Serum 25-hydroxyvitamin D concentration and its determinants in the very old: the Newcastle 85+ Study.

SUMMARY: Data on vitamin D status in very old adults are lacking. The aim of this study was to assess 25-hydroxyvitamin D [25(OH)D] concentrations and its predictors in 775 adults aged 85 years old living in North-East England. Low 25(OH)D was alarmingly high during winter/spring months, but its biological significance is unknown. INTRODUCTION: Despite recent concerns about the high prevalence of vitamin D deficiency in much of the British adult and paediatric population, there is a dearth of data on vitamin D status and its predictors in very old adults. The objective of the present study was to describe vitamin D status and its associated factors in a broadly representative sample of very old men and women aged 85 years living in the North East of England (55° N). METHODS: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were analysed in 775 participants in the baseline phase of the Newcastle 85+ cohort study. Season of blood sampling, dietary, health, lifestyle and anthropometric data were collected and included as potential predictors of vitamin D status in ordinal regression models. RESULTS: Median serum 25(OH)D concentrations were 27, 45, 43 and 33 nmol/L during spring, summer, autumn and winter, respectively. The prevalence of vitamin D deficiency according to North American Institute of Medicine guidelines [serum 25(OH)D <30 nmol/L] varied significantly with season with the highest prevalence observed in spring (51%) and the lowest prevalence observed in autumn (23%; P < 0.001). Reported median (inter-quartile range) dietary intakes of vitamin D were very low at 2.9 (1.2-3.3) µg/day. In multivariate ordinal regression models, non-users of either prescribed or non-prescribed vitamin D preparations and winter and spring blood sampling were associated with lower 25(OH)D concentrations. Dietary vitamin D intake, disability score and disease count were not independently associated with vitamin D status in the cohort. CONCLUSION: There is an alarming high prevalence of vitamin D deficiency (<30 nmol/L) in 85-year-olds living in North East England at all times of the year but particularly during winter and spring. Use of vitamin D containing preparations (both supplements and medications) appeared to be the strongest predictor of 25(OH)D concentrations in these very old adults.

25-hydroxyvitamin D and increased all-cause mortality in very old women: the Newcastle 85+ study.

OBJECTIVE: To investigate the associations between low and high concentrations of baseline serum 25-hydroxyvitamin D [25(OH)D] and all-cause mortality in very old (≥85 years) men and women over 6 years. DESIGN, SETTING AND SUBJECTS: Prospective mortality data from 775 participants in the Newcastle 85+ Study were analysed for survival in relation to 25(OH)D (season-specific quartiles and predefined cut-off values) and sex using Cox proportional hazards models. The models were fitted to the entire and restricted (nonusers of vitamin D-containing supplements and medication) cohorts. RESULTS: For the entire cohort, mortality was higher in both the lowest and highest 25(OH)D season-specific quartiles [SQ1: hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.01-1.69, P = 0.04; SQ4: HR 1.44, 95% CI 1.12-1.85, P = 0.004] compared with the combined middle quartiles (SQ2 + SQ3), after adjustment for sociodemographic factors. The increased risk for the highest quartile remained significant after further adjustment for lifestyle variables (SQ4: HR 1.37, 95% CI 1.06-1.77, P = 0.02) and was seen only in women in sex-specific analyses. Similarly, in sensitivity analyses with predefined 25(OH)D cut-off values, the highest 25(OH)D concentration (≥75 nmol L(-1) ) was associated with a 2.4-fold increased risk of mortality in women (restricted cohort) after adjusting for all covariates. CONCLUSION: Low and high season-specific 25(OH)D quartiles were associated with increased risks of mortality over 6 years in the very old; this effect was particularly noticeable in women, including those who reported taking vitamin D-containing supplements/medication.

Magnitude of fragility fracture risk in the very old--are we meeting their needs? The Newcastle 85+ Study.

UNLABELLED: Fractures due to osteoporosis are common in older people. This study assessed the management of osteoporosis in a group of 85-year-olds and found both assessment and current treatment to be suboptimal. INTRODUCTION: Fragility fractures are a major cause of excess mortality, substantial morbidity, and health and social service expenditure in older people. However, much less is known about fracture risk and its management in the very old, despite this being the fastest growing age group of our population. METHODS: Cross-sectional analysis of people who reached the age of 85 during the year of 2006 was carried out. Data were gathered by general practice record review (GPRR) and a multidimensional health assessment (MDHA). RESULTS: Seven hundred thirty-nine individuals were recruited. Mean age was 85.55 years (SD 0.44), and 60.2% were female; 33.7% (n = 249) had experienced one or more fragility fractures (F 45.2% vs M 16.3% p < 0.001); in total, 332 fractures occurred in these 249 individuals. A formal documented diagnosis of osteoporosis occurred in 12.4%, and 38% of individuals had experienced a fall in the last 12 months. When the fracture risk assessment tool (FRAX) and National Osteoporosis Guideline Group (NOGG) guidelines were applied, osteoporosis treatment would be recommended in 35.0%, with a further 26.1% identified as needing bone mineral density (BMD) measurement and 38.9% not requiring treatment or BMD assessment. Women were more likely than men to need treatment (47.4 vs 16.3%, p < 0.001, odds ratio (OR) 4.62 (3.22-5.63)) and measurement of BMD (40.0 vs 5.1%, p < 0.001, OR 12.4 (7.13-21.6)). Of the 259 individuals identified as requiring treatment, only 74 (28.6%) were on adequate osteoporosis treatment. CONCLUSION: The prevalence of high fracture risk in the very old is much higher than the documented diagnosis of osteoporosis or the use of adequate treatments.

A dynamic framework for the study of optimal birth intervals reveals the importance of sibling competition and mortality risks.

Human reproductive patterns have been well studied, but the mechanisms by which physiology, ecology and existing kin interact to affect the life history need quantification. Here, we create a model to investigate how age-specific interbirth intervals adapt to environmental and intrinsic mortality, and how birth patterns can be shaped by competition and help between siblings. The model provides a flexible framework for studying the processes underlying human reproductive scheduling. We developed a state-based optimality model to determine age-dependent and family-dependent sets of reproductive strategies, including the state of the mother and her offspring. We parameterized the model with realistic mortality curves derived from five human populations. Overall, optimal birth intervals increase until the age of 30 after which they remain relatively constant until the end of the reproductive lifespan. Offspring helping each other does not have much effect on birth intervals. Increasing infant and senescent mortality in different populations decreases interbirth intervals. We show that sibling competition and infant mortality interact to lengthen interbirth intervals. In lower-mortality populations, intense sibling competition pushes births further apart. Varying the adult risk of mortality alone has no effect on birth intervals between populations; competition between offspring drives the differences in birth intervals only when infant mortality is low. These results are relevant to understanding the demographic transition, because our model predicts that sibling competition becomes an important determinant of optimal interbirth intervals only when mortality is low, as in post-transition societies. We do not predict that these effects alone can select for menopause.

Serum 25-hydroxyvitamin D and cognitive decline in the very old: the Newcastle 85+ Study.

BACKGROUND AND PURPOSE: Studies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking. METHODS: Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles. RESULTS: Those in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06-2.60, P = 0.03; 1.62, 95% confidence interval 1.02-2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, ß = 0.023, P = 0.01; highest, ß = 0.021, P = 0.02), Digit Vigilance Task (lowest, ß = 0.009, P = 0.05; highest, ß = 0.01, P = 0.02) and Power of Attention (lowest, ß = 0.017, P = 0.02; highest, ß = 0.022, P = 0.002) and greater Reaction Time Variability (lowest, ß = 0.021, P = 0.02; highest, ß = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication. CONCLUSION: Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment.

The plastic fly: the effect of sustained fluctuations in adult food supply on life-history traits.

Many adult traits in Drosophila melanogaster show phenotypic plasticity, and the effects of diet on traits such as lifespan and reproduction are well explored. Although plasticity in response to food is still present in older flies, it is unknown how sustained environmental variation affects life-history traits. Here, we explore how such life-long fluctuations of food supply affect weight and survival in groups of flies and affect weight, survival and reproduction in individual flies. In both experiments, we kept adults on constant high or low food and compared these to flies that experienced fluctuations of food either once or twice a week. For these 'yoyo' groups, the initial food level and the duration of the dietary variation differed during adulthood, creating four 'yoyo' fly groups. In groups of flies, survival and weight were affected by adult food. However, for individuals, survival and reproduction, but not weight, were affected by adult food, indicating that single and group housing of female flies affects life-history trajectories. Remarkably, both the manner and extent to which life-history traits varied in relation to food depended on whether flies initially experienced high or low food after eclosion. We therefore conclude that the expression of life-history traits in adult life is affected not only by adult plasticity, but also by early adult life experiences. This is an important but often overlooked factor in studies of life-history evolution and may explain variation in life-history experiments.

Quality-quantity trade-off of human offspring under adverse environmental conditions.

A central paradigm in life-history theory is the trade-off between offspring number and quality. Several studies have investigated this trade-off in humans, but data are inconclusive, perhaps because prosperous socio-cultural factors mask the trade-off. Therefore, we studied 2461 offspring groups in an area under adverse conditions in northern Ghana with high fertility and mortality rates. In a linear mixed model controlling for differences in age and tribe of the mother and socioeconomic status, each additional child in the offspring group resulted in a 2.3% (95% CI 1.9-2.6%, P < 0.001) lower proportional survival of the offspring. Furthermore, we made use of the polygamous population structure and compared offspring of co-wives in 388 households, thus controlling for variation in resources between compounds. Here, offspring survival decreased 2.8% (95% CI 2.3-4.0%, P < 0.001) for each increase in offspring number. We interpret these data as an apparent quality-quantity trade-off in human offspring.

Cellular aging: further evidence for the commitment theory.

A large, transient reduction in the population size of human fibroblasts in early passages significantly increases the variability of the life-spans of cultures in comparison to control cultures, as predicted by the commitment theory of cellular aging. The theory also predicts that a constant population of noncycling cells will appear in the later part of the culture life-span. This was confirmed by labeling the cells in culture with tritiated thymidine.

Testing the commitment theory of cellular aging.

The commitment theory may explain both the finite lifespan of diploid fibroblasts and the apparent immortality of transformed lines. Potentially immortal cells are assumed on division to generate with some fixed probability cells committed to senesce after a specific number of divisions. During the period between commitment and senescence, cells are assumed to maintain normal growth so that the uncommitted cells are diluted by committed ones and may ultimately be lost in subculturing. A number of predictions of this model are described and experiments strongly supporting the theory are reported. We conclude that the limited growth of diploid fibroblasts is, in effect, an artifact of normal culturing procedures.

Neuronal precursor cells in the rat hippocampal formation contribute to more than one cytoarchitectonic area.

We have tested the hypothesis that cell lineage restriction boundaries define the borders between cytoarchitectonic areas in the cerebral cortex. Clonally related cells were identified using a retroviral marking technique, and the dispersion of neuronal clones was examined with respect to the transitions between cortical areas. We chose to study the hippocampal formation because we found that clones of hippocampal neurons, unlike those in neocortex, are compact and readily identifiable in the adult and that transitions between areas in the hippocampus are sharp relative to the spread of a typical clone. We conclude, contrary to the hypothesis, that clones of neurons transgress the boundaries between areas in the hippocampal formation, that border-crossing clones are observed as frequently as would be expected if clones spread freely over the hippocampus with no constraint imposed by area borders, and that different types of pyramidal neurons, characteristic of different areas, may appear to a single clone. different areas, may appear in a single clone.

Understanding ageing from an evolutionary perspective.

There is clear heritability of human longevity. However, the genetics of ageing is likely to be complex. Evolution theory tells us not to expect genes that have been selected to promote ageing. Ageing is not programmed but results from accumulation of somatic damage, owing to limited investments in maintenance and repair. Genes controlling the levels of activities, such as DNA repair and antioxidant defence, thus regulate longevity. In addition, there may be contributions either from late-acting deleterious genes that escape the force of natural selection or that trade benefit at an early age against harm at older ages. In some species, there is evidence that genes have evolved to detect and respond to changes in the environment, e.g. food supply. Evolutionary understanding can also help to understand important features of the human life history such as menopause.

If you would live long, choose your parents well.

Human longevity appears to have a modest but significant heritable component. A recent study in Iceland has added to this evidence by making a unique assessment based on records for an entire population. Although the evidence for inheritance of human lifespans appears robust, there remains considerable uncertainty about the extent of the genetic versus the nongenetic contribution and about the importance of gene-environment interactions. Sex-specific patterns of transmission of lifespan between parents and offspring might provide clues to the basis of lifespan heritability, but the reported patterns are neither conclusive nor consistent.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Defective interfering particles and virus evolution.

Almost all viruses produce replication-defective mutants that have complex effects on the growth and evolution of the virus in culture. These effects can be explained qualitatively by a simple mathematical model. However, the model shows that the quantitative effects of these mutants are intrinsically unpredictable.

Positive correlation between mammalian life span and cellular resistance to stress.

Identifying the mechanisms determining species-specific life spans is a central challenge in understanding the biology of aging. Cellular stresses produce damage, that may accumulate and cause aging. Evolution theory predicts that long-lived species secure their longevity through investment in a more durable soma, including enhanced cellular resistance to stress. To investigate whether cells from long-lived species have better mechanisms to cope with oxidative and non-oxidative stress, we compared cellular resistance of primary skin fibroblasts from eight mammalian species with a range of life spans. Cell survival was measured by the thymidine incorporation assay following stresses induced by paraquat, hydrogen peroxide, tert-butyl hydroperoxide, sodium arsenite and alkaline pH (sodium hydroxide). Significant positive correlations between cell LD90 and maximum life span were found for all these stresses. Similar results were obtained when cell survival was measured by the MTT assay, and when lymphocytes from different species were compared. Cellular resistance to a variety of oxidative and non-oxidative stresses was positively correlated with mammalian longevity. Our results support the concept that the gene network regulating the cellular response to stress is functionally important in aging and longevity.

Calorie restriction and aging: a life-history analysis.

The disposable soma theory suggests that aging occurs because natural selection favors a strategy in which fewer resources are invested in somatic maintenance than are necessary for indefinite survival. However, laboratory rodents on calorie-restricted diets have extended life spans and retarded aging. One hypothesis is that this is an adaptive response involving a shift of resources during short periods of famine away from reproduction and toward increased somatic maintenance. The potential benefit is that the animal gains an increased chance of survival with a reduced intrinsic rate of senescence, thereby permitting reproductive value to be preserved for when the famine is over. We describe a mathematical life-history model of dynamic resource allocation that tests this idea. Senescence is modeled as a change in state that depends on the resources allocated to maintenance. Individuals are assumed to allocate the available resources to maximize the total number of descendants. The model shows that the evolutionary hypothesis is plausible and identifies two factors, both likely to exist, that favor this conclusion. These factors are that survival of juveniles is reduced during periods of famine and that the organism needs to pay an energetic "overhead" before any litter of offspring can be produced. If neither of these conditions holds, there is no evolutionary advantage to be gained from switching extra resources to maintenance. The model provides a basis to evaluate whether the life-extending effects of calorie-restriction might apply in other species, including humans.

Comparative life spans of species: why do species have the life spans they do?

Proximate answers to questions about species longevity are to be found in the physiological processes that regulate duration of life. But what are these processes, and how are they themselves controlled? This leads to ultimate, evolutionary questions about longevity. What are the selection forces that favor one life span instead of another for a given species? To understand the evolution of life span we need also to understand the evolution of aging. A plausible hypothesis is that because of the requirement for reproduction, natural selection favors a strategy that invests fewer resources in maintenance of somatic cells and tissues than are necessary for indefinite survival. This "disposable soma" theory predicts that aging is due to the accumulation of unrepaired somatic defects and the primary genetic control of longevity operates through selection to raise or lower the investment in basic cellular maintenance systems in relation to the level of environmental hazard.

Calibration of reference thromboplastins and standardisation of the prothrombin time ratio.

Thromboplastins vary in their sensitivity to the haemostatic defect induced by oral anticoagulants. To provide a means of standardising prothrombin time tests, the World Health Organization adopted in 1977 a scheme for calibrating thromboplastins in terms of an International Reference Preparation. Unfortunately, the model on which this scheme was based does not always hold. A revised calibration model has therefore been developed and this has been tested in a recent collaborative study. The revised model, which retains fundamentally the same principle for standardising prothrombin time tests, has proved suitable for calibrating thromboplastins of different species and types and, moreover, has certain statistical advantages over its predecessor. In September 1982, the WHO Expert Committee on Biological Standardization adopted the revised model. This paper explains the nature and rationale of this change and considers its practical implications.