1,721,020 research outputs found
Does accelerated epigenetic ageing predict accelerated future musculoskeletal ageing?
No full textThe ability to predict those at risk of more rapid musculoskeletal ageing is vital if therapeutic strategies are to be successful. Precise description of the ageing musculoskeletal phenotype combined with the mapping of epigenetic changes, specifically those within the DNA methylome, enable precise age prediction and ‘epigenetic clocks’ have been formulated to capture ‘biological’ ageing. With this in mind, the broad aims of my thesis are:• To describe the longitudinal change in bone microarchitecture and muscle strength• To investigate the association between baseline epigenetic age acceleration and musculoskeletal outcomes• To identify novel epigenetic marks which are associated with key musculoskeletal indices of grip strength and bone mineral density through Epigenome-Wide Association StudyThis thesis is focused on the Hertfordshire Cohort Study (HCS); a group of community-dwelling, older adults in which baseline blood samples are available for epigenetic analysis. In 2017 I led a musculoskeletal phenotyping pass of the cohort including grip dynamometry, dual-energy X-ray absorptiometry (DXA) and High Resolution peripheral quantitative computed tomography (HR-pQCT) to complement the same assessments which had previously been performed in 2011-12. Longitudinal change in HR-pQCT parameters, grip strength and hip bone mineral density was analysed and the determinants of HR-pQCT parameter change were examined. Using DNA from whole blood leukocytes at HCS baseline (1998-2004) DNA methylation was measured and epigenetic age acceleration calculated (HorvathAge, GrimAge and PhenoAge). The relationship between epigenetic age acceleration at baseline (1998-2004) and musculoskeletal phenotype was examined. In additional exploratory analyses an epigenome-wide approach was utilised to elucidate specific CpG sites associated with cross-sectional grip strength and total femoral neck bone mineral density.Baseline values of HR-pQCT parameters and greater decline in trabecular Bone Mineral Density (BMD) were associated with fracture and change in trabecular BMD was associated with a single-nucleotide polymorphism (SNP) in the WNT16 gene (β= -0.28 (-0.50,-0.07), p=0.011). Greater epigenetic age acceleration, as calculated via the new iterations of the epigenetic clocks (in particular GrimAge), was associated with lower maximum grip strength (β= -1.25 (-2.24,-0.26), p<0.02) and gait speed (β= (-0.04 (-0.09,-0.00), p<0.05) at multiple time points in males. In epigenome-wide analyses, methylation of a CpG site proximal to ECE1 was associated with maximum grip strength (adjusted p<0.05) and biologically plausible pathways including those governing the regulation of the actin cytoskeleton were significantly associated with total femoral neck bone mineral density (p<0.05).These findings are largely hypothesis building and require further investigation and replication. However, they do add to our current understanding of skeletal changes associated with ageing, the ability of epigenetic clocks to predict future musculoskeletal phenotypes and identify novel loci of methylation which are associated with musculoskeletal ageing
Immune-endocrine biomarkers associated with mental health: a 9-year longitudinal investigation from the Hertfordshire Ageing Study
No full textBackground: The study of neural-endocrine-immune system interactions has led to substantial advances in our understanding of neuropsychiatric disorders. Growing evidence reveals the pivotal roles of inflammatory cytokines signalling the brain to produce neurochemical, neuroendocrine, and neuroimmune changes which affect mood and behaviour. Ageing is accompanied by the development of low-grade systemic inflammation which may promote changes in the neural systems predisposing to geriatric depression via the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the longitudinal associations between baseline values and conditional changes (independent of baseline) in immune-endocrine biomarkers and mental health status in a population-based cohort of older adults.
Methods: Data from 347 subjects (200 men, 147 women) who participated in the Hertfordshire Ageing Study at baseline (1994/5, mean age 67.3 years) and at 9-year follow-up were analysed. Serum samples for analysis of inflammatory and endocrinological measures were collected at baseline and follow-up. At follow-up, depression (Hospital Anxiety and Depression Scale) and mental health (Short Form-36 questionnaire) were assessed. Baseline values and changes in biomarkers in relation to risk of high depression scores (top sex-specific third) and low mental health scores (bottom sex-specific third) were examined using logistic regression.
Results: Lower baseline cortisol was related to greater risk of high depression scores; higher baseline cortisol: Dehydroepiandrosterone Sulphate ratio (men only) and higher baseline C-reactive protein (CRP) (women only) were related to greater risk of poor mental health scores. In addition, greater decline in cortisol was related to increased risk of high depression scores among men. These relationships were robust (p<0.05) after controlling for sex, age, BMI, smoking, alcohol consumption and number of systems medicated.
Conclusion: This study provides further evidence of the role of the HPA and inflammation in older adults with poor mental health. In addition, the findings highlight sex differences where increased inflammation in women and declines in cortisol in men was linked to poorer mental health. Further research is warranted to confirm these findings. This could lead to the search for potential biomarkers to stratify medications as well as developing novel intervention targets to improve mental health at older age
Immune-endocrine biomarkers associated with mental health: a 9-year longitudinal investigation from the Hertfordshire Ageing Study
No full textA review of epigenetics and its association with ageing of muscle and bone.
No full textAgeing is defined as the ‘increasing frailty of an organism with time that reduces the ability of that organism to deal with stress’. It has been suggested that epigenetics may underlie the observation that some individuals appear to age faster than others. Epigenetics is the study of changes which occur in an organism due to changes in expression of the genetic code rather than changes to the genetic code itself; that is, epigenetic mechanisms impact upon the function of DNA without changing the DNA sequence. It is important to recognise that epigenetic changes, in contrast to genetic changes, can vary according to different cell types and therefore can demonstrate significant tissue-specificity. There are different types of epigenetic mechanisms: histone modification, non-coding RNAs and DNA methylation. Epigenetic clocks have been developed using statistical techniques to identify the optimal combination of CpG sites (from methylation arrays) to correlate with chronological age. This review considers how epigenetic factors may affect rates of ageing of muscle and bone and provides an overview of current understanding in this area. We discuss studies using first-generation epigenetic clocks, as well as the second-generation iterations, which appear to show stronger associations with the ageing muscle phenotype. We also review epigenome-wide association studies that have been performed in various tissues examining relationships with osteoporosis and fracture. It is hoped that an understanding of this area will lead to interventions that might prevent or reduce rates of musculoskeletal ageing in later life
Epigenetic regulation of bone mass
No full textOsteoporosis, characterised by low bone mass, poor bone structure, and an increased risk of fracture, is a major public health problem. There is increasing evidence that the influence of the environment on gene expression, through epigenetic processes, contributes to variation in BMD and fracture risk across the lifecourse. Such epigenetic processes include DNA methylation, histone and chromatin modifications and non-coding RNAs. Examples of associations with phenotype include DNA methylation in utero linked to maternal vitamin D status, and to methylation of target genes such as OPG and RANKL being associated with osteoporosis in later life. Epigenome-wide association studies and multi-omics technologies have further revealed susceptibility loci, and histone acetyltransferases, deacetylases and methylases are being considered as therapeutic targets. This review encompasses recent advances in our understanding of epigenetic mechanisms in the regulation of bone mass and osteoporosis development, and outlines possible diagnostic and prognostic biomarker applications
Will social media banish the bleep? An analysis of hospital pager activity and instant messaging patterns.
No full textPagers or ‘bleeps’ have been used for intra-hospital communication for over 30 years but are time inefficient and antiquated. We compared pager activity with instant messaging patterns over a 6-month period in a large, UK, teaching hospital. We found that instant messaging was widely used for clinical communication, yet the introduction of an intra-hospital instant messaging platform only led to a modest reduction in pager activity, suggesting that phasing-out of pagers will require a managed transition to alternative messaging technologies. Social network analysis from instant messaging logs also provided insight into patterns of communication that could be used to optimise clinical care
Fracture risk and health profiles differ according to relationship status: findings from the Hertfordshire Cohort Study
Full text linkRegistry studies have suggested associations between relationship status and fracture risk. We considered associations between relationship status and incident fracture in the Hertfordshire Cohort Study, comprising community-dwelling older adults, and explored associations between socioeconomic and lifestyle factors with relationship status. 2997 participants completed a baseline questionnaire (1998–2004) and clinic visit. Participants were followed up until December 2018 using Hospital Episode Statistics, which report clinical outcomes using codes from the 10th revision of the International Classification of Diseases (ICD-10); these codes were used to ascertain incident fractures. Relationship status (not currently married/cohabiting vs currently married/cohabiting) at baseline was examined in relation to incident fracture using Cox regression. Associations between baseline characteristics and relationship status were examined using logistic regression. Mean baseline age was 66.2 years. 80% were married/cohabiting at baseline; 15% had an incident fracture (mean (SD) follow-up duration: 14.4 (4.5) years). The following were related to greater likelihood of not being married/cohabiting: older age (women only); higher BMI (women only); current smoking; high alcohol consumption (men only); poorer diet quality (men only); lower physical activity; leaving school before age 15 (women only); and not owning one’s home. Those not married/cohabiting had greater risk of incident fracture compared to those who were (age-adjusted hazard ratios (95% CI) 1.58 (1.06, 2.38) among men, 1.35 (1.06, 1.72) among women); associations were attenuated after accounting for the above factors associated with relationship status in the corresponding sex. This suggests that differences in health profiles and lifestyle according to relationship status may explain the association between relationship status and fracture risk.</p
Relationships between muscle parameters and history of falls and fractures in the Hertfordshire Cohort Study: do all muscle components relate equally to clinical outcomes?
No full textIn previous work, relationships between muscle and bone size and strength have been demonstrated and were stronger in females, suggesting possible sexual dimorphism. Here we examine sex-specific associations between individual muscle sarcopenia components with clinical outcomes (falls and fractures). 641 participants were recruited. Muscle mass was assessed as cross-sectional area (CSA) by peripheral quantitative computed tomography of the calf, grip strength (GpS) by Jamar dynamometry and function by gait speed (GtS). Falls and fractures were self-reported. Ordinal and logistic regression were used to examine the associations between muscle measurements and outcomes with and without adjustment for confounders. Mean (SD) age was 69.3 (2.6) years. CSA, GpS, and GtS were greater among males (p < 0.002). A higher proportion of females had fallen since age 45 (61.3% vs 40.2%, p < 0.001); in the last year (19.9% vs 14.1%, p = 0.053); and reported a previous fracture since age 45 (21.8% vs 18.5%, p = 0.302), than males. Among females, greater CSA was related to reduced risk of falling and fewer falls in the previous year in fully adjusted analysis only (p < 0.05); higher GpS was related to lower risk of falls since age 45 in unadjusted analysis (p = 0.045) and lower risk of fracture since age 45 in both unadjusted and fully adjusted analysis (p < 0.045). No statistically significant associations were observed for GtS among either sex for any relationships between muscle measurements and clinical outcomes studied. We observed relationships between muscle mass and strength but not function with falls and fractures in females only; further longitudinal studies are required to reproduce these results
60 is the new 40: preparing for better bone health in later life
Full text linkObjective: in this study we evaluated associations between nutritional factors, including calcium supplementation, and outcomes of fracture and cardiovascular mortality. We chose to report both outcomes as an illustration of the importance of nutritional factors in midlife to heart disease as this may be more impactful for supporting behavior change strategies, particularly in men.Methods: this study was nested in the Hertfordshire Cohort Study, a community dwelling cohort of 2,997 adults (47% women) who were extensively phenotyped at baseline and followed up for 20 years using Hospital Episode Statistics linkage.Results: mean (SD) age at baseline was 65.7 (2.9) among men and 66.6 (2.7) among women. There was some evidence that better diet quality was related to reduced risk of hip fracture after adjustment for sex (hazard ratio (95% CI): 0.82 (0.67, 1.00) per SD higher prudent diet score). Dietary calcium intake was not associated with either any fracture or hip fracture. Taking calcium supplements was associated with an increased risk of any fracture, possibly because of reverse causality as calcium supplements will typically be prescribed following an osteoporotic fracture. A higher dietary calcium intake was protective against cardiovascular-related mortality, while taking calcium supplements led to no excess risk (p = 0.870). Higher prudent diet scores, indicative of better diet quality, were related to other beneficial lifestyle choices such as reduced odds of ever smoking [odds ratio (95% CI) per SD higher diet score: 0.69 (0.63,0.74)], and higher physical activity (SD difference in physical activity score per SD higher diet score: 0.06 (0.02,0.10)).Conclusion: we have demonstrated the commonality of lifestyle factors to adverse clinical outcomes of fracture and heart disease in older adults. These data might be used in behavior change strategies aimed to improve nutrition and linked factors in midlife
Longitudinal change in peripheral quantitative computed tomography assessment in older adults: The Hertfordshire Cohort Study
No full textThere are few longitudinal data on change in bone structure and muscle mass, strength and function in later life. We report these, and consider bone–muscle interrelationships in older men and women. We studied 188 men and 166 women from the Hertfordshire Cohort Study, who underwent peripheral quantitative computed tomography (pQCT) of the radius and tibia in 2004–2005 and then again in 2011–2012. Grip strength and gait speed were also assessed at both timepoints. Percentage change per year was calculated for grip strength, gait speed, muscle cross-sectional area (mCSA), fat cross-sectional area (fCSA) and diaphyseal bone parameters [total area (Tt.Ar), cortical area (Ct.Ar), cortical density (cBMD) and trabecular density (tBMD)]. The mean (SD) age of men and women at baseline was 68.9 (2.5) and 69.2 (2.6) years, respectively. Rates of muscle area and strength loss did not differ by sex. Tt.Ar increased with age and faster in men [mean (SD) 1.78 (1.64) %/year] than women [mean (SD) 1.03 (1.69) %/year] in the radius (p < 0.001). In both the radius (p = 0.006) and tibia (p < 0.001), Ct.Ar reduced more rapidly in women than men. Change in Ct.Ar was associated with change in muscle area in the corresponding limb (radius; men: regression coefficient 0.36, 95% CI 0.20–0.52, p < 0.001; tibia; men: regression coefficient 0.14, 95% CI 0.00–0.27, p = 0.043, women: regression coefficient 0.16, 95% CI 0.01–0.30, p = 0.032). We have demonstrated that muscle strength and function decrease faster than muscle mass and have provided further evidence that changes in bone structure with age differ by sex
- …
