Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring.

We previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically. Liver glycogen, choline, and lipid concentrations were quantified by magnetic resonance spectroscopy. Mitochondrial respiration in primary hepatocytes under standard culture conditions and in response to metabolic (1 mM glucose) and oxidative (100 µM H2O2) stress were assessed with Seahorse XFe96. Hepatocyte mitochondrial membrane potential (MMP) and protein abundance were determined by tetramethylrhodamine ethyl ester staining and immunoblotting, respectively. Liver enzymes and metabolite concentrations were largely unaffected by MUN, except for higher aspartate aminotransferase levels in MUN offspring when male and female data were combined. Oxygen consumption rate, extracellular acidification rate, and MMP were significantly higher in male MUN offspring relative to control animals under standard culture. However, in females, cellular respiration was similar in control and MUN offspring. In response to low glucose challenge, only control male hepatocytes were resistant to low glucose-stimulated increase in basal and ATP-linked respiration. H2O2 did not affect hepatocyte mitochondrial respiration. Protein markers of mitochondrial respiratory chain subunits, biogenesis, dynamics, and antioxidant enzymes were unchanged. Male-specific increases in mitochondrial bioenergetics in MUN offspring may be associated with increased energy demand in these animals. The similarity in systemic liver parameters suggests that changes in hepatocyte bioenergetics capacity precede detectable circulatory hepatic defects in MUN offspring and that the mitochondria may be an orchestrator of liver programming outcome.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.

Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.

Biological resilience, broadly defined as ability to recover from acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3-17.8 years spanning across different tissues, tissue regions, and cell types including: (1) fibroblasts from skin and from heart separated into left ventricle (LV), right ventricle (RV), left atrium (LA) and right atrium (RA), (2) astrocytes from the prefrontal cortex and hippocampus and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50µM-H2O2), metabolic (1mM-glucose) and proteostasis (0.1µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor specific. For example, astrocytes were more energetic and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to age and developmental status of donors as potential predictive markers.

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway.

Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans. The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes. We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent ~30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid ß-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width. Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases.

Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders.

The prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found Gamma-aminobutyric acid (GABA) tissue content associated with these signaling pathways, providing 1 potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.

Multi-omics Analysis of Aging Liver Reveals Changes in Endoplasmic Stress and Degradation Pathways in Female Nonhuman Primates.

The liver is critical for functions that support metabolism, immunity, digestion, detoxification, and vitamin storage. Aging is associated with severity and poor prognosis of various liver diseases such as nonalcoholic fatty liver disease (NAFLD). Previous studies have used multi-omic approaches to study liver diseases or to examine the effects of aging on the liver. However, to date, no studies have used an integrated omics approach to investigate aging-associated molecular changes in the livers of healthy female nonhuman primates. The goal of this study was to identify molecular changes associated with healthy aging in the livers of female baboons ( Papio sp., n=35) by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. To integrate omics data, we performed unbiased weighted gene co-expression network analysis (WGCNA), and the results revealed 3 modules containing 3,149 genes and 33 proteins were positively correlated with age, and 2 modules containing 37 genes and 216 proteins were negatively correlated with age. Pathway enrichment analysis showed that unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were positively associated with age, whereas xenobiotic metabolism and melatonin and serotonin degradation pathways were negatively associated with age. The findings of our study suggest that UPR and a reduction in reactive oxygen species generated from serotonin degradation could protect the liver from oxidative stress during the aging process in healthy female baboons.

Maternal obesity alters offspring liver and skeletal muscle metabolism in early post-puberty despite maintaining a normal post-weaning dietary lifestyle.

Maternal obesity (MO) during pregnancy is linked to increased and premature risk of age-related metabolic diseases in the offspring. However, the underlying molecular mechanisms still remain not fully understood. Using a well-established nonhuman primate model of MO, we analyzed tissue biopsies and plasma samples obtained from post-pubertal offspring (3-6.5 y) of MO mothers (n = 19) and from control animals born to mothers fed a standard diet (CON, n = 13). All offspring ate a healthy chow diet after weaning. Using untargeted gas chromatography-mass spectrometry metabolomics analysis, we quantified a total of 351 liver, 316 skeletal muscle, and 423 plasma metabolites. We identified 58 metabolites significantly altered in the liver and 46 in the skeletal muscle of MO offspring, with 8 metabolites shared between both tissues. Several metabolites were changed in opposite directions in males and females in both liver and skeletal muscle. Several tissue-specific and 4 shared metabolic pathways were identified from these dysregulated metabolites. Interestingly, none of the tissue-specific metabolic changes were reflected in plasma. Overall, our study describes characteristic metabolic perturbations in the liver and skeletal muscle in MO offspring, indicating that metabolic programming in utero persists postnatally, and revealing potential novel mechanisms that may contribute to age-related metabolic diseases later in life.

Summary and Assessment of Studies on Cardiac Aging in Nonhuman Primates.

Nonhuman primates (NHP) are important translational models for cardiac aging. To assess progress in this research area and to provide a reference for other investigators, we identified papers indexed in PubMed to determine what species, ages, outcomes, treatments, and approaches have been studied. Since 1983, 33 studies of cardiac aging in NHP have been published. Of these, 27 used species of macaque, 6 baboon, 1 vervet, 1 orangutan, and 1 marmoset (some studies were multispecies). Common research approaches were echocardiography, ECG, and histology of the left ventricle. Only 10 studies performed sex-based analyses. The average age of the oldest macaque studied was 26 y. The reported mean lifespan of macaques in captivity is around 30 y. The age of the oldest baboon studied was 24 y. Baboons in captivity are reported to live on average to 21 y. Twelve studies took a "life course" approach, studying animals of a wide range of ages from less than or equal to 10 y through the late teens to thirties, and employing analyses designed to show change over time. Keeping NHP into old age is a major challenge for biomedical research. The ideal design is to start monitoring in early life and to track how cardiac structure and function change with age. Important issues for future research are an increased focus on life-course approaches, investment in existing life-course NHP cohorts, better reporting of study sample characteristics, more molecular studies to identify genetic risk factors and mechanisms, attention to sex as a biological variable, a move away from descriptive reports to mechanistic studies, development of biomarkers to predict disease risk, and exploration of interventions that are implemented early in life to prevent or delay age-related disease later in life. Reducing exposure to early life adversity, identifying early-life biomarkers of aging and age-related disease, and early treatment can contribute to longer health span.

Walking speed declines with age in male and female baboons (Papio sp.): Confirmation of findings with sex as a biological variable.

We measured walking speed in baboons (67 female, 36 male; 5-22 years) to develop regression formulas to predict biological age. The final model strongly predicted age from just speed and sex. Walking speed is a valuable baboon aging biomarker. We present the first male speed data in a nonhuman primate.

Perinatal maternal undernutrition does not result in offspring capillary rarefaction in the middle-aged male baboon at rest.

Microvascular health is a main determinant of coronary blood flow reserve and myocardial vascular resistance. Extracardiac capillary abnormality has been reported in subjects at increased coronary heart disease risk, such as prehypertension, hypertension, diabetes, hyperlipidemia, and atherosclerosis. We have reported cardiovascular dysfunction in a cohort of maternal nutrient reduction (MNR)-induced intrauterine growth restriction (IUGR) baboon offspring. Here we test the hypothesis that there is oral capillary rarefaction associated with MNR-induced IUGR. Capillary density was quantified using in vivo high-power capillaroscopy on seven middle-aged (~10.7 yr; human equivalent ~40 yr) male IUGR baboons and seven male age-matched controls in the lateral buccal and inferior labial mucosa. While no difference was found between groups in either area by fraction area or optical density for these vascular beds derived from fetal preductal vessels, further studies are needed on post-ductal vascular beds, retina, and function.

The nonhuman primate hypothalamo-pituitary-adrenal axis is an orchestrator of programming-aging interactions: role of nutrition.

Developmental programming alters life-course multi-organ function and significantly affects life-course health. Recently, interest has developed in how programming may influence the rate of aging. This review describes interactions of nutrition and programming-aging interactions in hypothalamo-pituitary-adrenal (HPA) development and function from fetal development to old age. A full picture of these interactions requires data on levels of HPA activity relating to the hypothalamic, adrenal cortical, circulating blood, and peripheral cortisol metabolism. Data are provided from studies on our baboon, nonhuman primate model both across the normal life course and in offspring of maternal baboons who were moderately undernourished by a global 30% diet reduction during pregnancy and lactation. Sex differences in offspring outcomes in response to similar challenges are described. The data clearly show programming of increased HPA axis activity by moderate maternal undernutrition. Increased postnatal circulating cortisol concentrations are related to accelerated aging of the brain and cardiovascular systems. Future studies should address peripheral cortisol production and the influence of aging advantage in females. These data support the view that the HPA is an orchestrator of interactions of programming-aging mechanisms.

Strength of nonhuman primate studies of developmental programming: review of sample sizes, challenges, and steps for future work.

Nonhuman primate (NHP) studies are crucial to biomedical research. NHPs are the species most similar to humans in lifespan, body size, and hormonal profiles. Planning research requires statistical power evaluation, which is difficult to perform when lacking directly relevant preliminary data. This is especially true for NHP developmental programming studies, which are scarce. We review the sample sizes reported, challenges, areas needing further work, and goals of NHP maternal nutritional programming studies. The literature search included 27 keywords, for example, maternal obesity, intrauterine growth restriction, maternal high-fat diet, and maternal nutrient reduction. Only fetal and postnatal offspring studies involving tissue collection or imaging were included. Twenty-eight studies investigated maternal over-nutrition and 33 under-nutrition; 23 involved macaques and 38 baboons. Analysis by sex was performed in 19; minimum group size ranged from 1 to 8 (mean 4.7 ± 0.52, median 4, mode 3) and maximum group size from 3 to 16 (8.3 ± 0.93, 8, 8). Sexes were pooled in 42 studies; minimum group size ranged from 2 to 16 (mean 5.3 ± 0.35, median 6, mode 6) and maximum group size from 4 to 26 (10.2 ± 0.92, 8, 8). A typical study with sex-based analyses had group size minimum 4 and maximum 8 per sex. Among studies with sexes pooled, minimum group size averaged 6 and maximum 8. All studies reported some significant differences between groups. Therefore, studies with group sizes 3-8 can detect significance between groups. To address deficiencies in the literature, goals include increasing age range, more frequently considering sex as a biological variable, expanding topics, replicating studies, exploring intergenerational effects, and examining interventions.

Effect of maternal baboon (Papio sp.) dietary mismatch in pregnancy and lactation on post-natal offspring early life phenotype.

BACKGROUND: Non-human primate models of developmental programing by maternal mismatch between pregnancy and lactation diets are needed for translation to human programing outcomes. We present baboon offspring morphometry from birth to 3 years, and blood cortisol and adrenocorticotropin (ACTH) from 2 to 24 months. METHODS: Control mothers ate chow; mismatch mothers ate 30% less than controls during pregnancy and high-fat high-energy diet through lactation. RESULTS: Mismatch mothers lost weight during pregnancy. At birth, there were trends toward lower weight in mismatch offspring of both sexes (P = 0.06). From 0-3 years, catch-up growth occurred. Mismatch offspring male and female body weight increased faster than controls (P < 0.001). Mismatch female offspring showed greater increase in BMI (P < 0.001) and abdominal circumference (P = 0.008) vs controls. ACTH and cortisol slopes from 2 to 24 months of age were similar between groups in both sexes. Cortisol and ACTH increased after weaning in all groups. CONCLUSIONS: Mismatch produces sexually dimorphic post-natal growth phenotypes.

Antenatal Synthetic Glucocorticoid Exposure at Human Therapeutic Equivalent Doses Predisposes Middle-Age Male Offspring Baboons to an Obese Phenotype That Emerges With Aging.

INTRODUCTION: Women threatening premature delivery receive synthetic glucocorticoids (sGC) to accelerate fetal lung maturation, reducing neonatal mortality and morbidity. Few investigations have explored potential long-term offspring side effects. We previously reported increased pericardial fat and liver lipids in 10-year-old (human equivalent 40 years) male baboons exposed to 3 antenatal sGC courses. We hypothesized middle-aged sGC male offspring show obesity-related morphometric changes. METHODS: Pregnant baboons received courses of 2 betamethasone injections (175 µg·kg-1·d-1 intramuscular) at 0.6, 0.64, and 0.68 gestation. At 10 to 12.5 years, we measured morphometrics and serum lipids in 5 sGC-exposed males and 10 age-matched controls. We determined whether morphometric parameters predicted amount of pericardial fat or lipids. Life-course serum lipids were measured in 25 males (7-23 years) providing normal regression formulas to compare sGC baboons' lipid biological and chronological age. RESULTS: Birth weights were similar. When studied, sGC-exposed males showed a steeper weight increase from 8 to 12 years and had increased waist and hip circumferences, neck and triceps skinfolds, and total and low-density lipoprotein cholesterol. Triceps skinfold correlated with apical and midventricular pericardial fat thickness, hip and waist circumferences with insulin. CONCLUSIONS: Triceps skinfold and waist and hip circumferences are useful biomarkers for identifying individuals at risk for obesity and metabolic dysregulation following fetal sGC exposure. Prenatal sGC exposure predisposes male offspring to internal adiposity, greater body size, and increased serum lipids. Results provide further evidence for developmental programming by fetal sGC exposure and call attention to potential emergence of adverse life-course effects.

Role of pregnancy and obesity on vitamin D status, transport, and metabolism in baboons.

Human studies show that obesity is associated with vitamin D insufficiency, which contributes to obesity-related disorders. Our aim was to elucidate the regulation of vitamin D during pregnancy and obesity in a nonhuman primate species. We studied lean and obese nonpregnant and pregnant baboons. Plasma 25-hydroxy vitamin D (25-OH-D) and 1α,25-(OH)2-D metabolites were analyzed using ELISA. Vitamin D-related gene expression was studied in maternal kidney, liver, subcutaneous fat, and placental tissue using real-time PCR and immunoblotting. Pregnancy was associated with an increase in plasma bioactive vitamin D levels compared with nonpregnant baboons in both lean and obese groups. Pregnant baboons had lower renal 24-hydroxylase CYP24A1 protein and chromatin-bound vitamin D receptor (VDR) than nonpregnant baboons. In contrast, pregnancy upregulated the expression of CYP24A1 and VDR in subcutaneous adipose tissue. Obesity decreased vitamin D status in pregnant baboons (162 ± 17 vs. 235 ± 28 nM for 25-OH-D, 671 ± 12 vs. 710 ± 10 pM for 1α,25-(OH)2-D; obese vs. lean pregnant baboons, P < 0.05). Lower vitamin D status correlated with decreased maternal renal expression of the vitamin D transporter cubulin and the 1α-hydroxylase CYP27B1. Maternal obesity also induced placental downregulation of the transporter megalin (LRP2), CYP27B1, the 25-hydroxylase CYP2J2, and VDR. We conclude that baboons represent a novel species to evaluate vitamin D regulation. Both pregnancy and obesity altered vitamin D status. Obesity-induced downregulation of vitamin D transport and bioactivation genes are novel mechanisms of obesity-induced vitamin D regulation.

Effect of maternal obesity on fetal and postnatal baboon (Papio species) early life phenotype.

BACKGROUND: Non-human primate models of developmental programming by maternal obesity (MO) are needed for translation to human programming outcomes. We present baboon offspring (F1) morphometry, blood cortisol, and adrenocorticotropic hormone (ACTH) from 0.9 gestation to 0-2 years. METHODS: Control mothers ate chow; MO mothers ate high-fat high-energy diet pre-pregnancy through lactation. RESULTS: Maternal obesity mothers weighed more than controls pre-pregnancy. Maternal obesity gestational weight gain was lower with no correlation with fetal or placenta weights. At 0.9 gestation, MO and control F1 morphometry and ACTH were similar. MO-F1 0.9 gestation male cortisol was lower, rising slower from 0-2 years vs control-F1. At birth, male MO-F1 and control-F1 weights were similar, but growth from 0-2 years was steeper in MO-F1; newborn female MO-F1 weighed more than control-F1 but growth from 0-2 years was similar. ACTH did not change in either sex. CONCLUSIONS: Maternal obesity produced sexually dimorphic fetal and postnatal growth and hormonal phenotypes.

Ageing changes in biventricular cardiac function in male and female baboons (Papio spp.).

KEY POINTS: Life course changes in cardiovascular function in a non-human primate have been comprehensively characterized. Age-related declines in normalized left ventricular stroke volume and cardiac output were found with corresponding decreases in biventricular ejection fractions and filling rates. There were age-related decreases in male and female baboon normalized left ventricular myocardial mass index, which declined at similar rates. Systolic functional declines in right ventricular function were observed with age, similar to the left ventricle. Sex differences were found in the rates and directions of right ventricular volume changes along with decreased end-systolic right ventricular sphericity. The results validate the baboon as an appropriate model for translational studies of cardiovascular functional decline with ageing. ABSTRACT: Previous studies reported cardiac function declines with ageing. This study determined changes in biventricular cardiac function in a well-characterized baboon model. Cardiac magnetic resonance imaging measured key biventricular parameters in 47 baboons (22 female, age 4-23 years). ANCOVA assessed sex and age changes with P < 0.05 deemed significant. Stroke volume, cardiac output and other cardiac functional parameters were normalized to body surface area. There were similar, age-related rates of decrease in male (M) and female (F) normalized left ventricular (LV) myocardial mass index (M: -1.2 g m-2  year-1 , F: -0.9 g m-2  year-1 ). LV ejection fraction declined at -0.96% year-1 (r = -0.43, P = 0.002) and right ventricular (RV) ejection fraction decreased at -1.2% year-1 (r = -0.58, P < 0.001). Normalized LV stroke volume fell at -1.1 ml m-2  year-1 (r = -0.47, P = 0.001), normalized LV ejection rate at -3.8 ml s-1  m-2  year-1 (r = -0.43, P < 0.005) and normalized LV filling rate at -4.1 ml s-1  m-2  year-1 (r = -0.44, P < 0.005). Also, RV wall thickening fraction decreased with age (slope = -1% year-1 , P = 0.008). RV ejection rate decreased at -3.6 ml s-1  m-2  year-1 (P = 0.002) and the normalized average RV filling rate dropped at -3.7 ml s-1  m-2  year-1 (P < 0.0001). End-systolic RV sphericity index also dropped with age (r = -0.33, P = 0.02). Many observed changes parallel previously reported data in human and animal studies. These measured biventricular functional declines in hearts with ageing from the closest experimental primate species to man underscore the utility of the baboon model for investigating mechanisms related to heart ageing.

Reproductive cycling in adult baboons (Papio species) that were intrauterine growth restricted at birth implies normal fertility but increased psychosocial stress.

We investigated menstrual cycles in intrauterine growth restricted (IUGR, 7-10 years, n = 8) and age-matched control (n = 10) baboons. Cycle duration and plasma anti-Mullerian hormone were similar. IUGR spent more days per cycle swollen and had elevated early morning fasted serum cortisol, suggesting normal fertility in the presence of increased psychosocial stress.

Maternal nutrient restriction in baboon programs later-life cellular growth and respiration of cultured skin fibroblasts: a potential model for the study of aging-programming interactions.

Compelling data exist for programming of chronic later-life diseases and longevity by perinatal developmental programming challenges. Understanding mechanisms by which life course health trajectory and longevity are set is fundamental to understanding aging. Appropriate approaches are needed to determine programming effects on cellular function. We have developed a baboon model in which control mothers eat ad libitum while a second group eat 70% of the global diet fed controls, leading to male and female offspring intrauterine growth restriction (IUGR). We have shown that IUGR suffer from acceleration of several age-related physiological declines. Here, we report on a skin-derived fibroblast model with potential relevance for mechanistic studies on how IUGR impacts aging. Fibroblasts were cultured from the skin biopsies taken from adult baboons from control and IUGR cohorts. IUGR-derived fibroblasts grew in culture less well than controls and those derived from male, but not female, IUGR baboons had a significant reduction in maximum respiration rate compared to control-derived fibroblasts. We also show that relative levels of several mitochondrial protein subunits, including NDUFB8 and cytochrome c oxidase subunit IV, were reduced in IUGR-derived fibroblasts even after serial passaging in culture. The lower levels of electron transport system components provide potential mechanisms for accelerated life course aging in the setting of programmed IUGR. This observation fits with the greater sensitivity of males compared with females to many, but not all, outcomes in response to programming challenges. These approaches will be powerful in the determination of programming-aging interactions.

Maternal activity, anxiety, and protectiveness during moderate nutrient restriction in captive baboons (Papio sp.).

BACKGROUND: We hypothesized that maternal nutrient restriction (NR) would increase activity and behavioral indicators of anxiety (self-directed behaviors, SDBs) in captive baboons (Papio sp.) and result in more protective maternal styles. METHODS: Our study included 19 adult female baboons. Seven females ate ad libitum (control group), and eight females ate 30% less (NR group) and were observed through pregnancy and lactation. RESULTS: Control females engage in higher rates of SDB than NR females overall (P ≤ .018) and during the prenatal period (P ≤ .001) and engage in more aggressive behavior (P ≤ .033). Control females retrieved infants more than NR females during weeks 5-8 postpartum (P ≤ .019). CONCLUSIONS: Lower SDB rates among prenatal NR females reduce energy expenditure and increase available resources for fetal development when nutritionally restricted. Higher infant retrieval rates by controls may indicate more infant independence rather than maternal style differences.