Evolutionary theory predicts that reproduction entails costs that detract from somatic maintenance, accelerating biological aging. Despite support from studies in human and non-human animals, ...mechanisms linking 'costs of reproduction' (CoR) to aging are poorly understood. Human pregnancy is characterized by major alterations in metabolic regulation, oxidative stress, and immune cell proliferation. We hypothesized that these adaptations could accelerate blood-derived cellular aging. To test this hypothesis, we examined gravidity in relation to telomere length (TL, n = 821) and DNA-methylation age (DNAmAge, n = 397) in a cohort of young (20-22 year-old) Filipino women. Age-corrected TL and accelerated DNAmAge both predict age-related morbidity and mortality, and provide markers of mitotic and non-mitotic cellular aging, respectively. Consistent with theoretical predictions, TL decreased (p = 0.031) and DNAmAge increased (p = 0.007) with gravidity, a relationship that was not contingent upon resource availability. Neither biomarker was associated with subsequent fertility (both p > 0.3), broadly consistent with a causal effect of gravidity on cellular aging. Our findings provide evidence that reproduction in women carries costs in the form of accelerated aging through two independent cellular pathways.
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide ...association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
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.
The survival and nutrition of children and, to a lesser extent, adolescents have improved substantially in the past two decades. Improvements have been linked to the delivery of effective biomedical, ...behavioural, and environmental interventions; however, large disparities exist between and within countries. Using data from 95 national surveys in low-income and middle-income countries (LMICs), we analyse how strongly the health, nutrition, and cognitive development of children and adolescents are related to early-life poverty. Additionally, using data from six large, long-running birth cohorts in LMICs, we show how early-life poverty can have a lasting effect on health and human capital throughout the life course. We emphasise the importance of implementing multisectoral anti-poverty policies and programmes to complement specific health and nutrition interventions delivered at an individual level, particularly at a time when COVID-19 continues to disrupt economic, health, and educational gains achieved in the recent past.
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.
Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in ...humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.
•Socioeconomic status (SES) predicts numerous health outcomes.•Chronic inflammation and immunosenescence are implicated pathways.•Studies on SES and immune function outside high income countries are ...limited.•In Cebu, Philippines, SES was negatively associated with measures of immunosenescence.•SES was positively associated with inflammation and mediated by adiposity.
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.
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.
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.
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.
Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the ...formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.
The contribution of copy-number variants to cleft lip with or without cleft palate (CL/P) has been relatively understudied. Using a strategy to identify likely higher effect size microdeletions, we identify COBLL1, RIC1, and ARHGEF38 as genes associated with CL/P that play important roles in vertebrate craniofacial development.
Objectives
Maternal experiences before pregnancy predict birth outcomes, a key indicator of health trajectories, but the timing and pathways for these effects are poorly understood. Here we test the ...hypothesis that maternal pre‐adult growth patterns predict pregnancy glucose and offspring fetal growth in Cebu, Philippines.
Methods
Using multiple regression and path analysis, gestational age‐adjusted birthweight and variables reflecting infancy, childhood, and post‐childhood/adolescent weight gain (conditional weights) were used to predict pregnancy HbA1c and offspring birth outcomes among participants in the Cebu Longitudinal Health and Nutrition Survey.
Results
Maternal early/mid‐childhood weight gain predicted birth weight, length, and head circumference in female offspring. Late‐childhood/adolescent weight gain predicted birth length, birth weight, skinfold thickness, and head circumference in female offspring, and head circumference in male offspring. Pregnancy HbA1c did not mediate relationships between maternal growth and birth size parameters.
Discussion
In Cebu, maternal growth patterns throughout infancy, childhood, and adolescence predict fetal growth via a pathway independent of circulating glucose, with stronger impacts on female than male offspring, consistent with a role of developmental nutrition on offspring fetal growth. Notably, the strength of relationships followed a pattern opposite to what occurs in response to acute pregnancy stress, with strongest effects on head circumference and birth length and weakest on skinfolds. We speculate that developmental sensitivities are reversed for stable, long‐term nutritional cues that reflect average local environments. These findings are relevant to public health and life‐history theory as further evidence of developmental influences on health and resource allocation across the life course.
Analyses of maternal preadult growth and birth outcomes found that the most canalized offspring traits, head size and birth length, were more sensitive to maternal growth variability than body fatness or birth weight, and effects were significantly stronger in female offspring. This is the opposite of the typical set of responses to acute pregnancy stress, wherein fat mass is most labile and males tend to be more impacted.
•Caregiving stress (CS) does not predict telomere length (TL) in 1233 adults.•There is no effect modification of CS-TL by sex, age, or relationship to caregiver.•Previously published results linking ...CS and TL are not replicated in our sample.•These and other recent findings suggest CS is not generally predictive of TL.•However, it is possible that specific types of severe caregiving stress predict TL.
Caring for chronically disabled family members is a stressful experience. In turn, psychosocial stress is linked to premature aging. Telomere length (TL) is a plastic genetic trait that is a biomarker of aging, and a possible mechanism linking psychosocial stress and accelerated aging.
TL was measured using qPCR method from blood samples in 1233 Filipino adults from Cebu, Philippines. Caregiving was measured as chronicity of care, or the sum total number of years an individual was the primary caregiver for any household member with a chronic illness or disability. Linear regression models were used to test for associations between chronicity of care and TL. Interaction terms were used to test whether or not the association between chronicity of care and TL differed by sex, age, and relationship to the caregiver. Specific statistical designs were publicly pre-registered before analysis began.
Chronicity of care was not associated with TL. Neither did we find any evidence for caregiving varying in its effect on TL by caregiver sex, age, or relationship to the chronically ill/disabled.
We found no evidence of an association between chronicity of care and TL. This result coupled with a recent study of a similarly sized cohort suggests that previous significant results linking caregiving and TL may be due to very particular types of caregiving populations or are possibly artifacts of small sample sizes.
PDF
