Health conditions change from year to year, with a general tendency in many countries for improvement. These conditions also change from one birth cohort to another: some generations suffer more ...adverse events in childhood, smoke more heavily, eat poorer diets, etc., than generations born earlier or later. Because it is difficult to disentangle period effects from cohort effects, demographers, epidemiologists, actuaries, and other population scientists often disagree about cohort effects’ relative importance. In particular, some advocate forecasts of life expectancy based on period trends; others favor forecasts that hinge on cohort differences. We use a combination of age decomposition and exchange of survival probabilities between countries to study the remarkable recent history of female life expectancy in Denmark, a saga of rising, stagnating, and now again rising lifespans. The gap between female life expectancy in Denmark vs. Sweden grew to 3.5 y in the period 1975–2000. When we assumed that Danish women born 1915–1945 had the same survival probabilities as Swedish women, the gap remained small and roughly constant. Hence, the lower Danish life expectancy is caused by these cohorts and is not attributable to period effects.
Summary
Short leukocyte telomere length (LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. LTL dynamics are defined by LTL at birth, which is highly variable, ...and its age‐dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether age‐dependent LTL attrition during adulthood can substantially affect individuals' LTL ranking (e.g., longer or shorter LTL) in relation to their peers. We measured LTL in samples donated 12 years apart on average by 1156 participants in four longitudinal studies. We observed correlations of 0.91–0.96 between baseline and follow‐up LTLs. Ranking individuals by deciles revealed that 94.1% (95% confidence interval of 92.6–95.4%) showed no rank change or a 1 decile change over time. We conclude that in adults, LTL is virtually anchored to a given rank with the passage of time. Accordingly, the links of LTL with atherosclerosis and longevity appear to be established early in life. It is unlikely that lifestyle and its modification during adulthood exert a major impact on LTL ranking.
FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus ...and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.
Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on ...chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
We analyzed data from twins to determine how much the familial risk of colorectal cancer can be attributed to genetic factors vs environment. We also examined whether heritability is distinct for ...colon vs rectal cancer, given evidence of distinct etiologies.
Our data set included 39,990 monozygotic and 61,443 same-sex dizygotic twins from the Nordic Twin Study of Cancer. We compared each cancer's risk in twins of affected co-twins relative to the cohort risk (familial risk ratio FRR). We then estimated the proportion of variation in risk that could be attributed to genetic factors (heritability).
From earliest registration in 1943 through 2010, there were 1861 individuals diagnosed with colon cancer and 1268 diagnosed with rectal cancer. Monozygotic twins of affected co-twins had an FRR for colorectal cancer of 3.1 (95% confidence interval CI, 2.4-3.8) relative to the cohort risk. Dizygotic twins of affected co-twins had an FRR for colorectal cancer of 2.2 (95% CI, 1.7-2.7). We estimated that 40% (95% CI, 33%-48%) of the variation in colorectal cancer risk could be attributed to genetic factors; unique environment only accounted for the remaining liability. For colon cancer, the FRR was 3.3 (95% CI, 2.1-4.5) for monozygotic twins and 2.6 (95% CI, 1.7-3.5) for dizygotic twins. For rectal cancer, comparable estimates were 3.3 (95% CI, 1.5-5.1) for monozygotic twins and 2.6 (95% CI, 1.2-4.0) for dizygotic twins. Heritability estimates for colon and rectal cancer were 16% (95% CI, 0-46%) and 15% (95% CI, 0-50%), common environment estimates were 15% (95% CI, 0-38%) and 11% (95% CI, 0-38%), and unique environment estimates were 68% (95% CI, 57%-79%) and 75% (95% CI, 61%-88%), respectively.
Interindividual genetic differences could account for 40% of the variation in susceptibility to colorectal cancer; risk for colon and rectal cancers might have less of a genetic component than risk for colorectal cancer. Siblings, and particularly monozygotic co-twins, of individuals with colon or rectal cancer should consider personalized screening.
Abstract
Background
The existence of a super-select group of centenarians that demonstrates increased survivorship has been hypothesized. However, it is unknown if this super-select group possesses ...similar characteristics apart from extreme longevity.
Methods
In this study, we analyse high-quality health and survival data of Danish centenarians born in 1895, 1905 and 1910. We use Latent Class Analysis to identify unobserved health classes and to test whether these super-select lives share similar health characteristics.
Results
We find that, even after age 100, a clear and distinct gradient in health exists and that this gradient is remarkably similar across different birth cohorts of centenarians. Based on the level of health, we identify three clusters of centenarians - robust, frail and intermediate - and show that these groups have different survival prospects. The most distinctive characteristic of the robust centenarians is the outperformance in different health dimensions (physical, functional and cognitive). Finally, we show that our health class categorizations are good predictors of the survival prospects of centenarians.
Conclusions
There is a clear stratification in health and functioning among those over 100 years of age and these differences are associated with survival beyond age 100.
Background Centenarians are used as a model of healthy ageing and longevity. Diet is a factor known to affect mortality in middle aged adults and elderly. However, it is unknown whether diet has an ...impact on survival to 100 + years. The aims of this systematic review were to summarize the evidence on (i) the association between dietary patterns in late adult life and survival to 100 + years and (ii) the common characteristics across dietary patterns that are shown to be positively associated with survival to 100 + years. Methods We performed a systematic literature search in MEDLINE and EMBASE, and a hand search at four longevity projects homepages up to 4 June 2021. We searched for cohort and case-control studies investigating the association between dietary patterns and all-cause mortality among individuals aged greater than or equai to 65 years at enrolment regardless of their health status and residence. Studies were excluded if follow-up was performed too soon to allow the population or a subgroup of it to have become 100 + years of age. Results Of 3,685 identified records 108 reports were retrieved and full text screened. No studies met our inclusion criteria, thus the review process resulted in no eligible studies found. Hence, no risk of bias assessment and no synthesis of data was performed. Conclusions No studies have investigated dietary patterns in late adult life in relation to survival to 100 + years of age. We have observed that as of June 2021 published cohort studies exist investigating all-cause mortality risk from different dietary patterns among the oldest old, but follow-up has been performed before the cohort could have reached 100 years of age. However, cohorts do exist where data on dietary habits in adult life has been collected decades ago and where follow-up in 2022 will allow the participants to have become 100 + years old. Registration The review protocol is published at University of Southern Denmark's Research Portal (Poulsen et al. Dietary Patterns and Survival to 100 + Years: Protocol for a Systematic Review of cohort and case-control studies University of Southern Denmark's Research Portal: University of Southern Denmark, 2021) available at Keywords: Centenarians, Diet, Survival, Exceptional longevity, Ageing
Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less ...X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.
Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency ...were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683,
= 2.52 × 10
; rs880179,
= 4.83 × 10
) mapped to the
gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10
<
< 7.35 × 10
), of which two were replicated (
< 3.10 × 10
). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.
With the continued rise in the proportion of the oldest-old in high-income countries, it is of interest to know whether the functional health of today's oldest-olds is better or worse than in ...previous cohorts. Using two Danish centenarian birth cohorts born 20 years apart we aimed at investigating if the later born cohort had better functioning in terms of activities of daily living (ADL).
Identification, methodology, and assessment instruments were identical in the 1895-West and 1915-West Birth Cohort Studies: All persons living in the western part of Denmark and turning 100 years old in 1995 and 2015, respectively. Data were collected through structured in-home interviews. Participation rates were 74% (n = 106) and 79% (n = 238), respectively.
The proportion of nondisabled women of the 1915-West cohort was more than twice as high compared to the 1895-West cohort and with corresponding lower proportions of moderately and severely disabled persons (17% vs 7%, 33% vs 40% and 50% vs 53% in the 1915-West and 1895-West cohorts, respectively, p = .047). Only nonsignificant improvements were seen among men in the 1915-West cohort. In both sexes, considerably higher proportions of the latest cohort used assistive devices than the former (statistically significant for the majority of assistive devices).
This comparative study shows improvements in reported ADL in the later born cohort of centenarians, even though only significant among women. As women constitute the majority of the oldest-olds, our findings are encouraging from a public health care view.
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