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

Hereditary haemochromatosis: associations with morbidity and iron supplement use in 451,243 UK Biobank participants

This is the author accepted manuscript. The final version is available from BMJ Publishing Group via the DOI in this recordSociety for Social Medicine and Population Health and International Epidemiology Association European Congress Annual Scientific Meeting 2019, Hosted by the Society for Social Medicine & Population Health and International Epidemiology Association (IEA), School of Public Health, University College Cork, Cork, Ireland, 4–6 September 2019Medical Research Council (MRC

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.)

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

This is the final version. Available on open access from Impact Journals via the DOI in this recordThe 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.National Institute on Agin

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

The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood

Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was funded by the Velux Stiftung Foundation (Grant Number 822) and supported in part by the Intramural Research Program of the NIH, National institute on Aging.published version, accepted version (12 month embargo

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

Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older UK Biobank Participants

This is the final version. Available on open access from Wiley via the DOI in this recordBACKGROUND/OBJECTIVES Delirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. DESIGN Prospective cohort analysis. SETTING Community‐based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank). PARTICIPANTS Adults aged 60 and older by the end of follow‐up in the linked hospital inpatient admissions data, up to 14 years after baseline (n = 351,320). MEASUREMENTS At baseline, serum vitamin D (25‐OH‐D) levels were measured. We used time‐to‐event models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D deficiency and incident hospital‐diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk. RESULTS A total of 3,634 (1.03%) participants had at least one incident hospital‐diagnosed delirium episode. Vitamin D deficiency (50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR = 1.38; 95% CI = 1.28–1.49; P = 4*10−18). The association was independent of calcium levels, hospital‐diagnosed fractures, dementia, and other relevant cofactors. In genetic analysis, participants carrying more vitamin D–increasing variants had a reduced likelihood of incident delirium diagnosis (HR = .80 per standard deviation increase in genetically instrumented vitamin D: .73–.87; P = 2*10−7). CONCLUSION Progressively lower vitamin D levels predicted increased risks of incident hospital‐diagnosed delirium, and genetic evidence supports a shared causal pathway. Because low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed.Alzheimer’s SocietyMedical Research Council (MRC)National Institute on Agin

Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise

This is the final version of the article. Available from Springer via the DOI in this record.In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t (1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.Wellcome TrustNational Institute for Health Researc

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