Protocol for the PreventIT feasibility randomised controlled trial of a lifestyle-integrated exercise intervention in young older adults

Introduction The European population is rapidly ageing. In order to handle substantial future challenges in the healthcare system, we need to shift focus from treatment towards health promotion. The PreventIT project has adapted the Lifestyle-integrated Exercise (LiFE) programme and developed an intervention for healthy young older adults at risk of accelerated functional decline. The intervention targets balance, muscle strength and physical activity, and is delivered either via a smartphone application (enhanced LiFE, eLiFE) or by use of paper manuals (adapted LiFE, aLiFE). Methods and analysis The PreventIT study is a multicentre, three-armed feasibility randomised controlled trial, comparing eLiFE and aLiFE against a control group that receives international guidelines of physical activity. It is performed in three European cities in Norway, Germany, and The Netherlands. The primary objective is to assess the feasibility and usability of the interventions, and to assess changes in daily life function as measured by the Late-Life Function and Disability Instrument scale and a physical behaviour complexity metric. Participants are assessed at baseline, after the 6 months intervention period and at 1 year after randomisation. Men and women between 61 and 70 years of age are randomly drawn from regional registries and respondents screened for risk of functional decline to recruit and randomise 180 participants (60 participants per study arm). Ethics and dissemination Ethical approval was received at all three trial sites. Baseline results are intended to be published by late 2018, with final study findings expected in early 2019. Subgroup and further in-depth analyses will subsequently be published. Trial registration number NCT03065088; Pre-results

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.Peer reviewe

Protocol for the PreventIT feasibility randomised controlled trial of a lifestyle-integrated exercise intervention in young older adults

Introduction The European population is rapidly ageing. In order to handle substantial future challenges in the healthcare system, we need to shift focus from treatment towards health promotion. The PreventIT project has adapted the Lifestyle-integrated Exercise (LiFE) programme and developed an intervention for healthy young older adults at risk of accelerated functional decline. The intervention targets balance, muscle strength and physical activity, and is delivered either via a smartphone application (enhanced LiFE, eLiFE) or by use of paper manuals (adapted LiFE, aLiFE). Methods and analysis The PreventIT study is a multicentre, three-armed feasibility randomised controlled trial, comparing eLiFE and aLiFE against a control group that receives international guidelines of physical activity. It is performed in three European cities in Norway, Germany, and The Netherlands. The primary objective is to assess the feasibility and usability of the interventions, and to assess changes in daily life function as measured by the Late-Life Function and Disability Instrument scale and a physical behaviour complexity metric. Participants are assessed at baseline, after the 6 months intervention period and at 1 year after randomisation. Men and women between 61 and 70 years of age are randomly drawn from regional registries and respondents screened for risk of functional decline to recruit and randomise 180 participants (60 participants per study arm). Ethics and dissemination Ethical approval was received at all three trial sites. Baseline results are intended to be published by late 2018, with final study findings expected in early 2019. Subgroup and further in-depth analyses will subsequently be published. Trial registration number NCT03065088; Pre-results

Protocol for the PreventIT feasibility randomised controlled trial of a lifestyle-integrated exercise intervention in young older adults

10.1136/bmjopen-2018-023526BMJ OPEN9

A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions

A computational solution for bolstering reliability of epigenetic clocks:Implications for clinical trials and longitudinal tracking

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show that technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components (PCs) from CpG-level data as input for biological age prediction. Our retrained PC versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or previous knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of PC-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies and clinical trials of aging interventions

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P &lt; 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P &lt; 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health

Blood Pressure Loci Identified with a Gene-Centric Array

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10−7 study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r2 = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10−7 at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies