Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
In contrast to the many studies in females, there are few data in males on the relationships between childhood growth and weight gain and the timing of pubertal maturation and its relevance to adult body mass index (BMI) and body composition.
A total of 2008 males in the 1946 British Birth Cohort Study had assessment of pubertal status including voice-breaking status (no change, starting, or complete) at age 14 yr. These responses were related to growth measurements at birth (weight only) and at 2, 4, 6, 7, 11, 14, 20, 26, 36, 43, 53, and 60–64 yr. Body composition was assessed by dual-energy x-ray absorptiometry at 60–64 yr.
Males with more advanced voice-breaking status at age 14 yr had similar birth weights compared with other males; they showed faster weight gain from 0–2 yr and had higher mean weight and BMI at age 2 yr. Subsequently, they continued to accelerate in weight and BMI, and also in height, and maximum differences in body size were seen at age 14 yr. Adult height did not differ between groups, but males with advanced voice breaking had higher adult BMI and greater whole-body lean mass and greater android fat mass at 60–64 yr.
Similar to females with earlier menarche, the trajectory to earlier sexual maturation in males is manifested by faster early postnatal growth and weight gain and leads to higher adult BMI. Timing of pubertal maturation has potential relevance to adult disease risks in males. We also describe conditional height difference in sd score as a proxy marker of pubertal timing in males.
Few studies have examined the impact of childhood obesity on later kidney disease, and consequently, our understanding is very limited.
Longitudinal population-based cohort.
Setting & Participants
The Medical Research Council National Survey of Health and Development, a socially stratified sample of 5,362 singletons born in 1 week in March 1946 in England, Scotland, and Wales, of which 4,340 were analyzed.
Early-life overweight latent classes (never, prepubertal only, pubertal onset, or always), derived from repeated measurements of body mass index between ages 2 and 20 years.
Outcomes & Measurements
The primary outcome was chronic kidney disease (CKD), defined as creatinine- or cystatin C–based estimated glomerular filtration rate (eGFRcr and eGFRcys, respectively) <60 mL/min/1.73 m2 or urine albumin-creatinine ratio (UACR) ≥3.5 mg/mmol measured at age 60-64 years. Associations were explored through regression analysis, with adjustment for socioeconomic position, smoking, physical activity level, diabetes, hypertension, and overweight at ages 36 and 53 years.
2.3% of study participants had eGFRcr <60 mL/min/1.73 m2, 1.7% had eGFRcys <60 mL/min/1.73 m2, and 2.9% had UACR ≥3.5 mg/mmol. Relative to being in the never-overweight latent class, being in the pubertal-onset– or always-overweight latent classes was associated with eGFRcys-defined CKD (OR, 2.04; 95% CI, 1.09-3.82). Associations with CKD defined by eGFRcr (OR, 1.27; 95% CI, 0.71-2.29) and UACR (OR, 1.33; 95% CI, 0.70-2.54) were less marked, but in the same direction. Adjustment for lifestyle and health factors had little impact on effect estimates.
A low prevalence of CKD resulted in low statistical power. No documentation of chronicity for outcomes. All-white study population restricts generalizability.
Being overweight in early life was found to be associated with eGFRcys-defined CKD in later life. The associations with CKD defined by eGFRcr and UACR were less marked, but in the same direction. Reducing or preventing overweight in the early years of life may significantly reduce the burden of CKD in the population.
Childhood obesity; chronic kidney disease; estimated glomerular filtration rate
Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.
Using data from four UK adult cohorts (ages 53–80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).
Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p = 0.08) after further adjustment.
Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.
Overweight and obesity in adulthood are established risk factors for adverse cardiovascular outcomes, but the contribution of overweight in childhood to later cardiovascular risk is less clear. Evidence for a direct effect of childhood overweight would highlight early life as an important target for cardiovascular disease prevention. The aim of this study was to assess whether overweight and obesity in childhood and adolescence contribute to excess cardiovascular risk in adults.
Methods and findings
Data from three British birth cohorts, born in 1946, 1958 and 1970, were pooled for analysis (n = 11,447). Individuals were categorised, based on body mass index (BMI), as being of normal weight or overweight/obese in childhood, adolescence and adulthood. Eight patterns of overweight were defined according to weight status at these three stages. Logistic regression models were fitted to assess the associations of patterns of overweight with self-reported type 2 diabetes, hypertension, and coronary heart disease (CHD) in adulthood (34–53 years). Compared to cohort members who were never overweight, those who were obese in adulthood had increased risk of all outcomes. For type 2 diabetes, the odds ratio was higher for obese adults who were also overweight or obese in childhood and adolescence (OR 12.6; 95% CI 6.6 to 24.0) than for those who were obese in adulthood only (OR 5.5; 95% CI 3.4 to 8.8). There was no such effect of child or adolescent overweight on hypertension. For CHD, there was weak evidence of increased risk among those with overweight in childhood. The main limitations of this study concern the use of self-reported outcomes and the generalisability of findings to contemporary child populations.
Type 2 diabetes and to a lesser extent CHD risk may be affected by overweight at all stages of life, while hypertension risk is associated more strongly with weight status in adulthood.
The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability.
We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = −0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.
Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.
Depressive symptoms and physical performance are inversely associated, but it is unclear whether their association is bidirectional. We examined whether the association between depressive symptoms and physical performance measured using gait speed is bidirectional.
We used a national sample of 4,581 community-dwelling people aged 60 years and older from the English Longitudinal Study of Ageing (from 2002–03 to 2008-09). We fitted Generalized Estimating Equation (GEE) regression models to analyse repeated measurements of gait speed (m/sec) and elevated depressive symptoms (defined as a score of ≥4 on the eight-item Center for Epidemiological Studies-Depression scale).
Slower gait speed was associated with elevated depressive symptoms both concurrently and two years later. After adjustment for previous depressive symptoms and sociodemographic, clinical, lifestyle, psychosocial, and cognitive factors the concurrent association was partially explained (Odds Ratio [OR] 0.42, 95% confidence interval [CI], 0.30 to 0.59, per 1m/sec increase in gait speed) and the two-year lagged association fully (OR 0.75, 95% CI, 0.56 to 1.00). Elevated depressive symptoms were associated with slower gait speed. Full adjustment for covariates (including previous gait speed) partially explained both the concurrent (β regression coefficient [β] -0.038, 95% CI, -0.050 to -0.026, for participants with elevated depressive symptoms compared with those with no or one symptom) and the two-year lagged associations (β -0.017, 95% CI, -0.030 to -0.005). Subthreshold depressive symptoms (defined as a score of two or three on the eight-item Center for Epidemiological Studies-Depression scale) were also associated with slower gait speed. Full adjustment for covariates partially explained both the concurrent (β -0.029, 95% CI, -0.039 to -0.019, for participants with subthreshold symptoms compared with those with no or one symptom) and the two-year lagged associations (β -0.011, 95% CI, -0.021 to -0.001).
The inverse association between gait speed and depressive symptoms appears to be bidirectional.
Physical capability in later life is influenced by factors occurring across the life course, yet exposures to area conditions have only been examined cross-sectionally. Data from the National Survey of Health and Development, a longitudinal study of a 1946 British birth cohort, were used to estimate associations of area deprivation (defined as percentage of employed people working in partly skilled or unskilled occupations) at ages 4, 26, and 53 years (residential addresses linked to census data in 1950, 1972, and 1999) with 3 measures of physical capability at age 53 years: grip strength, standing balance, and chair-rise time. Cross-classified multilevel models with individuals nested within areas at the 3 ages showed that models assessing a single time point underestimate total area contributions to physical capability. For balance and chair-rise performance, associations with area deprivation in midlife were robust to adjustment for individual socioeconomic position and prior area deprivation (mean change for a 1-standard-deviation increase: balance, −7.4% (95% confidence interval (CI): −12.8, −2.8); chair rise, 2.1% (95% CI: −0.1, 4.3)). In addition, area deprivation in childhood was related to balance after adjustment for childhood socioeconomic position (−5.1%, 95% CI: −8.7, −1.6). Interventions aimed at reducing midlife disparities in physical capability should target the socioeconomic environment of individuals—for standing balance, as early as childhood.
geography; Great Britain; health status disparities; longitudinal studies; multilevel analysis; physical endurance; residence characteristics; socioeconomic factors
Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: −0.05 (95% CI: −0.09, −0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D–raising allele of rs2282679 [pooled β per T allele: −0.03 (95% CI: −0.05, −0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
To investigate the associations of body mass index (BMI) and grip strength with objective measures of physical performance (chair rise time, walking speed and balance) including an assessment of sex differences and non-linearity.
Cross-sectional data from eight UK cohort studies (total N = 16 444) participating in the Healthy Ageing across the Life Course (HALCyon) research programme, ranging in age from 50 to 90+ years at the time of physical capability assessment, were used. Regression models were fitted within each study and meta-analysis methods used to pool regression coefficients across studies and to assess the extent of heterogeneity between studies.
Higher BMI was associated with poorer performance on chair rise (N = 10 773), walking speed (N = 9 761) and standing balance (N = 13 921) tests. Higher BMI was associated with stronger grip strength in men only. Stronger grip strength was associated with better performance on all tests with a tendency for the associations to be stronger in women than men; for example, walking speed was higher by 0.43 cm/s (0.14, 0.71) more per kg in women than men. Both BMI and grip strength remained independently related with performance after mutual adjustment, but there was no evidence of effect modification. Both BMI and grip strength exhibited non-linear relations with performance; those in the lowest fifth of grip strength and highest fifth of BMI having particularly poor performance. Findings were similar when waist circumference was examined in place of BMI.
Older men and women with weak muscle strength and high BMI have considerably poorer performance than others and associations were observed even in the youngest cohort (age 53). Although causality cannot be inferred from observational cross-sectional studies, our findings suggest the likely benefit of early assessment and interventions to reduce fat mass and improve muscle strength in the prevention of future functional limitations.
On average, older people remember less and walk more slowly than do younger persons. Some researchers argue that this is due in part to a common biologic process underlying age-related declines in both physical and cognitive functioning. Only recently have longitudinal data become available for analyzing this claim. We conducted a systematic review of English-language research published between 2000 and 2011 to evaluate the relations between rates of change in physical and cognitive functioning in older cohorts. Physical functioning was assessed using objective measures: walking speed, grip strength, chair rise time, flamingo stand time, and summary measures of physical functioning. Cognition was measured using mental state examinations, fluid cognition, and diagnosis of impairment. Results depended on measurement type: Change in grip strength was more strongly correlated with mental state, while change in walking speed was more strongly correlated with change in fluid cognition. Examining physical and cognitive functioning can help clinicians and researchers to better identify individuals and groups that are aging differently and at different rates. In future research, investigators should consider the importance of identifying different patterns and rates of decline, examine relations between more diverse types of measures, and analyze the order in which age-related declines occur.
aging; cognition; correlated change; longitudinal analysis; meta-analysis; physical functioning; systematic review
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
Older women and those of lower socioeconomic position (SEP) consistently constitute a larger portion of the disabled population than older men or those of higher SEP, yet no studies have examined when in the life course these differences emerge.
Prevalence of self-reported limitations in the upper body (gripping or reaching) and lower body (walking or stair climbing) at 43 and 53 years were utilized from 1,530 men and 1,518 women from the British 1946 birth cohort. Generalized linear models with a binomial distribution were used to examine the effects of gender, childhood and adult SEP, and the differences in the SEP effects by gender on the prevalence of limitations at age 43 years and changes in prevalence from 43 to 53 years.
For both genders, the prevalence of upper and lower body limitations were reported at 3%–5% at age 43 years. However, by age 53 years, women’s upper body limitations had increased to 28% and lower body limitations to 21%, whereas men’s limitations had only increased to 12% and 11%, respectively. Men and women whose father’s occupation was manual or whose adult head of household occupation was manual had higher prevalence of both limitations compared with those with non-manual backgrounds. These differences widened with age, especially in women. The effect of adult SEP on the prevalence of limitations was stronger than that of childhood SEP and was partly mediated by educational attainment.
Our findings provide the first evidence that prevention of disability in old age should begin early in midlife, especially for women from manual occupation households.
Gender; Social class; Functional limitations; Longitudinal studies; Middle aged
The common C allele of rs314276 in LIN28B has been robustly associated with earlier age at menarche in girls and associated with earlier timing of other pubertal traits in both sexes.
Our objective was to explore the associations between rs314276, as a marker of earlier pubertal timing, and body mass index (BMI), weight, and height across the life course.
The rs314276 in LIN28B was genotyped in 1242 men and 1209 women born in 1946 and participating in the Medical Research Council National Survey of Health and Development. Birth weight was recorded, and height and weight were measured or self-reported repeatedly at 11 time points between ages 2 and 53 yr. Polynomial mixed models were used to test whether additive genetic associations with SD scores (SDS) for BMI and height changed with age between 0 and 53 yr.
Longitudinal analyses revealed age-dependent associations between rs314276 genotype and BMI (P < 0.001 for genotype-by-age2 interaction) and body weight (P < 0.001 for genotype-by-age2 interaction) in women, but not in men. In women only, the C allele at rs314276 was associated with higher BMI SDS from ages 15–43 yr. In contrast, C allele associations with shorter height SDS were apparent in both men and women and did not vary with age.
A common genetic variant in LIN28B that confers earlier puberty was associated with a prolonged increase in BMI during adolescence and early to mid-adulthood in women only. Such genetic associations may provide insights into the direct effects of pubertal timing on obesity risk.
In this study, the authors investigate gender-specific effects of childhood socio-economic position (SEP) on adiposity and blood pressure at three time points in adulthood.
Mixed models were used to assess the association of childhood SEP with body mass index (BMI), waist circumference, systolic blood pressure (SBP) and diastolic blood pressure (DBP) at ages 36, 43 and 53 years in a British birth cohort.
The adverse effect of lower childhood SEP on adiposity increased between ages 36 and 53 years in women (BMI: trend test: p=0.03) and remained stable in men, but the opposite was seen for SBP, where inequalities increased in men (p=0.01). Childhood SEP inequalities in DBP were stable with age in both men and women. Educational attainment mediated some but not all of the effects of childhood SEP on adiposity and SBP, and their rate of change; adult social class was a less important mediator.
Childhood SEP is important for adult adiposity and blood pressure across midlife, especially for BMI in women and for blood pressure in men. Thus, pathways to adult health differ for men and women, and public health policies aimed at reducing social inequalities need to start early in life and take account of gender.
Adult body mass index (BMI) has been consistently related to mortality, but little is known about the impact of earlier life BMI on adult mortality. The aim is to investigate the impact of childhood, adolescent and early adult BMI on premature adult all-cause mortality.
The British 1946 cohort study was used to assess the association of BMI in childhood, adolescence and adulthood with mortality 26–60 years (332 deaths). 4462 (83%) respondents were available for analysis at age 26 years. Splines were used in Cox regression to model the associations between BMI and mortality.
In both genders, adult BMI from 20 years onwards showed a consistent U-shaped relationship with adult mortality (overall p value <0.05 for BMI at ages 20, 26 and 36 years). In women, a similar relationship was observed for adolescent BMI at 15 years (p=0.02); the HR comparing women with low BMI (2 SDs below mean) versus mean BMI was 2.96 (95% CI 1.26 to 6.97). The corresponding HR for women with BMI 2 SDs above the mean was 1.97 (0.95 to 4.10). BMI in childhood was generally not associated with adult mortality except female BMI at 4 years where a U-shaped relationship was observed (p=0.02); HR for BMI 2 SDs below mean versus mean was 2.13 (0.97 to 4.70) and the corresponding HR for 2 SDs above the mean was 1.67 (0.85 to 3.28). This association was not attenuated by subsequent BMI change or mediators.
High and low BMI from early adulthood were related to adult premature mortality suggesting that promoting a normal weight in early adulthood could prevent premature mortality.
The association between lifelong body mass index (BMI) and cognitive function has not been comprehensively studied.
In more than 2000 men and women born in 1946, we tested associations between BMI gain at 15, 20, 26, 36, 43, and 53 years with respect to the previous measure (gain at age 15 years with respect to BMI at age 11 years), and semantic fluency (animal naming) and cognitive reserve (the National Adult Reading Test) at age 53 years, and verbal memory (word list recall) and speed/concentration (letter cancellation) at ages 43 and 53 years. Measures of BMI gain were adjusted in stages for childhood intelligence, education, socioeconomic position (SEP), lifestyle, and vascular risk factors.
Independent of childhood intelligence, BMI gain between ages 26 and 36 years was associated with lower memory scores (β per SD increase in BMI in men = −0.11; 95% confidence interval [CI]: −0.19, −0.02), verbal fluency (β in women = −0.11; 95% CI: −0.20, −0.02), and lower National Adult Reading Test score (β in women = −0.08; 95% CI: −0.15, −0.01), but not with speed/concentration (β in men = 0.02; 95% CI: −0.11, 0.07). Associations were largely explained by educational attainment and SEP (P ≥ .10). However, BMI gain at 53 years in men was independently associated with better memory (β = 0.12; 95% CI: 0.03, 0.22), and both underweight (β = −1.54; 95% CI: −2.52, −0.57) and obese (β = −0.30; 95% CI: −2.52, −0.57) women at 53 years had significantly lower memory scores.
The adverse effect of higher BMI gain on midlife cognitive function and cognitive reserve is independent of childhood intelligence but not of education and SEP. The independent association between greater BMI gain in midlife and better cognitive function deserves further investigation.
Epidemiology; Cognitive function; Body size; Adiposity; Vascular risk factors
There is growing evidence of poor mental health and quality of life among survivors of intensive care. However, it is not yet clear to what extent the trauma of life-threatening illness, associated drugs and treatments, or patients' psychological reactions during intensive care contribute to poor psychosocial outcomes. Our aim was to investigate the relative contributions of a broader set of risk factors and outcomes than had previously been considered in a single study.
A prospective cohort study of 157 mixed-diagnosis highest acuity patients was conducted in a large general intensive care unit (ICU). Data on four groups of risk factors (clinical, acute psychological, socio-demographic and chronic health) were collected during ICU admissions. Post-traumatic stress disorder (PTSD), depression, anxiety and quality of life were assessed using validated questionnaires at three months (n =100). Multivariable analysis was used.
At follow-up, 55% of patients had psychological morbidity: 27.1% (95% CI: 18.3%, 35.9%) had probable PTSD; 46.3% (95% CI: 36.5%, 56.1%) probable depression, and 44.4% (95% CI: 34.6%, 54.2%) anxiety. The strongest clinical risk factor for PTSD was longer duration of sedation (regression coefficient = 0.69 points (95% CI: 0.12, 1.27) per day, scale = 0 to 51). There was a strong association between depression at three months and receiving benzodiazepines in the ICU (mean difference between groups = 6.73 points (95% CI: 1.42, 12.06), scale = 0 to 60). Use of inotropes or vasopressors was correlated with anxiety, and corticosteroids with better physical quality of life.
The effects of these clinical risk factors on outcomes were mediated (partially explained) by acute psychological reactions in the ICU. In fully adjusted models, the strongest independent risk factors for PTSD were mood in ICU, intrusive memories in ICU and psychological history. ICU mood, psychological history and socio-economic position were the strongest risk factors for depression.
Strikingly high rates of psychological morbidity were found in this cohort of intensive care survivors. The study's key finding was that acute psychological reactions in the ICU were the strongest modifiable risk factors for developing mental illness in the future. The observation that use of different ICU drugs correlated with different psychological outcomes merits further investigation. These findings suggest that psychological interventions, along with pharmacological modifications, could help reduce poor outcomes, including PTSD, after intensive care.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
The ACTN3 R577X (rs1815739) genotype has been associated with
athletic status and muscle phenotypes, although not consistently. Our objective
was to conduct a meta-analysis of the published literature on athletic status
and investigate its associations with physical capability in several new
population-based studies. Relevant data were extracted from studies in the
literature, comparing genotype frequencies between controls and sprint/power and
endurance athletes. For life course physical capability, data were used from two
studies of adolescents and seven studies in the Healthy Ageing across the Life
Course (HALCyon) collaborative research program, involving individuals aged
between 53 and 90+ years. We found evidence from the published literature
to support the hypothesis that in Europeans the RR genotype is more common among
sprint/power athletes compared with their controls. There is currently no
evidence that the X allele is advantageous to endurance athleticism. We found no
association between R577X and grip strength (P = 0.09,
n = 7,672 in males; P =
0.90, n = 7,839 in females), standing balance, timed get
up and go, or chair rises in our studies of physical capability. The
ACTN3 R577X genotype is associated with sprint/power
athletic status in Europeans, but does not appear to be associated with
objective measures of physical capability in the general population. Hum Mutat
32:1–11, 2011. © 2011 Wiley-Liss, Inc.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
The medical needs of older people are growing because the proportion of the older population is increasing and disease boundaries are widening. This study describes the distribution and clustering of 15 common clinical disorders requiring medical treatment or supervision in a representative British cohort approaching retirement, and how health tracked across adulthood.
Methods and Findings
The data come from a cohort of 2661 men and women, 84% of the target sample, followed since birth in England, Scotland and Wales in 1946, and assessed at 60–64 years for: cardio and cerebro-vascular disease, hypertension, raised cholesterol, renal impairment, diabetes, obesity, hypothyroidism, hyperthyroidism, anaemia, respiratory disease, liver disease, psychiatric problems, cancers, atrial fibrillation on ECG and osteoporosis. We calculated the proportions disorder-free, with one or more disorders, and the level of undiagnosed disorders; and how these disorders cluster into latent classes and relate to health assessed at 36 years. Participants had, on average, two disorders (range 0–9); only 15% were disorder-free. The commonest disorders were hypertension (54.3%, 95% CI 51.8%–56.7%), obesity (31.1%, 28.8%–33.5%), raised cholesterol (25.6%, 23.1–28.26%), and diabetes or impaired fasting glucose (25.0%, 22.6–27.5%). A cluster of one in five individuals had a high probability of cardio-metabolic disorders and were twice as likely than others to have been in the poorest health at 36 years. The main limitations are that the native born sample is entirely white, and a combination of clinical assessments and self reports were used.
Most British people reaching retirement already have clinical disorders requiring medical supervision. Widening disease definitions and the move from a disease-based to a risk-based medical model will increase pressure on health services. The promotion of healthy ageing should start earlier in life and consider the individual's ability to adapt to and self manage changes in health.
To identify the life course model that best describes the association between life course socioeconomic position (SEP) and cardiovascular (CVD) risk factors [body mass index (BMI), systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glycated haemoglobin] and explore BMI across the life course as mediators of the relationship.
The Medical Research Council (MRC) National Survey of Health and Development was used to compare partial F-tests of simpler nested life course SEP models corresponding to critical period, accumulation, and social mobility modes with a saturated model. Then, the chosen life course model for each CVD risk factor was adjusted for BMI at age 53 and lifetime BMI (ages 4, 26, 43, and 53 years).
Among women, SEP was generally associated with CVD risk factors in a cumulative manner; while childhood critical period was the prominent model for men. Using the best fitting SEP models, adjustment for BMI at age 53 reduced associations for all outcomes in both genders. Further adjustment for lifetime BMI (4, 26, 43 and 53 years) did not substantially alter most associations (except for triglycerides).
SEP at different points across life influences CVD risk factors differently in men and women.
UK; social class; life course; social mobility; accumulation; cardiovascular risk
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
Aging; ageing; middle-aged; telomere; cognition; physical
We investigated whether there are subgroups with different underlying (latent) trajectories of midlife systolic blood pressure (BP), diastolic BP and pulse pressure in a UK cohort.
Data are from 1840 men and 1819 women with BP measured at age 36, 43 and 53years. We used unconditional growth mixture models to test for the presence of latent trajectory classes. Extracted classes were described in terms of a number of known lifetime risk factors, and linked to the risk of undiagnosed angina (Rose questionnaire) at age 53 years.
In both sexes for systolic BP, diastolic BP and pulse pressure, there was a large “normative” class (>90% of the sample) characterized by gentle annual increases (eg an increase in male systolic BP of 0.9mmHg/year [95% confidence interval = 0.9 to1.0]), with a smaller class for whom the rate of increase was high (e.g. an increase in male systolic BP of 3.1mmHg/year [2.8 to3.4]). In women there was an additional class for whom BP was high at age 36 and remained high. Persons in the “normative” classes were, on average, heavier at birth and taller at age 7 years, had a lower midlife body mass index, and were less likely to be on antihypertensive medication compared with those in other classes. Among those with no diagnosed cardiovascular disease, those in the classes with more strongly increasing systolic BP and pulse pressure were at greatest risk of angina.
Our study suggests that in midlife the majority of the population have a gentle underlying increase in BP, but that there also exists an important subgroup in whom BP increases much more markedly. These classes may be useful for identifying those most at risk of cardiovascular disease.