Frailty, hospital use and mortality in the older population: findings from the Newcastle 85+ study.

BACKGROUND: Frailty is a significant determinant of health care utilisation and associated costs, both of which also increase with proximity to death. What is not known is how the relationships between frailty, proximity to death, hospital use and costs develop in a population aged 85 years and over. METHODS: This study used data from a prospective observational cohort, the Newcastle 85+ Study, linked with hospital episode statistics and death registrations. Using the Rockwood frailty index (cut off <0.25), we analysed the relationship between frailty and mortality, proximity to death, hospital use and hospital costs over 2, 5 and 7 years using descriptive statistics, Kaplan-Meier survival curves, Cox's proportional hazards and negative binomial regression models. RESULTS: Baseline frailty was associated with a more than two-fold increased risk of mortality after 7 years, compared to people who were non-frail. Participants classified as frail spent more time in hospital over 7 years than the non-frail, but this difference declined over time. Baseline frailty was not associated with increased time spent in hospital during the last 90 days of life. CONCLUSION: Evidence continues to accrue on the impact of frailty on emergency health care use. Hospital and community services need to adapt to meet the challenge of introducing new proactive and preventative approaches, designed to achieve benefits in clinical and/or cost effectiveness of frailty management.

Detecting translational regulation by change point analysis of ribosome profiling data sets.

Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While during normal translation, ribosome density is constant along the length of the mRNA coding region, this can be altered in response to translational regulatory events. In the present study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modeling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq data set obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artifacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g., premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new transcript isoforms.

Repeated-sprint cycling does not induce respiratory muscle fatigue in active adults: measurements from the powerbreathe® inspiratory muscle trainer.

This study examined respiratory muscle strength using the POWERbreathe® inspiratory muscle trainer (i.e., 'S-Index') before and after repeated-sprint cycling for comparison with maximal inspiratory pressure (MIP) values obtained during a Mueller maneuver. The S-Index was measured during six trials across two sessions using the POWERbreathe® and MIP was measured during three trials in a single session using a custom-made manometer in seven recreationally active adults. Global respiratory muscle strength was measured using both devices before and after the performance of sixteen, 6-s sprints on a cycle ergometer. Intraclass correlation coefficients for the POWERbreathe® S-index indicated excellent (p < 0.05) trial-to-trial (r = 0.87) and day-to-day (r = 0.90) reliability yet there was no significant correlation (r = -0.35, p = 0.43) between the S-Index measured using the POWERbreathe® and MIP measured during a Mueller maneuver. Repeated-sprint cycling had no effect on respiratory muscle strength as measured by the POWERbreathe® (p > 0.99) and during the Mueller maneuver (p > 0.99). The POWERbreathe® S-Index is a moderately reliable, but not equivalent, measure of MIP determined during a Mueller maneuver. Furthermore, repeated-sprint cycling does not induce globalized respiratory muscle fatigue in recreationally-active adults. Key pointsThe S-Index as measured by the POWERbreathe® is a reliable measure of respiratory muscle strengthThe S-Index does not accurately reflect maximal inspiratory pressure obtained from a Mueller maneuverRepeated-sprint cycling does not induce respiratory muscle fatigue as measured by the POWERbreathe® and the Manometer.

The mental wealth of nations.

Countries must learn how to capitalize on their citizens' cognitive resources if they are to prosper, both economically and socially. Early interventions will be key.

Evolution of the mitochondrial fusion-fission cycle and its role in aging.

Mitochondria are organelles of eukaryotic cells that contain their own genetic material and evolved from prokaryotic ancestors some 2 billion years ago. They are the main source of the cell's energy supply and are involved in such important processes as apoptosis, mitochondrial diseases, and aging. During recent years it also became apparent that mitochondria display a complex dynamical behavior of fission and fusion, the function of which is as yet unknown. In this paper we develop a concise theory that explains why fusion and fission have evolved, how these processes are related to the accumulation of mitochondrial mutants during aging, why the mitochondrial DNA has to be located close to the respiration complexes where most radicals are generated, and what selection pressures shaped the slightly different structure of animal and plant mitochondria. We believe that this "organelle control" theory will help in understanding key processes involved in the evolution of the mitochondrial genome and the aging process.

Shared Ageing Research Models (ShARM): a new facility to support ageing research.

In order to manage the rise in life expectancy and the concomitant increased occurrence of age-related diseases, research into ageing has become a strategic priority. Mouse models are commonly utilised as they share high homology with humans and show many similar signs and diseases of ageing. However, the time and cost needed to rear aged cohorts can limit research opportunities. Sharing of resources can provide an ethically and economically superior framework to overcome some of these issues but requires dedicated infrastructure. Shared Ageing Research Models (ShARM) ( www.ShARMUK.org ) is a new, not-for-profit organisation funded by Wellcome Trust, open to all investigators. It collects, stores and distributes flash frozen tissues from aged murine models through its biorepository and provides a database of live ageing mouse colonies available in the UK and abroad. It also has an online environment (MICEspace) for collation and analysis of data from communal models and discussion boards on subjects such as the welfare of ageing animals and common endpoints for intervention studies. Since launching in July 2012, thanks to the generosity of researchers in UK and Europe, ShARM has collected more than 2,500 tissues and has in excess of 2,000 mice registered in live ageing colonies. By providing the appropriate support, ShARM has been able to bring together the knowledge and experience of investigators in the UK and Europe to maximise research outputs with little additional cost and minimising animal use in order to facilitate progress in ageing research.

The impact of visual impairment on Mini-Mental State Examination Scores in the Newcastle 85+ study.

BACKGROUND: cognitive test scores and visual acuity are strongly associated in older people. This may be due to poor vision limiting performance on cognitive tasks specifically requiring vision, or an association between visual and neurodegenerative disorders. OBJECTIVE: to explore, using data from the Newcastle 85+ cohort study, the impact of sight impairment (SI) on Mini-Mental State Examination (MMSE) scores and whether reduced scores among SI participants are limited to tasks requiring vision. RESULTS: of 839 participants aged 85 years, 44 (5.2%) were registered SI. Median (inter-quartile range) sMMSE scores were 25 (22-29) for SI and 28 (25-29) for non-SI participants (P=0.006). SI participants had lower subscale scores on tasks requiring vision (P<0.001 for each) but also for some subscale scores not obviously requiring vision: orientation (P=0.018) and repetition (P=0.030). Excluding visual items, there was no significant difference in MMSE scores between those with/without SI. CONCLUSION: SI may be an obstacle to older people completing cognitive assessments including tasks requiring vision. People with SI also scored lower on some tasks not obviously requiring vision. An association between cognitive impairment and SI may exist beyond simply being unable to see the test material in cognitive tests.

An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.

Mitochondria are cellular organelles of crucial relevance for the survival of metazoan organisms. Damage to the mitochondrial DNA can give rise to a variety of mitochondrial diseases and is thought also to be involved in the aging process. The fate of mtDNA mutants is controlled by their synthesis as well as degradation and mathematical models can help to better understand this complex interplay. We present here a model that combines a replicative advantage for mtDNA mutants with selective degradation enabled by mitochondrial fission and fusion processes. The model not only shows that the cell has efficient means to deal with (many) types of mutants but, surprisingly, also predicts that under certain conditions a stable co-existence of mutant and wild-type mtDNAs is possible. We discuss how this new finding might explain how mitochondria can be at the heart of processes with such different phenotypes as mitochondrial diseases and aging.

No Evidence That Genetic Variation at the Klotho Locus Is Associated With Longevity in Caucasians from the Newcastle 85+ Study and the UK Biobank.

The demographics of Western populations are changing, with an increase in the proportion of older adults. There is evidence to suggest that genetic factors may influence the aging process: studying these may lead to interventions to help individuals live a longer and healthier life. Evidence from several groups indicates that Klotho (KL), a gene encoding a single-pass transmembrane protein that acts as an FGF23 co-receptor, may be associated with longevity and healthy aging. We aimed to explore this area further by comparing the genotype counts in 642 long-lived individuals from the Newcastle 85+ Study with 18 295 middle-aged Newcastle-based controls from the UK Biobank to test whether variants at the KL gene locus are over- or under-represented in older individuals. If KL is associated with longevity, then we would expect the genotype counts to differ between the 2 cohorts. We found that the rs2283368 CC genotype and the rs9536338 C allele, but not the KL-VS haplotype, were associated with reaching very old age. However, these associations did not replicate in the remainder of the UK Biobank cohort. Thus, our results do not reliably support the role of KL as a longevity factor.

Feedback between p21 and reactive oxygen production is necessary for cell senescence.

Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs.

BACKGROUND: Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care. METHODS: Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self-reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender. RESULTS: Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care-home places by 2030. CONCLUSIONS: This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found.

Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease.

BACKGROUND: Oxidative stress is proposed as an important factor in osteoarthritis (OA). OBJECTIVE: To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. METHODS: SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin-Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. RESULTS: All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin-Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. CONCLUSION: This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.

Developmental plasticity and human health.

Many plants and animals are capable of developing in a variety of ways, forming characteristics that are well adapted to the environments in which they are likely to live. In adverse circumstances, for example, small size and slow metabolism can facilitate survival, whereas larger size and more rapid metabolism have advantages for reproductive success when resources are more abundant. Often these characteristics are induced in early life or are even set by cues to which their parents or grandparents were exposed. Individuals developmentally adapted to one environment may, however, be at risk when exposed to another when they are older. The biological evidence may be relevant to the understanding of human development and susceptibility to disease. As the nutritional state of many human mothers has improved around the world, the characteristics of their offspring--such as body size and metabolism--have also changed. Responsiveness to their mothers' condition before birth may generally prepare individuals so that they are best suited to the environment forecast by cues available in early life. Paradoxically, however, rapid improvements in nutrition and other environmental conditions may have damaging effects on the health of those people whose parents and grandparents lived in impoverished conditions. A fuller understanding of patterns of human plasticity in response to early nutrition and other environmental factors will have implications for the administration of public health.

A comparison of computerized and pencil-and-paper tasks in assessing cognitive function in community-dwelling older people in the Newcastle 85+ Pilot Study.

OBJECTIVES: To compare the acceptability and feasibility of computerized and pencil-and-paper tests of cognitive function in 85-year-old people. DESIGN: Group comparison of participants randomly allocated to pencil-and-paper (Wechsler Adult Intelligence and Memory Scales) or computerized (Cognitive Drug Research) tests of verbal memory and attention. SETTING: The Newcastle 85+ Pilot Study was the precursor to the Newcastle 85+ Study a United Kingdom Medical Research Council/Biotechnology and Biological Sciences Research Council cohort study of health and aging in the oldest-old age group. PARTICIPANTS: Eighty-one community-dwelling individuals aged 85. MEASUREMENTS: Participant and researcher acceptability, completion rates, time taken, validity as cognitive measures, and psychometric utility. RESULTS: Participants randomized to computerized tests were less likely to rate the cognitive function tests as difficult (odds ratio (OR)=0.16, 95% confidence interval (CI)=0.07-0.39), stressful (OR=0.18, 95% CI=0.07-0.45), or unacceptable (OR=0.18, 95% CI=0.08-0.48) than those randomized to pencil-and-paper tests. Researchers were also less likely to rate participants as being distressed in the computer test group (OR=0.19, 95% CI=0.07-0.46). Pencil-and-paper tasks took participants less time to complete (mean+/-standard deviation 18+/-4 minutes vs 26+/-4 minutes) but had fewer participants who could complete all tasks (91% vs 100%). Both types of task were equally good measures of cognitive function. CONCLUSION: Computerized and pencil-and-paper tests are both feasible and useful means of assessing cognitive function in the oldest-old age group. Computerized tests are more acceptable to participants and administrators.

Genetics of healthy aging in Europe: the EU-integrated project GEHA (GEnetics of Healthy Aging).

The aim of the 5-year European Union (EU)-Integrated Project GEnetics of Healthy Aging (GEHA), constituted by 25 partners (24 from Europe plus the Beijing Genomics Institute from China), is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians, geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians, and statisticians has been set up. The working plan is to: (a) collect DNA and information on the health status from an unprecedented number of long-lived 90+ sibpairs (n = 2650) and of younger ethnically matched controls (n = 2650) from 11 European countries; (b) perform a genome-wide linkage scannning in all the sibpairs (a total of 5300 individuals); this investigation will be followed by linkage disequilibrium mapping (LD mapping) of the candidate chromosomal regions; (c) study in cases (i.e., the 2650 probands of the sibpairs) and controls (2650 younger people), genomic regions (chromosome 4, D4S1564, chromosome 11, 11.p15.5) which were identified in previous studies as possible candidates to harbor longevity genes; (d) genotype all recruited subjects for apoE polymorphisms; and (e) genotype all recruited subjects for inherited as well as epigenetic variability of the mitochondrial DNA (mtDNA). The genetic analysis will be performed by 9 high-throughput platforms, within the framework of centralized databases for phenotypic, genetic, and mtDNA data. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modeling, functional genomics and proteomics, molecular biology, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow (a) to identify gender-specific genes involved in healthy aging and longevity in women and men stratified for ethnic and geographic origin and apoE genotype; (b) to perform a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality; and (c) to develop mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socioeconomic factors, lifestyle habits.

The Newcastle 85+ study: biological, clinical and psychosocial factors associated with healthy ageing: study protocol.

BACKGROUND: The UK, like other developed countries, is experiencing a marked change in the age structure of its population characterised by increasing life expectancy and continuing growth in the older fraction of the population. There is remarkably little up-to-date information about the health of the oldest old (over 85 years), demographically the fastest growing section of the population. There is a need, from both a policy and scientific perspective, to describe in detail the health status of this population and the factors that influence individual health trajectories. For a very large proportion of medical conditions, age is the single largest risk factor. Gaining new knowledge about why aged cells and tissues are more vulnerable to pathology is likely to catalyse radical new insights and opportunities to intervene. The aims of the Newcastle 85+ Study are to expose the spectrum of health within an inception cohort of 800 85 year-olds; to examine health trajectories and outcomes as the cohort ages and their associations with underlying biological, medical and social factors; and to advance understanding of the biological nature of ageing. METHODS: A cohort of 800 85 year olds from Newcastle and North Tyneside will be recruited at baseline and followed until the last participant has died. Eligible individuals will be all those who turn 85 during the year 2006 (i.e. born in 1921) and who are registered with a Newcastle or North Tyneside general practice. Participants will be visited in their current residence (own home or institution) by a research nurse at baseline, 18 months and 36 months. The assessment protocol entails a detailed multi-dimensional health assessment together with review of general practice medical records. Participants will be flagged with the NHS Central Register to provide details of the date and cause of death. DISCUSSION: The Newcastle 85+ Study will address key questions about health and health-maintenance in the 85+ population, with a particular focus on quantitative assessment of factors underlying variability in health, and on the relationships between health, nutrition and biological markers of the fundamental processes of ageing.