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.

Mortality as a Function of Survival.

Everyone has a chronological age. Because survivorship declines relentlessly in populations with age-specific death rates greater than zero, everyone also has a survivorship age ("s-age"), the age at which a proportion s of the population is still alive. S-ages can be estimated for both periods and cohorts. While trajectories of mortality over chronological ages differ (e.g., across populations, over time, by sex, or by any subpopulation), mortality trajectories over s-ages are similar, a sign that populations experience similar mortality dynamics at specific levels of survivorship. We show that this important demographic regularity holds for 23 sex-specific populations analyzed during a period comprising more than 100 years.

High excess deaths in Sweden during the first wave of COVID-19: Policy deficiencies or 'dry tinder'?

AIMS: During the first wave of the COVID-19 pandemic, Sweden registered a high level of excess deaths. Non-pharmaceutical interventions adopted by Sweden have been milder compared to those implemented in Denmark. Moreover, Sweden might have started the pandemic with a large proportion of vulnerable elderly with a high mortality risk. This study aimed to clarify whether excess mortality in Sweden can be explained by a large stock of 'dry tinder' instead of being attributed to faulty lockdown policies. METHODS: We analysed weekly death counts in Sweden and Denmark from July 2007 to June 2020. We used a novel method for short-term mortality forecasting to estimate expected and excess deaths during the first COVID-19 wave in Sweden and Denmark. RESULTS: In the first part of the epiyear 2019-2020, deaths were low in both Sweden and Denmark. In the absence of COVID-19, a relatively low level of death would be expected for the later part of the epiyear. The registered deaths were, however, way above the upper bound of the prediction interval in Sweden and within the range in Denmark. CONCLUSIONS: 'Dry tinder' can only account for a modest fraction of excess Swedish mortality. The risk of death during the first COVID-19 wave rose significantly for Swedish women aged >85 but only slightly for Danish women aged >85. The risk discrepancy seems more likely to result from differences between Sweden and Denmark in how care and housing for the elderly are organised, coupled with a less successful Swedish strategy of shielding the elderly.

The long lives of primates and the 'invariant rate of ageing' hypothesis.

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.

Death rates at specific life stages mold the sex gap in life expectancy.

Why do women live longer than men? Here, we mine rich lodes of demographic data to reveal that lower female mortality at particular ages is decisive-and that the important ages changed around 1950. Earlier, excess mortality among baby boys was crucial; afterward, the gap largely resulted from elevated mortality among men 60+. Young males bear modest responsibility for the sex gap in life expectancy: Depending on the country and time, their mortality accounts for less than a quarter and often less than a 10th of the gap. Understanding the impact on life expectancy of differences between male and female risks of death by age, over time, and across populations yields insights for research on how the lives of men and women differ.

Short-term forecasts of expected deaths.

We introduce a method for making short-term mortality forecasts of a few months, illustrating it by estimating how many deaths might have happened if some major shock had not occurred. We apply the method to assess excess mortality from March to June 2020 in Denmark and Sweden as a result of the first wave of the coronavirus pandemic; associated policy interventions; and behavioral, healthcare, social, and economic changes. We chose to compare Denmark and Sweden because reliable data were available and because the two countries are similar but chose different responses to COVID-19: Denmark imposed a rather severe lockdown; Sweden did not. We make forecasts by age and sex to predict expected deaths if COVID-19 had not struck. Subtracting these forecasts from observed deaths gives the excess death count. Excess deaths were lower in Denmark than Sweden during the first wave of the pandemic. The later/earlier ratio we propose for shortcasting is easy to understand, requires less data than more elaborate approaches, and may be useful in many countries in making both predictions about the future and the past to study the impact on mortality of coronavirus and other epidemics. In the application to Denmark and Sweden, prediction intervals are narrower and bias is less than when forecasts are based on averages of the last 5 y, as is often done. More generally, later/earlier ratios may prove useful in short-term forecasting of illnesses and births as well as economic and other activity that varies seasonally or periodically.

Demographic perspectives on the rise of longevity.

This article reviews some key strands of demographic research on past trends in human longevity and explores possible future trends in life expectancy at birth. Demographic data on age-specific mortality are used to estimate life expectancy, and validated data on exceptional life spans are used to study the maximum length of life. In the countries doing best each year, life expectancy started to increase around 1840 at a pace of almost 2.5 y 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, individual life spans are becoming more equal, reducing inequalities, with octogenarians and nonagenarians accounting for most deaths in countries with the highest life expectancy. If the current pace of progress in life expectancy continues, most children born this millennium will celebrate their 100th birthday. Considerable uncertainty, however, clouds forecasts: Life expectancy and maximum life span might increase very little if at all, or longevity might rise much faster than in the past. Substantial progress has been made over the past three decades in deepening understanding of how long humans have lived and how 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.

Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study.

The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival.

National age and coresidence patterns shape COVID-19 vulnerability.

Based on harmonized census data from 81 countries, we estimate how age and coresidence patterns shape the vulnerability of countries' populations to outbreaks of coronavirus disease 2019 (COVID-19). We estimate variation in deaths arising due to a simulated random infection of 10% of the population living in private households and subsequent within-household transmission of the virus. The age structures of European and North American countries increase their vulnerability to COVID-related deaths in general. The coresidence patterns of elderly persons in Africa and parts of Asia increase these countries' vulnerability to deaths induced by within-household transmission of COVID-19. Southern European countries, which have aged populations and relatively high levels of intergenerational coresidence, are, all else equal, the most vulnerable to outbreaks of COVID-19. In a second step, we estimate to what extent avoiding primary infections for specific age groups would prevent subsequent deaths due to within-household transmission of the virus. Preventing primary infections among the elderly is the most effective in countries with small households and little intergenerational coresidence, such as France, whereas confining younger age groups can have a greater impact in countries with large and intergenerational households, such as Bangladesh.

On some stochastic properties of lives lived and left in non-stationary populations.

First, we revisit the "life lived equals life left" property for stationary populations and discuss it from a more general perspective. Specifically, we show that identically distributed random age and the remaining lifetime in stationary populations have the same distribution as the equilibrium distribution of the renewal theory. Then we consider specific non-stationary populations that are closed to migration and have a constant birth rate. We obtain some useful inequalities between random age and remaining lifetime for different instants of calendar time. We also discuss the aging properties of populations using different stochastic orders.

Dynamics of life expectancy and life span equality.

As people live longer, ages at death are becoming more similar. This dual advance over the last two centuries, a central aim of public health policies, is a major achievement of modern civilization. Some recent exceptions to the joint rise of life expectancy and life span equality, however, make it difficult to determine the underlying causes of this relationship. Here, we develop a unifying framework to study life expectancy and life span equality over time, relying on concepts about the pace and shape of aging. We study the dynamic relationship between life expectancy and life span equality with reliable data from the Human Mortality Database for 49 countries and regions with emphasis on the long time series from Sweden. Our results demonstrate that both changes in life expectancy and life span equality are weighted totals of rates of progress in reducing mortality. This finding holds for three different measures of the variability of life spans. The weights evolve over time and indicate the ages at which reductions in mortality increase life expectancy and life span equality: the more progress at the youngest ages, the tighter the relationship. The link between life expectancy and life span equality is especially strong when life expectancy is less than 70 y. In recent decades, life expectancy and life span equality have occasionally moved in opposite directions due to larger improvements in mortality at older ages or a slowdown in declines in midlife mortality. Saving lives at ages below life expectancy is the key to increasing both life expectancy and life span equality.

Are Advances in Survival Among the Oldest Old Seen Across the Spectrum of Health and Functioning?

BACKGROUND: Mortality rates have been reduced by half over the last 60 years for nonagenarians, and the progress is continuing. The greater survival might be due to overtreatment of severely physically and cognitively disabled individuals, which is a big concern for societies and individuals. METHODS: The study population comprised two Danish birth cohorts: the 1905 Cohort and the 1915 Cohort. At age 95, all from the two cohorts who were still alive and living in Denmark were invited to participate in a health survey that used the same assessment instrument. A total of 2,670 (56.8%) persons participated in the two surveys and survival was assessed through a 7.3-year follow-up period during which 2,497 (93.5%) had died, and with virtually no loss to follow-up. RESULTS: Despite the increasing chance of surviving to age 95, the 1915 Cohort had significantly better health and functioning than the 1905 Cohort. The survival advantage in the 1915 Cohort continued in the follow-up period after age 95: Median survival length was 2.4 months longer, p = .011. This advantage was not statistically associated with different levels of activities of daily living, physical performance, cognitive functioning, self-rated health and life satisfaction. However, the advantage tended to be more pronounced among people with better health. CONCLUSIONS: Life span and health increases among the oldest old. The improvement in survival for 95-year olds born in 1915 compared with 1905 was seen across the whole spectrum of health and functioning, with a tendency towards bigger improvement among those in good health.

Data gaps and opportunities for comparative and conservation biology.

Biodiversity loss is a major challenge. Over the past century, the average rate of vertebrate extinction has been about 100-fold higher than the estimated background rate and population declines continue to increase globally. Birth and death rates determine the pace of population increase or decline, thus driving the expansion or extinction of a species. Design of species conservation policies hence depends on demographic data (e.g., for extinction risk assessments or estimation of harvesting quotas). However, an overview of the accessible data, even for better known taxa, is lacking. Here, we present the Demographic Species Knowledge Index, which classifies the available information for 32,144 (97%) of extant described mammals, birds, reptiles, and amphibians. We show that only 1.3% of the tetrapod species have comprehensive information on birth and death rates. We found no demographic measures, not even crude ones such as maximum life span or typical litter/clutch size, for 65% of threatened tetrapods. More field studies are needed; however, some progress can be made by digitalizing existing knowledge, by imputing data from related species with similar life histories, and by using information from captive populations. We show that data from zoos and aquariums in the Species360 network can significantly improve knowledge for an almost eightfold gain. Assessing the landscape of limited demographic knowledge is essential to prioritize ways to fill data gaps. Such information is urgently needed to implement management strategies to conserve at-risk taxa and to discover new unifying concepts and evolutionary relationships across thousands of tetrapod species.

Human lifespan records are not remarkable but their durations are.

Has the maximum human lifespan been reached? The current record stands at 122 years, 164 days and has held for over 20 years and is more than four and three quarter years higher than the previous record. The value and persistence of this record have surprised some researchers, with some even questioning its veracity. There have been previous attempts in the literature to answer questions about how long this record might stand and whether it is truly exceptional but the focus has been mainly on the record ages, using ad hoc tools. This article contributes in two new ways. First we study lifespan records via the (inter-) record times and second we make use of specific tools from statistical Records Theory. We find that the occurrence of the present record was not surprising. We estimate around a 25% chance that the record would have survived until now and around a one in five chance that it will survive until 2050, demonstrating remarkable persistence.

Two stochastic processes shape diverse senescence patterns in a single-cell organism.

Despite advances in aging research, a multitude of aging models, and empirical evidence for diverse senescence patterns, understanding of the biological processes that shape senescence is lacking. We show that senescence of an isogenic Escherichia coli bacterial population results from two stochastic processes. The first process is a random deterioration process within the cell, such as generated by random accumulation of damage. This primary process leads to an exponential increase in mortality early in life followed by a late age mortality plateau. The second process relates to the stochastic asymmetric transmission at cell fission of an unknown factor that influences mortality. This secondary process explains the difference between the classical mortality plateaus detected for young mothers' offspring and the near nonsenescence of old mothers' offspring as well as the lack of a mother-offspring correlation in age at death. We observed that lifespan is predominantly determined by underlying stochastic stage dynamics. Surprisingly, our findings support models developed for metazoans that base their arguments on stage-specific actions of alleles to understand the evolution of senescence. We call for exploration of similar stochastic influences that shape aging patterns beyond simple organisms.

A Cohort Comparison of Lifespan After Age 100 in Denmark and Sweden: Are Only the Oldest Getting Older?

Although Denmark and Sweden have close cultural and historical ties, lifespans for Danes have generally been lower than those of Swedes. Recent improvements in Danish mortality after a period of stagnation have led to the suspicion that there may be positive trends at the very high ages at death within that population and that these trends could be quite different from those observed in Sweden. Although the mean ages at death for Danish and Swedish centenarians have been relatively constant at about 102 years for the cohorts born 1870-1904, the oldest-old in Denmark have been getting older, but no evidence has suggested any increase in lifespan for Swedes. Using quantile regression, we show that Danish centenarian lifespans in the 90th percentile have been lengthening, with those in 94th percentile (6 % longest-lived individuals) having a trend that is statistically significant at the 5 % level. We demonstrate that the increase observed is not due to the increasing sizes of birth cohorts and thus must be due to improving survival among this select top tier. We postulate that this super-select group in Denmark is best able to take advantage of the factors driving mortality reduction, whereas the majority of centenarians are not.

Response to Comment on "The plateau of human mortality: Demography of longevity pioneers".

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.

Sex Differences in Genetic Associations With Longevity.

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 < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women (P = 9.0 × 10-5) 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 < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci (P < 10-5) 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 × 10-70 to 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 × 10-50 to 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.