In recent years, research on how the human environment and lifestyle influence gene expression ha... more In recent years, research on how the human environment and lifestyle influence gene expression has generated considerable scientific and public interest. Articles in prominent international newspapers with headlines such as “Why your DNA isn't your destiny” (Time Magazine in 2010) or “Poverty leaves traces in children's genome” (Süddeutsche Zeitung in 2016) have drawn public interest to the emerging field of environmental epigenetics. It is a subdivision of the much more heterogeneous research field of epigenetics, which aims to understand how interactions between the environment and the genome can lead to epigenetic modifications that affect gene expression. Environmental epigenetics is often heralded as providing a revolutionary perspective on disease aetiology, particularly with regard to so‐called lifestyle diseases such as cardiovascular disease or diabetes. It is also often presented as a vital new framework for understanding differences in the susceptibility and resilience to mental illness and the long‐term damaging effects of a wide variety of environmental factors.
Early life cues of environmental harshness and unpredictability have been hypothesized to influen... more Early life cues of environmental harshness and unpredictability have been hypothesized to influence within-species variation in the timing of life history transitions and the dynamics of reproductive strategies, such as investments in mating and parenting. It is also believed that adolescence is an influential developmental period for male reproductive strategies, with those who achieve greater social and sexual success during that period maintaining faster life history strategies into adulthood. If correct, such early life and post-pubertal experiences could also help shape the psychobiological pathways that mediate reproductive strategies, including the well documented physiological shifts that occur when some men become parents. Drawing on a large sample of Filipino men (n = 417), we evaluate whether men who experienced cues of harshness or unpredictability in childhood or have earlier ages at sexual debut have elevated testosterone (T) as fathers. We also test whether males who experienced a combination of early life experiences of harshness or unpredictability and had earlier ages of sexual debut during adolescenece had the most elevated T as fathers. We found that fathers who experienced early life harshness and who engaged in sex at an earlier age had elevated waking T. Among men transitioning to fatherhood across the 4.5-year follow-up period of this study, those who experienced unpredictability and who engaged in sex at an earlier age showed attenuated declines in waking T between baseline and follow-up. Complementing these findings, we found that fathers who first engaged in sex at later ages had greater acute declines in T when they played with their toddlers. We suggest that these patterns could reflect programming effects of sociosexual experiences during the years following the marked biological transitions that accompany puberty, which occur along with the better-studied effects of earlier life exposures to stressors. Overall, our results support the hypothesis that early life circumstances and social and sexual experiences, from early life to young adulthood, help calibrate physiological axes as key mechanisms coordinating dynamic life history strategies.
Background and objectives Life history theory predicts resource allocation trade-offs between com... more Background and objectives Life history theory predicts resource allocation trade-offs between competing functions and processes. We test the hypothesis that relative investment towards innate versus acquired immunity in humans is subject to such trade-offs and that three types of early developmental exposures are particularly salient in shaping adult immunophenotype: (i) pathogen exposure, (ii) nutritional resources; and (iii) extrinsic mortality cues.
Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression.
Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity.
Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women.
Purpose Telomeres, DNA–protein structures that cap and
protect chromosomes, are thought to shorte... more Purpose Telomeres, DNA–protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/ obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. Methods In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8– 22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR, and diet was measured using multiple 24-h recalls. Results We found no associations between blood TL and any of the measures of adiposity or between blood TL and the seven dietary factors examined: processed meats, fried/ grilled meats and fish, non-fried fish, coconut oil, fruits and vegetables, bread and bread products, and sugar-sweetened beverages. Conclusions Considering the inconsistencies in the literature and our null results, small differences in body composition and consumption of any single pro- or anti-inflammatory dietary component may not by themselves have a meaningful impact on telomere integrity, or the impact may differ across distinct ecological circumstances.
Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes fr... more Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly , offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10 −6). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grand-children of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father's age at birth with TL. The lengthening of telomeres predicted by each year that the father's or grandfather's reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage. adaptation | epigenetics | evolution | parental effects | transgenerational plasticity T elomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide (1). In many tissues, telomere lengths (TL) are shortened by cellular proliferation, and as a result TL tends to decline with age (2–5). As cell replication generally requires a minimal TL, shortened TL is thought to contribute to senes-cence (6). Consistent with this, elderly persons with shorter telomeres (in blood) for their age have reduced survival (7–13). Although it is well established that TL shortens with age in most proliferating tissues (e.g., 4, 5), sperm TL is an exception— older men have sperm with longer telomeres (4, 14, 15). This may be explained by the fact that the activity of telomerase (an enzyme that extends TL) is high in testes (16, 17). Consistent with the fact that offspring inherit half their chromosomes from sperm, offspring of older fathers tend to have longer telomeres (4, 18, 19). In contrast, because the pool of ova is established in utero, TL in ova are thought to be stable with age, and there is no evidence for a maternal age effect on TL in offspring (e.g., 4, 20). We recently hypothesized that the age-related TL increase in sperm could lead to cumulative, and thus more biologically significant , multigenerational lengthening or shortening of TL in response to population trends in reproductive scheduling (21). If average reproductive age of recent patrilineal ancestors cumulatively influences TL, this might also lead to changes in TL of sufficient magnitude to influence late-life function and life ex-pectancies (17). To test the hypothesis that a man's age at reproduction influences TL in grandchildren, we used a large longitudinal, multigeneration sample from Cebu, Philippines (22) in which we measured TL (23) of DNA extracted from venous blood. We related TL in mothers (aged 36–69 y at blood collection) to their fathers' ages when the mothers were born. In their offspring (21–23 y at the time of blood collection), we related TL to their fathers' ages when the offspring were born and to their grandfathers' ages when their parents were born. Results Consistent with the expectations of age-related decline in TL, blood TL was inversely associated with age in the 36-to 69-y-old mothers (Fig. 1A) with a similar magnitude of effect as seen in previous comparable studies (4, 24). Longer age-adjusted maternal TL predicted longer offspring TL (Fig. 1B). This mother–off-spring TL correlation was similar in magnitude to previous studies (25–28) and did not vary depending on the sex of the offspring (maternal age adjusted TL × offspring sex interaction, P = 0.81). The TL of male offspring (n = 902, mean TL = 0.763 ± 0.006) was on average shorter than the TL of female offspring (n = 820, mean TL = 0.792 ± 0.006, t = 3.52, df = 1,720, P = 0.0005) (Fig. 1B). As observed in previous studies, we found that longer TL was predicted by older paternal age at reproduction in both the offspring cohort (Table 1, model 1, n = 1,681, P = 4.00 × 10 −5) and their mothers (Table 2, model 1, n = 342, P = 0.003; mother and offspring combined: n = 2,023, P = 1.84 × 10 −6). The association of paternal age with offspring TL was little changed by controlling for birth order, household income, or body mass index (BMI) at the time of blood collection in both the offspring (Table 1, model 2) and their mothers (Table 2, model 2). The paternal age association did not differ in sons versus daughters (paternal age × sex interaction, P = 0.844). Consistent with a linear association, paternal age did not exhibit a quadratic relationship with offspring TL (paternal age 2 , P = 0.689 for offspring and P = 0.995 for mothers). The association of paternal age with longer TL is thought to be due to direct inheritance from longer TL in sperm (4). To test an alternative hypothesis that offspring of older fathers have a slower age-related attrition rate of TL in adulthood, we examined if the association between offspring age and TL was reduced among offspring of older fathers, but found no support for this hypothesis (paternal age × offspring age interaction term in offspring, P = 0.341 and P = 0.472 in mothers).
Background: Birth weight (BW) predicts many health outcomes, but the relative contributions of ge... more Background: Birth weight (BW) predicts many health outcomes, but the relative contributions of genes and environmental factors to BW remain uncertain. Some studies report stronger mother-offspring than father-offspring BW correlations, with attenuated father-offspring BW correlations when the mother is stunted. These findings have been interpreted as evidence that maternal genetic or environmental factors play an important role in determining birth size, with small maternal size constraining paternal genetic contributions to offspring BW. Here we evaluate mother-offspring and father-offspring birth weight (BW) associations and evaluate whether maternal stunting constrains genetic contributions to offspring birth size.
ABSTRACT What makes us human? Considering how minor the changes in DNA sequence are between ourse... more ABSTRACT What makes us human? Considering how minor the changes in DNA sequence are between ourselves and our nearest primate relatives, this is a question of abiding interest. We have focused on the brain to address this question in a series of evolutionary genomic studies. The goal is to identify both biological processes and individual genes that have been important during human evolution. We first examined lineages (cetaceans and proboscideans) in addition to human that produced large brained species (dolphins and whales, and elephants). We utilized dN/dS, the ratio of nonsynonymous (amino acid replacing) nucleotide substitutions per nonsynonomous site to synonymous (amino acid unchanging) substitutions per synonymous site, as a measure of positive natural selection and identified the biological categories in which positively selected genes were found. Humans, dolphins, and elephants all showed genes expressed in mitochondria that are significantly overrepresented among positively selected genes. This finding underlines the evolutionarily parallel molecular trajectories of groups possessing a large brain, among the most energy consuming tissues. We then studied age-specific gene expression in human neocortex, which is characterized by protracted developmental intervals of synaptogenesis and myelination that allow for an extended period of learning, taken from the nondiseased margins of surgically resected tissue. We found 8 nonmessenger, long nonprotein-coding ribonucleic acid (lncRNA) molecules that are differentially expressed in an age-dependent way, 337 transcripts with greater inter-individual variance among children than among adults – many annotated to the immune system – and 40 transcripts with significant age-related trajectories in expression. These findings present some of the genetic underpinnings of the extended period of human cortical development with peak brain glucose metabolism between ages 4 and 10 years. (Supported by NSF BCS-0827546)
Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more r... more Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8-22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measu...
American journal of physical anthropology, Jan 4, 2015
Cross-species comparisons show that high extrinsic mortality favors the evolution of "faster... more Cross-species comparisons show that high extrinsic mortality favors the evolution of "faster" life histories. There is interest in applying this principle to human life history plasticity, based on the idea that psychosocial stressors that correlate with extrinsic mortality accelerate reproductive pace. Most prior studies have been conducted in settings in which psychosocial stressors co-occur with the maturation-accelerating influence of nutritional abundance. We evaluate cues of local mortality (sibling death) or low parental investment (paternal instability; maternal absence) and energetic measures during development as predictors of life history scheduling among males (n = 754) in a Philippine population with marginal developmental nutritional. Males who had more favorable nutritional status during childhood, as reflected in linear growth, skinfold thickness, and caloric intake, were more maturationally advanced in adolescence (all P < 0.05). Taller stature and high...
The human brain, and human cognitive abilities, are strikingly different from those of other grea... more The human brain, and human cognitive abilities, are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure di...
Depression is positively associated with chronic inflammation in industrialized settings with low... more Depression is positively associated with chronic inflammation in industrialized settings with low burdens of infectious disease, but the pattern of association in environments with higher levels of microbial exposure is not known. We measured C-reactive protein (CRP) and interleukin 6 (IL6) in community-based samples of young adults (20-22 years) and older women (35-69 years) in the Philippines. Concentrations of CRP and IL6 were low, and bivariate and multivariate regression analyses indicated no associations between depressive symptoms and inflammation in either sample. Results are interpreted in light of prior research indicating that higher levels of microbial exposure in infancy have lasting effects on the regulation of inflammation, and may prevent the emergence of a relationship between depression and inflammation in adulthood.
C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predi... more C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predicts elevated risk for cardiovascular disease. Influenza vaccination is a mild pro-inflammatory stimulus, and the CRP response to vaccination may provide additional information on individual differences in inflammatory response and risk for disease. To document the pattern of CRP response to influenza vaccination among a large sample of older women in the Philippines. The Philippines exemplifies current global trends toward increasing rates of overweight/obesity, but also maintains relatively high rates of infectious disease. The secondary aim of the study is to investigate the impact of infectious symptoms on the pattern of response to vaccination. A community-based sample of 934 women (mean age=55.4 years) received the influenza vaccine. CRP was assessed at baseline and 72h post-vaccination. Descriptive, non-parametric, and parametric analyses were implemented to assess the magnitude of...
American journal of human biology : the official journal of the Human Biology Council, Jan 7, 2015
Low socioeconomic status (SES) is associated with increased psychosocial stress among low-income ... more Low socioeconomic status (SES) is associated with increased psychosocial stress among low-income persons, which could contribute to differences in activity of the HPA axis (assessed by diurnal cortisol profiles). The current article investigates associations of SES from different developmental stages with cortisol profiles. Using data from a large, socioeconomically diverse birth cohort (N = 1,490) in Cebu, Philippines, the current study compares the relative and joint contributions of SES from five developmental periods, between the prenatal/birth period and early adulthood, to adult cortisol, and examines the effects of chronic exposure to low SES. Chronically low SES from infancy through early adulthood predicts the highest bedtime cortisol levels, lowest cortisol awakening responses (CARs), lowest total cortisol levels across the day (area under curve or AUC), and the flattest cortisol rhythms between wake up and bedtime, a profile associated with poorer health. Results indicate...
In recent years, research on how the human environment and lifestyle influence gene expression ha... more In recent years, research on how the human environment and lifestyle influence gene expression has generated considerable scientific and public interest. Articles in prominent international newspapers with headlines such as “Why your DNA isn't your destiny” (Time Magazine in 2010) or “Poverty leaves traces in children's genome” (Süddeutsche Zeitung in 2016) have drawn public interest to the emerging field of environmental epigenetics. It is a subdivision of the much more heterogeneous research field of epigenetics, which aims to understand how interactions between the environment and the genome can lead to epigenetic modifications that affect gene expression. Environmental epigenetics is often heralded as providing a revolutionary perspective on disease aetiology, particularly with regard to so‐called lifestyle diseases such as cardiovascular disease or diabetes. It is also often presented as a vital new framework for understanding differences in the susceptibility and resilience to mental illness and the long‐term damaging effects of a wide variety of environmental factors.
Early life cues of environmental harshness and unpredictability have been hypothesized to influen... more Early life cues of environmental harshness and unpredictability have been hypothesized to influence within-species variation in the timing of life history transitions and the dynamics of reproductive strategies, such as investments in mating and parenting. It is also believed that adolescence is an influential developmental period for male reproductive strategies, with those who achieve greater social and sexual success during that period maintaining faster life history strategies into adulthood. If correct, such early life and post-pubertal experiences could also help shape the psychobiological pathways that mediate reproductive strategies, including the well documented physiological shifts that occur when some men become parents. Drawing on a large sample of Filipino men (n = 417), we evaluate whether men who experienced cues of harshness or unpredictability in childhood or have earlier ages at sexual debut have elevated testosterone (T) as fathers. We also test whether males who experienced a combination of early life experiences of harshness or unpredictability and had earlier ages of sexual debut during adolescenece had the most elevated T as fathers. We found that fathers who experienced early life harshness and who engaged in sex at an earlier age had elevated waking T. Among men transitioning to fatherhood across the 4.5-year follow-up period of this study, those who experienced unpredictability and who engaged in sex at an earlier age showed attenuated declines in waking T between baseline and follow-up. Complementing these findings, we found that fathers who first engaged in sex at later ages had greater acute declines in T when they played with their toddlers. We suggest that these patterns could reflect programming effects of sociosexual experiences during the years following the marked biological transitions that accompany puberty, which occur along with the better-studied effects of earlier life exposures to stressors. Overall, our results support the hypothesis that early life circumstances and social and sexual experiences, from early life to young adulthood, help calibrate physiological axes as key mechanisms coordinating dynamic life history strategies.
Background and objectives Life history theory predicts resource allocation trade-offs between com... more Background and objectives Life history theory predicts resource allocation trade-offs between competing functions and processes. We test the hypothesis that relative investment towards innate versus acquired immunity in humans is subject to such trade-offs and that three types of early developmental exposures are particularly salient in shaping adult immunophenotype: (i) pathogen exposure, (ii) nutritional resources; and (iii) extrinsic mortality cues.
Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression.
Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity.
Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women.
Purpose Telomeres, DNA–protein structures that cap and
protect chromosomes, are thought to shorte... more Purpose Telomeres, DNA–protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/ obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. Methods In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8– 22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR, and diet was measured using multiple 24-h recalls. Results We found no associations between blood TL and any of the measures of adiposity or between blood TL and the seven dietary factors examined: processed meats, fried/ grilled meats and fish, non-fried fish, coconut oil, fruits and vegetables, bread and bread products, and sugar-sweetened beverages. Conclusions Considering the inconsistencies in the literature and our null results, small differences in body composition and consumption of any single pro- or anti-inflammatory dietary component may not by themselves have a meaningful impact on telomere integrity, or the impact may differ across distinct ecological circumstances.
Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes fr... more Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly , offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10 −6). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grand-children of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father's age at birth with TL. The lengthening of telomeres predicted by each year that the father's or grandfather's reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage. adaptation | epigenetics | evolution | parental effects | transgenerational plasticity T elomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide (1). In many tissues, telomere lengths (TL) are shortened by cellular proliferation, and as a result TL tends to decline with age (2–5). As cell replication generally requires a minimal TL, shortened TL is thought to contribute to senes-cence (6). Consistent with this, elderly persons with shorter telomeres (in blood) for their age have reduced survival (7–13). Although it is well established that TL shortens with age in most proliferating tissues (e.g., 4, 5), sperm TL is an exception— older men have sperm with longer telomeres (4, 14, 15). This may be explained by the fact that the activity of telomerase (an enzyme that extends TL) is high in testes (16, 17). Consistent with the fact that offspring inherit half their chromosomes from sperm, offspring of older fathers tend to have longer telomeres (4, 18, 19). In contrast, because the pool of ova is established in utero, TL in ova are thought to be stable with age, and there is no evidence for a maternal age effect on TL in offspring (e.g., 4, 20). We recently hypothesized that the age-related TL increase in sperm could lead to cumulative, and thus more biologically significant , multigenerational lengthening or shortening of TL in response to population trends in reproductive scheduling (21). If average reproductive age of recent patrilineal ancestors cumulatively influences TL, this might also lead to changes in TL of sufficient magnitude to influence late-life function and life ex-pectancies (17). To test the hypothesis that a man's age at reproduction influences TL in grandchildren, we used a large longitudinal, multigeneration sample from Cebu, Philippines (22) in which we measured TL (23) of DNA extracted from venous blood. We related TL in mothers (aged 36–69 y at blood collection) to their fathers' ages when the mothers were born. In their offspring (21–23 y at the time of blood collection), we related TL to their fathers' ages when the offspring were born and to their grandfathers' ages when their parents were born. Results Consistent with the expectations of age-related decline in TL, blood TL was inversely associated with age in the 36-to 69-y-old mothers (Fig. 1A) with a similar magnitude of effect as seen in previous comparable studies (4, 24). Longer age-adjusted maternal TL predicted longer offspring TL (Fig. 1B). This mother–off-spring TL correlation was similar in magnitude to previous studies (25–28) and did not vary depending on the sex of the offspring (maternal age adjusted TL × offspring sex interaction, P = 0.81). The TL of male offspring (n = 902, mean TL = 0.763 ± 0.006) was on average shorter than the TL of female offspring (n = 820, mean TL = 0.792 ± 0.006, t = 3.52, df = 1,720, P = 0.0005) (Fig. 1B). As observed in previous studies, we found that longer TL was predicted by older paternal age at reproduction in both the offspring cohort (Table 1, model 1, n = 1,681, P = 4.00 × 10 −5) and their mothers (Table 2, model 1, n = 342, P = 0.003; mother and offspring combined: n = 2,023, P = 1.84 × 10 −6). The association of paternal age with offspring TL was little changed by controlling for birth order, household income, or body mass index (BMI) at the time of blood collection in both the offspring (Table 1, model 2) and their mothers (Table 2, model 2). The paternal age association did not differ in sons versus daughters (paternal age × sex interaction, P = 0.844). Consistent with a linear association, paternal age did not exhibit a quadratic relationship with offspring TL (paternal age 2 , P = 0.689 for offspring and P = 0.995 for mothers). The association of paternal age with longer TL is thought to be due to direct inheritance from longer TL in sperm (4). To test an alternative hypothesis that offspring of older fathers have a slower age-related attrition rate of TL in adulthood, we examined if the association between offspring age and TL was reduced among offspring of older fathers, but found no support for this hypothesis (paternal age × offspring age interaction term in offspring, P = 0.341 and P = 0.472 in mothers).
Background: Birth weight (BW) predicts many health outcomes, but the relative contributions of ge... more Background: Birth weight (BW) predicts many health outcomes, but the relative contributions of genes and environmental factors to BW remain uncertain. Some studies report stronger mother-offspring than father-offspring BW correlations, with attenuated father-offspring BW correlations when the mother is stunted. These findings have been interpreted as evidence that maternal genetic or environmental factors play an important role in determining birth size, with small maternal size constraining paternal genetic contributions to offspring BW. Here we evaluate mother-offspring and father-offspring birth weight (BW) associations and evaluate whether maternal stunting constrains genetic contributions to offspring birth size.
ABSTRACT What makes us human? Considering how minor the changes in DNA sequence are between ourse... more ABSTRACT What makes us human? Considering how minor the changes in DNA sequence are between ourselves and our nearest primate relatives, this is a question of abiding interest. We have focused on the brain to address this question in a series of evolutionary genomic studies. The goal is to identify both biological processes and individual genes that have been important during human evolution. We first examined lineages (cetaceans and proboscideans) in addition to human that produced large brained species (dolphins and whales, and elephants). We utilized dN/dS, the ratio of nonsynonymous (amino acid replacing) nucleotide substitutions per nonsynonomous site to synonymous (amino acid unchanging) substitutions per synonymous site, as a measure of positive natural selection and identified the biological categories in which positively selected genes were found. Humans, dolphins, and elephants all showed genes expressed in mitochondria that are significantly overrepresented among positively selected genes. This finding underlines the evolutionarily parallel molecular trajectories of groups possessing a large brain, among the most energy consuming tissues. We then studied age-specific gene expression in human neocortex, which is characterized by protracted developmental intervals of synaptogenesis and myelination that allow for an extended period of learning, taken from the nondiseased margins of surgically resected tissue. We found 8 nonmessenger, long nonprotein-coding ribonucleic acid (lncRNA) molecules that are differentially expressed in an age-dependent way, 337 transcripts with greater inter-individual variance among children than among adults – many annotated to the immune system – and 40 transcripts with significant age-related trajectories in expression. These findings present some of the genetic underpinnings of the extended period of human cortical development with peak brain glucose metabolism between ages 4 and 10 years. (Supported by NSF BCS-0827546)
Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more r... more Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8-22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measu...
American journal of physical anthropology, Jan 4, 2015
Cross-species comparisons show that high extrinsic mortality favors the evolution of "faster... more Cross-species comparisons show that high extrinsic mortality favors the evolution of "faster" life histories. There is interest in applying this principle to human life history plasticity, based on the idea that psychosocial stressors that correlate with extrinsic mortality accelerate reproductive pace. Most prior studies have been conducted in settings in which psychosocial stressors co-occur with the maturation-accelerating influence of nutritional abundance. We evaluate cues of local mortality (sibling death) or low parental investment (paternal instability; maternal absence) and energetic measures during development as predictors of life history scheduling among males (n = 754) in a Philippine population with marginal developmental nutritional. Males who had more favorable nutritional status during childhood, as reflected in linear growth, skinfold thickness, and caloric intake, were more maturationally advanced in adolescence (all P < 0.05). Taller stature and high...
The human brain, and human cognitive abilities, are strikingly different from those of other grea... more The human brain, and human cognitive abilities, are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure di...
Depression is positively associated with chronic inflammation in industrialized settings with low... more Depression is positively associated with chronic inflammation in industrialized settings with low burdens of infectious disease, but the pattern of association in environments with higher levels of microbial exposure is not known. We measured C-reactive protein (CRP) and interleukin 6 (IL6) in community-based samples of young adults (20-22 years) and older women (35-69 years) in the Philippines. Concentrations of CRP and IL6 were low, and bivariate and multivariate regression analyses indicated no associations between depressive symptoms and inflammation in either sample. Results are interpreted in light of prior research indicating that higher levels of microbial exposure in infancy have lasting effects on the regulation of inflammation, and may prevent the emergence of a relationship between depression and inflammation in adulthood.
C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predi... more C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predicts elevated risk for cardiovascular disease. Influenza vaccination is a mild pro-inflammatory stimulus, and the CRP response to vaccination may provide additional information on individual differences in inflammatory response and risk for disease. To document the pattern of CRP response to influenza vaccination among a large sample of older women in the Philippines. The Philippines exemplifies current global trends toward increasing rates of overweight/obesity, but also maintains relatively high rates of infectious disease. The secondary aim of the study is to investigate the impact of infectious symptoms on the pattern of response to vaccination. A community-based sample of 934 women (mean age=55.4 years) received the influenza vaccine. CRP was assessed at baseline and 72h post-vaccination. Descriptive, non-parametric, and parametric analyses were implemented to assess the magnitude of...
American journal of human biology : the official journal of the Human Biology Council, Jan 7, 2015
Low socioeconomic status (SES) is associated with increased psychosocial stress among low-income ... more Low socioeconomic status (SES) is associated with increased psychosocial stress among low-income persons, which could contribute to differences in activity of the HPA axis (assessed by diurnal cortisol profiles). The current article investigates associations of SES from different developmental stages with cortisol profiles. Using data from a large, socioeconomically diverse birth cohort (N = 1,490) in Cebu, Philippines, the current study compares the relative and joint contributions of SES from five developmental periods, between the prenatal/birth period and early adulthood, to adult cortisol, and examines the effects of chronic exposure to low SES. Chronically low SES from infancy through early adulthood predicts the highest bedtime cortisol levels, lowest cortisol awakening responses (CARs), lowest total cortisol levels across the day (area under curve or AUC), and the flattest cortisol rhythms between wake up and bedtime, a profile associated with poorer health. Results indicate...
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Papers by Christopher Kuzawa
Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression.
Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity.
Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women.
protect chromosomes, are thought to shorten more rapidly
when exposed to chronic inflammation and oxidative stress.
Diet and nutritional status may be a source of inflammation
and oxidative stress. However, relationships between
telomere length (TL) and diet or adiposity have primarily
been studied cross-sectionally among older, overweight/
obese populations and yielded inconsistent results. Little is
known about the relationship between diet or body composition
and TL among younger, low- to normal-weight populations.
It also remains unclear how cumulative exposure
to a specific diet or body composition during the years of
growth and development, when telomere attrition is most
rapid, may be related to TL in adulthood.
Methods In a sample of 1459 young adult Filipinos, we
assessed the relationship between blood TL at ages 20.8–
22.5 and measures of BMI z-score, waist circumference,
and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR,
and diet was measured using multiple 24-h recalls.
Results We found no associations between blood TL and
any of the measures of adiposity or between blood TL and
the seven dietary factors examined: processed meats, fried/
grilled meats and fish, non-fried fish, coconut oil, fruits and
vegetables, bread and bread products, and sugar-sweetened
beverages.
Conclusions Considering the inconsistencies in the literature
and our null results, small differences in body composition
and consumption of any single pro- or anti-inflammatory
dietary component may not by themselves have a
meaningful impact on telomere integrity, or the impact may
differ across distinct ecological circumstances.
Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression.
Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity.
Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women.
protect chromosomes, are thought to shorten more rapidly
when exposed to chronic inflammation and oxidative stress.
Diet and nutritional status may be a source of inflammation
and oxidative stress. However, relationships between
telomere length (TL) and diet or adiposity have primarily
been studied cross-sectionally among older, overweight/
obese populations and yielded inconsistent results. Little is
known about the relationship between diet or body composition
and TL among younger, low- to normal-weight populations.
It also remains unclear how cumulative exposure
to a specific diet or body composition during the years of
growth and development, when telomere attrition is most
rapid, may be related to TL in adulthood.
Methods In a sample of 1459 young adult Filipinos, we
assessed the relationship between blood TL at ages 20.8–
22.5 and measures of BMI z-score, waist circumference,
and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR,
and diet was measured using multiple 24-h recalls.
Results We found no associations between blood TL and
any of the measures of adiposity or between blood TL and
the seven dietary factors examined: processed meats, fried/
grilled meats and fish, non-fried fish, coconut oil, fruits and
vegetables, bread and bread products, and sugar-sweetened
beverages.
Conclusions Considering the inconsistencies in the literature
and our null results, small differences in body composition
and consumption of any single pro- or anti-inflammatory
dietary component may not by themselves have a
meaningful impact on telomere integrity, or the impact may
differ across distinct ecological circumstances.