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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

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.

Background A rapidly increasing proportion of people in high-income countries are surviving into their tenth decade. Concern is widespread that the basis for this development is the survival of frail and disabled elderly people into very old age. To investigate this issue, we compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart. Methods People in the first cohort were born in 1905 and assessed at age 93 years (n=2262); those in the second cohort were born in 1915 and assessed at age 95 years (n=1584). All cohort members were eligible irrespective of type of residence. Both cohorts were assessed by surveys that used the same design and assessment instrument, and had almost identical response rates (63%). Cognitive functioning was assessed by mini-mental state examination and a composite of five cognitive tests that are sensitive to age-related changes. Physical functioning was assessed by an activities of daily living score and by physical performance tests (grip strength, chair stand, and gait speed). Findings The chance of surviving from birth to age 93 years was 28% higher in the 1915 cohort than in the 1905 cohort (6·50% vs 5·06%), and the chance of reaching 95 years was 32% higher in 1915 cohort (3·93% vs 2·98%). The 1915 cohort scored significantly better on the mini-mental state examination than did the 1905 cohort (22·8 [SD 5·6] vs 21·4 [6·0]; p

The goal of this study is to estimate the prevalence of MetS, together with its components and correlates, among elderly Russians. Our population-based sample included randomly selected residents of Moscow aged 55 and older: 955 women with an average age of 67.6, and 833 men with an average age of 68.9. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). The prevalence of MetS was found to be 41.7% in women and 26.8% in men. It tended to decrease with age in men, but not in women. MetS was inversely related to education in women, but not in men. The most prevalent individual components of MetS were as follows: hypertension (64.4%), abdominal obesity (55%), and decreased high density lipoprotein cholesterol (HDL C) (46%) for women; and hypertension (71%) and fasting hyperglycemia (35.2%) for men. An elevated level of triglycerides (TG) was the rarest MetS component, affecting 23.5% of women and 22.1% of men. The higher female prevalence of MetS was attributable to abdominal obesity. MetS was found to be associated with markers of insulin resistance (IR), low-grade inflammation, and insufficient fibrinolysis. Although the metabolic burden is an important contributor to high levels of ill-health and cardiovascular mortality among elderly Russians (especially women), it does not explain why cardiovascular mortality is much higher in Russia than in other industrialized countries.

Over the past two centuries, the life expectancy has more than doubled in many countries, for both males and females. The levels of the countries with the highest life expectancies have risen almost linearly. We exploit this regularity by using the classic univariate ARIMA model to forecast future levels of best-practice life expectancy. We then compare two alternative stochastic models for forecasting the gap between the best-practice level and life expectancy in a particular population. One of our approaches is based on the concept of discrete geometric Brownian motion; our other approach relies on a discrete model of geometric mean-reverting processes. A key advantage of our strategy is that the life expectancies forecast for different countries are positively correlated because of their tie to the forecast best-practice line. We provide illustrations based on Italian and US data.

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.

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 human HRAS1 belongs to an evolutionarily-conserved family of genes which enrolls among its members the yeast RAS2, a gene which regulates stress response and longevity in the Saccharomyces cerevisiae. In this paper we report that the frequency of the a3 allele of HRAS1 3 0 variable number tandem repeat (HRAS1 3 0 VNTR) decreases in centenarians in respect to young people, and we estimate that during aging a3 carriers have a relative mortality risk of 1.126 (95% CI ¼ 1.044–1.213). We propose that the germ-line variability at the HRAS1 locus impacts on the individual’s capacity to reach the extreme limits of human life-span. Furthermore, we provide suggestive evidence that a3 HRAS1 3 0 VNTR allele and inherited variants of the mitochondrial genome (mtDNA haplogroups) do not affect independently human longevity, thus recalling the nucleus-mitochondrion interaction which regulates stress response and life-span in the yeast. q 2002 Elsevier Science B.V. All rights reserved.

Although the increase in the number of centenarians is well documented today, at least in some countries, this is still not the case for people having reached the age of 110 years or more: the supercentenarians. The supercentenarians emerged in the mid-1960s. Their numbers have regularly increased since the mid-1970s. The current prevalence of known supercentenarians in countries involved in the database is approximately five to six times more than in the mid-1970s. In roughly 20 years the maximum age observed has increased by about 10 years from 112 to 122 years. The annual probability of death at age 110 is as low as 0.52 with the validated data (n=106) or with the exhaustive and validated data (n=73). The probabilities of death stagnate between 110 and 115 years, and all the computed probabilities fall below the ceiling of 0.6. Our results are compatible with the last extrapolations of mortality trajectories using a logistic or a quadratic model.

Aging, and the deterioration of biological performance that characterizes it, are routinely assumed to be due to a progressive global loss of homeostasis and a general increase in dysregulation [1–4]. We tested this hypothesis directly by measuring age-specific variability in gene expression. Analysis of the transcriptional activity of six genes in various inbred lines of Drosophila melanogaster unexpectedly failed to show an increase in variability among individuals as they age and die. Although regulation of gene expression is a central feature of life, a global decline in the control of gene expression does not appear to be either a cause or a consequence of the process of aging.

The effects on medfly age-specific mortality of three types of densities—initial, current, and cumulative—were examined using sex-specific data from two sets of studies: (1) previous research on mortality patterns in 1.2 million individuals maintained in 167 different cages (1992 Science 258,457) and ii)density experiments using a total of 210,000 individuals contained in 49 cages and maintained at one of three initial densities—2500, 5000 and 10,000 flies/cage. A central death rate was computed for each of the 216 cages at specified numerical levels (e.g., 5000, 4000, 1000, 500, 100, and so forth), which was distributed over a range of ages. This yielded a series of mortality schedules at “equivalent current densities.” Two main results are reported. First, the leveling off and decline in mortality at the most advanced ages as observed in the original study of 1.2 million medflies cannot be explained as an artifact of declining current densities at older ages. Second, increased initial density heightened the mortality level at each age but had essentially no effect on mortality pattern. The overall methodology and many of the results are believed to be general and thus both logistical and conceptual implications for gerontology and population biology are discussed.

Udgivelsesdato: 2009-Jul PURPOSE: This study examined whether the health-survival paradox could be due partially to sex-specific selection and information bias in surveys. METHODS: The study is based on the linkage of three population-based surveys of 15,330 Danes aged 46-102 years with health registers covering the total Danish population regarding hospitalizations within the last 2 years and prescription medicine within 6 months before the baseline surveys. RESULTS: Men had higher participation rates than women at all ages. Hospitalized women and women taking medications had higher participation rate compared with nonhospitalized women (difference=0.7%-3.0%) and female nonusers (difference=0.8%-7.6%), respectively, whereas no consistent pattern was found among men according to hospitalization or medication use status. Men used fewer medications than women, but they underreported medication use to a similar degree as did women. CONCLUSIONS: Hospitalized women, as well as women using prescription medicine, were slightly overrepresented in the surveys. Hence, the study found some evidence that selection bias in surveys may contribute to the explanation of the health-survival paradox, but its contribution is likely to be small. However, there was no evidence for sex-specific reporting of medication use among study participants.

The author develops "a method for applying frailty models based on biological theory to life-history data on related individuals and events....[He] concisely summarizes the essence of the proposed method and then adumbrates some illustrative applications. The article concludes with a brief discussion of the three general purposes of frailty modeling of life history data." The model is tested using Danish data on the longevity of twins. (EXCERPT)

We investigate whether heterogeneity can explain the differences in mortality between the United States and a more homogeneous country, i.e. Japan. The background of the analysis is the growing gap between life-expectancy in the United States and the world record leader since the 1980s. This development is mirrored in the decelerated improvements made against mortality during the last 25 years - especially for women. Our hypothesis is that it is possible to have survival improvements at a steady pace across all population subgroups. The proportion of the population subgroups which perform relatively well decreased over time whereas poor performing subgroups became more important. The consequence of this compositional change since the 1980s would be the observed levelling off in survival improvements on the population level. Since official mortality estimates in the US are of poor quality, we estimate mortality rates via the extinct cohort method using Medicare enrollment data from the Social Security Administration due to their higher quality. If our hypothesis was true, we should see little differences in the development of mortality rates between the best performing subgroups in the United States and Japan. We compared mortality rates between Japanese women and white women in the US from states who (a) either had the highest life expectancy or (b) the highest median household income or (c) the largest gross state product per head. Regardless of the choice of indicator, mortality rates levelled-off in the United States for those best performance subgroups as for the whole population. The preliminary conclusion is therefore that compositional changes (heterogeneity) in the US population can not explain the widening gap between US life expectancy and best practice life expectancy.

same social status but who had different numbers of children and who fell into different dental categories. In 28 of these pairs, the twin with more children had fewer teeth (p