Genetic associations with longevity are on average stronger in females than in males.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Beyond One Hundred: A Cohort Analysis of Italian Centenarians and Semisupercentenarians.

Although the increase in the number of centenarians is well documented today in countries with advanced demographic data, the same is not true for those aged 105 years and over. The first aim of this paper was to analyze the demographic characteristics of the 4,626 validated semisuper and 102 supercentenarians for the cohorts born between 1896 and 1910, referring to Italian Semi-Supercentenarians Survey. Then, starting from this data and from the survival histories in old ages-reconstructed by Vincent's Extinct - Cohort Method-for the cohorts born between 1870 and 1904, the most important aim was to analyze longevity history and the trend of gender gap of the Italian oldest cohorts beyond 100 years old. The Italian centenarians and semisupercentenarians increase from the first to the last cohort is due to the survival rise in old ages and the increase in the gender gap at extreme ages depends on the higher survival of women than men after 60 years old. Around 110-112 for both genders (for women in particular) a kind of resistance to further progress seems to appear in our analysis as in more recent studies on supercentenarians.

Mortality by education level at late-adult ages in Turin: a survival analysis using frailty models with period and cohort approaches.

OBJECTIVES: Neglecting the presence of unobserved heterogeneity in survival analysis models has been showed to potentially lead to underestimating the effect of the covariates included in the analysis. This study aimed to investigate the role of unobserved heterogeneity of frailty on the estimation of mortality differentials from age 50 on by education level. DESIGN: Longitudinal mortality follow-up of the census-based Turin population linked with the city registry office. SETTING: Italian North-Western city of Turin, observation window 1971-2007. POPULATION: 391 170 men and 456 216 women followed from age 50. PRIMARY OUTCOME MEASURES: Mortality rate ratios obtained from survival analysis regression. Models were estimated with and without the component of unobserved heterogeneity of frailty and controlling for mortality improvement over time from both cohort and period perspectives. RESULTS: In the majority of cases, the models without frailty estimated a smaller educational gradient than the models with frailty. CONCLUSIONS: The results draw the attention of the potential underestimation of the mortality inequalities by socioeconomic levels in survival analysis models when not controlling for unobserved heterogeneity of frailty.

Spatial analysis of the aptitude to late maternity on the island of Sardinia.

This study examines local heterogeneity in the aptitude of Sardinian mothers towards late reproduction, and explores its temporal persistence and association with both post-reproductive longevity and propensity to consanguineous marriage. Data on women's fertility from 1961 and birth records for 1980-1996 from Vital Statistics were analysed by means of the following indicators: the incidence of old mothers at last childbirth, female mortality (1980-2001) at 80 years of age and over and the proportion of consanguineous marriages (1930-1969). A variable kernel-smoothing method was used to create interpretable representations of the true spatial structure of the indicators, and to highlight areas of higher than expected intensity. In particular, an area of reproductive and post-reproductive longevity was identified where the traits combine with a higher tendency to relatedness. Intriguingly, this area corresponds approximately to the geographically and historically well defined central-eastern zone, which was the refuge of Sardinians during past invasions, and overlaps the Ogliastra region, which has been widely studied for its genetic homogeneity.

Differences in life expectancy by education and occupation in Italy, 1980-94: indirect estimates from maternal and paternal orphanhood.

In the present study, we use the modified orphanhood method to analyse mortality differences by socio-economic status in Italy. This technique permits the indirect estimation of adult mortality from survey-based information on parents' survival in developed populations and helps to overcome several limitations of conventional studies on mortality differences by social class. We estimate a time series of life tables by education and occupation and analyse the differences in life expectancy by socio-economic status along with their changes between 1980-84, 1985-89, and 1990-94. Whereas mortality differences between the highest social class and the other socio-economic status groups increased among men, they decreased among women. We speculate about the reasons for these sex-specific trends and evaluate the application of indirect estimation techniques to the populations of developed countries.

Pathophysiology of ageing, longevity and age related diseases.

On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life.

Family clustering in Sardinian longevity: a genealogical approach.

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.

Differentials in the femininity ratio among centenarians: variations between northern and southern Italy from 1870.

Significant differentials have been observed between Italian regions in the distribution of centenarians by sex, from two women per man in the south to over eight in certain regions in the north. In order to explain these differentials we studied the evolution of the femininity ratio (FR), using a longitudinal approach to follow the ageing process in two cohorts, and making use of nearly all the statistical data available since the time of the Unification of Italy in 1870. Significant differentials in the FR observed at the age of 100 are mainly due to mortality differentials among men over the age of 60. The high mortality of men in the north and their low mortality in the south are the main explanations of why the FRs are higher in the north and lower in the south. Mortality differentials among women have only a marginal impact.

Immunogenetics, gender, and longevity.

In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In Italy this female/male ratio is relatively lower (about 5/1; F/M ratios are usually 5-6:1 in other developed countries), but significant differences have been observed between Italian regions in the distribution of centenarians by gender--from two women per man in the South to more than eight in certain regions in the North. Thus, a complex interaction of environmental, historical, and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. This can be due to gender-specific cultural and anthropological characteristics of Italian society in the last 100 years. Age-related immunoinflammatory factors increase during proinflammatory status, and the frequency of pro/anti-inflammatory gene variants also show gender differences. There is some suggestion that people genetically predisposed to weak inflammatory activity may be at reduced chance of developing coronary heart disease (CHD) and, therefore, may achieve longer lifespan if they avoid serious life-threatening infectious disease thoroughout life. Thus, the pathogen burden, by interacting with host genotype, could determine the type and intensity of the immune-inflammatory response responsible for both proinflammatory status and CHD. These findings point to a strong relationship between the genetics of inflammation, successful aging, and the control of cardiovascular disease, but seem to suggest that the evidence for men is much stronger. The importance of these studies lies in the fact that half of the population (males) lives approximately 10% shorter lives than the other half (females). Understanding the different strategies that men and women seem to follow to achieve longevity may help us to comprehend better the basic phenomenon of aging and allow us to search for safe ways to increase male lifespan.

Three dimensions of the survival curve: horizontalization, verticalization, and longevity extension.

Three dimensions of the survival curve have been developed: (1) "horizontalization," which corresponds to how long a cohort and how many survivors can live before aging-related deaths significantly decrease the proportion of survivors; (2) "verticalization," which corresponds to how concentrated aging-related ("normal") deaths are around the modal age at death (M); and (3) "longevity extension," which corresponds to how far the highest normal life durations can exceed M. Our study shows that the degree of horizontalization increased relatively less than the degree of verticalization in Hong Kong from 1976 to 2001. After age normalization, the highest normal life durations moved closer to M, implying that the increase in human longevity is meeting some resistance.