Early-life disease exposure and associations with adult survival, cause of death, and reproductive success in preindustrial humans

A leading hypothesis proposes that increased human life span since 1850 has resulted from decreased exposure to childhood infections, which has reduced chronic inflammation and later-life mortality rates, particularly from cardiovascular disease, stroke, and cancer. Early-life cohort mortality rate often predicts later-life survival in humans, but such associations could arise from factors other than disease exposure. Additionally, the impact of early-life disease exposure on reproduction remains unknown, and thus previous work ignores a major component of fitness through which selection acts upon life-history strategy. We collected data from seven 18th- and 19th-century Finnish populations experiencing naturally varying mortality and fertility levels. We quantified early-life disease exposure as the detrended child mortality rate from infectious diseases during an individual’s first 5 y, controlling for important social factors. We found no support for an association between early-life disease exposure and all-cause mortality risk after age 15 or 50. We also found no link between early-life disease exposure and probability of death specifically from cardiovascular disease, stroke, or cancer. Independent of survival, there was no evidence to support associations between early-life disease exposure and any of several aspects of reproductive performance, including lifetime reproductive success and age at first birth, in either males or females. Our results do not support the prevailing assertion that exposure to infectious diseases in early life has long-lasting associations with later-life all-cause mortality risk or mortality putatively linked to chronic inflammation. Variation in adulthood conditions could therefore be the most likely source of recent increases in adult life span.

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Early-life reproduction is associated with increased mortality risk but enhanced lifetime fitness in pre-industrial humans

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2014.3053 ◽

2015 ◽

Vol 282 (1804) ◽

pp. 20143053 ◽

Cited By ~ 19

Author(s):

Adam D. Hayward ◽

Ilona Nenko ◽

Virpi Lummaa

Keyword(s):

Reproductive Success ◽

Evolutionary Theory ◽

Mortality Risk ◽

Early Life ◽

Later Life ◽

Lifetime Reproductive Success ◽

Reproductive Senescence ◽

Trade Offs ◽

Investment In Reproduction ◽

Using Data

The physiology of reproductive senescence in women is well understood, but the drivers of variation in senescence rates are less so. Evolutionary theory predicts that early-life investment in reproduction should be favoured by selection at the cost of reduced survival and faster reproductive senescence. We tested this hypothesis using data collected from preindustrial Finnish church records. Reproductive success increased up to age 25 and was relatively stable until a decline from age 41. Women with higher early-life fecundity (ELF; producing more children before age 25) subsequently had higher mortality risk, but high ELF was not associated with accelerated senescence in annual breeding success. However, women with higher ELF experienced faster senescence in offspring survival. Despite these apparent costs, ELF was under positive selection: individuals with higher ELF had higher lifetime reproductive success. These results are consistent with previous observations in both humans and wild vertebrates that more births and earlier onset of reproduction are associated with reduced survival, and with evolutionary theory predicting trade-offs between early reproduction and later-life survival. The results are particularly significant given recent increases in maternal ages in many societies and the potential consequences for offspring health and fitness.

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All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study

European Heart Journal ◽

10.1093/eurheartj/ehab028 ◽

2021 ◽

Cited By ~ 1

Author(s):

Jawad H Butt ◽

Emil L Fosbøl ◽

Thomas A Gerds ◽

Charlotte Andersson ◽

Kristian Kragholm ◽

...

Keyword(s):

Cardiovascular Disease ◽

Mortality Rate ◽

Hospital Mortality ◽

Location Of Death ◽

All Cause Mortality ◽

History Of ◽

Adjusted Incidence Rate ◽

Artery Disease ◽

Adjusted Incidence ◽

Overall Mortality

Abstract Background On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures. Methods and results Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87–0.95; IRR 0.95, 95% CI 0.89–1.02; and IRR 0.87, 95% CI 0.83–0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97–1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88–0.96; out-of-hospital, IRR 1.04, 95% CI1.01–1.08). These trends were consistent irrespective of sex and age. Conclusions Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

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Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease

Gerontology ◽

10.1159/000515390 ◽

2021 ◽

pp. 1-9

Author(s):

Timothy A. Donlon ◽

Randi Chen ◽

Kamal H. Masaki ◽

Bradley J. Willcox ◽

Brian J. Morris

Keyword(s):

Cardiovascular Disease ◽

Life Span ◽

Mortality Risk ◽

Regulatory Subunit ◽

Phosphatidylinositol 3 Kinase ◽

Survival Curves ◽

Genotypic Effect ◽

Hazard Ratios ◽

Phosphatidylinositol 3

Introduction: Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (PIK3R1) is associated with longevity. Objective: The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. Methods: We performed a longitudinal study of longevity-associated PIK3R1 single-nucleotide polymorphism rs7709243 genotype by CVD status in 3,584 elderly American men of Japanese ancestry. Results: At baseline (1991–1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (p = 1.7 × 10−5). However, survival curves of CVD subjects differed according to PIK3R1 genotype. Those with longevity-associated PIK3R1 TT/CC had survival curves similar to those of subjects without a CVD (p = 0.11 for TT/CC, and p = 0.054 for TC), whereas survival curves for CVD subjects with the CT genotype were significantly attenuated compared with survival curves of subjects without a CVD (p = 0.0000012 compared with TT/CC, and p = 0.0000028 compared with TC). Men without CVD showed no association of longevity-associated genotype with life span (p = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14–1.39; p = 0.0000043) for CT subject with CVD and 1.07 (95% CI 0.99–1.17; p = 0.097) for CC/TT subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. Conclusion: Our study provides novel insights into the basis for PIK3R1 as a longevity gene. We suggest that the PIK3R1 longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

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Changes in waist circumference and risk of all-cause and CVD mortality: results from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study

BMC Cardiovascular Disorders ◽

10.1186/s12872-019-1223-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 6

Author(s):

Angela A. Mulligan ◽

Marleen A. H. Lentjes ◽

Robert N. Luben ◽

Nicholas J. Wareham ◽

Kay-Tee Khaw

Keyword(s):

Weight Loss ◽

Waist Circumference ◽

Mortality Risk ◽

Total Mortality ◽

Later Life ◽

Central Adiposity ◽

Men And Women ◽

All Cause Mortality ◽

Cvd Mortality ◽

Prospective Investigation

Abstract Background Measures of abdominal adiposity are strongly associated with all-cause mortality and cardiovascular disease (CVD). However, data are limited and conflicting regarding the consequences of changes in body fat distribution. The main aims of this paper are to investigate the association between changes in waist circumference (WC) and all-cause and CVD mortality and to examine these changes in relation to concurrent changes in weight. Methods The European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study recruited 25,639 participants between 1993 and 1997, aged 39–79, a number of whom also attended a second examination (1998–2000), and were followed up to 2016 for mortality. Participants were eligible for inclusion if they had WC, weight and height measurements at both time-points; those with a self-reported history of CVD or cancer, body mass index < 18.5 kg/m2 or missing data on covariates were excluded, leaving 12,337 participants for analyses. The median (IQR) follow-up time was 16.4 (15.7, 17.2) years. Hazard Ratios (HRs) for all-cause (2866 deaths) and CVD mortality (822 deaths), by categories of WC change, were determined using Cox proportional hazards analyses. Results After multivariable adjustment, the HRs (95% CIs) for all-cause mortality for men and women with a WC gain (WCG) > 5 cm were 1.51 (1.29–1.75) and 1.25 (1.06–1.46) respectively. For CVD mortality in men and women with a WCG > 5 cm, the HRs were 1.84 (1.39–2.43) and 1.15 (0.85–1.55) respectively. In analyses of concurrent changes in WC and weight, the greatest risk (HRs) (95% CIs) in men occurred with weight loss and WCG: 1.80 (1.13–2.86) for all-cause and 2.22 (1.03–4.82) for CVD mortality. In women, the greatest risk for both all-cause (HR 1.50 (1.16–1.95)) and CVD mortality (HR 1.81 (1.15–2.85)) was observed in those with weight loss and maintenance of WC (WCM). Conclusions Objectively measured WCG > 5 cm, was associated with subsequent higher total mortality risk and higher CVD mortality risk in men. Interventions focusing on preventing increase in central adiposity rather than lowering weight per se in later life may potentially have greater health benefits.

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The influence of weather conditions during gestation on life histories in a wild Arctic ungulate

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.1760 ◽

2016 ◽

Vol 283 (1841) ◽

pp. 20161760 ◽

Cited By ~ 18

Author(s):

Mathieu Douhard ◽

Leif Egil Loe ◽

Audun Stien ◽

Christophe Bonenfant ◽

R. Justin Irvine ◽

...

Keyword(s):

Life History ◽

Reproductive Success ◽

Environmental Conditions ◽

Early Life ◽

Life Histories ◽

Weather Conditions ◽

Later Life ◽

Svalbard Reindeer ◽

Long Term Study ◽

Age Related

The internal predictive adaptive response (internal PAR) hypothesis predicts that individuals born in poor conditions should start to reproduce earlier if they are likely to have reduced performance in later life. However, whether this is the case remains unexplored in wild populations. Here, we use longitudinal data from a long-term study of Svalbard reindeer to examine age-related changes in adult female life-history responses to environmental conditions experienced in utero as indexed by rain-on-snow (ROS utero ). We show that females experiencing high ROS utero had reduced reproductive success only from 7 years of age, independent of early reproduction. These individuals were able to maintain the same annual reproductive success between 2 and 6 years as phenotypically superior conspecifics that experienced low ROS utero . Young females born after high ROS utero engage in reproductive events at lower body mass (about 2.5 kg less) than those born after low ROS utero . The mean fitness of females that experienced poor environmental conditions in early life was comparable with that of females exposed to good environmental conditions in early life. These results are consistent with the idea of internal PAR and suggest that the life-history responses to early-life conditions can buffer the delayed effects of weather on population dynamics.

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Increased mortality risk in patients with primary and secondary adrenal insufficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab096 ◽

2021 ◽

Author(s):

Kanchana Ngaosuwan ◽

Desmond G Johnston ◽

Ian F Godsland ◽

Jeremy Cox ◽

Azeem Majeed ◽

...

Keyword(s):

Cardiovascular Disease ◽

Adrenal Insufficiency ◽

Mortality Risk ◽

Reference Population ◽

Mortality Data ◽

Adrenal Crisis ◽

Malignant Neoplasms ◽

Geographical Differences ◽

All Cause Mortality

Abstract Context Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations. Objective To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Design Retrospective cohort study. Setting UK general practitioner database (CPRD). Participants 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcome measures All-cause and cause-specific mortality; hospital admission from adrenal crisis. Results With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 - 1.77]. HRs were greater in primary (1.83 [1.66 - 2.02]) than in secondary (1.52 [1.40 - 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 - 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 - 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years. Conclusion Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality.

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Pre-Eclamptic Pregnancies: An Opportunity to Identify Women at Risk for Future Cardiovascular Disease

Women s Health ◽

10.2217/17455057.4.2.133 ◽

2008 ◽

Vol 4 (2) ◽

pp. 133-135 ◽

Cited By ~ 25

Author(s):

Iasmina M Craici ◽

Steven J Wagner ◽

Suzanne R Hayman ◽

Vesna D Garovic

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

Risk Factor ◽

Meta Analysis ◽

Later Life ◽

Future Studies ◽

Increased Risk ◽

All Cause Mortality ◽

History Of

Evaluation of: Bellamy L, Casas JP, Hingorani AD, Williams DJ: Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. Br. Med. J. 335(7627), 974 (2007). Evidence has emerged over the years suggesting that women who develop hypertensive pregnancy disorders, most notably pre-eclampsia, are at an increased risk for cardiovascular disease later in life. In this study, a systematic review and meta-analysis were performed, assessing the future risks of cardiovascular disease, cancer and all-cause mortality in women with a history of pre-eclampsia and eclampsia. Women with a history of pre-eclampsia or eclampsia, compared with women without such a history, had an increased risk for cardiovascular disease, including a fourfold increased risk for hypertension, a twofold increased risk for ischemic heart disease, stroke and deep venous thrombosis, and a 1.5-times higher all-cause mortality. The study suggests that affected women may be eligible for preventive therapies at an earlier age, especially if future studies establish the role of pre-eclampsia as an independent cardiovascular risk factor.

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Vitamin K status, cardiovascular disease, and all-cause mortality: a participant-level meta-analysis of 3 US cohorts

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa082 ◽

2020 ◽

Vol 111 (6) ◽

pp. 1170-1177 ◽

Cited By ~ 1

Author(s):

M Kyla Shea ◽

Kathryn Barger ◽

Sarah L Booth ◽

Gregory Matuszek ◽

Mary Cushman ◽

...

Keyword(s):

Cardiovascular Disease ◽

Vitamin K ◽

Mortality Risk ◽

Vascular Tissue ◽

Meta Analysis ◽

Body Composition Study ◽

Increased Risk ◽

All Cause Mortality ◽

Cox Proportional Hazard Regression ◽

The Impact

Abstract Background Vitamin K-dependent proteins in vascular tissue affect vascular stiffness and calcification, which is associated with cardiovascular disease (CVD) and all-cause mortality. Objective To determine the association of circulating vitamin K concentrations with CVD and all-cause mortality by conducting a participant-level meta-analysis. Methods We obtained individual participant-level data from the Health, Aging, and Body Composition Study, the Multi-Ethnic Study of Atherosclerosis, and the Framingham Offspring Study, known cohorts with available measures of fasting circulating phylloquinone (vitamin K-1) and confirmed CVD events and mortality. Circulating phylloquinone was measured in a central laboratory from fasting blood samples and categorized as ≤0.5 nmol/L, >0.5–1.0 nmol/L, and >1.0 nmol/L. Multivariable Cox proportional hazard regression with multiple imputations was used to evaluate the association of circulating phylloquinone with incident CVD and all-cause mortality risk. Results Among 3891 participants (mean age 65 ± 11 y; 55% women; 35% nonwhite), there were 858 incident CVD events and 1209 deaths over a median of 13.0 y. The risk of CVD did not significantly differ according to circulating phylloquinone [fully adjusted HR (95% CI) relative to >1.0 nmol/L: ≤0.5 nmol/L, 1.12 (0.94, 1.33); >0.5–1.0 nmol/L, 1.02 (0.86, 1.20)]. Participants with ≤0.5 nmol/L circulating phylloquinone had an adjusted 19% higher risk of all-cause mortality compared with those with >1.0 nmol/L [fully adjusted HR (95% CI): 1.19 (1.03, 1.38)]. Mortality risk was similar in participants with >0.5–1.0 nmol/L compared with >1.0 nmol/L [fully adjusted HR (95% CI): 1.04 (0.92, 1.17)]. Conclusions Low circulating phylloquinone concentrations were associated with an increased risk of all-cause mortality, but not of CVD. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of increased phylloquinone intake on cardiovascular and other health outcomes in individuals with low vitamin K status.

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Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study

Acta Endocrinologica ◽

10.1530/eje-09-0284 ◽

2009 ◽

Vol 161 (3) ◽

pp. 435-442 ◽

Cited By ~ 105

Author(s):

Torkel Vikan ◽

Henrik Schirmer ◽

Inger Njølstad ◽

Johan Svartberg

Keyword(s):

Cardiovascular Disease ◽

Mortality Risk ◽

Free Testosterone ◽

Community Dwelling ◽

End Points ◽

Testosterone Levels ◽

Increased Risk ◽

All Cause Mortality ◽

Prospective Association ◽

The Impact

ObjectiveTo study the impact of endogenous testosterone levels in community-dwelling men on later risk for myocardial infarction (MI) and all-cause, cardiovascular disease (CVD), and ischemic heart disease (IHD) mortality.DesignPopulation-based prospective cohort study.MethodsFor the analyses, we used a cohort of 1568 randomly selected men, with sex-hormone data participating in the fourth Tromsø Study (1994–1995). Defined end points were first-ever MI (fatal or nonfatal), all-cause, CVD, and IHD mortality. A committee performed thorough ascertainment of end points, following a detailed protocol. Complete ascertainment of end points was until 30 September 2007 for all-cause mortality, until 31 December 2005 for CVD/IHD mortality, and until 31 December 2004 for first-ever MI. The prospective association between total and free testosterone and end points were examined using Cox proportional hazard regression, allowing for multivariate adjustment for age and cardiovascular risk factors.ResultsDuring follow-up, there were 395 deaths from all causes, 130 deaths from CVD and 80 deaths from IHD, while 144 men experienced a first-ever MI. There was a significant increase in all-cause mortality risk for men with free testosterone in the lowest quartile (<158 pmol/l) compared with the higher quartiles after age adjustment hazard ratios (HR 1.24, 95% confidence interval, CI 1.01–1.53) and after multivariate adjustments (HR 1.24, 95% CI 1.01–1.54). Total testosterone was not associated with mortality risk. Likewise, there were no significant changes in risk for first-ever MI across different total or free testosterone levels.ConclusionMen with free testosterone levels in the lowest quartile had a 24% increased risk of all-cause mortality.

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Early-life immune expression profiles predict later life health and fitness in a wild rodent

10.1101/2021.10.08.463659 ◽

2021 ◽

Author(s):

Klara M Wanelik ◽

Mike Begon ◽

Janette E Bradley ◽

Ida M Friberg ◽

Christopher H Taylor ◽

...

Keyword(s):

Reproductive Success ◽

Early Life ◽

Expression Profiles ◽

Natural Populations ◽

Later Life ◽

Immune Development ◽

Immune Genes ◽

Susceptibility To Infection ◽

Health And Fitness ◽

Longitudinal Sampling

Individuals differ in the nature of the immune responses they produce, affecting disease susceptibility and ultimately health and fitness. These differences have been hypothesised to have an origin in events experienced early in life that then affect trajectories of immune development and responsiveness. Here we investigate early life influences on immune expression profiles using a natural population of field voles, Microtus agrestis, in which we are able to monitor variation between and within individuals though time by repeat (longitudinal) sampling of individually marked animals. We analysed the co-expression of 20 immune genes in early life to create a correlational network consisting of three main clusters, one of which (containing Gata3, Il10 and Il17) was associated with later life reproductive success and susceptibility to chronic bacterial (Bartonella) infection. More detailed analyses supported associations between early life expression of Il17 and reproductive success later in life, and of increased Il10 expression early in life and later infection with Bartonella. We also found significant association between an Il17 genotype and the early life expression of Il10. Our results demonstrate that immune expression profiles can be manifested during early life with effects that persist through adulthood and that shape the variability among individuals in susceptibility to infection and fitness widely seen in natural populations.

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