Pregnancy is linked to faster epigenetic aging in young women.

A central prediction of evolutionary theory is that energy invested into reproduction comes at the expense of somatic maintenance and repair, accelerating biological aging. Supporting this prediction are findings that high fertility among women predicts shorter lifespan and poorer health later in life. However, biological aging is thought to begin before age-related health declines, limiting the applicability of morbidity and mortality for studying the aging process earlier in life. Here, we examine the relationship between reproductive history and biological aging in a sample of young (20 to 22yo) men and women from the Cebu Longitudinal Health and Nutrition Survey, located in the Philippines (n = 1,735). We quantify biological aging using six measures, collectively known as epigenetic clocks, reflecting various facets of cellular aging, health, and mortality risk. In a subset of women, we test whether longitudinal changes in gravidity between young and early-middle adulthood (25 to 31yo) are associated with changes in epigenetic aging during that time. Cross-sectionally, gravidity was associated with all six measures of accelerated epigenetic aging in women (n = 825). Furthermore, longitudinal increases in gravidity were linked to accelerated epigenetic aging in two epigenetic clocks (n = 331). In contrast, the number of pregnancies a man reported fathering was not associated with epigenetic aging among same-aged cohort men (n = 910). These effects were robust to socioecological, environmental, and immunological factors, consistent with the hypothesis that pregnancy accelerates biological aging and that these effects can be detected in young women in a high-fertility context.

DNA methylation-based estimators of telomere length show low correspondence with paternal age at conception and other measures of external validity of telomere length.

In humans, DNA methylation (DNAm) based estimators of telomere length (TL) have been shown to better predict TL-associated variables (e.g., age, sex, and mortality) than TL itself. The biological significance of DNAm-based estimators of TL (DNAmTL) is unclear. In vitro DNAmTL shortens with cell replications, even when telomerase is maintaining TL. Telomerase is typically suppressed in humans, except in testes. Accordingly, sperm TL increases with age, and offspring with greater paternal age at conception (PAC) have longer TL. Thus, we expect that PAC associations with DNAmTL can shed light on whether in vivo cell replications in the presence of high telomerase activity (production of sperm) shorten DNAmTL or if PAC-lengthened TL causes lengthened DNAmTL. In a pre-registered analysis, using data from 1733 blood samples from the Philippines, we examined the association between paternal age at conception (PAC) and offspring DNAmTL. We did not find an association between PAC and DNAmTL but found a positive association of paternal grandfather's age at father's conception predicting grandchild's DNAmTL. In post hoc analyses, we examined how DNAmTL versus qPCR-measured TL (qPCR-TL) correlated with measures typically associated with TL. Contrary to previous findings, on almost all measures of external validity (correlations with parental TLs, southern blot TL, and age), qPCR-TL outperformed DNAmTL. The "kilobase" units of DNAm-based estimators of TL showed considerable deviations from southern blot-derived kilobase measures. Our findings suggest that DNAmTL is not a reliable index of inherited aspects of TL and underscores uncertainty about the biological meaning of DNAmTL.

Intimate partner violence, depression, and chronic low-grade inflammation among middle-aged women in Cebu, Philippines.

OBJECTIVES: Recent discussions in human biology have highlighted how local ecological contexts shape the relationship between social stressors and health across populations. Chronic low-grade inflammation has been proposed as a pathway linking social stressors to health, with evidence concentrated in high-income Western contexts. However, it remains unclear whether this is an important pathway in populations where prevalence is lower due to lower adiposity and greater infectious exposures. To investigate this further, we tested associations between multiple types of intimate partner violence (IPV), a highly prevalent stressor and health crisis globally, and C-reactive protein (CRP), a commonly used measure of chronic low-grade inflammation, in Cebu, Philippines. For reference, we compared results for CRP to depression, a well-established and consistently observed health outcome of IPV. METHODS: Data came from 1601 currently partnered women (ages 35-69 years) as part of the Cebu Longitudinal Health and Nutrition Survey. IPV exposures included physical, emotional, and controlling behavior. Depression scores were measured using a modified version of the Center for Epidemiologic Studies-Depression Scale for this population, whereas plasma CRP was measured from overnight-fasted morning blood samples. RESULTS: All three types of IPV were associated with a higher depression score. However, none of the IPV measures were associated with CRP. In a post hoc interaction test, emotional IPV became positively associated with CRP as waist circumference increased above the mean. CONCLUSIONS: Our results suggest a complex relationship between social stressors and chronic low-grade inflammation, which is likely dependent on the population-specific context of lifestyle and environmental factors.

Socioeconomic status is negatively associated with immunosenescence but positively associated with inflammation among middle-aged women in Cebu, Philippines.

BACKGROUND: Socioeconomic status (SES) gradients in health are well-documented, and while biological pathways are incompletely understood, chronic inflammation and accelerated immune aging (immunosenescence) among lower SES individuals have been implicated. However, previous findings have come from samples in higher income countries, and it is unclear how generalizable they are to lower- and middle-income countries (LMIC) with different infectious exposures and where adiposity-an important contributor to chronic inflammation-might show different SES patterning. To address this gap, we explored associations between SES and inflammation and immunosenescence in a sample of women in Cebu, Philippines. METHODS: Data came from the mothers of the Cebu Longitudinal Health and Nutrition Survey birth cohort (mean age: 47.7, range: 35-69 years). SES was measured as a combination of annual household income, education level, and assets. Chronic inflammation was measured using C-reactive protein (CRP) in plasma samples from 1,834 women. Immunosenescence was measured by the abundance of exhausted CD8T (CD8 + CD28-CD45RA-) and naïve CD8T and CD4T cells, estimated from DNA methylation in whole blood in a random subsample of 1,028. Possible mediators included waist circumference and a collection of proxy measures of pathogen exposure. RESULTS: SES was negatively associated with the measures of immunosenescence, with slight evidence for mediation by a proxy measure for pathogen exposure from the household's drinking water source. In contrast, SES was positively associated with CRP, which was explained by the positive association with waist circumference. CONCLUSIONS: Similar to higher income populations, in Cebu there is an SES-gradient in pathogen exposures and immunosenescence. However, lifestyle changes occurring more rapidly among higher SES individuals is contributing to a positive association between SES and adiposity and inflammation. Our results suggest more studies are needed to clarify the relationship between SES and inflammation and immunosenescence across LMIC.

Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines.

OBJECTIVES: The drivers of human life expectancy gains over the past 200 years are not well-established, with a potential role for historical reductions in infectious disease. We investigate whether infectious exposures in infancy predict biological aging using DNA methylation-based markers that forecast patterns of morbidity and mortality later in life. METHODS: N = 1450 participants from the Cebu Longitudinal Health and Nutrition Survey-a prospective birth cohort initiated in 1983-provided complete data for the analyses. Mean chronological age was 20.9 years when venous whole blood samples were drawn for DNA extraction and methylation analysis, with subsequent calculation of three epigenetic age markers: Horvath, GrimAge, and DunedinPACE. Unadjusted and adjusted least squares regression models were evaluated to test the hypothesis that infectious exposures in infancy are associated with epigenetic age. RESULTS: Birth in the dry season, a proxy measure for increased infectious exposure in the first year of life, as well as the number of symptomatic infections in the first year of infancy, predicted lower epigenetic age. Infectious exposures were associated with the distribution of white blood cells in adulthood, which were also associated with measures of epigenetic age. CONCLUSIONS: We document negative associations between measures of infectious exposure in infancy and DNA methylation-based measures of aging. Additional research, across a wider range of epidemiological settings, is needed to clarify the role of infectious disease in shaping immunophenotypes and trajectories of biological aging and human life expectancy.

Growth patterns in childhood and adolescence and adult body composition: a pooled analysis of birth cohort studies from five low and middle-income countries (COHORTS collaboration).

OBJECTIVE: We examined associations among serial measures of linear growth and relative weight with adult body composition. DESIGN: Secondary data analysis of prospective birth cohort studies. SETTINGS: Six birth cohorts from Brazil, Guatemala, India, the Philippines and South Africa. PARTICIPANTS: 4173 individuals followed from birth to ages 22-46 years with complete and valid weight and height at birth, infancy, childhood and adolescence, and body composition in adult life. EXPOSURES: Birth weight and conditional size (standardised residuals of height representing linear growth and of relative weight representing weight increments independent of linear size) in infancy, childhood and adolescence. PRIMARY OUTCOME MEASURES: Body mass index, fat mass index (FMI), fat-free mass index (FFMI), fat mass/fat-free mass ratio (FM/FFM), and waist circumference in young and mid-adulthood. RESULTS: In pooled analyses, a higher birth weight and relative weight gains in infancy, childhood and adolescence were positively associated with all adult outcomes. Relative weight gains in childhood and adolescence were the strongest predictors of adult body composition (ß (95% CI) among men: FMI (childhood: 0.41 (0.26 to 0.55); adolescence: 0.39 (0.27 to 0.50)), FFMI (childhood: 0.50 (0.34 to 0.66); adolescence: 0.43 (0.32 to 0.55)), FM/FFM (childhood: 0.31 (0.16 to 0.47); adolescence: 0.31 (0.19 to 0.43))). Among women, similar patterns were observed, but, effect sizes in adolescence were slightly stronger than in childhood. Conditional height in infancy was positively associated with FMI (men: 0.08 (0.03 to 0.14); women: 0.11 (0.07 to 0.16)). Conditional height in childhood was positively but weakly associated with women's adiposity. Site-specific and sex-stratified analyses showed consistency in the direction of estimates, although there were differences in their magnitude. CONCLUSIONS: Prenatal and postnatal relative weight gains were positive predictors of larger body size and increased adiposity in adulthood. A faster linear growth in infancy was a significant but weak predictor of higher adult adiposity.

Maternal epigenetic clocks measured during pregnancy do not predict gestational age at delivery or offspring birth outcomes: a replication study in metropolitan Cebu, Philippines.

Adverse birth outcomes, such as early gestational age and low birth weight, can have lasting effects on morbidity and mortality, with impacts that persist into adulthood. Identifying the maternal factors that contribute to adverse birth outcomes in the next generation is thus a priority. Epigenetic clocks, which have emerged as powerful tools for quantifying biological aging and various dimensions of physiological dysregulation, hold promise for clarifying relationships between maternal biology and infant health, including the maternal factors or states that predict birth outcomes. Nevertheless, studies exploring the relationship between maternal epigenetic age and birth outcomes remain few. Here, we attempt to replicate a series of analyses previously reported in a US-based sample, using a larger similarly aged sample (n = 296) of participants of a long-running study in the Philippines. New pregnancies were identified prospectively, dried blood spot samples were collected during the third trimester, and information was obtained on gestational age at delivery and offspring weight after birth. Genome-wide DNA methylation was assessed with the Infinium EPIC array. Using a suite of 15 epigenetic clocks, we only found one significant relationship: advanced age on the epigenetic clock trained on leptin predicted a significantly earlier gestational age at delivery (ß = - 0.15, p = 0.009). Of the other 29 relationships tested predicting gestational age and offspring birth weight, none were statistically significant. In this sample of Filipino women, epigenetic clocks capturing multiple dimensions of biology and health do not predict birth outcomes in offspring.

Birth weight and maternal energy status during pregnancy as predictors of epigenetic age acceleration in young adults from metropolitan Cebu, Philippines.

Epigenetic clocks quantify regular changes in DNA methylation that occur with age, or in relation to biomarkers of ageing, and are strong predictors of morbidity and mortality. Here, we assess whether measures of fetal nutrition and growth that predict adult chronic disease also predict accelerated biological ageing in young adulthood using a suite of commonly used epigenetic clocks. Data come from the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a long-running cohort followed since birth in metropolitan Cebu, Philippines. Past work has shown that birth weight (BW) and the mother's arm fat during pregnancy (a measure of pregnancy energy status) relate inversely to health outcomes in the CLHNS but primarily in males. Genome-wide DNA methylation was assessed in whole blood using the Infinium EPIC array. Participants included males (n=895) and females (n=803) measured in 2005 (20.8-22.5 years). Clocks included the Hannum and Horvath clocks trained on chronological age, the DNAmPhenoAge and DNAmGrimAge clocks trained on clinical biomarkers, the Dunedin pace of ageing (DunedinPACE) clock trained on longitudinal changes in ageing biomarkers, and the DNAmTL clock trained on leukocyte telomere length. In males, lower BW predicted advanced biological ageing using the Hannum, DNAmPhenoAge, DunedinPoAm, and DNAmTL clocks. In contrast, BW did not predict any clock in female participants. Participants' mothers' pregnancy arm fat only predicted DNAmTL in males. These findings suggest that epigenetic clocks are a useful tool for gauging long-term outcomes predicted by fetal growth, and add to existing evidence in the CLHNS for sex differences in these relationships.

Changes in asset-based wealth across the life course in birth cohorts from five low- and middle-income countries.

BACKGROUND: Temporally-harmonized asset-based measures of wealth can be used to study the association of life-course wealth exposures in the same scale with health outcomes in low- and middle-income countries (LMICs). The within-individual longitudinal stability of asset-based indices of wealth in LMICs is poorly understood. METHODS: Using data from five birth cohorts from three continents, we developed temporally-harmonized asset indices over the life course through polychoric principal component analysis of a common set of assets collected consistently over time (18 years in Brazil to 50 years in Guatemala). For each cohort, we compared the harmonized index to cross-sectional indices created using more comprehensive asset measures using rank correlations. We evaluated the rank correlation of the harmonized index in early life and adulthood with maternal schooling and own attained schooling, respectively. RESULTS: Temporally-harmonized asset indices developed from a consistently-collected set of assets (range: 10 in South Africa to 30 in Philippines) suggested that mean wealth improved over time for all birth cohorts. Cross-sectional indices created separately for each study wave were correlated with the harmonized index for all cohorts (Brazil: r = 0.78 to 0.96; Guatemala: r = 0.81 to 0.95; India: 0.75 to 0.93; Philippines: r = 0.92 to 0.99; South Africa: r = 0.84 to 0.96). Maternal schooling (r = 0.15 to 0.56) and attained schooling (r = 0.23 to 0.53) were positively correlated with the harmonized asset index in childhood and adulthood respectively. CONCLUSIONS: Temporally-harmonized asset indices displayed coherence with cross-sectional indices as well as construct validity with schooling.

Stunting, IQ, and final school attainment in the Cebu Longitudinal Health and Nutrition Survey birth cohort.

School attainment is an important aspect of human capital, and a key determinant of long-term health and well-being. Early life deprivation and poor nutritional status are well known predictors of school entry and progression. We examine the persistence of early life influences and subsequent socioeconomic disadvantage (SED) across the multiple school continuation decisions that lead to final school attainment. Using data from a Philippine birth cohort followed for 35 years, we model 6 continuation decisions: Did not complete elementary school, elementary graduate only (completed grade 6), some secondary schooling, high school graduate, some postsecondary schooling, and college graduate, as well as total years of schooling. We estimate the association of school attainment with early life length for age Z-score (LAZ at 2 years of age) and cognitive development (IQ) as well as underlying indicators of SED and other family influences through early adulthood. The analysis sample includes >1900 participants in the Cebu Longitudinal Health and Nutrition Survey. Females completed, on average, one year more schooling than males, and twice as many females as males were college graduates (29.1 vs 15.0 %). LAZ and one standard deviation of IQ were each independently associated with 0.4 more years of attained schooling. A path model demonstrated strong direct associations of SED with years of schooling as well as indirect associations through LAZ and IQ. Sequential logits used to estimate continuing education decisions show persistent associations of early life LAZ and IQ and schooling even after accounting for changing SED of households over the schooling life course. Filipino parents had high but often unmet educational aspirations for their children because of the child's loss of interest in school and perceived financial barriers. Results further emphasize the importance of early life SED as a key risk factor for suboptimal school attainment.

Evolutionary life history theory as an organising framework for cohort studies: insights from the Cebu Longitudinal Health and Nutrition Survey.

By tracking a group of individuals through time, cohort studies provide fundamental insights into the developmental time course and causes of health and disease. Evolutionary life history theory seeks to explain patterns of growth, development, reproduction and senescence, and inspires a range of hypotheses that are testable using the longitudinal data from cohort studies. Here we review two decades of life history theory-motivated work conducted in collaboration with the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a birth cohort study that enrolled more than 3000 pregnant women in the Philippines in 1983 and has since followed these women, their offspring and grandoffspring. This work has provided evidence that reproduction carries "costs" to cellular maintenance functions, potentially speeding senescence, and revealed an unusual form of genetic plasticity in which the length of telomeres inherited across generations is influenced by reproductive timing in paternal ancestors. Men in Cebu experience hormonal and behavioural changes in conjunction with changes in relationship and fatherhood status that are consistent with predictions based upon other species that practice bi-parental care. The theoretical expectation that early life cues of mortality or environmental unpredictability will motivate a "fast" life history strategy are confirmed for behavioural components of reproductive decision making, but not for maturational tempo, while our work points to a broader capacity for early life developmental calibration of systems like immunity, reproductive biology and metabolism. Our CLHNS findings illustrate the power of life history theory as an integrative, lifecourse framework to guide longitudinal studies of human populations.

Seventeen-Year Changes in Body Mass Index, Waist Circumference, Elevated Blood Pressure, and Diabetes Phenotypes in a Cohort of Filipino Women.

Obesity, hypertension, and diabetes have risen dramatically in Asia, but few cohort studies track age and secular trends in these conditions. We use Cebu (The Philippines) Longitudinal Health and Nutrition survey data to document 1998 to 2015 prevalence and co-occurrence of body mass index (BMI; >25 kg/m2), high waist circumference (WC; >80 cm), elevated blood pressure (EBP; systolic ⩾130 or diastolic ⩾85 mm Hg), and type 2 diabetes among ~2000 women aged 29 to 62 years in 1998; and identify their relationship to community, household, and individual factors using longitudinal logistic regression. Prevalence (1998-2015) rates were 35% to 49%, BMI >25 kg/m2; 32% to 58% high WC; 21% to 59% EBP; and 2% to 14% diabetes. Only 20% of women had none of these conditions in 2015. Diabetes was strongly driven by age and secular trends in high WC related to higher socioeconomic status and urbanization. Hypertension increased with age in lower socioeconomic status rural and more affluent urban women. Results underscore the continuing need for public health measures to prevent obesity and to identify and treat hypertension and diabetes.

Waist circumference and the risk of hypertension and prediabetes among Filipino women.

OBJECTIVES: To examine waist circumference as a risk factor for having hypertension only, impaired fasting glucose only, or both hypertension and impaired fasting glucose, and assess whether the associations vary according to overweight status. Furthermore, optimal cut-offs for waist circumference in overweight women and non-overweight women were explored. DATA AND METHODS: Data from 1,871 women aged 35-68 years in the 2005 Cebu Longitudinal Health and Nutrition Survey were used. Multinomial logistic regressions were used to model how waist circumference influenced the likelihood of having the three illness categories compared to having neither condition. Waist circumference cut-offs were explored using receiver operating characteristic analysis. RESULTS: Adjusted for age and other confounders, each cm increase in waist circumference increased the odds of hypertension by 5 % for non-overweight women and 3 % for overweight women; impaired fasting glucose by 9 and 3 % for non-overweight and overweight women, respectively; and hypertension and impaired fasting glucose by 17 % among non-overweight versus 9 % for overweight women. Waist circumference cut-offs for non-overweight women were lower than overweight women. CONCLUSION: Waist circumference was significantly associated with impaired fasting glucose and both hypertension and impaired fasting glucose, and the associations vary by overweight status.

Early childhood length-for-age is associated with the work status of Filipino young adults.

Most studies on childhood health and human capital in developing countries examine how early childhood linear growth relates to later human productivity as reflected in schooling success. Work status is another important human capital outcome related to early child health. This study examines the relationship of linear growth restriction at 2 years of age to work status in young adults who have, for the most part completed their schooling and further explores whether this relationship differs by gender. The analysis sample of 1795 was drawn from participants in the Cebu Longitudinal Health and Nutrition Survey, which followed individuals from birth to age 20-22 years. Work status in 2005 was represented by three categories: not working, working in an informal job, and working in a formal job. Formal work in the Philippines, as in most countries, is associated with regular hours, higher wages and benefits. Analyses were stratified by gender and current school enrolment, and adjusted for socioeconomic status and attained years of schooling. Among males no longer in school, higher length-for-age Z-score (LAZ) at age 2 was associated with a 40% increase in likelihood of formal work compared to not working. In females, each 1 unit increase in LAZ was associated with 0.2 higher likelihood of formal vs. informal work. No significant associations were observed in the small sample of young adults still in school. To improve job prospects of young adults, it is important to provide proper nutrition in early childhood and adequate educational opportunities during schooling years.