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Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the ‘invariant rate of ageing’ hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed., The ‘invariant rate of ageing’ hypothesis suggests that the rate of ageing tends to be constant within species. Here, Colchero et al. find support for the hypothesis across primates, including humans, suggesting biological constraints on the rate of ageing.

NOTE: this is an early registration of the research idea and findings in form of slides for a talk presented at EAPS Mort workshop on 2021-09-22 (video: https://youtu.be/rOndHnuajH4?t=2370)Period Life Expectancy is the key summary measure of current mortality. Elimination of the direct influence of population age structure allows to meaningfully compare mortality levels and changes across the populations and over time. Calculation of life expectancy demands high quality detailed data on death and population counts disaggregated by sex and age. Such data is only available for the more developed countries. Moreover, even in the most developed countries, it becomes available with a considerable time lag. And for the majority of countries across the world timely and high quality deaths statistics is not available. In situations of mortality shocks such as the COVID–19 pandemic near real time mortality level comparisons are crucial.Building on the studied regularities of human mortality, we offer a method of reliable life expectancy short-casting based only on the time series of its previous values and the time series of total deaths counts observed in the population, not disaggregated by sex and age. The radical simplicity of the method allows to monitor changes in life expectancy in near real time, if time disaggregated (daily, weekly, or monthly) total death counts are available.

Demographers have always held great interest in extremal phenomena. Extreme value distributions are tailor made to model extremes but demographers do not often take advantage of them. We argue that demographers would benefit by using these models more often and present one potential usage: the Extreme Value Distribution as a candidate for modelling the error distribution in time series models. As an example, we use the so called best practice life expectancy. The residuals from the fitted models are tested for Normality. They are also fitted with Gaussian and Generalized Extreme Value distributions and the fit of these two distributions is compared. The results suggest that demographers ought to further explore and take greater advantage of extreme value models.

Background: This article reviews findings about the rise of life expectancy, current levels of life expectancy in countries with high life expectancies, and possible future trends in life expectancy. Maximum lifespans and the equality of lifespans are also considered. Methods: Demographic data on age-specific mortality are used to estimate life expectancy. Validated data on exceptional lifespans are used to study the maximum length of life. Findings of the most significant publications are critically summarized.Results: In the countries doing best, life expectancy started to increase around 1840 at a pace of almost 2.5 years per decade. This trend has continued until the present. Contrary to classical evolutionary theories of senescence and contrary to the predictions of many experts, the frontier of survival is advancing to higher ages. Furthermore, lifespans are becoming more equal, with octogenarians and nonagenarians accounting for most deaths in countries with high life expectancy. Extrapolation of the trend indicates that most children born this millennium will celebrate their 100th birthdays. Considerable uncertainty, however, clouds forecasts of life expectancy and maximum lifespans: life expectancy and maximum lifespan might increase very little if at all or longevity might rise much faster than in the past. Conclusions: Substantial progress has been made over the past three decades in deepening understanding of how long humans have lived and have long they might live. The social, economic, health, cultural and political consequences of further increases in longevity are so significant that the development of more powerful methods of forecasting is a priority.

Is it possible to slow the rate of aging, or do biological constraints limit its plasticity? We test this ‘invariant rate of aging’ hypothesis with an unprecedented collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of aging within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of aging, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of aging hypothesis, implying biological constraints on how much the human rate of aging can be slowed.

Differences in lifespan between populations, e.g. between females and males, are often measured by differences in summary statistics, such as life expectancy, which generally show an advantage of females over males across the whole age span. However, such statistics ignore the fact that two lifespan distributions are generally not mutually exclusive and that not all females outlive all males. Here we use a novel measure of inequality in lifespans: the outsurvival probability, which is interpreted as the probability of males to outlive females. The measure accounts for the similarities in lifespan between populations. It also considers the interaction between the mean and variance of two lifespan distributions and their combined effect on between-populations inequalities. Our results show that the probability of males outliving females varied between 25% and 50%, across 44 countries and regions since the middle of the 18th century. Thus, despite the usually male lower life expectancy and higher death rates at all ages, males have a substantial chance of outliving females. Our suggested approach is generalizable to any pair of populations.

Background: Inequality in lifespans between two populations, e.g., males and females or people with low and high SES, is a focus of demographic, economic and sociological research and of public policy analysis. Inequality is usually measured by differences in life expectancy.Objective: To devise a cogent measure of how much distributions of lifespans differ between two populations.Results: We propose an outsurvival statistic, φ, that measures the probability that an individual from a population with low life expectancy will live longer than an individual from a population with high life expectancy. This statistic can also be interpreted as an underdog probability—the chance that a random value from a distribution with a low mean will exceed a random value from a distribution with a higher mean.Contribution: Our outsurvival probability complements life expectancy to provide a more nuanced view of the inequality of lifespans between two populations. Our similar underdog probability provides a perspective on the more general question of how different two distributions are.

Publisher's version (útgefin grein)., Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity., Alexander von Humboldt-Stiftung

Senescence, the physiological deterioration resulting in an increase in mortality and decline in fertility with age, is widespread in the animal kingdom and has often been regarded as an inescapable feature of all organisms. This essay briefly describes the history of the evolutionary theoretical ideas on senescence. The canonical evolutionary theories suggest that increasing mortality and decreasing fertility should be ubiquitous. However, increasing empirical data demonstrates that senescence may not be as universal a feature of life as once thought and that a diversity of demographic trajectories exists. These empirical observations support theoretical work indicating that a wide range of mortality and fertility trajectories is indeed possible, including senescence, negligible senescence and even negative senescence (improvement). Although many mysteries remain in the field of biogerontology, it is clear that senescence is not inevitable.

After a brief introduction to the background, significance and unique features of the centenarian population in China, we describe the Chinese Longitudinal Healthy Longevity Study (CLHLS), which is the world's largest study of centenarians, nonagenarians, octogenarians, and compatible young-old aged 65-79. Based on the CLHLS data and other relevant studies, we summarize demographic and socioeconomic characteristics as well as self-reported and objectively-tested health indicators of centenarians in China, with an emphasis on gender differences and rural/urban disparities. We then compare five-year-age-specific trajectories of physical and cognitive functions, self-reported health, and life satisfactions from ages 65-69 to 100+, concluding that good psychological resilience and optimism are keys to the exceptional longevity enjoyed by centenarians. We discuss recent findings of novel loci and pathways that are significantly associated with longevity based on the genome-wide association study (GWAS) of the CLHLS centenarian sample, which is 2.7 times as large as prior GWAS of longevity. We also highlight colleagues' and our own studies on longevity candidate genes and gene-environment interaction analyses. Finally, we discuss limitations inherent in our studies of centenarians in China and further research perspectives. After a brief introduction to the background, significance and unique features of the centenarian population in China, we describe the Chinese Longitudinal Healthy Longevity Study (CLHLS), which is the world's largest study of centenarians, nonagenarians, octogenarians, and compatible young-old aged 65-79. Based on the CLHLS data and other relevant studies, we summarize demographic and socioeconomic characteristics as well as self-reported and objectively-tested health indicators of centenarians in China, with an emphasis on gender differences and rural/urban disparities. We then compare five-year-age-specific trajectories of physical and cognitive functions, self-reported health, and life satisfactions from ages 65-69 to 100+, concluding that good psychological resilience and optimism are keys to the exceptional longevity enjoyed by centenarians. We discuss recent findings of novel loci and pathways that are significantly associated with longevity based on the genome-wide association study (GWAS) of the CLHLS centenarian sample, which is 2.7 times as large as prior GWAS of longevity. We also highlight colleagues' and our own studies on longevity candidate genes and gene-environment interaction analyses. Finally, we discuss limitations inherent in our studies of centenarians in China and further research perspectives.

Background: The "male-female health-survival paradox" that women live significantly longer, but have lower physical performance and more adverse health outcomes at older ages than men, is a phenomenon observed everywhere in the world. This study aims to provide an understanding of the "male-female health-survival paradox", through investigating whether genetic associations with longevity are stronger in males or females. Methods: We conducted logistic regression and bio-demographic analyses, using the genome-wide association study (GWAS) datasets including 2,178 centenarians and 2,299 middle-aged controls of Chinese Longitudinal Healthy Longevity Study. Findings: We found that averages of probabilities of longevity, associated with each of the six mutually exclusive groups of 11 male-specific and 11 female-specific top loci (P

This note outlines a method for forecasting life expectancy. The method is based on the idea of structured conditional probabilistic estimation; it “scopes” out the range of possibilities the future may hold. I first described this SCOPE method at a workshop organized by Juha Alho several years ago in Finland. It is a kind of scenario method – with probabilities attached to scenarios, with scenarios structured conditionally, and with the possibility of stochastic scenarios. It is a simple method, and it is by no means original; many other people have used a similar approach in various settings. This method might be helpful to those who want to forecast life expectancy. This note summarizes my presentation.

Beltrán-Sánchez et al . based their comment on misleading calculations of the maximum survival age. With realistic numbers of people attaining age 105 and the estimated plateau, the Jeanne Calment record is indeed plausible.

Mortality rates level off at extreme age The demography of human longevity is a contentious topic. On the basis of high-quality data from Italians aged 105 and older, Barbi et al. show that mortality is constant at extreme ages but at levels that decline somewhat across cohorts. Human death rates increase exponentially up to about age 80, then decelerate, and plateau after age 105. Science , this issue p. 1459

Importance: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. Objective: To explore sex differences in genetic associations with longevity. Design, Setting, and Participants: This population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014. Main Outcomes and Measures: Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci. Results: Eleven male-specific and 11 female-specific longevity loci (P < 10 -5) and 35 male-specific and 25 female-specific longevity loci (10 -5≤ P < 10 -4) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex (P =.13-.97), and loci-sex interaction effects were significant (P -5) and US women (P = 4.6 × 10 -5) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women (P = 6.8 × 10 -5) and European women (P =.003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity (P -5) and 35 male-specific and 25 female-specific loci (10 -5≤P < 10 -4) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex (P = 2.9 × 10 -70to 1.3 × 10 -39) but not jointly significant in the other sex (P =.11 to.70), while interaction effects between PRS and sex were significant (P = 4.8 × 10 -50to 1.2 × 10 -16). Conclusion and Relevance: The sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals.

Introduction: Why do we visualize data and what is this book about? The introductory chapter describes the three rationales to visualize data: exploration, confirmation and presentation, and discusses the developments in computer hardware, software and connectivity that were instrumental for the recent increased interest in visualizing data.

OBJECTIVEThis article provides an overview of the AKeA2 study, with a particular focus on data collection concerning family genealogies of the Sardinian centenarians and controls, and on the quality of these data. A first analysis of the main characteristics of the survey data is also summarized and selected preliminary results are presented.METHODSWe use descriptive statistics to analyze data collected by the AKeA2 survey on Sardinian centenarians and controls.RESULTSCentenarian women have on average fewer children, and at an older age, particularly for their last child. The mothers of centenarians, especially centenarian women, lived longer on average than those of deceased controls and controls born between 1905 and 1910 but still living at the moment of the survey.1. IntroductionIn Sardinia, male death rates after age 80 are only modestly higher than female death rates, and are lower than female levels in some municipalities. The remarkably low mortality after age 80 has thus yielded a surprisingly large number of centenarian men compared with centenarian women (Robine and Caselli 2005). An area with a large number of centenarians has been identified in the Sardinian province of Nuoro (Deiana et al. 1999; Poulain et al. 2004), as well as a longevity area for men. This latter area comprises municipalities in Oristano as well as Nuoro where the standardized death rate across old ages for men is less than 10% higher than for women, whereas elsewhere in the two provinces the standardized male death rate is more than 30% higher (Caselli and Lipsi 2006). The higher number of centenarians and their more balanced sex ratio have led to considerable interest among demographers, geneticists, gerontologists, and clinicians specializing in genetic mapping (DNA) (Caselli, Robine, and Rasulo 2003).The bio-medical characteristics of Sardinian centenarians was investigated by Luca Deiana and Giovannella Baggio (Deiana et al. 1999) in the AKeA study, an acronym derived from an expression in the Sardinian dialect that means "may you live to 100." A second, larger and cross-disciplinary study, called AKeA2, was launched in 2003, which involved demographers, historians, biologists, geneticists, and gerontologists. The demographic survey was directed by James Vaupel.This article gives a short description of the AKeA2 demographic survey and of the data collection, and provides a preliminary analysis of the data.2. Overview of the AKeA2 study: Sample selection and data collection planThe data collection was time-consuming. Over a six-year period various types of information were gathered: individual demographic characteristics, data on survival rates, and archival data regarding family characteristics and early-life events.The AKeA2 demographic survey was planned to involve Sardinian centenarians (100 men and 100 women) and their controls, by differentiating between living and deceased controls. All the controls were of the same sex as the centenarian, born and still resident in the same place of birth, and their day and month of birth were as close as possible to that of the centenarian. Picking the person with the most similar day and month of birth is a convenient method of selecting a matched individual, and this strategy controls for season-of-birth effects, which are known to affect longevity (Doblhammer 1999; Doblhammer and Vaupel 2001; Gavrilov and Gavrilova 1999).As concerns the living controls, the plan was to identify three younger controls for each centenarian by finding people born around 1907, 1912, and 1922. We also identified, for each centenarian, two deceased controls that were born, as mentioned before, the same year (and around the same day and month) and in the same municipality as the centenarian and to find one who died in his or her late 60s and one who died in his or her late 70s.In choosing both controls it was required that the family names of their mothers and fathers had to be different from the family names of the centenarian's parents. …

Objectives The purpose of this study was to explore the pattern of mortality above the age of 100 years. In particular, we aimed to examine whether Scandinavian data support the theory that mortality reaches a plateau at particularly old ages. Whether the maximum length of life increases with time was also investigated. Methods The analyses were based on individual level data on all Swedish and Danish centenarians born from 1870 to 1901; in total 3006 men and 10 963 women were included. Birth cohort-specific probabilities of dying were calculated. Exact ages were used for calculations of maximum length of life. Whether maximum age changed over time was analysed taking into account increases in cohort size. Results The results confirm that there has not been any improvement in mortality among centenarians in the past 30 years and that the current rise in life expectancy is driven by reductions in mortality below the age of 100 years. The death risks seem to reach a plateau of around 50% at the age 103 years for men and 107 years for women. Despite the rising life expectancy, the maximum age does not appear to increase, in particular after accounting for the increasing number of individuals of advanced age. Conclusion Mortality among centenarians is not changing despite improvements at younger ages. An extension of the maximum life span and a sizeable extension of life expectancy both require reductions in mortality above the age of 100 years. This article is protected by copyright. All rights reserved.

Based on sex-stratified genome-wide association study (GWAS) of Han Chinese, 2,178 centenarians and 2,299 middle-aged controls, we identified 11 male- and 12 female-specific independent loci that are significantly associated with longevity (P-5), replicated in independent North and South regions in one sex, but are not significant (P>0.05) in the other sex. We found that the association of rs60210535 at LINC00871 with longevity replicated well between Chinese females (P=4.6x10-5) and U.S. females (P=9.0x10-5), but was not significant in both Chinese and U.S. males (P>0.05). We discovered that 11 male-specific and 34 female-specific pathways are significantly associated with longevity (PFDR) P-5 in one sex, P>0.05 in other sex), 44/58 male/female strong loci (10-5≤P-4 in one sex, P>0.4 or P>0.35 in other sex), and 191/311 male/female moderate loci (10-4≤P-3 in one sex, P>0.75 or P>0.7 in other sex) are jointly and highly associated with longevity exceeding a significance level P10-8 in one sex, but not jointly associated with longevity in the other sex (P>0.05). Our integrated PRS and novel sex-specific genetic relative benefit/loss ratio analyses indicate that females’ genetic constitution favors longevity more than males’. Further interdisciplinary collaborative efforts are warranted, such as replications from other populations, international meta-analyses with much larger sample size, lab tests, and in silico functional validations. Significance Statement: On average, women live significantly longer lives than men but they have lower physical performance and more adverse health outcomes at older ages compared to men: patterns that signify the male-female health-survival paradox (1). Research on sex differences in health and mortality has proliferated, but has yet to achieve a good understanding of the effects of genetic variants on the sex gap in longevity and health. Based on sex-stratified genome-wide association analysis (GWAS) of Han Chinese including centenarians with a sample size 2.7 times as large as other published largest single GWAS on longevity involving centenarians (2), the present study aims to contribute a better understanding of sex differences in genetic associations with longevity.

Jan Hoem died on Saturday in Stockholm after a long illness. Jan became Director of the Max Planck Institute for Demographic Research (MPIDR) in 1999; he and I jointly led the Institute for almost eight years. During this period he served as Editor of Demographic Research; he took on this responsibility shortly after the journal was launched and built the journal into a respected online source of cutting-edge analysis. Jan was a superb colleague, with very good judgment, a delightful sense of humor, and deep devotion to research quality. A pioneer of event history analysis, he understood the subtleties of the subject better than anyone else. Jan was born and educated in Norway and worked in Oslo before becoming Professor in Copenhagen and then Professor in Stockholm, where he established SUDA, a leading demographic research initiative. His dedication to high-quality, statistically sophisticated population research at SUDA and MPIDR as well as in the journal Demographic Research substantially advanced the discipline of demography. Jan was a warm and generous teacher, a loyal colleague, and a caring friend whom many people will long remember with gratitude and respect. James W. Vaupel Publisher, Demographic Research

Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915. Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele (P=0.026) or for the FOXO3A rs7762395 minor allele (P=0.048). For the APOE ε4 allele, the significance is further strengthened when restricting to women (P=0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100years. Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity. Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100. years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915.Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele (P = 0.026) or for the FOXO3A rs7762395 minor allele (P = 0.048). For the APOE ε4 allele, the significance is further strengthened when restricting to women (P = 0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100. years.Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.

The aims of this study are to analyse the two-way association between women fertility and longevity, and parental transmission of longevity. The wealth of information gathered in the AKeA2—demographic survey on Sardinian centenarians—have been used by applying Logistic Regression Models. For the association between longevity and fertility, we find evidence that *long livers benefit from factors related to the timing of fertility (in particular the age at birth of the last child) that the literature suggests may foster longevity. Regarding the association with parental transmission, it seems to have significant effects for women but not for men. We always found that a higher birth order decreases the probability of becoming a centenarian. There is a negative effect of a higher father age at birth on the longevity of female offspring. The latter suggests that long-lived women seem to have been favoured both by their own late fertility and young paternal age at the moment of their own procreation.

The human lifespan has traversed a long evolutionary and historical path, from short-lived primate ancestors to contemporary Japan, Sweden, and other longevity frontrunners. Analyzing this trajectory is crucial for understanding biological and sociocultural processes that determine the span of life. Here we reveal a fundamental regularity. Two straight lines describe the joint rise of life expectancy and lifespan equality: one for primates and the second one over the full range of human experience from average lifespans as low as 2 y during mortality crises to more than 87 y for Japanese women today. Across the primate order and across human populations, the lives of females tend to be longer and less variable than the lives of males, suggesting deep evolutionary roots to the male disadvantage. Our findings cast fresh light on primate evolution and human history, opening directions for research on inequality, sociality, and aging. The human lifespan has traversed a long evolutionary and historical path, from short-lived primate ancestors to contemporary Japan, Sweden and other longevity frontrunners. Analyzing this trajectory is crucial for understanding biological and sociocultural processes that determine the span of life. Here we reveal a fundamental regularity. Two straight lines describe the joint rise of life expectancy and lifespan equality: one for primates and the second one over the full range of human experience from average lifespans as low as 2 y during mortality crises to more than 87 y for Japanese women today. Across the primate order and across human populations, the lives of females tend to be longer and less variable than the lives of males, suggesting deep evolutionary roots to the male disadvantage. Our findings cast fresh light on primate evolution and human history, opening directions for research on inequality, sociality, and aging.

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P

The chance of surviving to the age of 90 has increased markedly over the last 50 years in high-income countries, and will probably continue to rise with successive cohorts.1,2 In the United States, the number of nonagenarians has increased from approximately 230,000 in 1960 to approximately 1.8 million in 2010, and in the five biggest countries in the European Union (Germany, France, the United Kingdom, Italy, Spain) the number has increased from approximately 250,000 to 1.6 million, which is almost 7 times as many nonagenarians, compared with 1.5 times as many people in the total population of these countries in 1960 as in 2010. With this growing number of oldest old adults, ageism has been decreasing in recent decades, and it has now become generally unacceptable to deny medical procedures to people aged 80 and older using advanced age as the sole argument.3 Research has also emerged that investigates medical procedures for very old adults,4–6 but life expectancy for very old adults is still short in most high-income countries, ranging from around 8 to 10 years for 80-year-olds to 4 to 5 years for 90-year-olds (online Table S1).7 Hence, overtreatment of very old adults is still a general concern, and potential side effects of treatment have to be balanced with the overall survival prognosis, which is generally based on the overall chance of survival to a given age or overall life expectancy.8 It has been argued that clinicians should offer to discuss the overall survival prognosis with patients aged 85 and older.8 There is large varivariation in health and life expectancy in very old adults, which also should be taken into consideration before treatment is provided. Comprehensive geriatric assessments exist, but they are generally time-consuming and mostly validated in people aged 70 to 80.9-11 Simple, easy-to-use tools that can help predict the chance of individual survival in very old adults would be useful in clinical decision-making for general practitioners, but only a few studies have investigated factors that predict mortality in very old adults. In a study of 186 Spanish nonagenarians, comorbidity and cognition assessed over a 5-year follow-up period were found to be the best predictors of mortality.12 In a study of 888 Finnish people aged 90 and older, activities of daily living (ADLs), self-rated health, and being institutionalized over a 9-year period were found to be associated with mortality.13 A study of 19,340 Americans, 335 of whom were nonagenarians, showed that functional limitation in nonagenarians was a better predictor of mortality than chronic conditions.14 In a study of 335 Italian people aged 80 and older, walking speed and five-time chair stand test were found to be associated with mortality.15 Walking speed and chair stands has also been shown to predict subsequent disability and mortality in people aged 70 and older.16,17 Unfortunately, most of these studies presented hazard ratios, which can be difficult to use in clinical decision-making and to communicate to people. This study comprised a Danish birth cohort followed from age 92 or 93 until the cohort was almost extinct. The aim was to identify measures that predict remaining lifespan and chance of surviving to 100 years and that can be easily administered in a primary care setting without specialized equipment.

Objective: To examine whether older parents in China would benefit more from daughters’ care than from sons’ emotional care. Method: Analysis of the unique data sets of the Chinese Longitudinal Healthy Longevity Survey conducted in 2002, 2005, and 2008-2009 in 22 provinces. Results: As compared with having son(s), having daughter(s) is significantly more beneficial at older ages in China, with regard to maintaining higher cognitive capacity and reducing mortality risk. Such daughter advantages in providing emotional care to older parents are more profound among the oldest-old aged 80+ as compared with the young-old aged 65 to 79 and surprisingly more profound in rural areas as compared with urban areas, even though son preference is much more common among rural residents. Discussion: We describe how educational campaigns aimed at informing the public about the benefits of daughter(s) for older parents’ health outcome could help promote gender equality and reduce traditional son preference, especially in rural China.

Despite the importance of trauma in healthspan and lifespan in humans as well as in non-human species, with one important exception the literature in both gerontology and ecology contains virtually no experimental demographic studies concerned with trauma in any species. We used dietary manipulation [full diet (F) versus sugar-only (S)] to produce four levels of frailty in 55-day old tephritid fruit flies (Anastrepha ludens) that were then subject to the trauma of cage transfer stress (n = 900/sex in each of the 4 treatments). The key results included the following: (1) there is a trauma effect caused by the transfer that depends on previous diet before transfer, new diet after transfer and gender of the fly; (2) males are more vulnerable than females; (3) if initial diet was F, flies are relatively immune against the trauma, and the subsequent diet (F or S) does not matter; (4) however if initial diet was S, then the effect of the trauma depends largely on the diet after the transfer; (5) flies transferred from S to F diets do very well in terms of remaining longevity (i.e. greatest remaining longevity), while flies transferred from S to S diet do poorly (i.e. shortest remaining longevity). We discuss both the strengths and weaknesses of this study and implications of the results.

Background: Demographers have long been interested in how compositional change, e.g., change in age structure, affects population averages. Objective: We want to deepen understanding of how compositional change affects population averages. Results: The difference between two averages of a variable, calculated using alternative weighting functions, equals the covariance between the variable and the ratio of the weighting functions, divided by the average of the ratio. We compare weighted and unweighted averages and also provide examples of use of the relationship in analyses of fertility and mortality. Comments: Other uses of covariances in formal demography are worth exploring.

Animal models have supported the idea that apoptosis and senescence, which are important cellular tumor suppressing mechanisms (1–5), could be antagonistically pleiotropic, that is, these mechanisms protect organisms from early life cancer, but in late life, they accelerate the aging phenotypes and the development of a host of age-related diseases. The role of p53 in activating cell cycle checkpoints and apoptosis has been suggested as a specific mechanism for serving as guardian and suppressor of longevity (6). In particular, p53 mutant mice with augmented p53 activity that display early aging sign and at the same time enhance the resistance to spontaneous tumors compared with wild types (7) have promoted the “better cancer protection–accelerated aging” hypothesis. However, an undefined 20 kb region upstream of the p53 gene was also deleted in the p53 mutant mice, and other mice strains do not confirm this association (3,4). An area that has received particular attention is telomeres and telomerase in cancer and aging. K5-mTert transgenic mice overexpress telomerase in a wide spectrum of tissues, which results in higher incidence of both induced and spontaneous tumors and, accordingly, increased mortality during the first year of life (8). However, despite this elevated tumor incidence and initial lower survival, the K5-mTert mice show a substantial extension of the maximum life span corresponding to a 10% increase in mean life span compared with wild types. This suggests that telomerase overexpression extends both the maximum life span and the cancer risk in mice (8). Notably, telomerase is a key element in most human cancers as well as central in the aging mechanisms in an interplay with p53 and mitochondrial dysfunctioning (9). The data for humans are rather sparse and conflicting; Van Heemst and colleagues (10) performed a meta-analysis of the published literature in 2005, showing that carriers of the TP53 codon 72 Pro/Pro have an increased cancer risk compared with Arg/Arg carriers, but at the same time, a significantly increased survival at the highest age, suggesting that human p53 protects against cancer but at the cost of longevity. Although it is expected that long-lived individuals have a lower cancer incidence (as cancer reduces the chances of exceptional longevity; 11), the family (co)occurrence of cancer and longevity is the optimal design for studying the cancer–longevity trade-offs. A study of 106 families with 295 offspring of centenarians in the New England Centenarian Study (12) compared with a similar-sized control group suggested that the offspring of centenarians had lower all-cause, cardiovascular, and cancer mortality compared with the control offspring. This was a small study, and the risk of socioeconomic confounding was considerable. A more powerful study (13) investigated individuals born from 1830 to 1963 using the Utah-population Database Cohort. The study focused on the effect of familial longevity and familial mortality for 10 of the leading causes of death. It was found that families with greater longevity did not die from causes distinct from other members of the cohort; they died from the same causes at reduced rate. Individuals of longer-lived families had lower mortality rate for most age-related diseases including heart disease, stroke, and diabetes but not from cancer. The study has the drawback of being conducted in a special population (Mormons) and only using cause of death data and not cancer incidence data. In this study, the closest possible relative of long-lived individuals, namely the cotwin of monozygotic (and dizygotic) twins, is used to study the potential cancer–longevity trade-off. The hypothesis is that longevity is positively associated with cancer risk in zero (monozygotic cotwin) and first-degree (dizygotic twins) relatives.

Summary We analyzed MBL2 gene variants in two cohorts of centenarians, octo-nonagenarians and nonagenarians, and in the general population, one from Sardinia Island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. We also assessed in vitro the effect of mannose-binding lectin (MBL) on various human cells at different stage of senescence. The frequency of high and null activity haplotypes was significantly lower, and the frequency of intermediate activity haplotype significantly higher in centenarians and in subjects between 80 and 99 years from both the cohorts as compared each to the general population from the same geographic area. Furthermore, serum MBL concentration (also after normalization to serum albumin) was significantly lower in centenarians and in octo- and nonagenarians as compared to the general population, suggesting that intermediate MBL haplotype/activity may be protective. We also demonstrated that in vitro MBL protein bound to senescent IMR90 fibroblasts thereby causing cell lysis, but not to other types of cycle-arrested cells not in senescence. This implicates a novel role of MBL in the clearance of senescent cells.

Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility. Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility.

Based on data from 760 centenarians and 1060 middle-age controls (all Han Chinese), this article contributes biodemographic insights and syntheses concerning the magnitude of effects of the FOXO genotypes on longevity. We also estimate independent and joint effects of the genotypes of FOXO1A and FOXO3A genes on long-term survival, considering carrying or not-carrying the minor allele of the single-nucleotide polymorphism of another relevant gene. We found substantial gender differences in the independent effects; positive effects of FOXO3A and negative effects of FOXO1A largely compensate each other if one carries both, although FOXO3A has a stronger impact. Ten-year follow-up cohort analysis shows that at very advanced ages 92–110, adjusted for various confounders, positive effects of FOXO3A on survival remain statistically significant, but no significant effects of FOXO1A alone; G × G interactions between FOXO1A-209 and FOXO3A-310 or FOXO3A-292 decrease survival likelihood by 32%–36% (p < .05); G × E interactions between FOXO1A-209 and regular exercise increase survival likelihood by 31%–32% (p < .05).

Humans, and many other species, suffer senescence: mortality increases and fertility decreases with adult age. Some species, however, enjoy sustenance: mortality and fertility remain constant. Here we develop simple but general evolutionary-demographic models to explain the conditions that favor senescence vs. sustenance. The models illustrate how mathematical demography can deepen understanding of the evolution of aging. (ProQuest: ... denotes formulae omitted.) 1. Introduction Why do humans deteriorate with age? And why is this senescence common across many species-but not all species? A brief answer is that we grow decrepit because we continually suffer damage and because some but not all of the damage is repaired. The cumulative imbalance between damage and repair produces senescence; with mortality rising and fertility falling with age (Kirkwood 1981; Baudisch 2008). The more an organism invests in repair, the less the organism will degenerate with age. If repair is sufficient, then the organism can maintain itself. Such sustenance, however, is costly and requires resources the organism could otherwise invest in greater reproduction. Darwinian evolution optimizes this trade-off for each species-producing age-specific trajectories of mortality and fertility that depend on the species' bauplan and environment (Stearns 1992; Roff 2002). Kirkwood pioneered this important perspective on aging and developed it focusing on senescence (Kirkwood 1977). This article builds on Kirkwood's core idea and expands it to explain when sustenance is optimal. Until recently it was generally thought that the evolutionary theory of aging implied that senescence is inevitable for multicellular iteroparous species (Medawar 1952; Williams 1957; Hamilton 1966). Many gerontologists assumed this was the case and the view is still widely held. As Williams observed, however, "it is indeed remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed" (Williams 1957: 398). Over the last decades, field and laboratory studies have demonstrated that some organisms suffer negligible senescence over the course of life (Finch 1990; 2009; Vaupel et al. 2004). Notable examples are queens in eusocial species (Holldobler and Wilson 1990; Keller and Genoud 1997; Keller 1998; Carey 2001) and hydra (Martinez 1998). And recently it has been found that sustenance can be an optimal evolutionary strategy under some conditions (Baudisch 2008). This article develops simple evolutionary-demographic models that yield general conditions for sustenance vs. senescence. The models aim to capture the gist of why evolution favors either sustenance or senescence. We focus on species that potentially would be able to achieve sustenance if sufficient resources are diverted from reproduction to maintenance. We simplify the models as much as we can while retaining some minimal realism about the basic cornerstones of the life cycle of a species. In particular, we focus on age-invariant vs. increasing mortality over adult ages. We assume that fertility is constant over age. This assumption might seem too drastic, but as a first step in studying senescence vs. sustenance, it is reasonable to focus on one process - mortality - instead of two. Senescence can be captured by an increase in mortality over adult ages and sustenance by an age-invariant mortality pattern. Relaxing the constant-fertility assumption in models to be developed in the future will permit study of mortality and fertility senescence together. In our models, age zero is defined as reproductive maturity. 2. A model with constant fertility and increasing mortality Evolution favors sustenance over senescence if Darwinian fitness of the former strategy exceeds that of the latter. Thus, if a strategy of sustenance corresponds to a fitness of Ro and that of senescence to R*, evolution favors sustenance over senescence if Ro > R*. …

INCREASES in longevity of the general population worldwide are an unprecedented phenomenon with significant health and social impact. Although environmental factors have led to an increase in life span, there is ample evidence that genetic factors are involved in extreme longevity both in humans (1–7) and in other organisms (8). The protective genetic factors that lead to longevity are likely to involve fundamental processes of aging that may be different from those associated with early mortality or premature onset of age-related diseases in younger individuals. The mechanisms of aging in humans are far from understood, but available evidence suggests that several pathways—inflammation, oxidative stress and stress responses, cellular senescence, DNA damage and repair, and the growth hormone or insulin-like growth factor and insulin (GH, IGF, INS) axis—may play key roles (9–12). Model organisms suggest that inhibiting the GH, IGF, or INS axis, which is involved in regulating cell proliferation, cell death, wound repair, and metabolism, may promote longevity by reducing oxidative stress and slowing the rate of cell replication and the accumulation of somatic-cell DNA mutations (13). There is also evidence for other important pathways such as the heat-shock proteins and heat-shock factors that are highly conserved across species and play a role in prolongevity transcription pathways. Clinical and epidemiological investigations, including candidate gene studies, have suggested that inflammation pathways may affect life span and risk of age-related conditions such as cardiovascular disease (CVD) and its risk factors (14–19). A combination of multiple genetic variants may be required for an individual to achieve exceptional longevity, which may account in part for its rarity. Two previous studies have used whole-genome screening to identify genetic variants associated with longevity (20,21). In a linkage analysis, the earliest report (20) identified a locus on chromosome 4 that has not been replicated. A recent report from the Framingham Heart Study (FHS) (22) identified modest associations between longevity (or age at death) and single-nucleotide polymorphisms (SNPs) in or near important candidate genes, including FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN, but none of the associations achieved conventional levels of statistical significance; the sample size was modest, and the genotyping platform did not cover the genome well by current standards. The advent of genome-wide association studies (GWAS) has successfully led to the discovery of novel genetic variants that have strong evidence for replication and that are outside of traditional candidate gene regions for several common diseases (23–29). The detection of novel genetic variants associated with longevity holds the promise to provide important insights to biologic pathways in the aging process and thus the potential to develop innovative strategies to promote a long and healthy life. We conducted a meta-analysis of GWAS findings for longevity within an international consortium of four longitudinal community-based cohort studies that followed adults over many years. Longevity was defined as survival to age 90 years or older, and a comparison group was drawn from each cohort. Furthermore, we identified two independent cohorts of long-lived individuals, the Leiden Longevity Study cohort and the Danish 1905 cohort, to evaluate initial findings for the strongest allelic associations for longevity in a second discovery stage.

This is an expanded version of comments on the future of the demography of aging at an invited session of the 2008 annual meeting of the Population Association of America. In an introduction, John Haaga offers reasons for a revival of interest in population aging, including greater realization of plasticity in aging trajectories at both individual and societal levels. Linda Martin proposes that population scientists working in aging emulate those studying fertility and family planning in previous decades, learning from interventions (in this case, aimed at increasing retirement savings and reducing disability at older ages). Changes in family structure will increasingly affect new cohorts of the elderly, and Linda Waite speculates on the ways in which changes in the economy, medicine, and the legal environment could affect the social context for aging. Research on mortality at older ages is “alive and well” asserts James Vaupel, who sets out six large questions on mortality trends and differentials over time and across species. Lastly, Wolfgang Lutz expands the scope of projections, showing the considerable uncertainty about the timing and pace of population aging in the developing world and the effects on future elderly of the increases in educational attainment in much of the world during the second half of the twentieth century.

Centenarians surpass the current human life expectancy with about 20-25 years. However, whether centenarians represent healthy aging still remains an open question. Previous studies have been hampered by a number of methodological shortcomings such as a cross-sectional design and lack of an appropriate control group. In a longitudinal population-based cohort, it was examined whether the centenarian phenotype may be a useful model for healthy aging. The study was based on a complete follow up of 39,945 individuals alive in the Danish 1905 birth cohort on January 1, 1977 identified through the Danish Civil Registration System (DCRS). Data from the Danish Demographic Database and The Danish National Patient Register (in existence since 1977) were used. The 1905 cohort was followed up from 1977 through 2004 with respect to hospitalizations and number of hospital days. Survival status was available until December 2006. Danish centenarians from the 1905 cohort were hospitalized substantially less than their shorter-lived contemporaries at the same point in time during the years 1977 through 2004. For example, at age 71-74, the proportion of nonhospitalized centenarians was 80.5% compared with 68.4% among individuals who died in their early 80s. This trend was evident in both sexes. As a result of their lower hospitalization rates and length of stay in hospital compared with their contemporaries, who died at younger ages, Danish centenarians represent healthy agers. Centenarians constitute a useful study population in the search for fixed traits associated with exceptional longevity, such as genotype.

For the species that have been most carefully studied, mortality rises with age and then plateaus or declines at advanced ages, except for yeast. Remarkably, mortality for yeast can rise, fall and rise again. In the present study we investigated (i) if this complicated shape could be modulated by environmental conditions by measuring mortality with different food media and temperature; (ii) if it is triggered by biological heterogeneity by measuring mortality in stationary phase in populations fractionated into subpopulations of young, virgin cells, and replicatively older, non-virgin cells. We also discussed the results of a staining method to measure viability instead of measuring the number of cells able to exit stationary phase and form a colony. We showed that different shapes of age-specific death rates were observed and that their appearance depended on the environmental conditions. Furthermore, biological heterogeneity explained the shapes of mortality with homogeneous populations of young, virgin cells exhibiting a simple shape of mortality in conditions under which more heterogeneous populations of older cells or unfractionated populations displayed complicated death rates. Finally, the staining method suggested that cells lost the capacity to exit stationary phase and to divide long before they died in stationary phase. These results explain a phenomenon that was puzzling because it appeared to reflect a radical departure from mortality patterns observed for other species.

Udgivelsesdato: 2008-Sep-9 Late-life loss of independence in daily living is a central concern for the aging individual and for society. The implications of increased survival to advanced age may be different at the population level than at the individual level. Here we used a longitudinal multi-assessment survey of the entire Danish 1905 cohort from 1998 to 2005 to assess the loss of physical and cognitive independence in the age range of 92 to 100 years. Multiple functional outcomes were studied, including independence, which was defined as being able to perform basic activities of daily living without assistance from other persons and having a MiniMental State Examination (MMSE) score of 23 or higher. In the aggregate, the 1905 cohort had only a modest decline in the proportion of independent individuals at the 4 assessments between age 92 and 100 years: 39%, 36%, 32%, and 33%, with a difference between first and last assessment of 6% [95% confidence interval (CI), -1-14%]. For participants who survived until 2005, however, the prevalence of independence was reduced by more than a factor of 2, from 70% in 1998 to 33% in 2005 (difference, 37%; 95% CI, 28-46%). Similar results were obtained for the other functional outcomes. Analyses of missing data resulting from nonresponse and death suggest that the discrepancy between the population trajectory and the individual trajectory is caused by increased mortality among dependent individuals. For the individual, long life brings an increasing risk of loss of independence. For society, mortality reductions are not expected to result in exceptional levels of disability in cohorts of the very old.

Udgivelsesdato: 2008-Feb To investigate the genetic contribution to familial similarity in longevity, we set up a novel experimental design where cousin-pairs born from siblings who were concordant or discordant for the longevity trait were analyzed. To check this design, two chromosomal regions already known to encompass longevity-related genes were examined: 6p21.3 (genes TNFalpha, TNFbeta, HSP70.1) and 11p15.5 (genes SIRT3, HRAS1, IGF2, INS, TH). Population pools of 1.6, 2.3 and 2.0 million inhabitants were screened, respectively, in Denmark, France and Italy to identify families matching the design requirements. A total of 234 trios composed by one centenarian, his/her child and a child of his/her concordant or discordant sib were collected. By using population-specific allele frequencies, we reconstructed haplotype phase and estimated the likelihood of Identical By Descent (IBD) haplotype sharing in cousin-pairs born from concordant and discordant siblings. In addition, we analyzed haplotype transmission from centenarians to offspring, and a statistically significant Transmission Ratio Distortion (TRD) was observed for both chromosomal regions in the discordant families (P=0.007 for 6p21.3 and P=0.015 for 11p15.5). In concordant families, a marginally significant TRD was observed at 6p21.3 only (P=0.06). Although no significant difference emerged between the two groups of cousin-pairs, our study gave new insights on the hindrances to recruiting a suitable sample to obtain significant IBD data on longevity-related chromosomal regions. This will allow to dimension future sampling campaigns to study-genetic basis of human longevity.European Journal of Human Genetics (2008) 16, 236-242; doi:10.1038/sj.ejhg.5201950; published online 7 November 2007.

Studies in fertility in the industrialized world primarily focus on the decline in average fertility and the determinants of this trend (Bongaarts 2002; UN Population Division 2003; Morgan 2003; Caldwell and Schindlmayr 2003). Variation in fertility within a population is used in an instrumental manner to link birth rates to explanatory variables by means of regressions and de compositions. The recent comprehensive work by Frejka and Sard?n (2004) reviewed changes in completed cohort fertility in industrialized countries and related them to changing age and parity patterns. The present study is interested primarily in the inter-individual diversity in fertility according to the parity distributions of women. This way of think ing about the inter-individual diversity is related to the concentration (or Lorenz) curve, showing what proportion of women have what proportion of children. Such a curve would demonstrate, for example, that 30 percent of American women born in 1931-32 have half of the children born to this cohort, while half of these women have 75 percent of the children. At the same time, 62 percent of children born to this cohort were born to mothers with four or more children, while only 3 percent were born to mothers with one child. These quantities describe something that might be called a division of labor in the matter of fertility (Vaupel and Goodwin 1987). The division of labor concept can be expressed also by an average inter-individual difference in childbearing "productivity" among women. It can be shown, for example, that the average difference between any pair of women (including women who remained childless) from the 1931-32 American cohort in the number

The author notes that the new use that the U.S. Congress has established for the census namely the allocation of revenue sharing and other grants requires exactitude and does not fit with the probability models that have been so effective in other fields. He concludes that as long as the census count is reasonably close to actuality as revealed by the checks now in use its acceptance for this purpose is reasonable. The need for external quality control is indicated but it should be on the institution itself and not on individual census results. (ANNOTATION)

PURPOSE: Familial clustering of longevity is well documented and includes both genetic and other familial factors, but the specific underlying mechanisms are largely unknown. We examined whether low incidence of specific cancers is a mechanism for familial clustering of longevity.METHODS: The study population of individuals from longevity-enriched families consisted of 3267 offspring from 610 Danish long-lived families defined by two siblings attaining an age of 90 years or more. The offspring of the long-lived siblings were followed from 1968 to 2009. Using high-quality registry data, observed numbers of cancers were compared with expected numbers based on gender-, calendar period-, and age-specific incidence rates in the general population.RESULTS: During the 41-year-follow-up period, a total of 423 cancers occurred in 397 individuals. The standardized incidence ratios (95% confidence interval) for offspring of long-lived individuals were 0.78 (0.70-0.86) for overall cancer; 0.66 (0.56-0.77) for tobacco-related cancer; 0.34 (0.22-0.51) for lung cancer; 0.88 (0.71-1.10) for breast cancer; 0.91 (0.62-1.34) for colon cancer.CONCLUSIONS: The low incidence of tobacco-related cancers in long-lived families compared with non-tobacco-related cancers suggests that health behavior plays a central role in lower early cancer incidence in offspring of long-lived siblings in Denmark.

This paper aims to discuss the validation and family determinants affecting the longevity of Sardinian centenarians, using a genealogical approach. This preliminary study presents the first results of a genealogical tree reconstruction of selected centenarians aged 105 and over, from certain areas. These are mostly situated in the province of Nuoro, an area with the highest rate of centenarians and where the female-to-male sex ratio tends to be male-biased. An accurate centenarian age validation was performed that required a meticulous examination of numerous civil status records and parish registers. An important finding was that longevity occurs among the ascendants of a particular branch of the family. The data used are still provisional but, should it apply to other validated cases, it would provide empirical evidence of a genetic component in longevity. A more thorough examination of the data available may yield deeper insights into the role played by endogamy and consanguinity.

Much research aimed at discovering the genetic bases of longevity focuses on the budding yeast Saccharomyces cerevisiae. Unfortunately, yeast researchers use a definition of longevity not applied to other species. We propose here a method that makes it possible to estimate for yeast the same measures of longevity calculated for other species. We also show that the conventional method (equating longevity with the number of offspring) is only an approximate measure of true chronological lifespan. Our method will allow results for yeast to be compared more correctly with those for other species.

Statistical analysis of a large and unique longitudinal data-set demonstrates that childbearing after age 35 or 40 is associated with survival and healthy survival among very old Chinese women and men. The association is stronger for women than for men. The estimates are adjusted for a variety of confounding factors: demographic characteristics, family support, social connections, health practices, and health conditions. Further analysis based on an extension of the Fixed-Attributes Dynamics method shows that late childbearing is positively associated with long-term survival and healthy survival from ages 80-85 to 90-95 and 100-105. This association exists among oldest-old women and men, but, again, the effects are substantially stronger for women than for men. We discuss four possible factors that may explain why late childbearing affects healthy longevity at advanced ages: (1) social factors; (2) biological changes caused by late pregnancy and delivery; (3) genetic and other biological characteristics; and (4) selection.

Mutations in RAS2, CYR1, and SCH9 extend the chronological life span in Saccharomyces cerevisiae by activating stress-resistance transcription factors and mitochondrial superoxide dismutase (Sod2). Here we show that mutations in CYR1 and SCH9 also extend the replicative life span of individual yeast mother cells. However, the triple deletion of stress-resistance genes MSN2/MSN4 and RIM15, which causes a major decrease in chronological life span, extends replicative life span. Similarly, the overexpression of superoxide dismutases, which extends chronological survival, shortens the replicative life span and prevents budding in 30–40% of virgin mother cells. These results suggest that stress-resistance transcription factors Msn2/Msn4 negatively regulate budding and the replicative life span in part by increasing SOD2 expression. The role of superoxide dismutases and of other stress-resistance proteins in extending the chronological life span of yeast, worms, and flies indicates that the negative effect of Sod2, Msn2/Msn4/Rim15 on the replicative life span of S. cerevisiae is independent of aging.

This study is based on survey data from a sample of 8,805 elders aged 80–105 in 22 provinces of China. Rural oldest old are significantly more active in daily living than urban oldest old; adaptation is perhaps the major explanation of this difference. Female oldest old are seriously disadvantaged in functional capacities and self–reported health as compared with their male counterparts. Percentages of being active in daily living, having good physical performance, normal cognitive function and well–being drop dramatically from age 80–84 to 100–105. Proportion reporting satisfaction in current life, however, remains almost constant from age 80–84 to 90–94 and declines slightly afterwards. This may suggest that being more positive in self–feeling of life is one of the secrets of longevity.

A new method based on the recently developed relative risk approach is introduced, and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10, as defined according to the number of repeats) may contribute in reducing or increasing the hazard of death with different patterns of influences. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity. # 2002 Elsevier Science Ireland Ltd. All rights reserved.

The exponential increase in the number of centenarians, which started just after World War II, is well documented in Europe and Japan. Much less is known about the population of extremely old persons reaching age 105—the semisupercentenarians—or age 110—the supercentenarians. The first cases of validated supercentenarians appeared in the 1960s, and their numbers have steadily increased since the mid-1980s. The current prevalence of known supercentenarians in low-mortality countries involved in the International Database on Longevity (IDL) is approximately 10 times higher than in the mid-1970s. In roughly 20 years, from 1980 to 2000, the maximum reported age at death, which was once assumed to indicate the maximum life span of the human species and seen as a stable characteristic of our species, has increased by about 10 years from 112 to 122 years. The annual probability of death at age 110 is about 50% and stays at that level through age 114. Our results strongly support the finding that mortali...

THE NUMBER OF oldest old persons in China, defined here as aged 80 and older, is calculated by the United Nations to climb from about 11.5 million in the year 2000 to 27 million in 2020, 39 million in 2030, 64 million in 2040, and 99 million in 2050. 1 Under the UN’s medium fertility assumption, 2 the percent aged 65 and older is expected to increase from 6.9 in 2000 to 15.7 in 2030 and 22.7 in 2050, while the share of the oldest old which in 2000 is 13 percent of the elderly population will be some 30 percent in 2050. The main reason the number of oldest old will climb so quickly after 2030 is that China’s “baby boomers,” who were born in the 1950s and 1960s, will fall into the category of “oldest old” at that time. During 2000‐50 the population of the oldest old will grow faster than any other age group in China. This phenomenon is not limited to China. The average annual rates of increase of oldest old persons between 2000 and 2050 are expected to be around 4.3 percent in China, India, and Mexico and 2.2‐2.8 percent in Canada, Japan, the United States, Germany, and France (UN 2001b). The rate of increase of the Chinese oldest old subpopulation is much faster (4.4 percent vs. 2.7 percent) than that of the entire elderly population aged 65 and older. The oldest old are much more likely to need help in daily living than the younger elderly. The oldest old consume medical care and other services and benefits of government and private transfers far out of proportion to their numbers. As evidenced later in this article, the proportion of individuals leading active daily lives declines and the disability rate increases dramatically with age among the Chinese oldest old. Torrey (1992: 382) estimated that in the United States, the Medicare costs of those aged 80 and older are 77, 60, and 36 percent higher than those of the younger elderly aged 65‐69, 70‐74, and