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

Thermal radiation of various gravitational backgrounds

We present a simple and general procedure for calculating the thermal radiation coming from any stationary metric. The physical picture is that the radiation arises as the quasi--classical tunneling of particles through a gravitational barrier. We show that our procedure can reproduce the results of Hawking and Unruh radiation. We also show that under certain kinds of coordinate transformations the temperature of the thermal radiation will change in the case of the Schwarzschild black holes. In addition we apply our procedure to a rotating/orbiting system and show that in this case there is no radiation, which has experimental implications for the polarization of particles in circular accelerators.Comment: 6 pages revtex, added references, publication version. To be published IJMP

APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort

This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.C.L.K., L.C.P., G.A.K., and D.M. are supported in part by an R21 grant (R21AG060018) funded by National Institute on Aging, National Instute of Health, USA, UK Medical Research Council award MR/S009892/1 (PI Melzer) supports J.L.A. J.A.H.M. is supported by National Institute for Health Research, UK Doctoral Research Fellowship DRF-2014-07-177.published version, accepted version (12 month embargo), submitted versio

The Longevity Associated Sh2b3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were from 379,758 European-descent UK Biobank participants, aged 40 to 70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers ≥96) was more common in CC versus TT (Odds Ratio =1.18, 95% CI: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR= 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR=1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.Medical Research Council (MRC)University of Exeter Medical SchoolUniversity of Connecticut School of Medicin

Development and Evaluation of an Intervention to Support Family Caregivers of People with Cancer to Provide Home-based Care at the End of Life: a Feasibility Study

Purpose: To design and evaluate an intervention to address carers’ needs for practical information and support skills when caring for a person with cancer at end of life. Method: Phase I 29 carers were interviewed about need for practical information, support skills and their preferences for information delivery. The preferred format was a booklet. Phase 2 evaluated the booklet. 31 carers and 14 district nurses participated. Validated questionnaires: on perceptions of caregiving and carer health before and after the booklet was used and interviews with both carers and nurses were undertaken.24 carers completed both interviews. Quantitative data were coded using scale manuals and analysed using SPSSv20 and interview data was analysed thematically. Results: Carers were aged 31-82 and cared for people aged 50-92; 8 carers were male and 23 female; 20 cared for a partner, 8 for a parent and 1 for a sibling (2 undisclosed). Carers were positive about the booklet, however many carers would have liked the booklet earlier. Carers reported feeling more positive about caregiving, and more reassured and competent in their role. District nurses found the booklet useful and reported receiving fewer phone calls from study carers than others in similar situations. Conclusions: The booklet intervention was a source of reassurance to carers and it has the potential to be incorporated into everyday practice. The challenge is in when and how to distribute the booklet and more work is required on the timing of delivery in order to maximise the usefulness of booklet to carers

ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants

The Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer's disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to assess their potential as targets for anti-aging interventions. Data were from 379,000 UK Biobank participants, aged 40 to 70 years. e2e3 (n=46,535) had mostly lower lipid-related biomarker levels including reduced total and LDL-cholesterol, and lower risks of CAD (Odds Ratio=0.87, 95% CI: 0.83 to 0.90, p=4.92×10-14) and hypertension (OR=0.94, 95% CI: 0.92 to 0.97, p=7.28×10-7) versus e3e3. However, lipid changes in e2e2 (n=2,398) were more extreme, including a marked increase in triglyceride levels (0.41 Standard Deviations, 95% CI: 0.37 to 0.45, p=5.42×10-92), with no associated changes in CAD risks. There were no associations with biomarkers of kidney function. The effects of both e2e2 and e2e3 were minimal on falls, muscle mass, grip strength or frailty. In conclusion, e2e3 has protective effects on some health outcomes, but the effects of e2e2 are not similar, complicating the potential usefulness of e2 as a target for anti-aging intervention.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This research was funded by the National Institute on Aging (R21AG060018) and conducted using the UK Biobank resource, under application 14631. UK Biobank received an approval from the UK Biobank Research Ethics Committee (REC) (REC reference 11/NW/0382).published versio

Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank

This is the final published version. Available from BMJ publishing group via the DOI in this record.Data are available on application to the UK Biobank (www.ukbiobank.ac.uk/register-apply).Objective To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent. Design Cohort study. Setting 22 centres across England, Scotland, and Wales in UK Biobank (2006-10). Participants 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification. Main outcome measure Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women. Results Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest. Conclusions In a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.Medical Research Council (MRC)University of Exeter Medical SchoolUniversity of Conneticut Health CentreNational Centre for AgeingPublic Health Englan

Foraging in the limpet Patella vulgata: The influence of rock slope on the timing of activity

Preliminary observations of limpet activity at Lough Hyne, in south-west Ireland, showed that individuals on steep slopes were primarily active at night, when emersed; while those on near-horizontal rocks were often active during daytime submersion. Observations over an 11 d period of limpet populations on a near-vertical and a near-horizontal site, only 45 m apart, confirmed that animals on the near-vertical site were active on nocturnal low tides, whilst those on the near-horizontal site were active on daytime high waters. A short-term survey at ten sites, which had limpets on both extremes of slope (i.e. either near-vertical or near-horizontal), showed that limpets on near-horizontal surfaces were, on average, more active at daytime high waters than those on near-vertical faces. In 1996 and 1997 surveys of activity at daytime high, and nocturnal low waters were conducted at sites (14 - 15) with varying rock slopes (~3 - 87°). In all cases, limpets on more steep slopes were active at nocturnal emersion whilst animals on more gentle slopes were active on daytime submersion periods. In most cases these trends were significant and explained between 22 - 40% and 37 - 44% of the variation in activity with site in 1996 and 1997 respectively. Analysis of the head orientation of limpets on their home scars showed that animals orientated in a down shore direction at all sites (1997 data) suggesting that limpets do perceive and respond to slope. Whilst slope does appear to influence the timing of limpets' activity (and especially on very steep or gently sloping sites) it does not account for a large degree of the variation in activity and, on sites with slopes between 30 and 60°, is likely to work in combination with other factors.published_or_final_versio

Sources and sinks of acetone, methanol, and acetaldehyde in North Atlantic air

International audienceMeasurements of acetone, methanol, acetaldehyde and a range of non-methane hydrocarbons have been made in North Atlantic marine air at the Mace Head observatory. Under maritime conditions the combination of OVOCs (acetone, methanol and 5 acetaldehyde) contributed up to 85% of the total mass of measured non methane organics in air and up to 80% of the OH radical organic sink, when compared with the sum of all other organic compounds including non-methane hydrocarbons, DMS and OH-reactive halocarbons (trichloromethane and tetrachloroethylene). The observations showed anomalies in the variance and abundance of acetaldehyde and acetone 10 over that expected for species with a remote terrestrial emission source and OH controlled chemical lifetime. A detailed model incorporating an explicit chemical degradation mechanism indicated in situ formation during air mass transport was on timescales longer than the atmospheric lifetime of precursor hydrocarbons or primary emission. The period over which this process was significant was similar to that of airmass mo15 tion on intercontinental scales, and formation via this route may reproduce that of a widespread diffuse source. The model indicates that continued short chain OVOC formation occurs many days from the point of emission, via longer lived intermediates of oxidation such as organic peroxides and long chain alcohols

Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

This is the final version. Freely available on open access from Impact Journals via the DOI in this recordA public use file of data from the WLS is available from the Wisconsin Longitudinal Study, University of Wisconsin-Madison, 1180 Observatory Drive, Madison, Wisconsin 53706 and at (http://www.ssc.wisc.edu/wlsresearch/data).We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p<5*10-8), including 8 previously identified for traits including survival, Alzheimer's and cardiovascular disease. Of these, 4 were also associated with longest 10% survival (mothers age ≥90 years, fathers ≥87 years), with 2 additional associations including MC2R intronic variants (coding for the adrenocorticotropic hormone receptor). Mother's age at death was associated with 3 additional loci (2 linked to autoimmune conditions), and 8 for fathers only. An attained age genetic risk score associated with parental survival in the US Health and Retirement Study and the Wisconsin Longitudinal Study and with having a centenarian parent (n=1,181) in UK Biobank. The results suggest that human longevity is highly polygenic with prominent roles for loci likely involved in cellular senescence and inflammation, plus lipid metabolism and cardiovascular conditions. There may also be gender specific routes to longevity.This work was generously funded by an award to DM and LH by the Medical Research Council MR/M023095/1. LF is supported by the Intramural Research Program of the National Institute on Aging, U.S. National Institutes of Health. Input from CK and GK was supported by the University of Connecticut Health Center. The Health and Retirement Study (HRS) is a longitudinal project sponsored by the National Institute on Aging (NIA U01AG009740) and the Social Security Administration. This research uses data from the Wisconsin Longitudinal Study (WLS) of the University of Wisconsin-Madison. Since 1991, the WLS has been supported principally by the National Institute on Aging (AG09775, AG21079 and AG33285), with additional support from the Vilas Estate Trust, the National Science Foundation, the Spencer Foundation and the Graduate School of the University of Wisconsin-Madison