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Estrogen is a steroidal hormone involved in several physiological functions in the female body including regulation of serum lipid metabolism and breast cancer (BC). Estrogen actions on serum lipids mostly occur through its binding to intracellular Estrogen Receptor alpha (ERalpha) isoform, expressed in most of tissues. This gene (ESR1) exhibit many polymorphic sites (SNPs) located either on translated and non-translated regions that regulate ERalpha protein expression and function. This paper aimed to investigate the association of two intronic SNPs of ESR1 gene, namely c454-397T>C (PvuII) and c454-351A>G (XbaI) to alterations in serum levels of total cholesterol (T-chol), total lipid (TL), low density lipoprotein cholesterol (LDL), high density lipoprotein (HDL), and triglycerides (TG) in a cohort of post-menopausal women. In addition, we aimed to associate presence of these SNPs to development of BC along 5 years period. To do so, a group of healthy 499, highly miscigenated, post-menopausal Brazilian women, were carried using PCR-FRLP technique and further confirmed by automatic sequence analysis as well followed through 5 years for BC incidence. Measurements of serum lipid profile by standard commercial methods were carried individually whereas Dual Energy X-ray Absorciometry (DXA) measured Body Mass Indexes (BMI), Fat Mass (FM), Lean Body Mass (LBM), and Body Water Content (BWC). No effects of PvuII SNP on ESR1 gene were observed on patient´s serum T-chol, TL, LDL, HDL, and TG. However, c454-397T>C PvuII SNP is associated to lower body fat and higher levels of lean mass and body water and lower incidence of BC. On the other hand, statistically significant effect of XbaI c454-351A>G SNP on serum TG and TL levels. Patients homozygous for X allele were followed up from 2010–2015. They showed higher incidence of breast cancer (BC) when compared to either heterozygous and any P allele combination. Moreover, the increasing of TG and TL serum concentrations associated to SNP XbaI c454-351A>G on ESR1 gene is enhanced in both obese (higher BMI) and elder women. Taken together, these results suggested that XbaI c454-351A>G SNP is associated to changes in lipid profile, particularly in serum TG and TL, in this cohort of post-menopausal woman. Also, this paper shows another link between obesity and BC corroborating the current thesis that both diseases are interlinked.

Drawing on job design theories and a conceptual framework of work-related goals and motivation in later adulthood, the aim of this paper is to explore how work-related and individual factors are separately and jointly related to psychological work ability and bridge employment intentions via late job mobility. The cross-sectional study is based on a sample of 171 older Spanish workers aged 45-65 and beyond. We differentiated between groups of older workers in mid career (45-55 years of age) and in their later careers (56 years and beyond). Our results confirm that task characteristics and, secondarily, knowledge characteristics are the most relevant factors in perceptions of psychological work ability among aged workers. Both age groups display a very marked personal mastery trait, which mediates the relationships between job characteristics and both psychological work ability and late job mobility intentions. The paper concludes with a discussion of theoretical and practical implications and suggestions for future research on the issues implied in the psychological adjustment of older workers in their mid and late careers.

The average age at which U.S. researchers receive their first grant from NIH has increased from 34.3 in 1970, to 41.7 in 2004. These data raise the crucial question of the effects of aging on the scientific productivity and impact of researchers. Drawing on a sizeable sample of 6,388 university professors in Quebec who have published at least one paper between 2000 and 2007, our results identify two turning points in the professors' careers. A first turning point is visible at age 40 years, where researchers start to rely on older literature and where their productivity increases at a slower pace--after having increased sharply since the beginning of their career. A second turning point can be seen around age 50, when researchers are the most productive whereas their average scientific impact is at its lowest. Our results also show that older professors publish fewer first-authored papers and move closer to the end of the list of co-authors. Although average scientific impact per paper decreases linearly until about age 50, the average number of papers in highly cited journals and among highly cited papers rises continuously until retirement. Our results show clearly that productivity and impact are not a simple and declining function of age and that we must take into account the collaborative aspects of scientific research. Science is a collective endeavor and, as our data shows, researchers of all ages play a significant role in its dynamic.

ObjectivesThis paper examines the ethnic and gender differentials in high blood pressure (HBP), diabetes, coronary heart disease (CHD), arthritis and asthma among older people in Malaysia, and how these diseases along with other factors affect self-rated health. Differentials in the prevalence of non-communicable diseases among older people are examined in the context of socio-cultural perspectives in multi-ethnic Malaysia.MethodsData for this paper are obtained from the 2004 Malaysian Population and Family Survey. The survey covered a nationally representative sample of 3,406 persons aged 50 and over, comprising three main ethnic groups (Malays, Chinese and Indians) and all other indigenous groups. Bivariate analyses and hierarchical logistic regression were used in the analyses.ResultsArthritis was the most common non-communicable disease (NCD), followed by HBP, diabetes, asthma and CHD. Older females were more likely than males to have arthritis and HBP, but males were more likely to have asthma. Diabetes and CHD were most prevalent among Indians, while arthritis and HBP were most prevalent among the Indigenous groups. Older people were more likely to report poor health if they suffered from NCD, especially CHD. Controlling for socio-economic, health and lifestyle factors, Chinese were least likely to report poor health, whereas Indians and Indigenous people were more likely to do so. Chinese that had HBP were more likely to report poor health compared to other ethnic groups with the same disease. Among those with arthritis, Indians were more likely to report poor health.ConclusionPerceived health status and prevalence of arthritis, HBP, diabetes, asthma and CHD varied widely across ethnic groups. Promotion of healthy lifestyle, early detection and timely intervention of NCDs affecting different ethnic groups and gender with socio-cultural orientations would go a long way in alleviating the debilitating effects of the common NCDs among older people.

Background: Following the active ageing model based on the Health, Lifelong Learning, Participation and Security pillars, this research has a twofold objective: i) to classify older adults according to active ageing profiles, taking into account the four pillars, and ii) to ascertain the relationship between the profiles and personal and contextual factors, as well as well-being and quality of life in old age. Methods: A study sample of 5,566 Spanish older adults who participated in wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE) was included. Data were analysed in different steps applying several statistical analyses (Principal Component, Cluster, Discriminant, Multiple Correspondence and bivariate analysis with Pearson chi-square and ANOVA). Results: Five older adult profiles were obtained (I: with moderate activity; II: quasi-dependents; III: with active ageing-limiting conditions; IV: with diverse and balanced activity; V: with excellent active ageing conditions). The first three profiles were characterised by subjects with a high average age, low educational level, who were retired or housewives, and who perceived a moderate level of loneliness, satisfaction with the social network and quality of life, as well as having a larger family network, but living in small households or alone. In contrast, the latter two profiles showed better personal and contextual conditions, well-being and quality of life. Discussion and conclusions: The multidimensional approach to active ageing followed in this article has revealed the presence of several older adult profiles, which are confined to groups with better or worse active ageing conditions. In this context, if ageing is a process that reflects the previous way of life, intervention priorities will have to consider actions that promote better conditions during the life cycle., Research of this paper is a part of i) the QASP research project, funded by the Institute of Health Carlos III, Intramural Strategical Action in Health AESI 2018 (PI18CIII/00046); ii) it has also been partially funded by REDISSEC (RD16/0005/0002 and RD16/0001/0005, co-funded by European Regional Development Fund/European Social Fund “A way to make Europe” / ”Investing in your future”) projects; iii) the R&D Activities Program ENCAGEn-CM (H2019/HUM-5698) funded by the Community of Madrid and co-funded by the European Social Fund; iv) the ENVACES R&D+i project (MINECO-FEDER, ref. CSO2015-64115-R). Authors acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

The community and home-based elderly care service system has been proved an effective pattern to mitigate the elderly care dilemma under the background of accelerating aging in China. In particular, the participation of social organizations in community and home-based elderly care service has powerfully fueled the multi-supply of elderly care. As the industry of the elderly care service is in the ascendant, the management lags behind, resulting in the waste of significant social resources. Therefore, performance evaluation is proposed to resolve this problem. However, a systematic framework for evaluating performance of community and home-based elderly care service centers (CECSCs) is absent. To overcome this limitation, the SBM-DEA model is introduced in this paper to evaluate the performance of CECSCs. 186 social organizations in Nanjing were employed as an empirical study to develop the systematic framework for performance evaluation. Through holistic analysis of previous studies and interviews with experts, a systematic framework with 33 indicators of six dimensions (i.e., financial management, hardware facilities, team building, service management, service object and organization construction) was developed. Then, Sensitivity Analysis is used to screen the direction of performance optimization and specific suggestions were put forward for government, industrial associations and CECSCs to implement. The empirical study shows the proposed framework using SBM-DEA and sensitivity analysis is viable for conducting performance evaluation and improvement of CECSCs, which is conducive to the sustainable development of CECSCs.

Household time-use patterns are expected to reflect each household member’s daily activity participation and duration with intra-household interactions constrained by multiple budgets. Among various activities, the allocated activity derived from undertaking a household task is studied relatively less in the literature. Who will take an allocated activity is a discrete choice problem of household task assignment, and once a household member is assigned with one household task, other members will have more time to do other activities. To better understand household time-use patterns affected by household task assignment, this paper proposed a joint household-level multiple discrete-continuous extreme value-multinomial logit (MDCEV-MNL) model with multiple constraints. The Karush-Kuhn-Tucker (KKT) method combined with the simulation-based maximum likelihood estimation method is proposed to estimate the proposed model. Based on the household activity-travel data from Beijing of China, the proposed model is customized to explore elderly couples’ time-use patterns with intra-household interactions affected by household task assignment. Following the findings, policy implications are suggested to build an age-friendly society.

Associative memory deficit underlies a part of older adults’ deficient episodic memory due to the reduced ability to bind units of information. In this article we further assess the mechanism underlying this deficit, by assessing the degree to which we can model it in young adults under conditions of divided attention. We shall describe two experiments in this paper; these experiments investigate item and associative recognition in young adults under full- or divided-attention conditions. The secondary tasks employed were N-back like (NBL), which serves as a working memory updating task, and parity judgement and visuospatial (VS) tasks, which serve as non-working memory tasks. The results of both experiments show that only the NBL specifically affected associative recognition, while the other tasks affected item and associative memory to the same degree, indicating a general resource competition. These results presented a convergence of evidence for the associative deficit in older adults by modelling it in young adults.

Funding: Both grants – 2P01AG031719, US National Institute of Health and ”On the edge of societies: Vulnerable populations, emerging challenges for social policies and future demands for social innovation. The experience of the Baltic Sea States (2016-2021)” – were received by Prof. James W. Vaupel, Interdisciplinary Centre on Population Dynamics, University of Southern Denmark (https://portal.findresearcher.sdu.dk/en/persons/jvaupel), who is not a co-author on this paper. The experience of the Baltic Sea States (2016-2021) provided by the Max Planck Society has no number. Background Population aging will pose huge challenges for healthcare systems and will require a promotion of positive attitudes towards older people and the encouragement of careers in geriatrics to attract young professionals into the field and to meet the needs of a rapidly growing number of old-aged patients. We describe the current demographic profile of hospital care use in Denmark and make projections for changes in the patient profile up to 2050. Methods The Danish population in 2013 (N = 5.63 million) was followed up for inpatient and emergency admissions recorded in Danish hospitals in 2013 using population-based registers. We combined age- and sex-specific hospital care use in 2013 with official population estimates to forecast the profile of hospital days up to 2050 with respect to age and sex. Results The total number of hospital days per year is projected to increase by 42% between 2013 and 2050, from 4.66 to 6.72 million days. While small changes are projected for the population aged 0–69, the largest change is projected to occur for the population aged 70+. The 2013 levels were 0.82 and 0.93 million days for men and women aged 70+, respectively. By 2050, these levels are projected to have reached 1.94 and 1.84 million days. While the population aged 70+ accounted for 37.5% of all days in 2013, its contribution is projected to increase to 56.2% by 2050. Conclusion Our study shows one possible scenario for changes in the hospital days due to population aging by 2050: Assuming no changes in hospital care use over the forecast period, the absolute contribution of individuals aged 70+ to the total hospital days will more than double, and the relative contribution of persons aged 70+ will account for nearly 60% of all hospital days by 2050, being largest among men. Publisher PDF

Shanghai has experienced rapid urbanization and has a serious housing aging problem. The situation of urban housing safety management needs to be strengthened. However, in China, housing safety management (HSM) is just in its beginning stage and it lacks thorough research. Housing safety awareness is one of the most significant aspects of housing safety management. Therefore, in order to investigate the housing safety awareness of Shanghai residents, this paper investigates the safety attitudes of residents living in housing of different ages using consulting questionnaires and Statistical Package for Social Science (SPSS) software. The results show that in Shanghai, the residents lack an understanding of housing management law, policy, and awareness of safety use and have low willingness to buy commercial insurance. Based on these results, the factors that affect the safety awareness of Shanghai residents are summarized as follows: (1) asymmetric information; (2) assessment of the safety status of the premises; and (3) differences in house users.

Network modeling is a challenging task due to non-trivial evolution dynamics. We introduce multiple-selection-procedure with 'N' possible growth mechanisms (MSP-N). In MSP-N, an incoming node chooses a single option among N available options to link to pre-existing nodes. Some of the potential options, in case of social networks, can be standard preferential or random attachment and node aging or fitness. In this paper, we discuss a specific case, MSP-2, and shows its efficacy in reconstructing several non-trivial characteristic properties of social networks, including networks with power-law degree distribution, power-law with an exponential decay (exponential cut-off), and exponential degree distributions. We evaluate the proposed evolution mechanism over two real-world networks and observe that the generated networks highly resembles the degree distribution of the real-world networks. Besides, several other network properties such as high clustering and triangle count, low spectral radius, and community structure, of the generated networks are significantly closer to the real-world networks.

In line with the dimensional theory of emotional space, we developed affective norms for words rated in terms of valence, arousal and dominance in a group of older adults to complete the adaptation of the Affective Norms for English Words (ANEW) for Italian and to aid research on aging. Here, as in the original Italian ANEW database, participants evaluated valence, arousal, and dominance by means of the Self-Assessment Manikin (SAM) in a paper-and-pencil procedure. We observed high split-half reliabilities within the older sample and high correlations with the affective ratings of previous research, especially for valence, suggesting that there is large agreement among older adults within and across-languages. More importantly, we found high correlations between younger and older adults, showing that our data are generalizable across different ages. However, despite this across-ages accord, we obtained age-related differences on three affective dimensions for a great number of words. In particular, older adults rated as more arousing and more unpleasant a number of words that younger adults rated as moderately unpleasant and arousing in our previous affective norms. Moreover, older participants rated negative stimuli as more arousing and positive stimuli as less arousing than younger participants, thus leading to a less-curved distribution of ratings in the valence by arousal space. We also found more extreme ratings for older adults for the relationship between dominance and arousal: older adults gave lower dominance and higher arousal ratings for words rated by younger adults with middle dominance and arousal values. Together, these results suggest that our affective norms are reliable and can be confidently used to select words matched for the affective dimensions of valence, arousal and dominance across younger and older participants for future research in aging.

The assessment of gait variability using stochastic signal processing techniques such as detrended fluctuation analysis (DFA) has been shown to be a sensitive tool for evaluation of gait alterations due to aging and neuromuscular disease. However, previous studies have suggested that the application of DFA requires relatively long recordings (600 strides), which is difficult when working with clinical populations or older adults. In this paper we propose a model for predicting DFA variance in experimental data and conduct a Monte Carlo simulation to estimate the sample size and number of trials required to detect a change in DFA scaling exponent. We illustrate the model in a simulation to detect a difference of 0.1 (medium effect) between two groups of subjects when using short gait time series (100 to 200 strides) in the context of between- and within-subject designs. We assumed that the variance of DFA scaling exponent arises due to individual differences, time series length, and experimental error. Results showed that sample sizes required to achieve acceptable power of 80% are practically feasible, especially when using within-subject designs. For example, to detect a group difference in the DFA scaling exponent of 0.1, it would require either 25 subjects and 2 trials per subject or 12 subjects and 4 trials per subject using a within-subject design. We then compared plausibility of such power predictions to the empirically observed power from a study that required subjects to synchronize with a persistent fractal metronome. The results showed that the model adequately predicted the empirical pattern of results. Our power simulations could be used in conjunction with previous design guidelines in the literature when planning new gait variability experiments.

Background Leptin is one of the major adipokines in obesity that indicates the severity of fat accumulation. It is also an important etiological factor of consequent cardiometabolic and autoimmune disorders. Aging has been demonstrated to aggravate obesity and to induce leptin resistance and hyperleptinemia. Hyperleptinemia, on the other hand, may promote the development of age-related abnormalities. While major weight loss has been demonstrated to ameliorate hyperleptinemia, obese people show a poor tendency to achieve lasting success in this field. The question arises whether training intervention per se is able to reduce the level of this adipokine. Objectives We aimed to review the literature on the effects of training intervention on peripheral leptin level in obesity during aging, in order to evaluate the independent efficacy of this method. In the studies that were included in our analysis, changes of adiponectin levels (when present) were also evaluated. Data sources 3481 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 19 articles were suitable for analyses. Study eligibility criteria Empirical research papers were eligible provided that they reported data of middle-aged or older (above 45 years of age) overweight or obese (body mass index above 25) individuals and included physical training intervention or at least fitness status of groups together with corresponding blood leptin values. Statistical methods We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. To assess publication bias Egger’s test was applied. In case of significant publication bias, the Duval and Tweedie's trim and fill algorithm was used. Results Training intervention leads to a decrease in leptin level of middle-aged or older, overweight or obese male and female groups, even without major weight loss, indicated by unchanged serum adiponectin levels. Resistance training appears to be more efficient in reducing blood leptin level than aerobic training alone. Conclusions Physical training, especially resistance training successfully reduces hyperleptinemia even without diet or major weight loss.

Background Bhutan, a small land-locked country in the eastern Himalayas has been undergoing an epidemiological and nutritional transition in the last two decades. The objective of this paper was to determine the prevalence and explore the risk factors of self-reported diabetes among Bhutanese adults. Methods We conducted a secondary data analysis among adults 18 years and older Bhutanese using the data from the National Health Survey 2012 (NHS, 2012) of Bhutan. The self-reported information on risk factors was obtained using standard protocols of the WHO STEPwise approach to Surveillance. The outcome of interest was self-reported diabetes on medication. Adjusted and unadjusted logistic regression analyses were performed to identify the risk factor of diabetes. Results A total of 31,066 participants aged 18 years and older were included for the analysis. The prevalence of self-reported hypertension was 1.8% (491). Risk factors for diabetes were: age groups: 35–44 years adjusted odds ratio (AOR) = 2.82 (95% CI, 1.07, 7.41), 45–54 years AOR = 6.02 (95% CI, 2.29, 15.83), 55–64 year AOR = 15.7 (95% CI 5.93, 41.55) and >65 years AOR = 19.60 (95% CI, 6.93, 55.71); high school and diploma/certificate education AOR = 2.57, (95% CI 1.62, 4.07) and AOR = 3.92 (95% CI 1.70, 9.07); and urban dwellers AOR = 2.37, (95% 1.58, 3.57); hypertension AOR = 3.3, (95% CI 2.47, 4.41); and fruit servings of 1–3 per week AOR = 1.63 (95% CI 1.15, 2.31). Conclusion The number of Bhutanese adults with diabetes and co-morbidities associated with it is likely to increase with the ageing of the population, nutrition transition, and high rural-urban migration in the near future. This calls for an urgent need to implement strategies to prevent diabetes in the Bhutanese population targeting risk factors including healthy lifestyle with increased physical activities and reduced smoking. At the same time treating other chronic morbidities including hypertension.

Background Obesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations. Objectives We aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies. Data Sources 3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses. Study Eligibility Criteria Empirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol). Statistical Methods We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger’s test was used. Results Obesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups. Conclusions Our analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.

BACKGROUND: Smoking, alcohol consumption, poor diet and low levels of physical activity significantly contribute to the burden of illness in developed countries. Whilst the links between specific and multiple risk behaviours and individual chronic conditions are well documented, the impact of these behaviours in mid-life across a range of later life outcomes has yet to be comprehensively assessed. This review aimed to provide an overview of behavioural risk factors in mid-life that are associated with successful ageing and the primary prevention or delay of disability, dementia, frailty and non-communicable chronic conditions. METHODS: A literature search was conducted to identify cohort studies published in English since 2000 up to Dec 2014. Multivariate analyses and a minimum follow-up of five years were required for inclusion. Two reviewers screened titles, abstracts and papers independently. Studies were assessed for quality. Evidence was synthesised by mid-life behavioural risk for a range of late life outcomes. FINDINGS: This search located 10,338 individual references, of which 164 are included in this review. Follow-up data ranged from five years to 36 years. Outcomes include dementia, frailty, disability and cardiovascular disease. There is consistent evidence of beneficial associations between mid-life physical activity, healthy ageing and disease outcomes. Across all populations studied there is consistent evidence that mid-life smoking has a detrimental effect on health. Evidence specific to alcohol consumption was mixed. Limited, but supportive, evidence was available relating specifically to mid-life diet, leisure and social activities or health inequalities. CONCLUSIONS: There is consistent evidence of associations between mid-life behaviours and a range of late life outcomes. The promotion of physical activity, healthy diet and smoking cessation in all mid-life populations should be encouraged for successful ageing and the prevention of disability and chronic disease.

An increase in the exposure and predisposition of civilian populations to disasters has been recorded in the last decades. In major disasters, as demonstrated recently in Nepal (2015) and previously in Haiti (2010), external aid is vital, yet in the first hours after a disaster, communities must usually cope alone with the challenge of providing emergent lifesaving care. Communities therefore need to be prepared to handle emergency situations. Mapping the needs of the populations within their purview is a trying task for decision makers and community leaders. In this context, the elderly are traditionally treated as a susceptible population with special needs. The current study aimed to explore variations in the level of community resilience along the lifespan. The study was conducted in nine small to mid-size towns in Israel between August and November 2011 (N = 885). The Conjoint Community Resiliency Assessment Measure (CCRAM), a validated instrument for community resilience assessment, was used to examine the association between age and community resilience score. Statistical analysis included spline and logistic regression models that explored community resiliency over the lifespan in a way that allowed flexible modeling of the curve without prior constraints. This innovative statistical approach facilitated identification of the ages at which trend changes occurred. The study found a significant rise in community resiliency scores in the age groups of 61–75 years as compared with younger age bands, suggesting that older people in good health may contribute positively to building community resiliency for crisis. Rather than focusing on the growing medical needs and years of dependency associated with increased life expectancy and the resulting climb in the proportion of elders in the population, this paper proposes that active "young at heart" older people can be a valuable resource for their community.

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work has demonstrated that increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms. Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan – elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms., Author Summary The accumulation of oxidative damage caused by reactive oxygen species (ROS) has been proposed to be one of the main causes of aging. However, recent work indicates that low levels of ROS can be beneficial and promote longevity. In this paper, we use a long-lived mitochondrial mutant C. elegans strain clk-1 to further examine the relationship between ROS and lifespan. While it was originally believed that clk-1 mutants had increased lifespan as a result of decreased ROS production, ROS levels have been shown to be increased in clk-1 worms. We show that this increase in ROS is required for the longevity of clk-1 worms as treatment with antioxidants decreases clk-1 lifespan. Further, by using a genetic approach to increase ROS in specific subcellular compartments, we show that the location of the ROS is crucial in determining its effect on lifespan. Increasing ROS in the mitochondria markedly increases clk-1 lifespan, while increasing ROS in the cytoplasm decreases it. Finally, we show that the effect of increased ROS on stress resistance and physiologic rates is also dependent on the location of ROS within the cell but that both of these factors can be experimentally dissociated from lifespan.

People in different subgroups age at different rates. Surveys containing biomarkers can be used to assess these subgroup differences. We illustrate this using hand-grip strength to produce an easily interpretable, physical-based measure that allows us to compare characteristic-based ages across educational subgroups in the United States. Hand-grip strength has been shown to be a good predictor of future mortality and morbidity, and therefore a useful indicator of population aging. Data from the Health and Retirement Survey (HRS) were used. Two education subgroups were distinguished, those with less than a high school diploma and those with more education. Regressions on hand-grip strength were run for each sex and race using age and education, their interactions and other covariates as independent variables. Ages of identical mean hand-grip strength across education groups were compared for people in the age range 60 to 80. The hand-grip strength of 65 year old white males with less education was the equivalent to that of 69.6 (68.2, 70.9) year old white men with more education, indicating that the more educated men had aged more slowly. This is a constant characteristic age, as defined in the Sanderson and Scherbov article "The characteristics approach to the measurement of population aging" published 2013 in Population and Development Review. Sixty-five year old white females with less education had the same average hand-grip strength as 69.4 (68.2, 70.7) year old white women with more education. African-American women at ages 60 and 65 with more education also aged more slowly than their less educated counterparts. African American men with more education aged at about the same rate as those with less education. This paper expands the toolkit of those interested in population aging by showing how survey data can be used to measure the differential extent of aging across subpopulations.

Leaf senescence, an indicator of plant age and ill health, is an important phenotypic trait for the assessment of a plant's response to stress. Manual inspection of senescence, however, is time consuming, inaccurate and subjective. In this paper we propose an objective evaluation of plant senescence by color image analysis for use in a high throughput plant phenotyping pipeline. As high throughput phenotyping platforms are designed to capture whole-of-plant features, camera lenses and camera settings are inappropriate for the capture of fine detail. Specifically, plant colors in images may not represent true plant colors, leading to errors in senescence estimation. Our algorithm features a color distortion correction and image restoration step prior to a senescence analysis. We apply our algorithm to two time series of images of wheat and chickpea plants to quantify the onset and progression of senescence. We compare our results with senescence scores resulting from manual inspection. We demonstrate that our procedure is able to process images in an automated way for an accurate estimation of plant senescence even from color distorted and blurred images obtained under high throughput conditions. Refereed/Peer-reviewed

Effective and efficient spatial normalization of a large population of brain images is critical for many clinical and research studies, but it is technically very challenging. A commonly used approach is to choose a certain image as the template and then align all other images in the population to this template by applying pairwise registration. To avoid the potential bias induced by the inappropriate template selection, groupwise registration methods have been proposed to simultaneously register all images to a latent common space. However, current groupwise registration methods do not make full use of image distribution information for more accurate registration. In this paper, we present a novel groupwise registration method that harnesses the image distribution information by capturing the image distribution manifold using a hierarchical graph with its nodes representing the individual images. More specifically, a low-level graph describes the image distribution in each subgroup, and a high-level graph encodes the relationship between representative images of subgroups. Given the graph representation, we can register all images to the common space by dynamically shrinking the graph on the image manifold. The topology of the entire image distribution is always maintained during graph shrinkage. Evaluations on two datasets, one for 80 elderly individuals and one for 285 infants, indicate that our method can yield promising results.

Organismal aging is influenced by a multitude of intrinsic and extrinsic factors, and heterochromatin loss has been proposed to be one of the causes of aging. However, the role of heterochromatin in animal aging has been controversial. Here we show that heterochromatin formation prolongs lifespan and controls ribosomal RNA synthesis in Drosophila. Animals with decreased heterochromatin levels exhibit a dramatic shortening of lifespan, whereas increasing heterochromatin prolongs lifespan. The changes in lifespan are associated with changes in muscle integrity. Furthermore, we show that heterochromatin levels decrease with normal aging and that heterochromatin formation is essential for silencing rRNA transcription. Loss of epigenetic silencing and loss of stability of the rDNA locus have previously been implicated in aging of yeast. Taken together, these results suggest that epigenetic preservation of genome stability, especially at the rDNA locus, and repression of unnecessary rRNA synthesis, might be an evolutionarily conserved mechanism for prolonging lifespan., Author Summary Aging is characterized by a progressive decline in vitality and tissue function, leading to the demise of the organism. Many models have been proposed to explain the aging phenomenon. Among the many competing and/or overlapping models is the heterochromatin loss model of aging, which posits that heterochromatin domains (which are set up early in embryogenesis) are gradually lost with aging, resulting in de-repression of silenced genes and aberrant gene expression patterns associated with old age. In this paper, we genetically tested the role of heterochromatin in Drosophila aging. We find that heterochromatin levels indeed affect animal lifespan and that heterochromatin represses, among other things, rRNA transcription. Loss of heterochromatin thus leads to an increase in rRNA transcription, a rate-limiting step in ribosome biogenesis and protein synthesis. We suggest that the biological functions of heterochromatin formation include controlling rRNA transcription, which might play an important role in general protein synthesis and animal longevity.

Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia., Author Summary Alström syndrome is a rare genetic disorder caused by mutations in the ALMS1 gene. The disease is characterized by blindness, deafness, and metabolic disorders. These symptoms are reminiscent of diseases affecting the primary cilium, a cellular appendage with a role in sensing changes to the extracellular environment. In addition, kidney failure is a frequent cause of death in Alström syndrome patients, and recent studies have suggested a causal relationship between defects in primary cilia and cystic kidney diseases. In this paper, we show that ALMS1 protein is required to form cilia in kidney cells. Mutant alleles of the gene that are similar to those seen in the human disease are able to support cilia formation in cell culture and in animals. However, a defect in the function of the disease alleles is uncovered in older mice: cilia are lost from the kidney cells, and this is associated with an increase in cellular proliferation and cell death. The data are consistent with a requirement for ALMS1 in ciliogenesis and suggest inclusion of Alström syndrome among the growing class of cilia-related pathologies.

Although the prostate is androgen-dependent, it is also influenced by estrogens, which act via the estrogen receptors ERα and ERβ. In the prostate, ERβ is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation. Evidence shows that ERβ is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. Despite the relationship between reductions in ERβ and abnormal growth of the gland, little is known about the age-dependent variation of this receptor. Therefore, we aimed to investigate ERβ expression in the prostatic lobes of aging Wistar rats (3 to 24 months). Histopathological alterations, including hyperplasia, intraluminal concretions, nuclear atypia and prostate intraepithelial neoplasias (PIN), were observed in the prostates of aging rats. Epithelial proliferation led to cribriform architecture in some acini, especially in the ventral prostate (VP). In the VP, areas of epithelial atrophy were also observed. Furthermore, in the lateral prostate, there was frequent prostatitis. Immunohistochemistry revealed that the expression of ERβ is reduced in specific areas related to PIN, atrophic abnormalities and cellular atypia in the prostate epithelium of senile rats. Corroborating the involvement of the receptor with proliferative activity, the punctual reduction in ERβ paralleled the increase in cell proliferation especially in areas of PIN and nuclear atypies. The decrease in ERβ reactivity occurred in a hormonal milieu characterized by a constant concentration of estradiol and decreased plasmatic and tissue DHT. This paper is a pioneering study that reveals focal ERβ reduction in the prostate of aging rats and indicates a potential disorder in the ERβ pathway. These data corroborate previous data from humans and dogs that silencing of this receptor may be associated with premalignant or malignant conditions in the prostate.

This paper establishes reference ranges for hematologic and plasma biochemistry values in wild Black flying-foxes (Pteropus alecto) captured in South East Queensland, Australia. Values were found to be consistent with those of other Pteropus species. Four hundred and forty-seven animals were sampled over 12 months and significant differences were found between age, sex, reproductive and body condition cohorts in the sample population. Mean values for each cohort fell within the determined normal adult reference range, with the exception of elevated levels of alkaline phosphatase in juvenile animals. Hematologic and biochemistry parameters of injured animals showed little or no deviation from the normal reference values for minor injuries, while two animals with more severe injury or abscessation showed leucocytosis, anaemia, thrombocytosis, hyperglobulinemia and hypoalbuminemia.

We construct a model to study tradeoffs associated with aging in the adaptive immune system, focusing on cumulative effects of replacing naive cells with memory cells. Binding affinities are characterized by a stochastic shape space model. System loss arising from an individual infection is associated with disease severity, as measured by the total antigen population over the course of an infection. We monitor evolution of cell populations on the shape space over a string of infections, and find that the distribution of losses becomes increasingly heavy-tailed with time. Initially this lowers the average loss: the memory cell population becomes tuned to the history of past exposures, reducing the loss of the system when subjected to a second, similar infection. This is accompanied by a corresponding increase in vulnerability to novel infections, which ultimately causes the expected loss to increase due to overspecialization, leading to increasing fragility with age (i.e., immunosenescence). In our model, immunosenescence is not the result of a performance degradation of some specific lymphocyte, but rather a natural consequence of the built-in mechanisms for system adaptation. This “robust, yet fragile” behavior is a key signature of Highly Optimized Tolerance., Synopsis The immune system can be viewed as a complex system, which adapts, over time, to reflect the history of infections experienced by the organism. This paper describes a model that captures this adaptation and corresponding robust, yet fragile behavior. To model immunological processes that rely on binding specificity, researchers typically utilize abstract shape space models. These models describe the binding characteristics of a receptor or antigen as points in a high dimensional vector space. Stromberg and Carlson have incorporated the concept of shape space into a dynamical model of immune response. They use this model to examine the development of the system over a series of infections and monitor the severity of disease for each infection. The diseases are drawn at random from a distribution having a few frequently reoccurring and many rare. The system is observed to adapt over a series of infections, becoming robust to the frequent diseases while developing fragility to the rare diseases. This age-correlated weakness arises from the underlying dynamics of system adaptation rather than from an accumulation of defects. This robust, yet fragile behavior is a signature of Highly Optimized Tolerance, a mechanism for complexity based on robustness tradeoffs.

Quantifying human weight and height dynamics due to growth, aging, and energy balance can inform clinical practice and policy analysis. This paper presents the first mechanism-based model spanning full individual life and capturing changes in body weight, composition and height. Integrating previous empirical and modeling findings and validated against several additional empirical studies, the model replicates key trends in human growth including A) Changes in energy requirements from birth to old ages. B) Short and long-term dynamics of body weight and composition. C) Stunted growth with chronic malnutrition and potential for catch up growth. From obesity policy analysis to treating malnutrition and tracking growth trajectories, the model can address diverse policy questions. For example I find that even without further rise in obesity, the gap between healthy and actual Body Mass Indexes (BMIs) has embedded, for different population groups, a surplus of 14%–24% in energy intake which will be a source of significant inertia in obesity trends. In another analysis, energy deficit percentage needed to reduce BMI by one unit is found to be relatively constant across ages. Accompanying documented and freely available simulation model facilitates diverse applications customized to different sub-populations., National Institutes of Health (U.S.). Office of Behavioral and Social Sciences Research (Contract HHSN276201000004C), National Institutes of Health (U.S.). Office of Behavioral and Social Sciences Research (Contract 1R21HL113680-01))

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889-90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

BACKGROUND:Age-related macular degeneration (AMD) is the main cause of blindness in the developed world. The etiology of AMD is multifactorial due to the interaction between genetic and environmental factors. IL-8 has a role in inflammation and angiogenesis; we report the genetic characterization of IL-8 allele architecture and evaluate the role of SNPs or haplotypes in the susceptibility to wet AMD, case-control study. METHODS:Case-control study including 721 AMD patients and 660 controls becoming from Italian population. Genotyping was carried out by Real Time-PCR. Differences in the frequencies were estimated by the chi-square test. Direct sequencing was carried out by capillary electrophoresis trough ABI3130xl. RESULTS:rs2227306 showed a p-value of 4.15*10(-5) and an Odds Ratio (OR) for T allele of 1.39 [1.19-1.62]. After these positive results, we sequenced the entire IL-8 regulatory and coding regions of 60 patients and 30 controls stratified for their genotype at rs2227306. We defined two different haplotypes involving rs4073 (A/T), rs2227306 (C/T), rs2227346 (C/T) and rs1126647 (A/T): A-T-T-T (p-value: 2.08*10(-9); OR: 1.68 [1.43-1.97]) and T-C-C-A (p-value: 7.07*10(-11); OR: 0.60 [0.51-0.70]). To further investigate a potential functional role of associated haplotypes, we performed an expression study on RNA extracted from whole blood of 75 donors to verify a possible direct correlation between haplotype and gene expression, failing to reveal significant differences. CONCLUSIONS:These results suggest a possible secondary role of IL-8 gene in the development of the disease. This paper outlines the importance of association between inflammation and AMD. Moreover IL-8 is a new susceptibility genomic biomarker of AMD.

In this paper, a high-dimensional pattern classification framework, based on functional associations between brain regions during resting-state, is proposed to accurately identify MCI individuals from subjects who experience normal aging. The proposed technique employs multi-spectrum networks to characterize the complex yet subtle blood oxygenation level dependent (BOLD) signal changes caused by pathological attacks. The utilization of multi-spectrum networks in identifying MCI individuals is motivated by the inherent frequency-specific properties of BOLD spectrum. It is believed that frequency specific information extracted from different spectra may delineate the complex yet subtle variations of BOLD signals more effectively. In the proposed technique, regional mean time series of each region-of-interest (ROI) is band-pass filtered (0.025 ≤ ƒ ≤ 0.100 Hz) before it is decomposed into five frequency sub-bands. Five connectivity networks are constructed, one from each frequency sub-band. Clustering coefficient of each ROI in relation to the other ROIs are extracted as features for classification. Classification accuracy was evaluated via leave-one-out cross-validation to ensure generalization of performance. The classification accuracy obtained by this approach is 86.5%, which is an increase of at least 18.9% from the conventional full-spectrum methods. A cross-validation estimation of the generalization performance shows an area of 0.863 under the receiver operating characteristic (ROC) curve, indicating good diagnostic power. It was also found that, based on the selected features, portions of the prefrontal cortex, orbitofrontal cortex, temporal lobe, and parietal lobe regions provided the most discriminant information for classification, in line with results reported in previous studies. Analysis on individual frequency sub-bands demonstrated that different sub-bands contribute differently to classification, providing extra evidence regarding frequency-specific distribution of BOLD signals. Our MCI classification framework, which allows accurate early detection of functional brain abnormalities, makes an important positive contribution to the treatment management of potential AD patients.

This paper describes the construction and characterization of a system of transcriptional reporter genes for monitoring the activity of signaling pathways and gene regulation mechanisms in intact Drosophila, dissected tissues or cultured cells. Transgenic integration of the reporters into the Drosophila germline was performed in a site-directed manner, using ΦC31 integrase. This strategy avoids variable position effects and assures low base level activity and high signal responsiveness. Defined integration sites furthermore enable the experimenter to compare the activity of different reporters in one organism. The reporter constructs have a modular design to facilitate the combination of promoter elements (synthetic transcription factor binding sites or natural regulatory sequences), reporter genes (eGFP, or DsRed.T4), and genomic integration sites. The system was used to analyze and compare the activity and signal response profiles of two stress inducible transcription factors, AP-1 and Nrf2. To complement the transgenic reporter fly lines, tissue culture assays were developed in which the same synthetic ARE and TRE elements control the expression of firefly luciferase.

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline., Author Summary In recent decades, our understanding of Alzheimer's disease (AD) has increased; however, some basic questions still remain unresolved. One of them is: how homogeneous is AD? Is the course of progression more or less the same for most patients, or are there large variations? Our paper studies a large cohort of AD patients which comes from a 23-year-long study, and performs a statistical analysis of progression speed. We quantify the amount of spread in GDS/FAST stage durations (a staging system widely used by clinicians). We arrive at an astonishing conclusion that the mean length of AD stages is comparable with their standard deviation! This means that individual courses of AD progression may differ very much from each other, and from the textbook mean values. This has implications both for clinical trials (how do we assess if a new drug is effective, if the amount of natural spread is so large in untreated patients?), and for our understanding of this disease, which appears to be comprised of sub-diseases with different patterns of decline.

Parkinson disease (PD) is the most common neurodegenerative movement disorder in humans, but its cause in the majority of patients is unknown. Fewer than 10% of cases appear to be inherited, and only rarely are the known Mendelian mutations identified in patients with PD. In addition to genetic factors, environmental toxins—especially those affecting mitochondrial function—have also been implicated [1,2], demonstrating a clear role for gene–environment interactions in most cases of sporadic PD. Patients afflicted with PD experience slow, selective, often asymmetric loss of dopaminergic (DA) neurons projecting from the substantia nigra (SN) to the striatum, but not of DA neurons located elsewhere in the brain (e.g., ventral tegmental area and retina). Once more than 80%–90% of DA neurons in the SN are lost, patients suffer the characteristic symptoms of tremor, slow movements (bradykinesia), rigidity, and postural instability. To study PD, researchers have used two basic types of animal models: (1) acute lesioning of DA neurons/tracts, either by surgery or toxic insult, and (2) genetic models that rely on expression of one of the rare, dominant, and highly penetrant mutations that cause PD or knockout of a similar, recessively inherited allele (e.g., α-synuclein, Parkin, and leucine-rich repeat kinase-2 [LRRK2]). Although these models have led to huge advances in our understanding of PD—implicating mitochondrial dysfunction, oxidative damage, and protein handling systems in pathogenesis—they typically either fail to recapitulate the gradual nature of this degenerative disease or lack the defining pathology (e.g., Parkin and α-synuclein transgenic mice fail to show progressive nigrostriatal degeneration, although rotenone-treated mice do show Lewy bodies (intracytoplasmic inclusions that are composed primarily of α-synuclein and ubiqutin)) [3,4]. Because no single animal model is likely to be sufficient for the study of any particular human neurodegenerative disease, new models are needed to accelerate our ability to devise and test improved disease-altering therapies. It is in this regard that a new paper in PLoS Biology by Kittappa et al. [5] warrants special attention. They demonstrate that knockout of a transcription factor FoxA2, which is critical for DA neuron specification and survival in mice causes a late-onset, asymmetric degenerative condition affecting motor systems in a manner very similar to PD. This model is entirely distinct in its basic mechanism from the aforementioned models, because it involves partial loss of a transcription factor that is critical for DA neuron cell fate. One of the most striking features of the majority of adult-onset neurodegenerative diseases is their regional or cell-type specificity in humans. Yet, many of the known causative mutations reside in proteins that are widely expressed throughout the central nervous system, such as synuclein, LRK2, and Parkin in PD, beta amyloid and presenilin-1 (PS1) in Alzheimer disease, and tau and progranulin in frontotemporal dementia. The current study in mice, and previous work in humans and other model organisms, highlight the potential role that neurodevelopmental factors may play in the cell-type–specific or regional neuronal vulnerability seen in neurodegenerative disease [6,7] As this work by Kittappa and colleagues demonstrates, understanding early developmental processes such as cell-type specification and survival may have major implications for aging-related diseases.