health ; 64(7): 1025-1036, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236603

RESUMO

OBJECTIVES: To examine sex differences in prevalent comorbidity and frailty across age and European regions. METHODS: This is a cross-sectional study based on 113,299 Europeans aged 50+ participating in the Survey of Health, Ageing and Retirement in Europe from 2004-2005 to 2015. Sex differences in the Comorbidity Index and the Frailty Phenotype were investigated using ordinal logistic regressions. RESULTS: European women had generally higher odds of prevalent comorbidity (OR 1.11, 95% CI 1.07-1.15) and frailty (OR 1.56, 95% CI 1.51-1.62). Sex differences increased with advancing age. No overall sex difference in comorbidity was found in Western Europe, but women had more comorbidity than men in Eastern (OR 1.30, 95% CI 1.18-1.44), Southern (OR 1.23, 95% CI 1.15-1.30), and Northern (OR 1.08, 95% CI 1.01-1.16) Europe. Women were frailer than men in all regions, with the largest sex difference in Southern Europe (OR 1.84, 95% CI 1.72-1.96). CONCLUSIONS: European women are frailer and have slightly more comorbidity than European men lending support for the male-female health survival paradox.

9.
Biogerontology ; 20(5): 627-647, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254144

RESUMO

Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55-90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73-90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.

10.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172578

RESUMO

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31086986

RESUMO

BACKGROUND: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this paper was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. METHODS: We examined 7-year change in physical (free of ADL difficulty), cognitive (Mini Mental State Examination score≥24) and overall independence (physically/cognitively independent) in adults aged 90.3±6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics and physical/cognitive performance tasks and were determined using generalized estimating equations (α: p<0.05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. RESULTS: At baseline (n=1442), 67.3%, 83.8% and 79.7% were overall, physically and cognitively independent, respectively. After 7 years, 66% died,7.5% were lost-to-follow-up and the prevalence of overall independence decreased, to 59.1% in survivors (-8.2%, 95% CI: -14.1, 2.2%). Of those with baseline independence, 156/226 (69.0%), remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery (SPPB) score and lung function, smaller waist-circumference and lower soluble receptor for advanced glycation end-product (sRAGE) levels (p<0.05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p<0.05). CONCLUSIONS: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.

12.
Neurology ; 93(2): e135-e142, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31127070

RESUMO

OBJECTIVE: To verify the previously reported association between long-term use of ß2-adrenoreceptor (ß2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively. METHODS: We obtained odds ratios (ORs) associating time of ß2AR agonist and antagonist use with PD risk in nationwide Danish health registries. RESULTS: We included 2,790 patients with PD and 11,160 controls. Long-term ß2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term ß2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because ß2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all ß2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use. CONCLUSION: We confirmed ß2AR agonist use to be associated with reduced PD risk and ß2AR antagonist use with increased PD risk. However, our data indicate the association of ß2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of ß2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than ß2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between ß2AR agonists and antagonists and PD risk.

13.
Twin Res Hum Genet ; 22(2): 99-107, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31020942

RESUMO

The Nordic countries have comprehensive, population-based health and medical registries linkable on individually unique personal identity codes, enabling complete long-term follow-up. The aims of this study were to describe the NorTwinCan cohort established in 2010 and assess whether the cancer mortality and incidence rates among Nordic twins are similar to those in the general population. We analyzed approximately 260,000 same-sexed twins in the nationwide twin registers in Denmark, Finland, Norway and Sweden. Cancer incidence was determined using follow-up through the national cancer registries. We estimated standardized incidence (SIR) and mortality (SMR) ratios with 95% confidence intervals (CI) across country, age, period, follow-up time, sex and zygosity. More than 30,000 malignant neoplasms have occurred among the twins through 2010. Mortality rates among twins were slightly lower than in the general population (SMR 0.96; CI 95% [0.95, 0.97]), but this depends on information about zygosity. Twins have slightly lower cancer incidence rates than the general population, with SIRs of 0.97 (95% CI [0.96, 0.99]) in men and 0.96 (95% CI [0.94, 0.97]) in women. Testicular cancer occurs more often among male twins than singletons (SIR 1.15; 95% CI [1.02, 1.30]), while cancers of the kidney (SIR 0.82; 95% CI [0.76, 0.89]), lung (SIR 0.89; 95% CI [0.85, 0.92]) and colon (SIR 0.90; 95% CI [0.87, 0.94]) occur less often in twins than in the background population. Our findings indicate that the risk of cancer among twins is so similar to the general population that cancer risk factors and estimates of heritability derived from the Nordic twin registers are generalizable to the background populations.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30982845

RESUMO

BACKGROUND: Human life expectancy continues to rise in most populations. This rise not only leads to longer lives but is accompanied by improved health at a given age, i.e. recent cohorts show a reduction of biological age for a given chronological age. Despite or even because of the diversity of biomarkers of ageing, an accurate quantification of a general shift in biological age across time has been challenging. METHODS: Here, we compared age perception of facial images taken in 2001 over a decade and related these changes in age perception to changes in life expectancy. RESULTS: We show that age perception changes substantially across time and parallels the progress in life expectancy. In 2012, people aged 70+ needed to look 2.3 years younger to be rated the same age as in 2002. CONCLUSIONS: Our results suggest that age perception reflects the past life events better than predicts future length of life, i.e. it is written in your face how much you have aged so far. We draw this conclusion since age perception among elderly paralleled changes in life expectancy at birth but not changes in remaining life expectancies. We suggest that changes in age perception should be explored for younger age classes to inform on ageing processes, including whether ageing is delayed or slowed with increasing life expectancy.

15.
Eur J Hum Genet ; 27(7): 1101-1112, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30850703

RESUMO

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30874797

RESUMO

Aging is a multifactorial trait caused by early as well as late life circumstances. A society trend that parents deliberately delay having children is of concern to health professionals, e.g. since advanced parental age at conception increases disease risk profiles in offspring. We here aim to study if advanced parental age at conception affects mitochondria DNA content, a cross species biomarker of general health, in adult human twin offspring and in a model organism. We find no deteriorated mitochondria DNA content at advanced parental age at conception, but human mitochondria DNA content was higher in females than males, and the difference was two fold higher at advanced maternal age at conception. Similar parental age effects and sex-specific differences in mitochondria DNA content were found in Drosophila melanogaster. In addition, parental longevity in humans associates with both mitochondria DNA content and parental age at conception thus we carefully propose that a poorer disease risk profile from advanced parental age at conception might be surpassed by superior effects of parental successful late-life reproduction that associate with parental longevity.

17.
Genes (Basel) ; 10(2)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791679

RESUMO

Studies with twins provide fundamental insights to lifespans of humans. We aim to clarify if monozygotic and dizygotic twin individuals differ in lifespan, that is, if zygosity matters. We investigate whether a possible difference in mortality after infancy between zygosities is stable in different age cohorts, and whether the difference remains when twins with unknown zygosity are taken into account. Further, we compare the distribution of long-livers, that is, the upper-tail of the lifespan distribution, between monozygotic and same-sex dizygotic twin individuals. The Danish Twin Registry provides a nationwide cohort of 109,303 twins born during 1870 to 1990 with valid vital status. Standard survival analysis is used to compare mortality in monozygotic and dizygotic twin individuals and twin individuals with unknown zygosity. The mortality of monozygotic and dizygotic twin individuals differs slightly after taking into consideration effects of birth- and age-cohorts, gender differences, and that twins are paired. However, no substantial nor systematic differences remain when taking twins with unknown zygosity into account. Further, the distribution of long-livers is very similar by zygosity, suggesting the same mortality process. The population-based and oldest twin cohort ever studied suggests that monozygotic and dizygotic twins have similar lifespans.

18.
Clin Epigenetics ; 11(1): 23, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736859

RESUMO

BACKGROUND: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated. METHODS: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples. RESULTS: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death. CONCLUSION: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.


Assuntos
Ilhas de CpG , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Taxa de Sobrevida/tendências , Fatores Etários , Idoso , Epigênese Genética , Feminino , Humanos , Masculino , Análise de Sobrevida
19.
J Geriatr Oncol ; 10(5): 792-798, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30797708

RESUMO

BACKGROUND: The incidence of most cancers increases with age from early adulthood into old age but tends to level off or decrease at the highest ages. This decline may be caused by age-related mechanisms or due to lower diagnostic activity, leaving some cancers undiagnosed at the oldest ages. METHODS: For breast, colon, lung, and all sites except non-melanoma skin cancer, age-specific incidence rates of verified as well as suspected cancer were estimated up to ages 95+ years for a random sample of the Danish population, 1994-2011, based on nationwide health registers (40,008 verified and 9110 suspected cancers). Moreover, for cancers diagnosed in Denmark, 1978-2012 (613,384 cancers), age-specific percentages of tumors with microscopic verification (histological/cytological/hematological examination) were calculated. RESULTS: The age-specific cancer incidence rates reached a peak between ages 65-89 years after which rates declined. The corresponding incidence pattern of suspected but not verified cancer was similar, with a trend of a slight absolute and relative decrease with age compared to verified cancer incidence. The proportion of cancers with microscopic verification decreased linearly from approximately 95% at ages 0-69 years all years to 70% (1978-1982) and to 80% (2010-2012) at ages 90+ years. CONCLUSIONS: The lower diagnostic verification of cancer at the highest ages suggests a lower diagnostic activity among the oldest-old. However, the proportion of suspected but not verified cancers did not increase with age, possibly partially due to lack of registration. The declining cancer incidence at oldest ages is probably partly due to lower diagnostic activity.

20.
Aging Cell ; : e12907, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30793472

RESUMO

The Y chromosome, a sex chromosome that only exists in males, has been ignored in traditional epigenetic association studies for multiple reasons. However, sex differences in aging-related phenotypes and mortality could suggest a critical role of the sex chromosomes in the aging process. We obtained blood-based DNA methylation data on the Y chromosome for 624 men from four cohorts and performed a chromosome-wide epigenetic association analysis to detect Y-linked CpGs differentially methylated over age and cross-validated the significant CpGs in the four cohorts. We identified 40-219 significant CpG sites (false discovery rate <0.05) with >82% of them hypermethylated with increasing age, which is in strong contrast to the patterns reported on the autosomal chromosomes. Comparing the rate of change in the Y-linked DNA methylation across cohorts that represent different age intervals revealed a trend of acceleration in DNA methylation with increasing age. The age-dependent DNA methylation patterns on the Y chromosome were further examined for their association with all-cause mortality with results suggesting that the predominant pattern of age-related hypermethylation on the Y chromosome is associated with reduced risk of death.

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