Demographic Research

Background Vaccination programs have greatly reduced the burden of infectious diseases, particularly in childhood. As populations age, however, the burden of respiratory infections such as influenza A, respiratory syncytial virus (RSV), and SARS-CoV-2 increasingly falls on older adults. Because infection fatality rates rise steeply with age, vaccination strategies that alter the age distribution of infections may have complex population-level consequences. We used transmission models to examine how the timing and frequency of vaccination influence infection-induced mortality and years of life lost (YLL) in aging populations. Methods and findings We analyzed age-structured transmission models that incorporate demographic change, age-specific infection fatality rates, and waning immunity after infection or vaccination. We varied the age at first vaccination, vaccination intervals, and coverage across a wide range of pathogen characteristics, including transmissibility and the duration of natural and vaccine-induced immunity. For single-dose vaccination programs with long-lived protection (5-50 years), the age at vaccination minimizing mortality in older adults for pathogens with strongly age-increasing fatality risk typically ranges from 60 to 80 years. The optimal age shifted toward older ages when transmissibility was higher or natural immunity lasted longer. Repeated vaccination produced qualitatively different outcomes. When vaccine-induced immunity was short-lived ($<$5 years), vaccination can shift infections toward the oldest ages where fatality risks are highest, increasing both mortality and YLL compared with no vaccination. This study has limitations. Our analysis used stylized transmission models and assumed vaccines that fully prevent infection, which may overestimate age-shifting effects compared with real-world vaccines that primarily reduce disease severity. Conclusions Optimal adult vaccination strategies depend jointly on pathogen transmissibility, the duration of immunity, and population demography. Vaccination programs that suppress infections earlier in life without protecting individuals into late life may shift infections toward ages with higher fatality risk. These findings highlight the need to evaluate adult vaccination strategies across the full life course and have important implications for vaccination policies against influenza A and other pathogens with strongly age-dependent infection fatality rates.

Demographic shifts are reshaping population age structures worldwide, with implications for infectious disease dynamics. Since contact patterns, susceptibility and infectiousness often vary by age, the risk that pathogen introductions initiate a substantial outbreak depends on the populations age distribution and associated behavioural characteristics. We develop an age-structured mathematical model to estimate the risk that a single pathogen introduction leads to sustained transmission (the probability of a major outbreak) under long-term demographic transitions, incorporating changes in age-specific contact patterns and behavioural adaptation. Using the Republic of Korea (projected to become the worlds oldest population by 2050) as a case study, we show that population ageing generally reduces the probability of a major outbreak due to older individuals lower contact rates. However, this effect is attenuated for pathogens with increasing susceptibility or infectiousness with age, and if future older cohorts have higher contact levels than at present (e.g. through extended workforce participation in an ageing society). These findings demonstrate that, while outbreak risks are affected by demographic changes, they are further modified by associated behavioural responses, highlighting the importance of accounting for demographic and socio-behavioural context when assessing future infectious disease outbreak risks. Author SummaryIn the early stages of an infectious disease outbreak, the risk that initial cases lead to a substantial outbreak is shaped by a range of factors including the characteristics of the host population. Demographic changes, such as population ageing, are transforming societies worldwide, yet their implications for infectious disease emergence remain unclear. Here, we show that ageing populations reduce the likelihood that imported infections trigger major infectious disease outbreaks due to lower contact rates between individuals of older ages. However, this effect depends on how susceptibility, infectiousness and host behaviour vary with age. For example, increased social and economic activity among future older adults (due to a higher retirement age) could offset the decrease in the outbreak risk. These findings underscore the need to account for demographic and socio-behavioural factors, in addition to biological factors, when assessing future outbreak risks and designing robust public health strategies, particularly in societies undergoing rapid demographic change.

Socioeconomic inequalities in health and well-being are a major public health concern, particularly in ageing populations. Education is a key determinant shaping multiple aspects of health outcomes. We used cross-sectional data from wave 9 of the German sample (n=4,148) of the Survey of Health, Ageing and Retirement in Europe (SHARE) to test whether formal education is associated with well-being in later adulthood, with health literacy, self-rated health, and preventive health behaviours as possible mediators. Our results showed that education was positively associated with greater well-being, but only via indirect pathways. Specifically, self-rated health, health literacy, and fruit and vegetable consumption mediated the relationship between education and well-being accounting for 54.7, 24.7, and 12.6 percent of the total effect, respectively. In addition, there were significant positive correlations between education and health literacy, as well as high-intensity physical activity, daily fruit and vegetable consumption, more preventive health check-ups, and less smoking. In contrast, alcohol consumption was more common among those with higher levels of education. All health behaviours and health literacy were correlated directly or indirectly (i.e., mediated by health) with well-being. These findings highlight the importance of examining indirect pathways linking education to well-being in later life. Interventions aimed at improving health literacy and promoting healthy behaviours may help reduce educational inequalities in quality of life among older adults. About the SHARE Working Paper SeriesThe SHARE Working Paper Series started in 2011 and collects pre-publication versions of papers or book chapters, technical and methodological reports as well as policy papers based on SHARE data. The working papers are not reviewed by the publisher (SHARE-ERIC), layout and editing are not standardized. The publisher takes no responsibility for the scientific content of the paper. Working Papers can be updated - a version number is indicated on the front page. Previous versions are available upon request.

Background and Objectives: Arts and cultural engagement may contribute to well-being in later life. However, evidence from longitudinal studies from Asia, including Japan, remains limited. This study examined the association of arts and cultural engagement with subsequent multidimensional well-being among older adults in Japan, one of the fastest-aging countries. Research Design and Methods: This longitudinal study used panel data from 354 individuals aged 60 and older (mean age 74.0 years; 78.6% women) who completed self-administered questionnaires by mail between 2022 and 2024. The PERMA-Profiler was used to assess five multifaceted aspects of psychological well-being: positive emotion, engagement, relationships, meaning, and accomplishment. Frequencies of arts and cultural engagement at baseline were measured for active (e.g., activities by individuals and participation in groups, such as music and painting) and receptive (e.g., visiting museums, galleries, and theaters) forms. Results: Multivariable linear regression analysis, adjusted for the covariates including baseline PERMA scores, showed that higher frequencies of active engagement were positively associated with higher PERMA scores for all domains. Higher frequencies of receptive engagement were associated with the domains of positive emotion, meaning, and accomplishment, but not clearly associated with engagement and relationships. Restricted cubic spline analyses suggested clearer positive frequency-response patterns for active engagement than for receptive engagement. Discussion and Implications: Arts and cultural engagement, both active and receptive forms, was associated with subsequent multiple aspects of well-being in later life. These findings suggest the importance of ensuring access to arts and cultural opportunities for older adults to create, participate, and connect.

Background: It is well-established that males have a higher mortality risk than females. Immune cells and their function are known to undergo characteristic changes during aging, and immune cells are known to have sex differences. Immune cells and their function have been linked to mortality risk, but no studies have investigated to what degree, if at all, Immune Cell Biomarkers (ICBs) contribute to the known differences in mortality risk by sex. Methods: Using participant data from the Health and Retirement Study (n = 8,822), we applied multivariable linear regressions adjusting for age, cytomegalovirus (CMV) serostatus, sex, and race/ethnicity to identify differences by sex in 48 immune cell biomarker (ICB, e.g. T cells, B cells, Monocytes, etc.) percentages and counts (measured in 2016). We studied how the associations between ICBs and mortality risk differ by sex using stratified Cox Proportional Hazard (CPH) models. We estimated how inclusion of sex explained the relationship between ICBs and all-cause mortality, and conversely, how inclusion of individual and all ICBs combined explain the relationship between sex and all-cause mortality using multivariable modeling approaches. Results: Differences in ICBs by sex range between 2-38% (39/48 statistically significant). 9 ICBs were significantly associated with mortality risk in the entire sample. While different ICBs were significantly associated with mortality risk in the stratified analyses, particularly with respect to monocyte, B cell, and NK cell populations, adjusting for sex modestly influenced the hazard ratios of the ICBs (sex: 8 ICBs, percent change <5.4%). Furthermore, individual and cumulative contributions of ICBs in explaining the differences in mortality risk by sex were not significant.

Background Literature investigating mediation of the association between child abuse and dementia has largely considered composite adverse childhood experience scores rather than individual adverse experiences, despite evidence that different experiences have different impacts on dementia risk. Additionally, prior studies consider mediators in isolation, despite known associations between mediators which may impact indirect pathways from child abuse to dementia. Objectives To investigate whether potentially modifiable health and lifestyle factors mediate the association between child abuse and dementia. Methods We used data from the English Longitudinal Study of Ageing to investigate associations between child abuse and dementia (N:5,448). Indirect pathways through four mediator categories (education, health behaviours, mental health and cardiovascular health) were examined. We used regression modelling to estimate associations between child abuse, mediators and dementia, and causal mediation analysis using the g-formula to estimate the joint indirect effect through the mediators. Results Individuals who experienced child abuse had, on average, an 80% higher hazard of dementia, compared to those who did not (RTE HR:1.80, 95% CI:1.21-2.39). Mental health mediators showed strong associations with both child abuse and dementia. Evidence for other mediators was weaker. Education, health behaviours, mental health and cardiovascular health mediated approximately 18% of the association. Sensitivity analysis revealed that almost all this mediation occurred through mental health. Conclusions Child abuse was associated with higher risk of dementia. Joint mediation analysis suggested that education, health behaviours, cardiovascular health, and mental health accounted for a relatively small proportion of the observed association, with most mediation occurring through mental health. Future research must focus on other potential pathways from child abuse to dementia, including biological and social mechanisms.

Background. Given uncertainty about whether later-life health at similar ages is improving over time, we examined trends across multiple health domains. Methods. We analysed data from community-dwelling adults aged 50 and older in the English Longitudinal Study of Ageing in 2004/05, 2012/13, and 2023/24 (main survey: N=8389, 8549, and 6090, respectively). Outcomes included self-rated health, limiting long-standing illness, pain, mobility limitations, cardiometabolic and chronic conditions, obesity, inflammation, mental health, quality of life and memory. Weighted pooled modified Poisson and linear regressions compared outcomes over time, overall, and by age group and education, with additional adjustment for sex and wealth. Results. Adjusted estimates showed divergent trends. Fair/poor self-rated health increased from 27% to 34%, and any pain from 37% to 47%, whereas mobility impairments declined from 58% to 52%. Self-reported high cholesterol increased from 19% to 39%, while biomarker-defined high cholesterol declined from 78% to 54%; diabetes increased on both measures. Psychiatric problems increased from 6% to 10%, quality of life declined, and memory improved. However, trends differed by age and education, particularly for limiting long-standing illness, mobility limitations, cholesterol biomarkers, and mental health, indicating that aggregate trends masked unevenly distributed changes. Conclusion. Later-life health in England has not improved uniformly. Gains in functioning, biomarkers, and cognition coexist with rising pain and poorer mental health. Trends were also socially and age patterned, producing increasingly multidimensional and socially patterned health outcomes. Multidomain health monitoring is essential for interpreting population health trends and planning healthy ageing, prevention, long-term care, and work policies.

Socioeconomic, demographic, and health system structures may have shaped COVID-19 pandemic impact across populations, but past analyses typically examined few factors. We systematically examined correlates of COVID-era excess mortality, considering 2,745 county-level variables of demography, race/ethnicity, income, insurance, education, employment, housing, and health system. Pearson correlation coefficients (CCs) were obtained for the most recent available pre-pandemic value against age-standardized county excess-death for each year during 2020-2024. Counties were population-weighted. Variables were grouped by meaning into 11 semantic super-clusters. Overall, 17.3% of variables reached at least a moderate correlation level (|CC| > 0.30) and 2.8% reached strong correlations (|CC| > 0.45). Strongest correlations were seen for college attainment (CC -0.54), uninsurance among adults 40-64 (+0.53), and high income (-0.53). At least moderate correlations were seen for 9.1% of variables in 2020 and 8.5% in 2021, but only 1.8%, 0%, and 1.3% in 2022, 2023, and 2024, respectively. Similar patterns of concentration of moderate correlations in the first two pandemic years appeared in both elderly and non-elderly populations. Of 472 variables with |CC| > 0.30, 362/395 moderate-band and 77/77 strong-band variables belonged to demography and socioeconomic super-clusters. Only 7% of health system variables reached |CC| > 0.30, versus 31% of socioeconomic and demographic variables. Using the most recent available value until 2023 or 2015, different population weighting, and Spearman correlations yielded similar results. Overall, these ecological analyses suggest strong relationships of socioeconomic structure and demographics rather than health-care resources/supply with excess mortality across US counties especially during 2020-2021.

Age-dependent survival is central to understanding population dynamics and life-history evolution. We analysed carcass weight and age-at-harvest data from 6022 red foxes (Vulpes vulpes) collected across Sweden between 1967 and 1971 to evaluate latitudinal effects on body mass and age-dependent survival. Carcass weights decreased from south to north in both adults and sub-adults, contrary to Bergmann's rule, with southern foxes weighing approximately 1.27 times more than northern foxes. The latitudinal weight gradient exceeded the sex difference in both age classes, and no sex x region interaction was detected. The decrease in weight with latitude is consistent with reduced prey availability and harsher winter conditions in the north, which limit growth and body size during development. Using a Bayesian age-at-harvest model with region-specific population growth rates (lambda), we estimated age-dependent survival probabilities for four latitudinal regions and both sexes. Despite the strong latitudinal gradient in weight, survival did not show a corresponding pattern - regional differences were uncertain, with all credible intervals spanning zero. Regional population growth rates were consistent with slight decline in the north and near-stability in the south-central region, which suggests that body condition and population dynamics are coupled at the regional scale despite no survival gradient. The decoupling of body condition and survival across regions suggests that mortality patterns are similar across the latitudinal gradient. We discuss these patterns in terms of latitudinal productivity gradients, prey availability, and life-history trade-offs in a widely distributed carnivore.

Standard demographic models of age-related hearing loss (presbycusis) predominantly utilize symmetric functions, such as log-normal distributions for age-binned thresholds and 4-parameter logistic curves for prevalence estimates. While these models capture early-to-moderate degradation effectively, they structurally struggle to characterize the heavy tails associated with severe clinical impairment. In this study, we present a statistical critique using a secondary analysis of the historical Medical Research Council (MRC) National Study of Hearing (1980-1986) dataset. By applying Generalized Extreme Value (GEV) distribution theory, we demonstrate that as severity increases, the underlying statistical geometry of hearing loss shifts. The asymmetric, heavy-tailed GEV distribution provides a parsimonious description of severe impairment, requiring fewer parameters than standard symmetric models. However, we explicitly acknowledge that utilizing static population data to infer progression introduces an ecological fallacy. Furthermore, the dataset's historical nature embeds unquantified generational cohort effects. We conclude that while extreme value statistics offer a compelling mathematical framework for modeling the variance of severe presbycusis, true longitudinal datasets are required to isolate physiological degradation from historical cohort variance.

Introduction Frailty is an ageing-related state associated with disability and mortality. Women often experience higher frailty but lower mortality than men, a pattern described as the male-female health-survival paradox. Evidence from low- and middle-income settings is limited. We examined sex differences in frailty trajectories and terminal decline in Mexico. Methods We analysed five waves (2001-2018) of the nationally representative Mexican Health and Aging Study (MHAS) including 12,440 adults ([&ge;]50 years at baseline). Frailty was measured using a 31-deficit frailty index (FI score; 0-1). We used survey-weighted linear mixed-effects models with time interactions, adjusted for sociodemographic, behavioural and health covariates to model sex differences in frailty trajectories. Terminal decline in FI was modelled among those who died using mixed-effects models on the time-to-death scale. Results A total of 12,440 adults aged 50 to 105 years were included, with a mean age of 62.1 years (SD 9.6); 5,698 men (45.8%) and 6,742 women (54.2%). Mean baseline FI was 0.17 (SD 0.12), higher in women than men (0.19 vs 0.16; P<0.001). After adjusting, women had a 0.014 higher mean FI than men at baseline (adjusted mean difference; 95%CI 0.008, 0.020), with difference widening over follow-up, increasing from 0.016 at 2 years to 0.029 at 17 years. Analysis of terminal decline found that accumulation of frailty accelerated in the years preceding death; with results suggesting that women reached death with higher frailty than men (difference 0.029; 95%CI 0.009, 0.048). Conclusion Women experienced higher and more rapidly increasing frailty compared to men and carried a greater frailty burden in the years preceding death. These findings underscore the importance of considering sex differences in frailty trajectories when developing healthy ageing strategies that address the life-course vulnerabilities disproportionately driving frailty accumulation in women in low- and middle-income countries.

Early-life exposures are important to several late-life health outcomes. We sought to study the effect of an in utero nutritional environment and its interaction with Alzheimer's disease (AD) genetic risk on late-life cognitive function. We used a natural experiment created by the pellagra epidemic, a nutritional disease caused by a vitamin B3 deficiency, to evaluate the association between in utero pellagra epidemic exposure and late-life cognitive function in the Health and Retirement Study (N = 18,285). We also evaluated whether the in utero exposure could modify the AD polygenic score's (PGS) effect on cognition. In utero pellagra epidemic exposure was significantly associated with cognition ({beta} = -0.025). However, these effects were not isolated to the prenatal period as exposure during childhood periods also had an effect. The interaction between the in utero exposure and the AD PGS was significant, where the genetic effect on cognition was amplified with increasing (progressively worse) in utero exposure levels. These associations imply that the early-life nutritional environment affects late-life cognitive function and that these effects can modify genetic risk.

Background: Cognitive function is crucial for healthy aging, and its impairment reduces quality of life and increases healthcare and societal burden. Social vulnerability, shaped by factors like income, education, and access to healthcare, has been associated with cognitive health, but reliance on community-level assessments may limit understanding of risk at the individual level. Objectives, Design, Setting, Participants: We examined the cross-sectional association between a proposed individual-level Social Vulnerability Index (iSVI) and cognitive function among 5,989 participants aged [&ge;]60 years in the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 and 2011-2014 cycles. Measurements: Cognitive performance was measured using the Digit Symbol Substitution Test (DSST). iSVI was constructed by summing six risk indicators (income, education, health insurance, employment, housing tenure, and food security). Health insurance and employment were scored on a three-level scale (0/0.5/1); other indicators were binary (0/1). Survey-weighted linear regression estimated associations between iSVI and DSST scores, adjusting for age, sex, race and Hispanic origin, and survey cycle. Estimates were benchmarked against adjusted associations between age and DSST. Results: Higher iSVI was associated with poorer cognition, with each one-unit increase corresponding to a 5.30-point lower DSST score (95% CI: -5.71, -4.89). This difference was comparable to nearly 5 years of age-related difference in DSST performance, as each additional year of age was associated with a 1.08-point lower DSST score (95% CI: -1.14, -1.03). Conclusions: Increased iSVI was associated with lower cognitive function in older adults, highlighting individual-level social vulnerability as a key intervention opportunity to prevent cognitive impairment.

Inflation affects human fertility and survival, and persistent inflation can translate into fluctuations in annual population growth rate. However, existing studies have not yet systematically examined the impact of inflation on long-term growth rates across multiple populations. Here, using high-resolution inflation and demographic data for 32 countries from 1971-2024, we examine whether high inflation variance and autocorrelation amplify the sensitivity of the long-term growth rate to inflation. Additionally, we examine whether increasing inflation variance and autocorrelation adversely affect humans capacity for demographic buffering, i.e., reducing the temporal variance in vital rates most sensitive to growth. To do so, we construct inflation-dependent matrix population models using a hierarchical Bayesian framework. We then calculate the stochastic sensitivity and elasticity of population growth rate to inflation to quantify demographic buffering across a variance-autocorrelation parameter space for inflation. Our results show that the stochastic sensitivities of growth rate increase with variance and autocorrelation in inflation. However, we find partial support for the expected adverse effects of inflation variance and autocorrelation on humans capacity to buffer against inflation. Our framework offers a valuable tool to examine the impact of resource uncertainty on life history strategies in stochastic environments. We discuss how our framework can be extended to study the resource-dependent population dynamics within variable environments and across the tree of life.

Objectives: Oral health conditions impact a significant proportion of the global population. Chronological age is a known risk factor; however, characterization of epigenetic age remains limited and is expected to provide additional insight into biological mechanisms. Materials and Methods: The National Health and Nutrition Examination Survey (NHANES) was used to analyze the effect of epigenetic age measures of DunedinPoAm, and epigenetic age acceleration (EAA) of Horvath, Hannum, Weidner, Lin, VidalBralo, PhenoAge, GrimAge, and GrimAge2, on various oral health outcomes from survey and examination results. Univariable and multivariable logistic regression were performed, adjusting for sex, race-ethnicity, education, poverty income ratio categories, and dental insurance coverage status. Results: DunedinPoAm was associated with the last dental appointment being for an existing issue (p=0.0093), poor general oral condition (p=0.0226), limiting food due to teeth problems (p=0.0031), and recommendation to see a dentist within the next two weeks (p=0.0171). EAAs for PhenoAge, GrimAge, and GrimAge2, were associated with a smaller number of oral health outcomes, whereas EAAs for Horvath, Hannum, Weidner, Lin, and Vidal-Bralo showed no associations. Conclusions: In a representative U.S. population, DunedinPoAm was most consistently positively associated with different adverse oral health outcomes compared with other epigenetic aging measures. Tracking specific epigenetic ages such as DunedinPoAm, EAA GrimAge, EAA GrimAge2, and PhenoAge, may aid in additional monitoring of oral health outcomes. Understanding specific aging-related CpGs associated with oral health may aid in elucidating underlying molecular mechanisms.

We examined the impact of COVID-19 pandemic onset (2020 April) on homicide mortality in the United States. We conducted a single interrupted time series analysis using homicide events from the National Vital Statistics System that occurred over six years (2017-2022), with COVID-19 onset as an interruption. Monthly homicide deaths rates were calculated per 100,000 person-years to create a monthly time series. We used autoregressive integrated moving average regression, adjusted for seasonality, to model the immediate and sustained trend changes in the homicide mortality rate ratios due to the pandemic. We stratified models by length of stay-at-home order, race and ethnicity, sex, age, and weapon used to examine effect measure modification. In Jan 2017, the US homicide mortality rate was 5.9/100,000 PY. While there were annual seasonal changes, the overall time trend before April 2020 was stable. However, with COVID-19 onset, the overall homicide mortality rate ratio increased by 32% (95% CI: 0.23, 0.41), which persisted through 2022 without additional trend changes, but with seasonal variations. Immediate increases with stable sustained trends in homicide rates were also observed in most stratified analyses. COVID-19 pandemic onset is associated with US homicide mortality rates immediately increasing and remaining stable and higher afterwards.

Background: Epigenetic clocks are markers of biological aging that may vary in their sensitivity to environmental stressors and lifestyle modifiers. To evaluate the utility of these biomarkers as sensors of the human exposome, we investigated how they respond to two powerful and opposing exposures: smoking, a source of oxidative stress, and the antioxidant-rich Mediterranean diet. Objectives: We assessed the sensitivity of eleven epigenetic clocks to diet and smoking and evaluated whether Mediterranean diet adherence modifies associations between smoking and epigenetic aging. Methods: We analysed 928 participants (mean age 41 years, 59% male) from the Airwave Health Monitoring Study. Linear regression models assessed associations between Mediterranean Diet Score (MDS) and epigenetic age acceleration (EAA), alongside smoking status and blood cotinine. Interaction terms between smoking status and MDS were included to detect dietary attenuation of smoking-related EAA. Models were adjusted for demographic, socioeconomic, lifestyle, and psychological covariates. Results: Higher MDS was associated with lower EAA for GrimAge ({beta} = -0.07 SD; 95% CI: -0.13, -0.01) and Bernabeu ({beta} = -0.08 SD; 95% CI: -0.14, -0.02) after false discovery rate correction. Smoking was strongly associated with increased EAA, particularly for GrimAge, Bernabeu, and DunedinPACE. Among current smokers, effect sizes were greater in those with lower dietary adherence (e.g. GrimAge: 1.79 SD, 95% CI: 1.54, 2.04) compared with those with higher adherence (1.35 SD, 95% CI: 1.01, 1.68; P_interaction < 0.001). Similar attenuation patterns were observed for Bernabeu. Higher intake of fruits, vegetables, and whole grains contributed most to the attenuation of smoking-related EAA. Conclusions: Our findings indicate that certain epigenetic clocks effectively capture the tension between harmful and protective exposures within the exposome. Rather than suggesting that diet neutralises the risks of tobacco, these results demonstrate that specific clocks are sensitive enough to monitor how lifestyle factors modify molecular responses to environmental toxins. This highlights the value of second-generation clocks in quantifying biological resilience.

People with Down syndrome have higher age-specific mortality rates compared to the general population as well as peers with other intellectual and developmental disabilities. While a large proportion of mortality is attributable to Alzheimers disease, many die prior to Alzheimers diagnosis and some live to old ages, dying without Alzheimers. Our objectives were to use 11 years of Medicaid and Medicare data to describe characteristics and factors related to death in adults with Down syndrome and use machine learning to identify which conditions most strongly predict death in the full population and stratified by age. We identified death using Center for Medicare and Medicaid Systems reported date of death health conditions using ICD 9 and 10 codes. We used a case-control design with risk set sampling to have that controls to mimic the distribution of times of incident Alzheimers disease. We trained gradient boosted trees to identify strongest predictors. Our cohort included 137,293 adults with Down syndrome. Among those, 30,894 (22.5%) died during the study period. Mean age at death among those who died was 55 years (SD=10). Mean age of death in those with Alzheimers disease was 59 (SD=7) and those without was 52 (SD=12). The most influential predictors of mortality were any claim for dementia, any claim for pneumonia, re-occurring claim for cardiovascular disease three years before index death, and any claim for heart failure and epilepsy. Our results align with previous clinical work and highlight intervenable areas to reduce mortality in the Down syndrome population.

Most organisms become increasingly likely to die as they grow older, a phenomenon known as demographic senescence. Despite this statement saying nothing about the particular shape of a mortality curve, the Gompertz-Makeham law remains remarkably accurate in a broad range of species. We develop a general mathematical framework in which individuals are modelled as comprising a fixed number of interacting intra-organismal sub-systems, each characterised by stochastic failure and repair rates, such that the number of failed sub-systems follows a birth-death process. In many organisms, failure begets failure because sub-systems are typically interdependent. We use diffusion approximations to demonstrate that this interdependence generically produces Gompertz-Makeham mortality curves. Since individuals who die can no longer age, observed cohorts become increasingly composed of lucky individuals that avoided death by (stochastically) taking paths in failure space associated with lower mortality despite no intrinsic differences in their quality. Selective disappearance of unlucky individuals generates deviations from Gompertz-Makeham predictions at advanced ages, producing a late-life mortality plateau. We show that while these deviations must always exist, they may often be too small to detect, either because the failure accumulation process is stereotyped or because detection requires unreasonably large cohort sizes. Our work establishes Gompertz-Makeham curves arising from stochastic failure accumulation as a null expectation in organisms with many interdependent sub-systems.

ABSTRACT Background: Onset of cancer is linked to psychological distress and cancer is prevalent in older adults. Yet, the association to suicide is scarcely examined. The aim of this study was to assess whether cancer diagnosed in older adults is associated with suicide incidence. Methods: All older adults (65+ years) who lived in Austria in the years 2014-2021 (n=2,175,134) were followed. Of these, 223,932 were diagnosed with a new cancer. We used non-parametric survival models with inverse-probability-treatment weights to compare risk ratios (relative risk) and risk differences (absolute risk) of older adults with and without cancer. Results: Out of 2,158 suicide deaths, 442 (20.5%; 83.7% males) occurred among older adults with a new cancer diagnosis. The incidence rate was 74 among those with a new cancer diagnosis versus 23 per 100,000 person-years among those with no new cancer. One year after being diagnosed, older adults with a new cancer had a 4 times higher relative risk of dying by suicide compared to those without. The risk was highest within the first three months after diagnosis and for cancers with a poor prognosis (disseminated disease; lung, oesophagus, stomach, liver, pancreas, and brain cancers). The absolute risk of dying by suicide within 5 years after cancer diagnosis was 0.18% versus to 0.11% among those with no new cancer. Discussion: Older adults who received a new cancer diagnosis had elevated suicide risks. Provision of support to cope with mental distress should be considered at cancer diagnosis, especially for older adults with a poor prognosis.