Mortality Plateaus Research Articles

The plateau of human mortality: Demography of longevity pioneers.

Theories about biological limits to life span and evolutionary shaping of human longevity depend on facts about mortality at extreme ages, but these facts have remained a matter of debate. Do hazard curves typically level out into high plateaus eventually, as seen in other species, or do exponential increases persist? In this study, we estimated hazard rates from data on all inhabitants of Italy aged 105 and older between 2009 and 2015 (born 1896-1910), a total of 3836 documented cases. We observed level hazard curves, which were essentially constant beyond age 105. Our estimates are free from artifacts of aggregation that limited earlier studies and provide the best evidence to date for the existence of extreme-age mortality plateaus in humans.

Corticotropin-releasing factor regulates caspase-3 and may protect developing zebrafish from stress-induced apoptosis

The corticotropin-releasing factor (CRF) system is expressed in the earliest stages of zebrafish development, long before its canonical function in the endocrine stress response is realized, and yet its function during embryogenesis is unknown. We tested the hypothesis that CRF protects embryos from stress-induced apoptosis. Here we confirm that a 1 h heat shock applied at either 6 h post-fertilization (hpf) or 30 hpf elicits an increase in caspase-3 activity, a key effector of apoptosis. Temporal changes in the expression of crf and its binding protein (crf-bp) during recovery from heat shock indicate that the CRF system is responsive to stressors experienced as early as gastrulation. Next, we heat shocked embryos that were microinjected with crf mRNA, and showed that caspase-3 induction is significantly reduced in embryos that overexpress CRF relative to control embryos. In addition, incubating embryos in the presence of the CRF receptor type 1 (CRF-R1) antagonist, antalarmin, during recovery from heat shock significantly increased caspase-3 activity, suggesting that CRF regulates caspase-3 via a CRF-R1-dependent pathway. Finally, we show that most heat shock-induced mortality occurred during the first hour of recovery, long before a significant increase in caspase-3 activity was detected. Indeed, the delayed caspase-3 induction coincided with a mortality plateau, and neither CRF overexpression nor antalarmin treatment altered heat shock induced mortality, supporting previous in vitro evidence that CRF-mediated cytoprotection occurs through the slow and tightly controlled apoptotic pathway. This study provides novel in vivo evidence that CRF regulates stress-induced apoptosis in a vertebrate model species, and demonstrates for the first time a function for the CRF system in early development that precedes its role in the endocrine stress response.

Population density shapes patterns of survival and reproduction in Eleutheria dichotoma (Hydrozoa: Anthoathecata)

Budding hydromedusae have high reproductive rates due to asexual reproduction and can occur in high population densities along the coasts, specifically in tidal pools. In laboratory experiments, we investigated the effects of population density on the survival and reproductive strategies of a single clone of Eleutheria dichotoma. We found that sexual reproduction occurs with the highest rate at medium population densities. Increased sexual reproduction was associated with lower budding (asexual reproduction) and survival probability. Sexual reproduction results in the production of motile larvae that can, in contrast to medusae, seek to escape unfavorable conditions by actively looking for better environments. The successful settlement of a larva results in starting the polyp stage, which is probably more resistant to environmental conditions. This is the first study that has examined the life-history strategies of the budding hydromedusa E. dichotoma by conducting a long-term experiment with a relatively large sample size that allowed for the examination of age-specific mortality and reproductive rates. We found that most sexual and asexual reproduction occurred at the beginning of life following a very rapid process of maturation. The parametric models fitted to the mortality data showed that population density was associated with an increase in the rate of aging, an increase in the level of late-life mortality plateau, and a decrease in the hidden heterogeneity in individual mortality rates. The effects of population density on life-history traits are discussed in the context of resource allocation and the r/K-strategies’ continuum concept.

Population‐level variation in senescence suggests an important role for temperature in an endangered mollusc

AbstractAge‐related declines in survival and function (senescence) were thought not to exist in wild populations, as organisms, and particularly in invertebrates, do not live long enough. While recent evidence has demonstrated that senescence is both common and measurable even in wild populations under field conditions, there are still organisms that are thought to exhibit ‘negligible senescence’. We explore variation in rates and patterns of senescence in the biogerontological model organism, the freshwater pearl mussel Margaritifera margaritifera, across five populations, which differ in their age profile. In particular, we tested the theory of negligible senescence using time‐at‐death records for 1091 specimens of M. margaritifera. There is clear evidence of senescence in all populations, as indicated by an increase in mortality with age, but the nature of the relationship varies subtly between populations. We find strong evidence of a mortality plateau at later ages in some populations, but this is unequivocally absent from others. We then demonstrate that the temporal scaling of the rates of senescence between five populations of M. margaritifera can be explained by the variation in the thermal environment of the population. Hence, climate change may pose a threat to the demography of this long‐lived, endangered species, and a greater understanding of the relationship between river temperature and population structure will be essential to secure the species against global temperature increases. Our findings demonstrate that useful insights can be drawn from a non‐invasive monitoring method to derive demographic data, and we suggest a wide‐scale application of this method to monitor populations across the whole latitudinal (and, hence, thermal) range of the species.

Temporal changes in the cervical cancer burden in Bulgaria: Implications for eastern european countries going through transition

IntroductionIn most developed countries, incidence of cervical cancer declined likely due to well-established cervical cancer screening programs. However, such decline has not been identified in Eastern Europe, where such programs are not well established. MethodsThis study utilized data of the Bulgarian Cancer Registry for the period 1993–2013. Age-standardized incidence and mortality trends were analyzed using Joinpoint regression. Maps were created to illustrate spatial distributions of rates. ResultsThe northern region of Bulgaria showed a larger cervical cancer burden than the southern region and rural women tended to be diagnosed at older ages (p<0.0001) and later stages (p<0.0001) than urban women. The distribution of disease stages changed over the 21 years, with most common stages of diagnosis being stage II in 1993 (39.2%) to stage I in 2013 (44.7%; p<0.0001). While age-standardized mortality slightly increased over the 21 years (from 4.8 to 5.2 per 100,000; p=0.009), age-standardized incidence increased from 14.0 to 21.4 per 100,000 up until 2006 (p<0.001), after which it plateaued. ConclusionsThe lack of a similar plateau in mortality may be because the second most prevalent stage of diagnosis in recent years was stage III, indicating diagnosis at advanced symptomatic stages. Cervical cancer incidence is expected to continue to decrease if screening programs are strengthened and human papillomavirus vaccines are widely utilized. As Bulgaria has shared cervical cancer trends with other Eastern European countries in the past, it may be beneficial to develop future prevention interventions based on a regional, rather than a country-specific level.

Retired flies, hidden plateaus, and the evolution of senescence in Drosophila melanogaster.

Late-life plateaus in age-specific mortality have been an evolutionary and biodemographic puzzle for decades. Although classic theory on the evolution of senescence predicts late-life walls of death, observations in experimental organisms document the opposite trend: a slowing in the rate of increase of mortality at advanced ages. Here, I analyze published life-history data on individual Drosophila melanogaster females and argue for a fundamental change in our understanding of mortality in this important model system. Mortality plateaus are not, as widely assumed, exclusive to late life, and are not explained by population heterogeneity-they are intimately connected to individual fecundity. Female flies begin adult life in the working stage, a period of active oviposition and low but accelerating mortality. Later they transition to the retired stage, a terminal period characterized by limited fecundity and relatively constant mortality. Because ages of transition differ between flies, age-synchronized cohorts contain a mix of working and retired flies. Early- and mid-life plateaus are obscured by the presence of working flies, but can be detected when cohorts are stratified by retirement status. Stage-specificity may be an important component of Drosophila life-history evolution.

Life equations for the senescence process

The Gompertz law of mortality quantitatively describes the mortality rate of humans and almost all multicellular animals. However, its underlying kinetic mechanism is unclear. The Gompertz law cannot explain the mortality plateau at advanced ages and cannot give an explicit relationship between temperature and mortality. In this study a reaction kinetics model with a time dependent rate coefficient is proposed to describe the survival and senescence processes. A temperature-dependent mortality function was derived. The new mortality function becomes the Gompertz mortality function with the same relationship of parameters prescribed by the Strehler–Mildvan correlation when age is smaller than a characteristic value δ, and reaches the mortality plateau when age is greater than δ. A closed-form analytical expression for describing the relationship of average lifespan with temperature and other equations are derived from the new mortality function. The derived equations can be used to estimate the limit of average lifespan, predict the maximal longevity, calculate the temperature coefficient of lifespan, and explain the tendency of the survival curve. This prediction is consistent with the most recently reported mortality trajectories for single-year birth cohorts. This study suggests that the senescence process results from the imbalance between damaging energy and protecting energy for the critical chemical substance in the body. The rate of senescence of the organism increases while the protecting energy decreases. The mortality plateau is reached when the protecting energy decreases to its minimal levels. The decreasing rate of the protecting energy is temperature-dependent. This study is exploring the connection between the biochemical mechanism and demography.

Practical Applications of A Conversation with Moshe Milevsky

I sat down with Moshe A. Milevsky—Professor at York University, Executive Director of the IFID Cenre and Managing Director of the Pi Longevity Extension Corp. in Toronto-to discuss two of his recent Journal of Retirement articles: Mortality Plateaus and the Pricing of Longevity Insurance (JOR, Fall 2014) and Can Collars Reduce Retirement Sequencing Risk? Analysis of Portfolio Longevity Extension Overlays (JOR, Spring 2014). This report comprises excerpts from our video interview, edited for clarity. The two-part video can be found at http://bit.ly/13Mo9PP. Click through from the videos to read the full articles for a deeper understanding on the issue of whether human aging stops and death rates flatten at advanced ages and whether a capital markets solution to partially mitigate the impact of individual longevity risk is right for you.

Research Spotlights

This issue contains two Research Spotlights articles in disparate fields of applied math. The first paper, “Mortality Implications of Mortality Plateaus” by Trifon I. Missov and James W. Vaupel, focuses on probabilistic models for hazard analysis in biological systems. It has long been observed in many different biological populations that the force of mortality (also known as the hazard rate) becomes constant for very long-lived individuals, a concept known as a mortality plateau. Such a mortality plateau is observed, for example, in human populations among those older than 110 years. By assuming the existence of a mortality plateau in a mathematical model for mortality in a heterogeneous population, the authors are able to give a number of implications of restrictions on the model. For example, one standard mortality model is a Gompertz model, in which for each individual the mortality rate increases exponentially, which implies that the population hazard function has an asymptotic mortality plateau; however, the article shows a set of other possible shapes of mortality functions that would also give rise to such a mortality plateau. This paper will appeal to SIAM Review readers with an interest in actuarial science, demography, epidemiology, evolutionary biology, survival analysis, or probabilistic modeling techniques. The second Research Spotlights paper, “Natural Preconditioning and Iterative Methods for Saddle Point Systems” by Jennifer Pestana and Andrew J. Wathen, provides a mini-survey of iterative solution methods for locally quadratic extremal problems with linear constraints. Saddle point problems arise in computational optimization and partial differential equations. The article gives an application-independent overview of the types of iterative numerical methods that can be used to solve such saddle point problems, with a focus on Krylov subspace methods. The methods are illustrated for three examples: Stokes fluid flow, interpolation, and circuits in a resistive network. The application-independent approach proves to be useful. By viewing saddle point problems in a unified way, the authors are able to specify efficient preconditioning methods. This article would be of interest to readers in many different fields such as fluid dynamics, structural mechanics, economics, data reconstruction, and optimization.

Mortality Plateaus and the Pricing of Longevity Insurance

The article examines the implications for the pricing of longevity insurance and life annuities of a plateauing in the instantaneous force of mortality (IFM) at advanced ages. Given the increasing popularity of advanced life delayed annuities (ALDAs, or deferred-income annuities) and the current low-interest-rate environment, the present-value cost of misestimating the dynamics of late-life mortality can be substantial. The article also offers some comments about the possibility of using ALDA prices to imply market expectations of mortality dynamics and plateaus in a manner similar to implied volatility in the options market. All this has obvious implications for annuity buyouts, buy-ins, and other forms of longevity risk transfer as well the most pressing retirement problem for individuals—how to make their money last for the remainder of their lives. <b>TOPICS:</b>Retirement, fixed income and structured finance, wealth management

Life equations for the senescence process (1009.2)

Gompertz law of mortality quantitatively describes the mortality rate of humans and almost all multicellular animals. However, this law was found empirically nearly 200 years ago and its underlying kinetic mechanism is still unclear. Research has shown that the mortality rate does not follow the Gompertz law at very advanced ages and the Gompertz law cannot explain why temperature can affect lifespan. The author proposed a reaction kinetic model with a time dependent rate coefficient to describe the survival and senescence processes. A new mortality rate equation is established. From this new mortality rate equation, we can obtain the Gompertz law of mortality and show that the Gompertz law is only true when age is less than a characteristic value of life, can derive some important equations reported in Nature (Shaw RF, et al. Temperature and life‐span in poikilothermous animals. Nature 196:454‐457, 1962) and Science (Strehler BL, et al. General theory of mortality and aging. Science 132(3418):14‐21, 1960), and can explain the important observation on mortality plateau at very advanced ages reported in Science (Carey JR, et al. Slowing of mortality rates at older ages in large medfly cohorts. Science 258(5081):457‐461, 1992). Equations derived from the new mortality rate equation can be used to estimate the limitation for average lifespan, the maximal longevity. The predicted results are consistent with human mortality and survival data and tendency. The derived equations can also explain experimental data regarding the effect of temperature on lifespan and predict the effect of body temperature on human lifespan. This study gives theoretical answers to questions such as: Why do we age? How long can we live? How can lifespan be extended?

Mortality and Management of Surgical Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Prospective Cohort Study

Necrotizing enterocolitis (NEC) is a leading cause of death in very low birth weight (VLBW) neonates. The overall mortality of NEC is well documented. However, those requiring surgery appear to have increased mortality compared with those managed medically. The objective of this study was to establish national birth-weight-based benchmarks for the mortality of surgical NEC and describe the use and mortality of laparotomy vs peritoneal drainage. There were 655 US centers that prospectively evaluated 188,703 VLBW neonates (401 to 1,500 g) between 2006 and 2010. Survival was defined as living in-hospital at 1-year or hospital discharge. There were 17,159 (9%) patients who had NEC, with mortality of 28%; 8,224 patients did not receive operations (medical NEC, mortality 21%) and 8,935 were operated on (mortality 35%). On multivariable regression, lower birth weight, laparotomy, and peritoneal drainage were independent predictors of mortality (p < 0.0001). In surgical NEC, a plateau mortality of around 30% persisted despite birth weights >750 g; medical NEC mortality fell consistently with increasing birth weight. For example, in neonates weighing 1,251 to 1,500 g, mortality was 27% in surgical vs 6% in medical NEC (odds ratio [OR] 6.10, 95% CI 4.58 to 8.12). Of those treated surgically, 6,131 (69%) underwent laparotomy only (mortality 31%), 1,283 received peritoneal drainage and a laparotomy (mortality 34%), and 1,521 had peritoneal drainage alone (mortality 50%). Fifty-two percent of VLBW neonates with NEC underwent surgery, which was accompanied by a substantial increase in mortality. Regardless of birth weight, surgical NEC showed a plateau in mortality at approximately 30%. Laparotomy was the more frequent method of treatment (69%) and of those managed by drainage, 46% also had a laparotomy. The laparotomy alone and drainage with laparotomy groups had similar mortalities, while the drainage alone treatment cohort was associated with the highest mortality.

Aging Differently: Diet- and Sex-Dependent Late-Life Mortality Patterns in Drosophila melanogaster

Diet effects on age-dependent mortality patterns are well documented in a large number of animal species, but studies that look at the effects of nutrient availability on late-life mortality plateaus are lacking. Here, we focus on the effect of dietary protein content (low, intermediate, and high) on mortality trajectories in late life in the fruit fly Drosophila melanogaster. According to the two theories that are mainly implicated in explaining the deceleration of mortality rate in late life (the heterogeneity/frailty theory and the Hamiltonian theory), we predict, in general, the occurrence of late-life mortality deceleration under most circumstances, independent of sex and dietary regime. However, the heterogeneity theory of late life is more flexible in allowing no mortality deceleration to occur under certain circumstances compared with the Hamiltonian theory. We applied a novel statistical approach based on Bayesian inference of age-specific mortality rates and found a deceleration of late-life mortality rates on all diets in males but only on the intermediate (standard) diet in females. The difference in mortality rate deceleration between males and females on extreme diets suggests that the existence of mortality plateaus in late life is sex and diet dependent and, therefore, not a universal characteristic of large enough cohorts.

Autosomal inheritance of alphamethrin, a synthetic pyrethroid, resistance in Anopheles stephensi – Liston, a malaria mosquito

Anopheles stephensi–Liston (Culicidae: Diptera) is an important urban malarial vector in the Indian sub-continent, accounting for about 15% of the total annual malaria incidence. Chemical control represents a key strategy in the management of this insect vector. However, owing to erratic and continuous application of insecticides, resistance has become a common phenomenon among them and their control has become an uphill task. The genetics of alphamethrin, a synthetic pyrethroid resistance was studied to determine its mode of inheritance. The late third instar larvae were selectively inbred for 27 and ten generations to synthesize homozygous resistant (R) and susceptible (S) stocks, respectively, to the diagnostic dose of 0.12 mg l−1. The log-dosage probit mortality relationships and degree of dominance (D) were calculated. Resistance was observed in both sexes, the dosage-mortality (d-m) line of F 1 was towards the resistant parent and the ‘D’ value was found to be 0.8 indicating alphamethrin resistant (amr) gene to be autosomal and incompletely dominant. The d-m lines of F 2/backcross exhibited a clear plateau of mortality across a range of doses indicating monogenic resistance. The null hypothesis for monogenic resistance was tested from mortality data of backcross progeny compared with theoretical expectations using the χ2 test and was found to be non-significant. Understanding genetics of insecticide resistance is significant in prediction and management of resistant insects. The amr genes can be used as genetic marker in A. stephensi, which can be used in several applications in conducting basic and applied genetic research.

Immigration, Wealth and the 'Mortality Plateau' in Emergent Urban-Industrial Towns of Nineteenth-Century Massachusetts.

The mortality transition in Western Europe and the U.S. encompassed a much more complex set of conditions and experiences than earlier thought. Our research addresses the complex set of relationships among growing urban communities, family wealth, immigration and mortality in New England by examining individual-level, socio-demographic mortality correlates during the nineteenth-century mortality plateau and its early twentieth-century decline. In contrast to earlier theories that proposed a more uniform mortality transition, we offer an alternative hypothesis that focuses on the impact of family wealth and immigration on individual-level mortality during the early stages of the mortality transition in Northampton and Holyoke, Massachusetts.

On ordered subpopulations and population mortality at advanced ages

We consider hazard (mortality) rates in heterogeneous populations consisting of ordered (in the defined stochastic sense) subpopulations. This setting can be interpreted via the fixed frailty models with one or more frailty parameters. The shape of the hazard rate is of main interest in this paper. Specifically, the deceleration and leveling off in the hazard rates (mortality plateaus) are discussed and some examples of lifetime distributions that can result in asymptotically flat hazard rates are considered. These examples are based on vitality models when an organism’s initial vitality (resource) is ‘consumed’ in the course of life in accordance with a simple stochastic process (e.g., the Wiener process with drift or the gamma process).

A New Definition of Aging?

A New Definition of Aging?

Gene expression in late-life.

Gene expression in late-life.

Aging: an evolutionarily derived condition.

Aging: an evolutionarily derived condition.

Differential Bacteriophage Mortality on Exposure to Copper

Many studies report that copper can be used to control microbial growth, including that of viruses. We determined the rates of copper-mediated inactivation for a wide range of bacteriophages. We used two methods to test the effect of copper on bacteriophage survival. One method involved placing small volumes of bacteriophage lysate on copper and stainless steel coupons. Following exposure, metal coupons were rinsed with lysogeny broth, and the resulting fluid was serially diluted and plated on agar with the corresponding bacterial host. The second method involved adding copper sulfate (CuSO(4)) to bacteriophage lysates to a final concentration of 5 mM. Aliquots were removed from the mixture, serially diluted, and plated with the appropriate bacterial host. Significant mortality was observed among the double-stranded RNA (dsRNA) bacteriophages Φ6 and Φ8, the single-stranded RNA (ssRNA) bacteriophage PP7, the ssDNA bacteriophage ΦX174, and the dsDNA bacteriophage PM2. However, the dsDNA bacteriophages PRD1, T4, and λ were relatively unaffected by copper. Interestingly, lipid-containing bacteriophages were most susceptible to copper toxicity. In addition, in the first experimental method, the pattern of bacteriophage Φ6 survival over time showed a plateau in mortality after lysates dried out. This finding suggests that copper's effect on bacteriophage is mediated by the presence of water.