Arthur Roger Thatcher's contributions to longevity research: A Reflexion

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International trends in the rate of logistic mortality increase

Meeting Theme: Are sex differences in health expectancy a social issue?BACKGROUND: Thatcher et al. (2010) used the simple logistic model with two parameters, which is known to fit data on old-age mortality well (Thatcher 1999), to investigate the old-age mortality compression and estimated the rate of logistic mortality increase, denoted by b, for ages 70-90. They concluded that if logit m(x) tends to fall faster at younger ages, then the slope b of the logit line will become steeper and mortality compression will occur. In this paper, we aim to estimate the rate of logistic mortality increase, denoted by b, for ages 70-90 in 23 countries with good and acceptable quality of data from Human Mortality Database and examine whether there is a universal trend in b. METHODS: We adopt a special case of the logistic model of mortality, which has only two parameters as does the Lexis model, and it is usually written in the form of model (1) μ(x) = a ebx / (1 + a ebx) (1) RESULTS: Our results show that the rate of logistic increase has steadily risen for females and males from about 0.10 in the 1950s to about 0.13 in recent years for most established market-economy countries in Europe as shown in group A (19 European countries). Among males, the value of parameter b is about 0.02 smaller than that for females and the rate of logistic mortality increase always lags behind females about 20 years. However, for Japanese females, although the increase was similar to the common pattern from 0.10 in 1947 to 0.13 in 1984, then the value of parameter b reached the highest 0.14 and became levelling off in the decade 1984-1995. Afterwards, it reverted to the level of 1984. In Canada, b increased at a relatively slower pace from 0.10 in 1950 to 0.12 in 2006 among females, whereas in the US the value of b tended to stay at 0.10-0.11 throughout the whole period 1921-2006. In Australia, b for females fluctuated around 0.10-0.11 before 1980, then a noticeable increase was observed from 0.12 in 1980 to 0.14 in 2007. CONCLUSIONS: The results show that the rate of logistic increase has steadily risen for females and males from about 0.10 in the 1950s to about 0.13 in recent years for most established market-economy countries. Deviant patterns such as slow increase, plateau and decrease are observed for some periods in Australia, Canada, Denmark, Japan and the USA. Possible reasons for those dominant and deviant trends are discussed.postprin

The effect of smoking on the duration of life with and without disability, Belgium 1997-2011

Background: Smoking is the single most important health threat yet there is no consistency as to whether non-smokers experience a compression of years lived with disability compared to (ex-)smokers. The objectives of the manuscript are (1) to assess the effect of smoking on the average years lived without disability (Disability Free Life Expectancy (DFLE)) and with disability (Disability Life Expectancy (DLE)) and (2) to estimate the extent to which these effects are due to better survival or reduced disability in never smokers. Methods. Data on disability and mortality were provided by the Belgian Health Interview Survey 1997 and 2001 and a 10 years mortality follow-up of the survey participants. Disability was defined as difficulties in activities of daily living (ADL), in mobility, in continence or in sensory (vision, hearing) functions. Poisson and multinomial logistic regression models were fitted to estimate the probabilities of death and the prevalence of disability by age, gender and smoking status adjusted for socioeconomic position. The Sullivan method was used to estimate DFLE and DLE at age 30. The contribution of mortality and of disability to smoking related differences in DFLE and DLE was assessed using decomposition methods. Results: Compared to never smokers, ex-smokers have a shorter life expectancy (LE) and DFLE but the number of years lived with disability is somewhat larger. For both sexes, the higher disability prevalence is the main contributing factor to the difference in DFLE and DLE. Smokers have a shorter LE, DFLE and DLE compared to never smokers. Both higher mortality and higher disability prevalence contribute to the difference in DFLE, but mortality is more important among males. Although both male and female smokers experience higher disability prevalence, their higher mortality outweighs their disability disadvantage resulting in a shorter DLE. Conclusion: Smoking kills and shortens both life without and life with disability. Smoking related disability can however not be ignored, given its contribution to the excess years with disability especially in younger age groups

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.This work was generously funded by an award to DM, TF, AM, LH and CB by the Medical Research Council MR/M023095/1. This research has been conducted using the UK Biobank Resource, under application 1417. The authors wish to thank the UK Biobank participants and coordinators for this unique dataset. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). A.R.W. H.Y., and T.M.F. are supported by the European Research Council grant: 323195:GLUCOSEGENES-FP7-IDEAS-ERC. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Framingham Heart Study is supported by Contract No. N01-HC-25195 and HHSN268201500001I and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The phenotypegenotype association analyses were supported by National Institute of Aging R01AG29451. This work has made use of the resources provided by the University of Exeter Science Strategy and resulting Systems Biology initiative. Primarily these include high-performance computing facilities managed by Konrad Paszkiewicz of the College of Environmental and Life Sciences and Pete Leggett of the University of Exeter Academics services unit

Assessing heat-related health risk in Europe via the Universal Thermal Climate Index (UTCI)

In this work the potential of the Universal Thermal Climate Index (UTCI) as a heat-related health risk indicator in Europe is demonstrated. The UTCI is a bioclimate index that uses a multi-node human heat balance model to represent the heat stress induced by meteorological conditions to the human body. Using 38 years of meteorological reanalysis data, UTCI maps were computed to assess the thermal bioclimate of Europe for the summer season. Patterns of heat stress conditions and non-thermal stress regions are identified across Europe. An increase in heat stress up to 1°C is observed during recent decades. Correlation with mortality data from 17 European countries revealed that the relationship between the UTCI and death counts depends on the bioclimate of the country, and death counts increase in conditions of moderate and strong stress, i.e. when UTCI is above 26°C and 32°C. The UTCI’s ability to represent mortality patterns is demonstrated for the 2003 European heatwave. These findings confirm the importance of UTCI as a bioclimatic index that is able to both capture the thermal bioclimatic variability of Europe, and relate such variability with the effects it has on human health

Obesity, smoking, alcohol consumption and years lived with disability: A Sullivan life table approach

Background: To avoid strong declines in the quality of life due to population ageing, and to ensure sustainability of the health care system, reductions in the burden of disability among elderly populations are urgently needed. Life style interventions may help to reduce the years lived with one or more disabilities, but it is not fully understood which life style factor has the largest potential for such reductions. Therefore, the primary aim of this paper is to compare the effect of BMI, smoking and alcohol consumption on life expectancy with disability, using the Sullivan life table method. A secondary aim is to assess potential improvement of the Sullivan method by using information on the association of disability with time to death. Methods. Data from the Dutch Permanent Survey of the Living Situation (POLS) 1997-1999 with mortality follow-up until 2006 (n = 6,446) were used. Using estimated relative mortality risks by risk factor exposure, separate life tables were constructed for groups defined in terms of BMI, smoking status and alcohol consumption. Logistic regression models were fitted to predict the prevalence of ADL and mobility disabilities in relationship to age and risk factor exposure. Using the Sullivan method, predicted age-specific prevalence rates were included in the life table to calculate years lived with disability at age 55. In further analysis we assessed whether adding information on time to death in both the regression models and the life table estimates would lead to substantive changes in the results. Results: Life expectancy at age 55 differed by 1.4 years among groups defined in terms of BMI, 4.0 years by smoking status, and 3.0 years by alcohol consumption. Years lived with disability differed by 2.8 years according to BMI, 0.2 years by smoking and 1.6 by alcohol consumption. Obese persons could expect to live more years with disability (5.9 years) than smokers (3.8 years) and drinkers (3.1 years). Employing information on time to death led to lower estimates of years lived with disability, and to smaller differences in these years according to BMI (2.1 years), alcohol (1.2 years), and smoking (0.1 years). Conclusions: Compared with smoking and drinking alcohol, obesity is most strongly associated with an increased risk of spending many years of life with disability. Although employing information on the relation of disability with time to death improves the precision of Sullivan life table estimates, the relative importance of risk factors remained unchanged

Research on sablefish (Anoplopoma fimbria) suggests that limited capacity to increase heart function leaves hypoxic fish susceptible to heat waves

Studies of heart function and metabolism have been used to predict the impact of global warming on fish survival and distribution, and their susceptibility to acute and chronic temperature increases. Yet, despite the fact that hypoxia and high temperatures often co-occur, only one study has examined the effects of hypoxia on fish thermal tolerance, and the consequences of hypoxia for fish cardiac responses to acute warming have not been investigated. We report that sablefish (Anoplopoma fimbria) did not increase heart rate or cardiac output when warmed while hypoxic, and that this response was associated with reductions in maximum O2 consumption and thermal tolerance (CTmax) of 66% and approximately 3°C, respectively. Further, acclimation to hypoxia for four to six months did not substantially alter the sablefish's temperature-dependent physiological responses or improve its CTmax. These results provide novel, and compelling, evidence that hypoxia can impair the cardiac and metabolic response to increased temperatures in fish, and suggest that some coastal species may be more vulnerable to climate change-related heat waves than previously thought. Further, they support research showing that cross-tolerance and physiological plasticity in fish following hypoxia acclimation are limited.publishedVersio

BUILDING BRIDGES FOR INNOVATION IN AGEING : SYNERGIES BETWEEN ACTION GROUPS OF THE EIP ON AHA

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).Peer reviewe

Contribution of chronic conditions to functional limitations using a multinomial outcome: results for the older population in Belgium and Brazil

Background: The global phenomenon of population ageing is creating new challenges in both high and middle income countries, as functional limitations are expected to increase with age. The attribution method has been proposed to identify which conditions contribute most to disability using cross-sectional data. Although the original method was based on binary outcomes, we recently proposed an extension to multinomial responses, since different disability levels are often investigated in surveys. This is the first application of the extended method to evaluate differences in the contribution of chronic conditions to functional limitations in the older population of Brazil and Belgium. Methods: Representative data from individuals aged ≥65 years who participated in the 2008 or 2013 Health Interview Surveys in Belgium (N = 4521) or in the 2008 National Household Sample Survey in Brazil (N = 28,437) were analysed. Individuals were classified as without, moderate or severe functional limitations, based on three activities of daily living: eating, showering, and toileting. Six chronic conditions common to the surveys - diabetes, heart diseases, musculoskeletal conditions, depression, chronic respiratory diseases, and cancer - were included in the analysis. Separate multinomial additive hazards models by gender for each country were fitted. Results: The prevalence of moderate functional limitations was larger in men in Brazil (8.4%) compared to Belgium (6.0%) and similar in women (approximately 12.0%). Conversely, the severe prevalence in men was similar in the two countries (around 8.0%) and higher in women from Belgium (16.6%) than from Brazil (9.1%). Musculoskeletal conditions were the main contributors to the prevalence of functional limitations in men and women in Belgium but only in men and women with moderate functional limitations in Brazil. Depression and heart diseases contributed most to the severe prevalence of functional limitations in men and women in Brazil, respectively. Conclusions: Our findings provide a better understanding of differences in the prevalence of different levels of functional limitations in Brazil and Belgium. These differences can be related to differences in socioeconomic conditions, health care access and quality, disease diagnosis, stage of epidemiology transition, life expectancy, and the prevalence of lifestyle risk factors in the two countries