Midlife Mortality Research Articles

Pervasive Stagnation: Flat and Rising Cardiovascular Disease Mortality Post-2010 Across US States and Counties.

Since 2010, the U.S. has experienced adverse trends in cardiovascular disease (CVD) mortality, which dramatically slowed long-standing life expectancy improvements. The extent to which the national trend in CVD mortality masks heterogeneity in trends across states and counties is poorly understood. We provide a detailed accounting of post-2010 trends in CVD mortality by U.S. state and county to understand how features of place relate to trends. We compare trends during 2010-2019 to that of 2000-2009. We observe flattening declines in CVD mortality in nearly every state at both midlife (ages 40-64) and old age (ages 65-84) across the two decades. Many states exhibited increases in midlife CVD mortality in 2010-2019. Old age CVD mortality was still declining in most states post-2010, although much slower compared to the previous decade. States in the Southeast recorded some of the fastest post-2010 declines in CVD mortality at old age. County-level median household income was associated with level of CVD mortality, but all income deciles, even the wealthiest counties, experienced stagnating CVD mortality declines. Findings highlight the ubiquitous nature of CVD stagnation, pointing to the need to identify risk factor affecting trends across regions and socioeconomic strata across the United States.

24-Hour movement guidelines during adolescence and midlife mortalityAdolescent 24-Hour movement and midlife mortality

24-Hour movement guidelines during adolescence and midlife mortalityAdolescent 24-Hour movement and midlife mortality

Daily exposure to stressors, daily perceived severity of stress, and mortality risk among US adults.

Prior studies of perceived stress and mortality have yielded mixed results, but most are based on one-time measurements of perceived stress. We use daily diary data from the Midlife in the United States study to measure exposure to stressors and perceived severity of stress and investigate their associations with mortality. We also explore whether the associations vary by age and assess whether the associations are stronger for extrinsic than intrinsic mortality, which is more likely to be aging-related. The analysis included 4,756 observations for 2,915 respondents aged 21-95 who participated in at least one of three waves (1996-97, 2004-09, 2017-19) of the National Study of Daily Experiences. Participants reported daily stressors and perceived severity on 8 consecutive evenings at each wave. Mortality was followed through December 31, 2021. In fully-adjusted models, daily exposure to stressors was associated with mortality, but only at younger ages (HR = 1.20 per SD at age 50, 95% CI: 1.01‒1.42). The association was slightly stronger for extrinsic (HR = 1.31 per SD at age 50, 95% CI: 1.01‒1.69) than for intrinsic mortality, which was not significant (HR = 1.24 per SD at age 50, 95% CI: 0.98‒1.56). When we used an alternative measure of daily perceived severity of stress, the demographic-adjusted association appeared to be similar in magnitude, but after careful adjustment for potential confounding with health status, the association weakened and was no longer statistically significant (HR = 1.17 per SD at age 50, 95% CI: 0.99-1.37). Perceived severity was not significantly associated with either extrinsic or intrinsic mortality even at age 50. Most Americans die at older ages, where stress exposure does not appear to be significantly associated with mortality. Nonetheless, our results suggest that stress exposure is more strongly associated with midlife mortality, which has an undue influence on overall life expectancy.

Midlife diseases of despair and cardiometabolic risk: testing shared origins in adolescent psychopathology.

Rising midlife mortality in the United States is largely attributable to 'deaths of despair' (deaths from suicide, drug poisonings, and alcohol-related diseases) and deaths from cardiometabolic conditions. Although despair- and cardiometabolic-related mortality are increasing concurrently, it is unclear whether they share common developmental origins. We tested adolescent psychopathology as a potential common origin of midlife diseases of despair and cardiometabolic risk. Participants (N = 4578) were from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort followed from adolescence to early midlife. Adolescent psychopathology included depression, anxiety, eating disorders, PTSD, conduct disorder, and ADHD at ages 11-18. Diseases of despair (suicidality, substance misuse, pain, and sleep problems) and cardiometabolic risk (hypertension, hyperlipidemia, high-risk waist circumference, diabetes, and cardiovascular conditions) were multi-modally measured at ages 33-43. At midlife, adolescents who experienced psychopathology exhibited more indicators of despair-related diseases and cardiometabolic risk (IRRs = 1.67 [1.46-1.87] and 1.13 [1.04-1.21], respectively), even after accounting for demographics, adolescent SES, and adolescent cognitive ability. Associations were evident for internalizing and externalizing conditions, and in a dose-response fashion. In mediation analyses, low education explained little of these associations, but early-adult substance use explained 21.5% of psychopathology's association with despair-related diseases. Midlife despair-related diseases and cardiometabolic risk co-occurred within individuals (IRR = 1.12 [1.08-1.16]). Adolescent psychopathology accounted for 8.3% of this co-occurrence, and 16.7% together with adolescent SES and cognitive ability. Adolescent psychopathology precedes both diseases of despair and cardiometabolic risk. Prevention and treatment of psychopathology may mitigate multiple causes of poor midlife health, reducing premature mortality.

Weight Gain in Midlife Women.

To summarize the evidence and clinical implications of weight and body composition changes during midlife in women and provide an overview of weight gain prevention and management in this population. Aging-related changes such as decreased energy expenditure and physical activity are important culprits for weight gain in midlife women. The hormonal changes of menopause also influence body adiposity distribution and increase central adiposity. These body changes can have health consequences including the development of cardiometabolic diseases, osteoarthritis, cancer, worsening in cognition, mental health, and menopause symptoms. Midlife women experience changes related to aging, menopause, and lifestyle which favor weight gain. Clinical practice should focus on early counseling and anticipatory guidance on the importance of dietary changes and physical activity to attenuate this phenomenon. Future research should focus on the longitudinal relationship between weight trends in midlife and health consequences and mortality.

US exceptionalism? International trends in midlife mortality.

Rising midlife mortality in the USA has raised concerns, particularly the increase in 'deaths of despair' (due to drugs, alcohol and suicide). Life expectancy is also stalling in other countries such as the UK, but how trends in midlife mortality are evolving outside the USA is less understood. We provide a synthesis of cause-specific mortality trends in midlife (25-64years of age) for the USA and the UK as well as other high-income and Central and Eastern European (CEE) countries. We document trends in midlife mortality in the USA, UK and a group of 13 high-income countries in Western Europe, Australia, Canada and Japan, as well as seven CEE countries from 1990 to 2019. We use annual mortality data from the World Health Organization Mortality Database to analyse sex- and age-specific (25-44, 45-54 and 55-64years) age-standardized death rates across 15 major cause-of-death categories. US midlife mortality rates have worsened since 1990 for several causes of death including drug-related, alcohol-related, suicide, metabolic diseases, nervous system diseases, respiratory diseases and infectious/parasitic diseases. Deaths due to homicide, transport accidents and cardiovascular diseases have declined since 1990 but saw recent increases or stalling of improvements. Midlife mortality also increased in the UK for people aged 45-54year and in Canada, Poland and Sweden among for those aged 25-44 years. The USA is increasingly falling behind not only high-income, but also CEE countries, some of which were heavily impacted by the post-socialist mortality crisis of the 1990s. Although levels of midlife mortality in the UK are substantially lower than those in the USA overall, there are signs that UK midlife mortality is worsening relative to that in Western Europe.

Does educational mobility in mid-life affect mortality? A cohort study covering 1.3 million individuals in Sweden

•Studies on how increased formal educational level in mid-life affects mortality is lacking.•We found that women who increased their educational level in mid-life had a reduced risk of mortality.•In men, mortality was reduced only for those who increased their education from a low level.

THE “DOUBLE JEOPARDY” OF MIDLIFE AND OLD AGE MORTALITY TRENDS IN THE UNITED STATES

Abstract Since 2010, U.S. life expectancy growth has stagnated. Much research on U.S. mortality has focused on working age adults given adverse trends in drug overdose deaths, other external causes of death, and cardiometabolic deaths in midlife. We show that the adverse mortality trend at retirement ages (65+ years) has in fact been more consequential to the U.S. life expectancy stagnation since 2010, as well as excess deaths and years of life lost in 2019, than adverse mortality trends at working ages. These results reveal that the U.S. is experiencing a “double jeopardy” that is driven by both mid-life and older-age mortality trends, but more so by older-age mortality. Understanding and addressing the causes behind the worsening mortality trend in older ages will be essential to returning to the pace of life expectancy improvements that the U.S. had experienced for decades.

BEHAVIORAL HEALTH PREDICTORS OF PREMATURE MORTALITY IN A BLACK AMERICAN LONGITUDINAL COHORT

Abstract Life expectancy among Americans is now the lowest it has been in 15 years. While startling, more alarming are the persistent racial disparities in mortality. Black Americans continue to die at significantly younger ages with Black men living, on average, 7.0 fewer years and Black women living 4.4 fewer years than their White counterparts. To inform intervention strategies and resource allocation, we need a complete understanding of the role that malleable factors, such as substance use and depression early in the life course, play in premature mortality for aging Black Americans. This study illuminates behavioral health factors that can be targeted to eliminate mortality disparities among a longitudinal cohort followed from childhood into their 60s. Utilizing data from the Woodlawn Study, a well-defined neighborhood cohort study of 1,242 Black Americans that began in 1966 (age 6), we examined the predictive value of family history of substance use, adolescent substance use and depression, and young adult substance use and depression. Through 2021 (modal age 61), based on National Death Index reports, 21.6% of the original cohort (n=268) has passed away. The poster will present cause and timing of death by gender and adjusted logistic regression findings showing that depression symptoms as early as adolescence (age 16) predict midlife mortality occurring between ages 32 and 60 (p=.003) and that those diagnosed with depression or a substance use disorder in young adulthood are 61% (p=.025) and 85% (p=.001) more likely to die by age 60. Policy and prevention implications will be presented.

A 7-year longitudinal association of total cholesterol with premature structural and functional cardiac damage progression in youth: the ALSPAC birth cohort study

Abstract Background Recent evidence suggests that childhood total cholesterol was associated with midlife cardiovascular mortality. Cumulative total cholesterol has been associated with subclinical atherosclerosis during growth from mid-adolescence through young adulthood. It remains unexamined whether total cholesterol independently associates with signs of premature cardiac damage in apparently healthy youth due to the paucity of repeated measures of cardiac structure and function. Purpose To investigate the longitudinal association of changes in total cholesterol with structural and functional cardiac damage progression during growth from adolescence through young adulthood. Methods From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1595 adolescents aged 17 years who had fasting plasma total cholesterol measured at 17- and 24-year clinic visits were included. Repeated echocardiography measured LVM indexed for height2.7 (LVMI2.7), relative wall thickness (RWT), LV diastolic function from mitral E/A ratio (LVDF), and LV filling pressure from E/e´ ratio (LVFP) were available at baseline and follow-up. LVMI2.7 ≥51g/m2.7, RWT ≥0.44, LVDF <1.5, and LVFP ≥8 were categorised as LV hypertrophy, high RWT, LVD dysfunction, and high LVFP, respectively. Multivariable adjusted associations were examined using generalized linear mixed-effect models and generalized logit mixed-effect models and adjusted for sex, and time-varying covariates measured at both baseline and follow-up such as age, insulin, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, sedentary time, light physical activity, and moderate to vigorous physical activity. Results Among 1595 adolescents (mean [SD] age at baseline, 17.74 [0.38] years; 955 [59.8%] females]) mean total cholesterol values increased in males from 3.55 mmol/L to 4.25 mmol/L and in females from 3.97 mmol/L to 4.46 mmol/L, over 7 years. The prevalence of LV hypertrophy increased in males from 3.6% to 11.9% and in females from 1.6% to 4% over 7 years. The prevalence of LVD dysfunction increased in males from 7.8% to 16.6% and in females from 10.3% to 15.4%. In a fully adjusted model, each 1 mmol increase in total cholesterol was significantly associated with higher odds of LV hypertrophy progression (odds ratio 1.18; [95% CI, 1.09 – 1.27], p<0.0001), high RWT (1.11; [1.02 – 1.21], p=0.015), and high LVFP (1.12; [1.05 – 1.20], p=0.001) but not LVD dysfunction (1.03 [0.95 – 1.13], p=0.461), over 7 years. Conclusion Increased total cholesterol was independently associated with progressive structural and functional cardiac damage in asymptomatic youth during growth from adolescence through young adulthood.

Impact of COVID-19 on mortality and excess mortality of midlife from 40 to 64 age groups

The COVID-19 pandemic has significantly affected the middle-aged population in the US. Leveraging the CDC dataset, this study quantifies the number of fatalities across various midlife age brackets, specifically 40–44, 45–49, 50–54, 55–59, and 60–64 for both males and females, spanning the years 2015 to 2020. A novel Python Package Index (PyPI) application, midlife was developed to compute and visualize these findings. The PyPI midlife application was also validated via Code Ocean for reproducibility of the application. The analysis revealed that males aged 55–59 and females aged 50–54 experienced the highest excess mortality due to COVID-19, likely due to a previously declining death trend in these groups. This research not only provides a method to visualize and calculate the impact of COVID-19 on midlife mortality by age and sex, but also highlights the potential economic repercussions of rising midlife mortality rates.

Is the Pain killing you? Could Pain interference be a warning signal for midlife mortality?

Although prior studies have documented an association between various measures of pain and mortality, none of those studies has evaluated whether the association between pain and mortality varies significantly by age. We suspect that pain—particularly pain that interferes with the ability to lead a normal life—could be an early warning sign that may portend increased risk of physical impairment and mortality later in life. In this paper, we investigated whether pain was associated with increased mortality risk, particularly in midlife. Data came from the Midlife in the US study, which sampled non-institutionalized, English-speaking adults aged 25–74 in the contiguous United States in 1995-96. Our analysis included 4041 respondents who completed a follow-up self-administered questionnaire in 2004-05, 2703 of whom completed another self-administered questionnaire in 2013-14. We modeled mortality through December 31, 2021. In demographic-adjusted models, pain interference was more strongly associated with mortality than other pain measures, and the association was stronger at younger ages. The hazard ratio for pain interference declined from 1.39 per SD (95% CI 1.26–1.54) at age 60 to 1.14 (95% CI 1.04–1.24) at age 90. Although potential confounders accounted for more than 60% of the association with premature mortality, pain interference remained significantly associated with increased mortality rates (HR = 1.13 at age 60, 95% CI 1.02–1.26). We found no evidence that the association between pain and mortality was driven by cancer. If anything, pain interference was more strongly associated with cardiovascular than cancer mortality. At the oldest ages, physical function is likely to be a better predictor of mortality than pain. Yet, pain interference may be a useful warning sign at younger ages, when there are fewer physical limitations and mortality rates are low. It may be particularly helpful in identifying risk of premature mortality in midlife, before the emergence of severe physical limitations.

Inflammatory proteins are associated with mortality in a middle-aged diverse cohort.

Recent data indicate a decline in overall longevity in the United States. Even prior to the COVID-19 pandemic, an increase in midlife mortality rates had been reported. Life expectancy disparities have persisted in the United States for racial and ethnic groups and for individuals living at low socioeconomic status. These continued trends in mortality indicate the importance of examining biomarkers of mortality at midlife in at-risk populations. Circulating levels of cytokines and inflammatory markers reflect systemic chronic inflammation, which is a well-known driver of many age-related diseases. In this study, we examined the relationship of nine different inflammatory proteins with mortality in a middle-aged socioeconomically diverse cohort of African-American and White men and women (n=1122; mean age=47.8 years). We found significant differences in inflammatory-related protein serum levels between African-American and White middle-aged adults. E-selectin and fibrinogen were significantly higher in African-American adults. IFN-γ, TNF-α trimer, monocyte chemoattractant protein-1 (MCP-1), soluble receptor for advanced glycation end-products (sRAGE) and P-selectin were significantly higher in White participants compared to African-American participants. Higher levels of E-selectin, MCP-1 and P-selectin were associated with a higher mortality risk. Furthermore, there was a significant interaction between sex and IL-6 with mortality. IL-6 levels were associated with an increased risk of mortality, an association that was significantly greater in women than men. In addition, White participants with high levels of sRAGE had significantly higher survival probability than White participants with low levels of sRAGE, while African-American participants had similar survival probabilities across sRAGE levels. These results suggest that circulating inflammatory markers can be utilized as indicators of midlife mortality risk in a socioeconomically diverse cohort of African-American and White individuals.

Comparing trends in mid-life ‘deaths of despair’ in the USA, Canada and UK, 2001–2019: is the USA an anomaly?

ObjectivesIn recent years, ‘deaths of despair’ due to drugs, alcohol and suicide have contributed to rising mid-life mortality in the USA. We examine whether despair-related deaths and mid-life mortality trends...

Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults

Frailty is an age-related syndrome characterized by reduced recovery from stressors and increased risks of morbidity and mortality. Although frailty is usually studied in those over 65 years, our previous work showed that frailty is both present and a risk factor for premature mortality in midlife. We identified altered gene expression patterns and biological pathways associated with inflammation in frailty. Evidence suggests DNA oxidation damage related to inflammation accumulates with age, and that DNA repair capacity (DRC) declines with age and age-related conditions. We hypothesized that inter-individual differences in DNA oxidation damage and DRC are associated with frailty status and poverty level. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H2O2)-induced DNA oxidation damage and DRC in non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty. Analysis of baseline single-strand breaks showed no associations with frailty, poverty, race, or sex. However, we identified an interaction between frailty and poverty in H2O2-induced DNA oxidation damage. We also identified interactions between sex and frailty as well as sex and poverty status with DRC. The social determinant of health, poverty, associates with DRC in men. Baseline DNA damage, H2O2-induced DNA damage as well as DRC were associated with serum cytokine levels. IL-10 levels were inversely associated with baseline DNA damage as well as H2O2-induced DNA damage, DRC was altered by IL-4 levels and sex, and by TNF-α levels in the context of sex and poverty status. This is the first evidence that DRC may be influenced by poverty status at midlife. Our data show that social determinants of health should be considered in examining biological pathways through which disparate age-related health outcomes become manifest.

Physical activity during early life and the risk of all-cause mortality in midlife: findings from a birth cohort study.

The objective of this study was to examine the association between physical activity during childhood and adolescence and the risk of all-cause mortality in midlife. We analyzed data from a birth cohort (The 1958 National Child Development Survey), including births in England, Wales and Scotland. Physical activity was assessed using questionnaires at ages 7, 11 and 16. Death certificates defined all-cause mortality. Cumulative exposure, sensitive and critical periods, and physical activity trajectory from childhood to adolescence were tested using multivariate Cox proportional hazard models. The sweep the death was confirmed was defined as the time event. From age 23 to 55, 8.9% of participants (n = 9398) died. Physical activity in childhood and adolescence affected the risk of all-cause mortality in midlife. In men, physical activity at ages 11 [hazard ratio (HR): 0.77; 95% confidence interval (CI): 0.60-0.98] and 16 (HR: 0.60; 95% CI: 0.46-0.78) was associated with reduced risk of all-cause mortality. In women, physical activity at age 16 (HR: 0.68; 95% CI: 0.48-0.95) was associated with reduced risk of all-cause mortality. Physical activity in adolescence eliminated the risk of all-cause mortality associated with physical inactivity in adulthood in women. Physical activity during childhood and adolescence was associated with reduced risk of all-cause mortality with different effects by sex.

Prepubertal castration eliminates sex differences in lifespan and growth trajectories in genetically heterogeneous mice.

Sex differences in aging and longevity have been widely observed, with females consistently outliving males across human populations. However, the mechanisms driving these disparities remain poorly understood. In this study, we explored the influence of post-pubertal testicular effects on sex differences in aging by prepubertally castrating genetically heterogeneous (UM-HET3) mice, a unique mouse model that emulates human sex differences in age-related mortality. Prepubertal castration eliminated the longevity disparity between sexes by reducing the elevated early- to mid-life mortality rate observed in males and extending their median lifespan to match that of females. Additionally, castration extended the duration of body weight growth and attenuated the inverse correlation between early-age body weight and lifespan in males, aligning their growth trajectories with those of females. Our findings suggest that post-pubertal testicular actions in genetically diverse mice are primarily responsible for sex differences in longevity as well as growth trajectories. These findings offer a foundation for further investigation into the fundamental mechanisms driving sex-specific aging patterns and the development of potential pro-longevity interventions.

Ketone bodies: A double-edged sword for mammalian life span.

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of β-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.

Considerations on research in the field of lifestyle medicine

Healthcare systems from numerous countries are predominantly built on a disease-treatment model rather than a proactive health-prevention model. As the life expectancy has increased over time, the quality of one’s longevity is compromised by numerous chronic diseases which can be prevented. Unforeseeably, midlife mortality (among people aged 24 to 44) has increased in the last two decades as a 60-years review of mortality in the United States reveals. The most critical causes of these changes are linked to unhealthy behaviors such as unhealthy food consumption, sedentarism, smoking, alcohol use, drug addiction, workaholism, inadequate stress management or sleeplessness, all representing starting points or risk factors for diabetes, obesity, atherosclerosis, cardiovascular, neuropsychological and autoimmune diseases. Lifestyle Medicine is based on six pillars: whole-food, plant predominant diet, regular physical activity, quality sleep, stress management, avoidance of risky substances and social connection, all playing a major role in treating health problems. Furthermore, being given the lack of studies focused on lifestyle medicine, leading national experts were summoned to analyze the existing data and gaps regarding behaviors, chronic diseases including cardiovascular diseases, diabetes, cancer, inflammatory and autoimmune imbalances or other pathologies.

Offending and the Long-Term Risk of Death: An Examination of Mid-Life Mortality Among an Urban Black American Cohort.

Research on the long-term relationship between offending and mortality is limited, especially among minorities who have higher risk of premature mortality and criminal offending, particularly arrest. Using Cox proportional hazard models, we estimate the relationship between young adult offending and later mortality (to age 58) among a community cohort of Black Americans (n = 1,182). After controlling for a wide range of covariates, results indicate that violent offenders are at heightened risk of mortality from young adulthood through midlife compared with both non-violent only offenders and non-offenders. Further analysis shows that this result is driven by the frequent, largely non-violent, arrests incurred among violent offenders. Criminal justice reform and collaboration with public health practitioners might be fruitful avenues to reduce mortality disparities.