The genetics of human ageing

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordThe past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.University of ExeterUniversity of ConnecticutMedical Research Council (MRC)National Institute on Agin

Marky: a lightweight web tracking tool for document annotation

Document annotation is an elementary task in the development of Text Mining applications, notably in defining the entities and relationships that are relevant to a given domain. Many annotation software tools have been implemented. Some are particular to a Text Mining framework while others are typical stand-alone tools. Regardless, most development efforts were driven to basic functionality, i.e. performing the annotation, and to interface, making sure operation was intuitive and visually appellative. The deployment of large-scale annotation jamborees and projects showed the need for additional features regarding inter- and intra-annotation management. Therefore, this paper presents Marky, a new Web-based document annotation tool that integrates a highly customisable annotation environment with a robust project management system. Novelty lays on the annotation tracking system, which supports per user and per round annotation change tracking and thus, enables automatic annotation correction and agreement analysis

Molecular signals from primordial clouds at high redshift

The possibility to detect cosmological signals from the post-recombination Universe is one of the main aims of modern cosmology. In a previous paper we emphasized the role that elastic resonant scattering through LiH molecules can have in dumping primary CBR anisotropies and raising secondary signals. Here we extend our analysis to all the evolutionary stages of a primordial cloud, starting with the linear phase, through the turn-around and to the non linear collapse. We have done calculations for proto-clouds in a CDM scenario and, more generally, for a set of clouds with various masses and various turn-around redshifts, in this case without referring to any particular structure formation scenario. We found that the first phase of collapse, for $t/t_{free-fall}=0.05\div 0.2$ is the best one for simultaneous detection of the first two LiH rotational lines. The observational frequency falls between 30 and 250 GHz and the line width ${\Delta \nu\over \nu}$ is between $10^{-5}$ and $10^{-4}$. As far as we know this is the most favourable process to detect primordial clouds before they start star formation processes.Comment: 26 pages, uuencoded compressed postscript, 7 figures included. Accepted for publication in Ap.

Obesity and Longer Term Risks of Dementia in 65-74 Year Olds

Background: overweight or obesity at ages <65 years associates with increased dementia incidence, but at ≥65 years estimates are paradoxical. Weight loss before dementia diagnosis, plus smoking and diseases causing weight loss may confound associations. Objective: to estimate weight loss before dementia diagnosis, plus short and longer-term body mass index associations with incident dementia in 65-74 year olds within primary care populations in England. Methods: we studied dementia diagnosis free subjects: 257,523 non-smokers without baseline cancer, heart failure or multi-morbidity (group A) plus 161,927 with these confounders (group B), followed ≤14.9 years. Competing hazard models accounted for mortality. Results: in group A, 9,774 were diagnosed with dementia and in those with repeat weight measures, 54% lost ≥2.5 kg during 10 years pre-diagnosis. During <10 years obesity (≥30.0 kg/m2) or overweight (25.0 to <30.0) were inversely associated with incident dementia (versus 22.5 to <25.0). However, from 10 to 14.9 years, obesity was associated with increased dementia incidence (hazard ratio [HR] 1.17; 95% CI: 1.03-1.32). Overweight protective associations disappeared in longer-term analyses (HR, 1.01; 95% CI: 0.90-1.13). In group B, (n = 6,070 with incident dementia), obesity was associated with lower dementia risks in the short and longer-term. Conclusions: in 65-74 year olds (free of smoking, cancer, heart failure or multi-morbidity at baseline) obesity associates with higher longer-term incidence of dementia. Paradoxical associations were present short-term and in those with likely confounders. Reports of protective effects of obesity or overweight on dementia risk in older groups may reflect biases, especially weight loss before dementia diagnosis.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.Supported by the National Institute for Health Research School for Public Health Research (Ageing Well Programme) and the Intramural Research Program of the National Institutes of Health National Institute on Aging.published version, accepted version (12 month embargo), submitted versio

Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: Ethical approval for UK Biobank study was obtained from the North West Multi-Centre Research Ethics Committee. All of the UK Biobank data used in this research is available to bona fide researchers following an application to the UK Biobank (http://www.ukbiobank.ac.uk/register-apply/). The UK Biobank data provided for our approved research project cannot be released by the authors to third parties, this is a legal obligation as part of our Material Transfer Agreement. The authors did not have any special access privileges that others would not have.Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40-70 years at baseline, with outcomes ascertained during follow-up (≤9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (≥15% variation, n = 6,050) compared to low (<12.5% n = 20,844) was strongly associated with mortality (HR 3.10: 95% CI 2.57 to 3.74), adjusted for age, sex, smoking status, education level, mean cell volume and hemoglobin concentration. Higher RDW was also associated with incident CAD (sub-HR 1.67: 1.40 to 1.99), heart failure, peripheral vascular disease, atrial fibrillation, stroke, and cancer (sHR 1.37: 1.21 to 1.55; colorectal cancer sHR 1.92: 1.36 to 2.72), especially leukemia (sHR 2.85: 1.63 to 4.97). Associations showed dose-response relationships, and RDW had long-term predictive value (≥4.5 years after assessment) for the majority of outcomes, which were similar in younger and older persons. In conclusion, higher RDW predicted onsets of a wide range of common conditions as well as mortality in a large healthy volunteer cohort. RDW is not just a short term predictor, as high levels were predictive 4.5 to 9 years after baseline in healthy volunteers. The wide range of outcomes reflects known RDW genetic influences, including diverse disease risks. RDW may be a useful clinical marker for inclusion in wellness assessments.This work is supported by internal funding from the University of Exeter Medical School (L.C.P. and D.M.), a UK Medical Research Council (grant number MR/M023095/1) award (D.M. and J.L.A.), internal funding from the University of Connecticut Health Center (G.A.K.), and the Intramural Research Program of the National Institute on Aging, U.S. National Institutes of Health (L.F.)

Vitamin D: beyond bone.

In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging

Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants.

This is the final version. Available from Wiley Open Access via the DOI in this recordInherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.the National Institute on Agin

Genomics and successful aging: grounds for renewed optimism?

This is a pre-copyedited, author-produced PDF of an article accepted for publication in the Journals of Gerentology following peer review. The version of record is available online at: doi: 10.1093/gerona/gls091.Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned.Dunhill Medical TrustU.S. National Institutes of Healt