Advances in our understanding of the biology of skeletal muscle ageing are being made at pace, with great potential for these findings to inform the identification of novel treatments for sarcopenia. However, translation of findings from animal models to humans has been hampered by limitations of existing human muscle biopsy studies. Devised to directly address this challenge, the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse is a unique resource for the study of human muscle ageing across adulthood. This deep-phenotyped observational study of 260 community-dwelling men and women aged 18 to 85 years living in North East England includes muscle biopsy samples and detailed characterisation of physical function, health status and sociodemographic and behavioural risk factors. Underpinned by broad interdisciplinary research and clinical expertise this study is catalysing cutting-edge translational research on human muscle ageing across the adult life course.

Abstract Background Loneliness is an important public health issue associated with mortality and morbidity. Often researched amongst older people, less is known about risk factors for loneliness among adults aged 50–64 years who are in work. We investigated (a) if exit from the workforce increases the odds of loneliness; (b) whether adverse psychosocial work factors are associated with increased odds of loneliness over 2 years of follow-up; and (c) whether the association is stronger among subjects still working compared with those who have exited the workforce. Methods Data came from the Health and Employment After Fifty (HEAF) study, a large population cohort who provided questionnaire information about work and health at baseline and 2 annual follow-ups. Logistic regression was used to explore the association between psychosocial risk factors and loneliness at follow-up 2, with adjustment for loneliness at baseline, sex, age, self-rated health, living alone, and mental health diagnosis. Results Of the initial 8134 participants, 4521 were working at baseline and provided data for this analysis. Of those, 507 (11.2%) were defined as lonely at 2 years’ follow-up. Exiting the workforce was not significantly associated with loneliness (OR = 1.1, 95%CI: 0.7–1.7). However, negative psychosocial work factors predicted loneliness at follow-up. After mutual adjustment, lack of choice at work (OR: 1.5, 95%CI: 1.1–1.9), often lying awake worrying about work (OR: 1.4, 95%CI: 1.0–1.9) and perceived not coping with physical demands of the job (OR: 1.3, 95%CI: 1.0–1.7) were independent predictors, with associations robust to adjustment for demographic factors and health. Associations were only slightly altered when we restricted the sample to those who remained in work until the end of follow-up. Conclusions Loneliness amongst middle-aged working adults is not predicted by permanent work exit but is predicted by individuals’ perceptions about their work. Provision of good-quality work, matched to the capacity of the older worker, could prevent loneliness.

Aim Generally, good work is good for health but there are few objective data about the effect of permanent exit from work (either through normal retirement, or health-related job exit) on health at older ages. We aimed to explore if exit from the workforce is followed by a change in self-rated health, using longitudinal data from the Health and Employment After Fifty (HEAF) Study. Methods A cohort of participants aged 50–64 years were recruited from 24 English general practices in 2013–14 and have been followed-up annually by postal questionnaire. At baseline, information was collected about demographic and employment circumstances, physical workload, psychosocial aspects of work and their general health. At each subsequent follow-up, participants self-rated their health and additionally reported whether they were still in paid employment or whether they had exited the workforce, and if so, whether the reason for exit was at least partly due to their health. We used logistic regression modelling to explore the effect of exit from the workforce on changes in self-rated health after adjustment for self-rated health at baseline, before and after controlling for demographic, employment, and socio-demographic factors. Results HEAF recruited a total of 8,134 people aged 50–64 years at baseline, amongst whom 5,059 were in paid employment and were successfully followed-up. Of these, 3,617 were still working 5 years later, 947 exited work permanently not for health reasons, and 333 exited work permanently at least partly due to their health. Self-rated health remained the same for: 53% of those still in paid employment; 55% of those who exited the workforce not on health grounds; and 47% of those who exited due to their health. Self-rated health improved from baseline to 5-year of follow-up for: 21% of those still in paid employment; 25% of those who exited the workforce not on health grounds; and 18% among those who exited due to their health. Regression analysis showed that normal exit from the workforce was associated with improving health subsequently (OR: 1.32, 95%CI: 1.07,1.61), while health-related exit was associated with poorer health subsequently (OR: 2.88, 95% CI: 2.16,3.85). These effects were stronger among males than females, and were robust to adjustments for demographic, employment, and socio-demographic factors. Conclusion This study highlights the need for more in-depth exploration of the dynamic impact of work exit on health amongst older people, aiming to develop effective policy measures for a healthy transition from work to retirement.

Background Population demographics are changing due to increased longevity and declining birth rates, precipitating a demand to encourage people to work to older ages. Whilst legislative changes have enabled this, little is currently known about factors which employers could influence within workplaces to encourage later working. We investigated the role of work-related factors in retirement decisions in the UK, utilising the Health and Employment After Fifty (HEAF) prospective cohort study. Methods The HEAF cohort was incepted in 2013–14 using the sampling frame of 24 GP surgeries across England. People aged 50–64 years at baseline completed annual questionnaires about health, work and retirement plans. HEAF FIRST involves mixed-methods research starting with qualitative interviews and a systematic review preceding and informing the design of a nested case-control study. A questionnaire was designed to investigate the role of work-related factors on retirement status. Questionnaires were sent to people who were employed at baseline but self-reported retirement by 2018 (cases) and people who were working at baseline and remained employed in 2018, matched on age +/- 2 years and sex. Those who retired mainly for health reasons were excluded. The relationship between work-related factors and retirement was investigated using logistic regression models adjusted for age and sex (matching factors), finances, marital, and socio-economic status. Results Questionnaires were posted to 570 cases and 570 controls. In total, responses were received from 488 retirees and 448 current workers. On average, retirees (61% women) were one-year older, financially better off and of higher socio-economic position than workers (62% women). Retirees had retired at mean age 61.6 years, 64% pre-State Pension Age (SPA), 11% at SPA (+/-6 months) and 25% post-SPA. The following work factors were associated with increased odds of retirement (all results adjusted for factors detailed above): effort reward imbalance, (OR 1.43, 95%CI 1.26,1.63), less flexibility (OR 1.25, 95%CI 1.10,1.42), constant availability (OR 1.30 95%CI 1.14,1.49) work-life conflict (OR 1.35 95%CI 1.18,1.55) high demand/low control (OR 2.00, 95%CI 1.33,3.01). Discussion Our results suggest that work-related factors play an important role in retirement. People who are working in jobs which offer flexibility, are rewarding, minimise conflict with home life and offer autonomy are more likely to report working to older ages. The work-related factors identified can be utilised to inform employer-based interventions to encourage people to work to older ages.

IntroductionIn the UK, workers who were essential to maintain communications, travel, food and healthcare were deemed ‘key workers’. There is scarce evidence about the effect that the pandemic had on this group of workers as compared with people who were home working, furloughed or retired.ObjectivesTo compare measures of health and lifestyle amongst older key workers as opposed to other older adults working or not working during the pandemic.MethodsIn February 2021 participants in the Health and Employment After Fifty (HEAF) study (aged 55–73) were sent an online survey, enquiring about changes to their mental/physical health and lifestyle during the first UK lockdown (starting late March 2020). Logistic regression was used to explore the association between being a keyworker (healthcare/not healthcare) and adverse outcomes, with adjustment for age and sex. Participants in work but not identifying themselves as key workers were used as the reference category.ResultsA total of 2,040 (46%) returned a usable questionnaire and completed the question about key worker status. 281 were in work but not as key workers;50 were key workers in healthcare;298 were key workers not in healthcare;1,411 were retired. Key workers were predominantly women. Key workers not in healthcare were more likely to see a worsening of mental health (OR=1.6;95%CI 1.0 to 2.4) physical health (OR=1.5;95%CI 1.0 to 2.3), to report that their diet was less healthy (OR=1.8;95% CI 1.2 to 2.8) and to report eating more than pre-lockdown (OR=1.6;95%CI 1.1 to 2.4) compared with participants in work but not as key workers. Associations were similar among key workers in healthcare, however they did not reach statistical significance.ConclusionBeing a key worker during the pandemic (especially not in healthcare) was associated with a deterioration of health and lifestyle choices.

ObjectivesHealth and job satisfaction are key independent determinants of ability to work to older ages. We investigated the interaction of these two important factors on health-related job loss (HRJL) over 2 years of follow-up comparing male and female older workers.MethodsA population sample of adults aged 50–64 years, recruited from 24 English general practices in the Health and Employment After Fifty (HEAF) study, completed questionnaires at baseline with follow-ups at 12 and 24 months. Multiple-record Cox proportional hazards models were performed to explore the main effects of, and potential interactions between, job satisfaction and self-rated health (SRH) as predictors of time to first HRJL.ResultsOf the initial 8134 participants, 5143 were ever in work in the study period. Among men, 5.7% and 14.3% reported job dissatisfaction (those in good and poor SRH, respectively), while among women these percentages were 4.6 and 12.9. HRJL was reported by 106 men and 176 women. Men in good health dissatisfied with their job had a sixfold (HR=6.4; 95% CI 3.3 to 12.4) increased risk of HRJL compared with men satisfied with their job (significant multiplicative interaction). Women dissatisfied with their job were more likely to have an HRJL within 2 years of follow-up irrespective of their SRH.ConclusionsSRH and job dissatisfaction have important individual effects on the risk of stopping work for health among older workers. These findings point to the importance of job satisfaction in reducing health-related exit from paid work among older workers.

Introduction Ageing populations (caused by increased longevity and declining birth-rates) have changed workforce demographics in high-income countries, placing strain on pension systems. Recent policy changes have sought to encourage work at older ages. Modifiable work-related factors may present a further opportunity to extend working lives. Objectives To establish the influence of work-related factors on the decision to retire in a contemporary UK cohort. Methods The HEAF study is a cohort of English participants aged 50–64 years in 2013–2014. Participants complete annual questionnaires asking about work and health. HEAF FIRST involved qualitative interviews with retirees which informed the design of a nested case-control study. Qualitative - Retirees were sampled by socio-economic status (SES) and sex. Semi-structured telephone interviews were conducted asking about reasons for retirement and were thematically analysed. Questionnaire - Questionnaires were sent to employees in 2013–2014, who had reported retirement by 2018 (cases) or had remained employed (controls), matched on age (+/-2 years) and sex. Logistic regression models adjusted for sex, age, SES, finances, and marital status were used to investigate associations between work-related factors and retirement. Results Qualitative - Work-related factors both pushed towards retirement and pulled back towards work. Retirement decisions seemed multi-factorial and work-related factors played an important role. Questionnaire - 936 responses were received from workers (n=448) and retirees (n=488). Increased retirement was associated with the following factors: (adjusted as described above): job strain (OR 2.00, 95%CI 1.33,3.01), effort/reward imbalance (OR 1.43, 95%CI 1.26,1.63), longer commutes (OR 1.36, 95%CI 1.02,1.82), lower flexibility (OR 1.25, 95%CI 1.10,1.42), perceived declining standards 2.01 (1.51,2.68), and perceived isolation (OR 1.79, 95%CI 1.18,2.71). Conclusion In this cohort retirement seemed to be influenced by work-related factors. Later working was more likely where workers perceived appreciation, autonomy or flexibility in their jobs. Employers may be able to encourage later working by implementing interventions based on these findings.

A growing evidence base links individual lifestyle factors to physical performance in older age, but much less is known about their combined effects, or the impact of lifestyle change. In a group of 937 participants from the MRC National Survey of Health and Development, we examined their number of lifestyle risk factors at 53 and 60–64 years in relation to their physical performance at 60–64, and the change in number of risk factors between these ages in relation to change in physical performance. At both assessments, information about lifestyle (physical activity, smoking, diet) was obtained via self-reports and height and weight were measured. Each participant’s number of lifestyle risk factors out of: obesity (body mass index ≥ 30 kg/m 2 ); inactivity (no leisure time physical activity over previous month); current smoking; poor diet (diet quality score in bottom quarter of distribution) was determined at both ages. Physical performance: measured grip strength, chair rise and standing balance times at both ages and conditional change (independent of baseline) in physical performance outcomes from 53 to 60–64 were assessed. There were some changes in the pattern of lifestyle risk factors between assessments: 227 (24%) participants had fewer risk factors by age 60–64; 249 (27%) had more. Reductions in risk factors were associated with better physical performance at 60–64 and smaller declines over time (all p < 0.05); these associations were robust to adjustment. Strategies to support reduction in number of lifestyle risk factors around typical retirement age may have beneficial effects on physical performance in early older age.

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr−1 faster in smokers than in non-smokers (95% CI: −2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr−1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

Citation for published version: Bateson, M, Aviv, A, Bendix, L, Benetos, A, Ben-shlomo, Y, Bojesen, SE, Cooper, C, Cooper, R, Deary, IJ, Hägg, S, Harris, SE, Kark, JD, Kronenberg, F, Kuh, D, Labat, C, Martin-ruiz, CM, Meyer, C, Nordestgaard, BG, Penninx, BWJH, Pepper, GV, Révész, D, Said, MA, Starr, JM, Syddall, H, Thomson, WM, Van Der Harst, P, Whooley, M, Von Zglinicki, T, Willeit, P, Zhan, Y & Nettle, D 2019, 'Smoking does not accelerate leucocyte telomere attrition: A meta-analysis of 18 longitudinal cohorts', Royal Society Open Science, vol. 6, 190420. https://doi.org/10.1098/rsos.190420

JBMR PlusVolume 2, Issue S1 p. S1-S50 Society AbstractsOpen Access Bone Research Society Abstracts First published: 01 October 2018 https://doi.org/10.1002/jbm4.10073Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat The Bone Research Society (BRS; www.boneresearchsociety.org), formerly the Bone and Tooth Society, was founded in 1950. The BRS is one of the largest national scientific societies in Europe dedicated to clinical and basic research into mineralized tissues and is the oldest such society in the world. Meetings are held annually, attracting a wide audience from throughout the UK and beyond. The presentations are traditionally balanced between clinical and laboratory studies. The participation of young scientists and clinicians is actively encouraged. The Annual Meeting this year was organized by a team from The University of Southampton, co-chaired by Dr Kate Ward and Professor Nicholas Harvey, and also including Dr Claire Clarkin, Professor Richard Oreffo, and Professor Cyrus Cooper. The program brought together world leaders in musculoskeletal clinical and basic science. A multidisciplinary faculty provided a breadth of education and research from the Developmental Origins of disease through tissue regeneration and biomechanical engineering. The sessions this year were: Rare bone diseases Muscle bone interactions Tissue engineering and regenerative medicine Cellular senescence Imaging: from mice to men Osteocytes Prevention of osteoporotic fracture through the lifecourse (Dent Award—Cyrus Cooper) Early-life origins of disease Ageing Osteo-angiogenic coupling More than 120 abstracts were submitted, and those that were accepted and presented at the meeting are listed here. Invited Speaker Abstracts I will describe the suite of tools and technologies developed within the Bradley group (typically with collaborators) that are focused on controlling or modulating cellular behavior—with a key vision being that the material itself should provide the cues and stimuli that drive cell fate and behavior. In my talk, I will describe a variety of high-throughput approaches developed in the group, from the use of combinatorial delivery strategies to microarray platforms that allow a deep analysis of how substrate morphology and structure drive cellular behavior. Citing Literature Biological processes leading to tissue formation during embryonic development are characterized by a large stability and reproducibility of events, typically referred to as “robustness.” Would regenerative medicine approaches be more repeatable and effective if they targeted the recapitulation of molecular pathways typical of tissue development? Within the exemplifying context of cartilage and bone repair, this lecture will introduce and discuss the challenges and opportunities of regenerative concepts based on mimicking developmental processes. Rather than engineering a tissue, the strategy would target the use of cells (eg, mesenchymal stromal cells) to engineer temporally staged processes, recapitulating events of development (eg, endochondral ossification for bone or joint cavitation for articular cartilage). The product would be a construct containing the necessary and sufficient cues to autonomously remodel into the target repair tissue upon grafting. In this perspective, however, cells in adults may strongly differ from multipotent embryonic cells, and typically reside in an environment, which is tightly regulated by post-natal mechanical conditioning or immune/inflammatory processes. Thus, shouldn't tissue regeneration strategies be inspired by development but adapted to be effective in a context, which is different from the embryo? This would require the redesign of the developmental machinery for regenerative purposes by establishing artificial events or conditions. Will the resulting approach of “developmental re-engineering” offer a chance for enhanced regeneration to those tissues with limited capacity to recover from injuries or within pathological settings, reducing the potential for endogenous repair? Citing Literature In recent years, skeletal stem and progenitor cell populations have been identified in bone marrow based on markers such as Nestin, Leptin receptor (LepR), and Gremlin1. Genetic lineage tracing models in mice have provided important insights in their roles in bone homeostasis, fracture repair, and hematopoiesis. More recently, the stem and progenitor cells that are resident in the synovial joint are beginning to be defined and their functions elucidated. Lineage tracing of progenitor cells in cartilage has provided important new insights into the process of articular cartilage formation and maintenance. Work in our lab has focused on characterizing stem and progenitor cells in the synovial membrane. During development, synovial joints form from a stripe of tissue in the limb bud that is characterized by expression of growth/differentiation factor 5 (Gdf5). Tracing of Gdf5-expressing cells showed that Gdf5-lineage cells persist in adult knee synovium up to at least 1 year of age. They express a range of mesenchymal stromal cell markers, such as Pdgfrα and Sca1, but show little overlap with cells expressing the skeletal stem/progenitor markers Nestin, LepR, and Gremlin1, suggesting they are a self-contained lineage within the skeletal system. FACS-sorted and culture-expanded Gdf5-lineage cells are highly chondrogenic but poorly osteogenic in vitro, and they promote cartilage repair upon orthotopic transplantation into cartilage defects of mice. Endogenously, Gdf5-lineage cells proliferate in synovium in response to traumatic cartilage injury, leading to synovial lining hyperplasia, and underpin spontaneous repair of cartilage defects. Both processes are dependent on the activity of the transcriptional co-factor Yes-associate protein (Yap) in these cells. In pathology, using the destabilization of the medial meniscus model of osteoarthritis, Gdf5-lineage cells were found to contribute to chondro-osteophyte formation and subchondral bone remodeling. In conclusion, recent findings are starting to unravel distinct mesenchymal stromal cell subsets in adult joint tissues, identifying the key players in joint pathophysiology and promising therapeutic targets for cartilage repair and treatment of osteoarthritis. Citing Literature With the aging of the population and projected increase in osteoporotic fractures, coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (eg, atherosclerosis, diabetes, frailty), all sharing aging itself as the leading risk factor, there is growing interest in the “Geroscience Hypothesis,” which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying risk factor—age. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. There is now convincing evidence that senescent cells accumulate with age and drive age-related tissue dysfunction. Consistent with this, senescent cells have been shown to increase with aging in the bone microenvironment in mice and in humans. These cells produce a pro-inflammatory secretome that leads to increased bone resorption and decreased bone formation, and approaches that either eliminate senescent cells or impair the production of their pro-inflammatory secretome have been shown to prevent age-related bone loss in mice. Moreover, targeting senescent cells leads to a reduction in bone resorption and either a maintenance (trabecular bone) or increase (cortical bone) in bone formation, thus making this approach fundamentally different from conventional anti-resorptive therapy, which leads to a reduction in bone resorption and a coupled decrease in bone formation. Thus, targeting cellular senescence represents a novel therapeutic strategy to prevent not only bone loss but also potentially multiple age-related diseases simultaneously. Citing Literature In this talk, I would describe our work using label-free, non-invasive, and non-destructive techniques of Raman spectroscopy and multimodal non-linear microscopies such as coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) in the area of skeletal repair and regeneration for quantitative understanding and objective assessment of cell behavior and tissue development. Using Raman spectroscopy, we have studied osteogenesis in primary bone cells from mice and humans. We characterized signatures of early osteoblast behavior by quantifying changes in DNA, phosphate species, and collagen matrix during different stages of osteogenic commitment.1 It was found the Raman spectroscopy could detect changes in phosphates earlier than the alkaline phosphatase assay as well as distinguish different species. We have further aimed to quantitatively understand and objectively assess cell behavior and tissue development for applications in skeletal repair and regeneration using multimodal techniques. We combine CARS, SHG, and two-photon excited autofluorescence (TPEF) on a single platform for simultaneous interrogation. These techniques image the chemical and structural composition allowing us to study the differentiation of skeletal stem cells (SSCs) and visualization of temporal changes accompanying adipogenesis2 and chondrogenesis3 in a completely label-free, non-invasive, and non-destructive way. We also verified both visually as well as through gene expression analysis that the SSC-differentiated live tissue constructs remain viable and are unaffected by CARS and SHG imaging. Furthermore, elucidation of the architecture of the differentiated tissue is especially important for cartilage tissue engineering. The application of 3D in place of 2D imaging thus enabled us to obtain a comprehensive understanding of the collagen fiber network during the chondrogenic development of SSCs. Quantitation of the various molecular and structural readouts allowed us to develop assessment parameters to track the differentiation of SSCs and their in vitro tissue development. The non-invasive and non-destructive 3D imaging opens new avenues for real-time applications, while the label-free quantitation allows unprecedented insight and characterization of the development stages of skeletal “engineered-tissue” in the clinic for optimal use in therapy. References 1 Smith, SJ, Emery, R, Pitsillides, A, Clarkin, CE, Mahajan, S. Detection of early osteogenic commitment in primary cells using Raman spectroscopy. Analyst. 2017;142:1962–73. 2 Smus, JP, Costa, Moura C, McMorrow, E, Tare, RS, Oreffo, ROC, Mahajan, S. Tracking adipogenic differentiation of skeletal stem cells by label-free chemically selective imaging. Chem Sci. 2015;6:2282–6. 3 Moura, CC, Lanham, SA, Monfort, T, Bourdakos, KN, Tare, RS, Oreffo, ROC, Mahajan, S. Quantitative temporal interrogation in 3D of bioengineered human cartilage using multimodal label-free imaging [unpublished data]. Citing Literature It is well accepted that mechanics play an important role for the biological processes that occur during musculoskeletal regeneration and healing. The local mechanical environment is a result of a complex interaction between the soft and hard tissues at the organ, limb, and patient level of the musculoskeletal system as motion occurs. Identification of key parameters that influence and modify the internal loading conditions is therefore essential in order to better understand the mechanisms that govern and regulate musculoskeletal healing and regeneration. Computational models informed by imaging data provide an effective means for characterizing the mechanical environment. This talk will explore the fidelity of such computational methods in their application to human and animal models alike and discuss differences and similarities in their respective organ- and tissue-level loading conditions. Providing a quantitative understanding of the mechanical boundary conditions across animals will provide the essential basis for unravelling the detailed mechanisms governing the biology of musculoskeletal regeneration. Citing Literature Significant progress has been made over the last two decades to scrutinize bone porosity and particularly intracortical microstructure down to a cellular level, with important implications for our understanding of bone physiology, mechanics, and mechanobiology. However, this focus on bone porosity can divert the attention from the important interplay between angiogenesis and osteogenesis and the role of the vasculature for bone health and bone diseases for instance. On this account, recent advancements in high-resolution 3D X-ray and electron microscopy imaging will be presented here, which can be used to assess hard and soft tissues simultaneously, including mineralized bone tissue and soft tissues. The presentation will also shortly touch on our recent development of a novel micro-computed tomographic system that is optimized for soft tissues, an area traditionally considered suboptimal or unsuitable for X-ray imaging. Citing Literature It is not only osteoblasts and osteoclasts that are critical for bone remodeling but also the osteocyte, a central regulator of the activity of these two bone cell types in the growing, mature, and aging skeleton. The osteocyte is not only the bone mechanosensor but also a hormonally responsive cell that translates these two types of stimuli into signals that synchronize osteoblast and osteoclast activity. This synchronization is accomplished through both positive and negative signals sent by the osteocyte. For example, the osteocyte can send negative signals to osteoblasts such as sclerostin and DKK1 and positive signals of bone formation such as prostaglandin and wnts. Osteocytes can produce both M-CSF and RANKL for osteoclast formation. With menopause and aging, the osteocyte takes on more of its role as a negative regulator of skeletal mass. This long-lived cell becomes senescent, a state that is more likely to support resorption. The osteocyte can also function similarly to the osteoclast by producing factors such as TRAP and Cathepsin K to remove their perilacunar matrix under calcium-demanding conditions. Under physiological conditions, this perilacunar matrix is replaced, whereas under pathological conditions, this process continues and becomes detrimental with regard to bone mass. The osteocyte is also an endocrine cell that produces factors that target distant organs such as the kidney through factors such as FGF23. FGF23 is regulated by Phex and Dmp1, early osteocyte factors, and MEPE, a protein made by the mature osteocyte. Muscle function and myogenesis can be increased by factors made by osteocytes such as Wnt3a and prostaglandin; however, with aging, osteocytes produce unknown factors that decrease muscle mass. Ideally, manipulating the osteocyte so that it functions on the side of bone formation and/or maintenance of bone mass is a major goal. Recently, it has also been described that muscle factors such as irisin or BAIBA can also retain bone mass under conditions of unloading. Mechanical loading (exercise) maintains and extends healthy functions of osteocytes to retain bone mass. Loading of bone and factors made by contracted muscle may be a new avenue for designing therapeutics to maintain bone health. Citing Literature There is now substantial evidence from both human epidemiological studies and animal models that an adverse intrauterine environment induced by a variety of environmental and maternal factors such as diet, body composition, or endocrine factors can induce a phenotype in the offspring that is characterized by an increased risk of developing chronic non-communicable diseases in later life. The mechanism by which cues about nutrient availability in the postnatal environment are transmitted to the fetus and the process by which different, stable phenotypes are induced are beginning to be understood and involve the epigenetic regulation of specific genes. Epigenetic processes induce heritable change in gene expression without altering gene sequence. The major epigenetic mechanisms include DNA methylation, histone modification and non-coding RNAs. The epigenetic changes induced in response to nutritional cues from the mother may allow the fetus to adjust its developmental program in order to be better adapted to the future environment, while inappropriate adaptations may predispose an individual to increased risk of a range of non-communicable diseases. This talk will describe how both maternal and paternal diet can influence the health of the child through the altered epigenetic regulation of genes, how epigenetic changes in early life may be used as predictive markers of future disease risk, and how nutritional interventions in postnatal life may be able to reverse the epigenetic and phenotypic changes induced by an adverse early life environment. Citing Literature Non-communicable diseases (NCDs) pose an increasing threat to global health and economic sustainability in both high- and low-income countries, accounting for >70% of deaths globally. Fixed genetic variation accounts for only a small fraction of inherited NCD risk, and adult lifestyle interventions have had disappointing impact. Risk of NCDs is set partly during early life, when environmental influences including mother's (and to an extent father's) diet, body composition, exposure to stress and smoking or unhealthy alcohol intake affect development of the fetus and newborn, conditioning its responses to later environmental challenges such as an obesogenic lifestyle. If the cues that the baby detects are inaccurate, eg, as a result of unbalanced maternal diet or because lifestyle transition occurs between generations through migration or rapid economic development, its responses are mismatched to later environmental challenges, leading to greater NCD risk. Additionally, parents with obesity and NCDs such as diabetes can pass risk to their children, perpetuating the cycle across multiple generations. Gestational diabetes is also increasing and carries risk of later type 2 diabetes for both mother and child. Epidemiological, clinical, and basic science research has indicated underlying mechanisms, many of which involve epigenetic processes. These can serve as early markers of later risk, may be reversible, and could be used to monitor efficacy of interventions. Adopting a life course approach to the primary prevention of NCDs is now essential, starting in the preconception period by promoting healthy diets, body composition, and behavior among adolescents and young adults, not only for their later health but also for that of the next generation. While the problem of NCDs is global, sustainable solutions will have to be country—and culturally—specific. The life course approach to NCD prevention is now included in UN and WHO initiatives. Citing Literature Based on recent systematic reviews and meta-analyses, the risk of hip fracture is increased by at least twofold in patients with Parkinson's disease, recent stroke, dementia, HIV, heart failure, previously hospitalized with chronic obstructive pulmonary disease (COPD), end-stage renal disease, and type 1 (but not type 2) diabetes. Patients over age 65 years with Parkinson's disease also have more than a 10% per year risk of clinical fractures. In the United States, there are more patients with a high risk of fracture due to these conditions than patients with “osteoporosis” defined by a hip T-score ≤ −2.5. Besides the increased risk of fracture, patients with these comorbidities generally have poorer outcomes after hip fracture. For this reason, the “treatment threshold” probability of fracture that warrants drug treatment should be substantially lower for patients with these conditions than for other patients. Nevertheless, relatively few patients with these conditions receive treatment; for example, in the US, fewer than 5% of older patients with Parkinson's disease have received a prescription for an approved treatment for osteoporosis and only half of those received 2 prescriptions. Specialists who care for them have little experience with assessments and drug treatments to prevent fracture, and extra screening is barrier to many patients with comorbid conditions. Because these patients have generally been excluded from fracture prevention trials, there is no evidence that improving BMD would reduce their fracture risk. Compared with standard practice, treating older patients with these comorbid conditions without individual risk screening would reach many more patients at high risk of disabling fractures and treatment with zoledronic acid would overcome their poor persistence. Citing Literature A critical step during endochondral ossification in bone development as well as homeostatic bone renewal and fracture repair is the invasion of avascular cartilage by blood vessels and the recruitment of immature osteoprogenitor cells (OPCs) to sites of bone formation. The invasion of OPCs and blood vessels occurs in a tightly spatio-temporally synchronized manner, with some OPCs being wrapped around blood vessels as pericytes. This temporal and local synchronization of osteogenesis and angiogenesis is referred to as osteo-angiogenic coupling. Interestingly, many perivascular subpopulations in the bone marrow environment are thought to function as “reserve” skeletal progenitors or stem cells and as regulators of the local bone marrow microenvironment, including supporting roles for hematopoietic stem cell maintenance and functioning. Previous findings underline the significance of osteo-angiogenic coupling for skeletal physiology and hematopoietic integrity, and suggest an intense crosstalk between osteogenic cells and endothelial cells (ECs) that is conceivably involved in skeletal health and disease and could bear significant therapeutic value. However, the molecular mechanisms mediating the osteo-angiogenic crosstalk and the recruitment of OPCs to the vessels are far from completely characterized to date. Researchers at the KU Leuven SCEBP Lab aim to gain novel insights in the molecular control of skeletal cell functioning, with a focus on mesenchymal progenitors and osteoblast lineage cells and their interplay with the skeletal vasculature. The lab's research program is directed at understanding the mechanisms underlying bone formation in development, adult homeostasis, and fracture healing, but also in the significance of osteogenic cell biology in the broader physiological context of the organism, including hematopoiesis and global energy metabolism. Prime working models are genetically modified mice, including conditional and inducible knockout mice, in combination with fluorescent reporters and lineage tracing strategies. Citing Literature Oral Presentation Abstracts Social deprivation predicts a range of adverse health outcomes; however, its impact on outcomes after a hip fracture is not established. We examined the effect of area-level social deprivation on outcomes after hospital admission with a hip fracture in England. We used English Hospital Episodes Statistics linked by NHS Digital to the National Hip Fracture Database (04/2011–03/2015) and Office for National Statistics mortality database to identify patients admitted with hip fracture, aged 60+ years. Deprivation was measured using quintiles of the Index of Multiple Deprivation (Q1 = least deprived; Q5 =most deprived). Associations between deprivation and 30-day mortality and emergency 30-day readmission are described using odds ratios (ORs); logistic regression was used to adjust for age. Mean length of stay (LOS) in NHS acute and rehabilitation hospitals (“superspell”) was calculated; the association between deprivation and mean LOS was estimated using linear regression. Total NHS bed occupancy within 1 year post-fracture was also calculated. We identified 218,907 hospital admissions with an index hip fracture over 4 years. Median [IQR] was age 84 [78–89] years; 72.6% female. Overall 30-day mortality was 7.8% (n = 17,072/218,907). Among survivors, median superspell was 16 (10–28)days, and 12.4% were readmitted within 30 days (n = 19,497/157,303), median 1-year bed occupancy 21 (11–41) days. Greater deprivation was associated with higher 30-day mortality (Q5: 8.4% [n = 3,229/38,434] versus Q1: 7.2% [n = 3143/43,866]), age-adjusted OR 1.30 (95% CI [1.24, 1.37], p < 0.001), equating to on average 2697 excess deaths per year occurring among those who are deprived (quintiles 2–5 versus 1). Among survivors, age-adjusted mean superspell was longer in the most deprived versus least deprived quintile (Q5: 16.2 [15.3–17.1] days, Q1: 14.2 [13.6–14.7], p < 0.001). The 30-day readmission rate was higher in those most deprived 13.7% (Q5: n = 3708/27,001) compared with those least deprived 11.4% (Q1: n = 3693/32,353), age-adjusted OR 1.27 [1.21, 1.34], p < 0.001. A similar trend was observed when assessing mean 1-year NHS bed occupancy in the 71.9% who survive to 1 year (Q5: 24.7 [23.2–26.2] days; Q1: 20.8 [19.9–21.7], p < 0.001). Greater deprivation is associated with reduced 30-day survival and among those who do survive, longer hospital stays and a greater need to be readmitted to hospital once discharged. The extent to which the configuration of English hospital services, rather than patient case-mix, explains these apparent health inequalities remains to be determined. Citing Literature Osteoporosis is the commonest skeletal disorder, affecting millions and costing billions of pounds annually. Bone mineral density is highly heritable, but only 12% of the phenotype variance is currently accounted for. Treatments reduce fracture risk by only 50%, and there is urgent need to define new pathways that regulate bone turnover and strength. We hypothesized that rapid-throughput phenotyping of knockout mice would identify novel susceptibility alleles for bone and mineral disorders and provide in vivo models to elucidate their molecular basis. Translocation-associated membrane protein-2 knockout mice (Tram2-/-) were identified in this screen with reduced body weight, deafness, and spontaneous fractures, despite normal serum biochemistry. Detailed analysis (X-ray microradiography, micro-CT, backscattered-electron scanning-electron microscopy, biomechanical testing, n = 6 per sex, per genotype) demonstrated short stature (p < 0.001, ANOVA), grossly reduced bone mineral content and mineralization (p < 0.001, Kolmogorov-Smirnov test), profoundly reduced cortical (p < 0.001, ANOVA) and trabecular bone mass (p < 0.001, ANOVA), and decreased bone strength and stiffness (p < 0.001, ANOVA) in Tram2-/-mice. Tram2-/- primary osteoblasts had reduced proliferation (p < 0.001, t test) and mineralization, while osteoclasts had more nuclei (p < 0.001, t test) and increased resorption (p < 0.01, t test) compared with wild type. Tram2 lies downstream of BMP/Runx2 in osteoblasts and is associated with fracture in genomewide association studies. Tram2 is a component of the translocon responsible for the folding of type 1 collagen; however, we detected no abnormalities of type 1 collagen structure by electron microscopy or protein amount by Western blot in Tram2-/- mice. These data demonstrate that Tram2 is required for normal bone mineralization, structure, and strength. The abnormal skeletal phenotype in Tram2-/- mice likely results from impaired bone formation during growth, together with uncoupling of adult bone turnover, resulting in severe bone loss. Elucidation of the cellular and molecular mechanisms underlying this gross skeletal phenotype may identify novel tractable therapeutic targets for prevention and treatment of osteoporosis. Citing Literature Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current anti-resorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard-of-care anti-resorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice treated with combined Zol and 1D11 resulted in a 48% increase (p ≤ 0.001) in trabecular bone volume fraction compared with Zol alone and a 65% (p ≤ 0.0001) increase compared with 1D11 alone. The most significant finding was the substantial repair of U266-induced bone lesions with combination therapy, which resulted in a significant reduction in lesion area compared with vehicle (p ≤ 0.01) or Zol alone (p ≤ 0.01). These results reveal a novel finding and demonstrate that combined anti-resorptive and bone anabolic therapy are significantly more effective at treating established myeloma-induced bone disease than Zol alone. Th

1950. The BRS is one of the largest national scientific societies in Europe dedicated to clinical and basic research into mineralized tissues and is the oldest such society in the world. Meetings are held annually, attracting a wide audience from throughout the UK and beyond. The presentations are traditionally balanced between clinical and laboratory studies. The participation of young scientists and clinicians is actively encouraged. The Annual Meeting this year was organized by a team from The University of Southampton, co-chaired by Dr Kate Ward and Professor Nicholas Harvey, and also including Dr Claire Clarkin, Professor Richard Oreffo, and Professor Cyrus Cooper. The program brought together world leaders in musculoskeletal clinical and basic science. A multidisciplinary faculty provided a breadth of education and research from the Developmental Origins of disease through tissue regeneration and …

Background Populations of Western countries are ageing; in response to this, governments encourage longer working lives. However, many workers leave paid employment prematurely. We have examined the combined importance of poor health, lifestyle and work-related characteristics as risk factors for health-related job loss among older workers. Methods 8134 men and women aged 50–64 were recruited from 24 English general practices to the HEAF study. Participants provided information on their socio-demographic, lifestyle, health (self-rated health, depression, chronic disabling musculoskeletal pain, severe difficulties in daily activities), and employment characteristics. Those in paid employment at baseline were categorised at 1 year follow-up as: ‘still in work and didn’t change job on health grounds’ (n=4,232) versus ‘not in work due to health reasons (n=101)’. The remaining participants were excluded from this analysis. Multivariate Poisson regression with robust standard errors was used to analyse the data. Results All ill-health measures were strongly associated with health-related exit from the workplace (RR for poor self-rated health=4.5, (95%CI 3.1, 6.6)). Adjustment for smoking, leisure-time physical activity (LTPA) and job dissatisfaction attenuated these associations (RR for poor self-rated health=3.1, (95%CI 2.0, 4.8)). Smoking, lack of LTPA, and job dissatisfaction (RR=5.4; (95% CI 3.4, 8.5)) were associated with health-related job loss independently of health variables. Conclusions Poor self-rated health, depression, chronic disabling musculoskeletal pain and severe problems with daily activities significantly increased the risk of leaving employment on health grounds. Tackling unhealthy behaviours and improving job satisfaction could reduce the risk of exiting the workforce for older workers with poor health.

Background Demographic changes in developed countries are requiring people to work longer. No previous studies, however, have focussed on whether the “frailty” syndrome (which predicts falls, hospitalisations, institutional care, dependency, and mortality in the elderly) causes difficulties in employment. To provide information, we assessed relationships in a population-based cohort of 50-64 year-olds from the HEAF study. Methods Subjects, who were recruited from 24 English general practices, completed a baseline postal questionnaire on pre-frailty and frailty and several work outcomes, including health-related job loss (HRJL), prolonged sickness absence (>20 days vs. less, past 12 months), having to cut down substantially at work and difficulty coping with work’s demands. Associations were assessed using logistic regression. Also, we calculated population attributable fractions (PAFs), representing the proportion of the population burden that is potentially preventable, assuming that risk factors are causal and can be eliminated. Results In all, 3.9% of 8,095 eligible respondents were classed as frail and 31.6% as pre-frail. Three-quarters of the former were not in work, while 60% had left their last job on health grounds (odds ratio (OR) for HRJL, vs. non-frail subjects, 30.0 (95% Confidence Interval 23.0–39.2). Among those in work, ORs for prolonged sickness absence, cutting down substantially at work and struggling with work’s physical demands were 10.7 (95% CI: 6.5–17.7), 17.2 (95% CI: 10.5–28.4) and 14.8 (95% CI: 8.2–26.6) respectively. The PAF for HRJL when any frailty marker was present was 51.8% and that for prolonged sickness absence was 32.5%. Associations were strongest with slow reported walking speed. Several associations were stronger in manual workers than in managers. Conclusions Frailty and pre-frailty are not uncommon in 50–64 year-olds. Both are very strongly linked with adverse and economically important employment outcomes. In particular, features of frailty may contribute importantly to HRJL and represent an important target for prevention.

AbstractIntroductionSarcopenia is the loss of muscle mass and physical performance with age, and recognition of its importance in clinical practice is growing. Age‐related decline in muscle mitochondrial function has been described although less is known about the role of mitochondrial dysfunction in sarcopenia. The aim of this study was to investigate whether respiratory chain deficiency is associated with muscle mass and physical performance among a sample of healthy older men participating in the Hertfordshire Sarcopenia Study.MethodsWe used immunofluorescence on biopsies of the vastus lateralis to measure levels of the NDUFB8 subunit of complex I and the COX‐1 subunit of complex IV per fibre. We measured muscle mass using dual‐energy x‐ray absorptiometry. We assessed physical performance using grip strength, gait speed, chair rise time, timed up and go and standing balance time, and composed an aggregate performance score on the scale of 0 (worst) and 5 (best performance). We used linear regression with a cluster sandwich estimator to test relationships between complex I / IV and muscle mass / physical performance. Study approval was granted by the Hertfordshire Research Ethics Committee.ResultsSamples were available from 77 participants of mean age 72.6 (2.5) years. The median number of fibres analysed per participant was 157 (104, 237). We expressed complex I and IV levels as Z‐scores relative to that expected in young controls. The overall participant mean Z‐scores were 0.3 (1.3) and ‐1.5 (0.9) for complex I and IV, respectively. We saw no relationship between complex I or IV and muscle mass. Each unit (SD) increase in complex I was associated with an increase in aggregate performance score of 0.06 (95% CI: 0.02, 0.09, P = 0.003), whilst the relationship for complex IV did not reach significance.ConclusionWe saw marked heterogeneity in complex I and IV levels, both between and within participants, as well as lower overall levels of complex IV. The finding of a small but statistically significant positive association between complex I levels and physical performance suggests that mitochondrial dysfunction may have a role in the development of sarcopenia. These findings will help inform the design of future studies across a wider range of ages and in both women and men.

Background:weak hand grip strength in later life is a risk factor for disability, morbidity and mortality and is central to definitions of sarcopenia and frailty. It is unclear whether rate of change in grip strength adds to level of grip strength as a risk factor for poor ageing outcomes. Methods:study participants were 292 community-dwelling men and women whose grip strength was measured during the 1994/5 (average age 67) and 2003/5 (average age 76) phases of the Hertfordshire Ageing Study, UK. Individual rate of change in grip strength was estimated using a residual change method. Mortality was followed-up to 2011 (42 men and 21 women died). Results:average grip strengths in 2003/5 were 38.4 kg (standard deviation [SD] = 8.1) and 23.7 kg (SD = 6.6) for men and women respectively. Average annualised rates of change in grip strength (2003/5 minus 1994/5) were modest owing to a healthy-participant effect (men: -0.12 kg/y, SD = 0.71; women: 0.08 kg/y, SD = 0.54) but varied widely. Mortality risk varied according to level and rate of change in grip strength (P = 0.03); death rates per 100 person years of follow-up were 6.7 (95% CI: 4.6, 9.6) among participants who lost grip over time and had low grip in 2003/5, in contrast with 0.8 (95% CI: 0.1, 5.8) among participants whose grip changed little over time and remained high in 2003/5. Conclusions:levels of grip strength in later life should be considered in conjunction with estimates of change in grip strength identified by repeat measurement over time. Normative data for longitudinal change in grip strength are required.

Background Studies such as Whitehall II have shown that poor psychosocial work conditions are associated with ill health among employees; it is unclear whether these effects persist and affect health in later life. We have addressed this question using data from the Hertfordshire Cohort Study (HCS). Method 1021 men and 753 women (59–73 years of age) underwent a home interview and clinical examination and completed a social health questionnaire detailing job-strain (JS) and effort-reward imbalance (ERI) in the current or most recent job. Logistic and linear regression were used to compare the health of participants who reported JS and/or ERI with those who reported neither. Results 61% reported neither JS or ERI whilst 10% reported both. 72% were no longer working. JS/ERI was not associated with cardiovascular outcomes (stroke, ischaemic heart disease, hypertension) or type II diabetes. However, participants who reported both JS and ERI had increased odds of poor physical function (SF-36) in comparison with those who reported neither (odds ratios: 2.3 [95%CI 1.5,3.7] men; 2.0 [95%CI 1.2,3.6] women). Average grip strength was 1.7 kg [95% CI 0.2,3.3] lower among men who reported both JS and ERI compared to those reporting neither. Similarly, participants reporting both JS and ERI had poorer SF-36 mental health in comparison with those reporting neither (odds ratios: 2.8 [95%CI 1.8,4.4] men; 3.1 [95%CI 1.8,5.3] women). Conclusions JS and ERI in combination are associated with poor physical and mental health outcomes in later life. Further prospective research is required to determine the causal chain of these associations.

This chapter describes a life course approach for understanding later life sustainability, focusing on grip strength as a marker of physical sustainability, and explaining how a life course approach recognizes that muscle strength in later life reflects not only rate of loss in later life, but also the peak attained earlier in life. We present evidence that risk factors operating throughout the life course have an impact on physical sustainability in later life with particular consideration of the effects of body size, socioeconomic position, physical activity, diet, and smoking. We have shown that low birth weight is associated with weaker grip strength across the life course and that there is considerable evidence for developmental influences on ageing skeletal muscle. Finally, a life course approach suggests opportunities for early intervention to promote later life physical sustainability; but optimal strategies and timings for intervention are yet to be identified.