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IMPORTANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models. CASE PRESENTATION: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon (Papio hamadryas), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-ß deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant. CONCLUSIONS AND RELEVANCE: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging.
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OBJECTIVE: Maternal obesity (MO) increases the risk of later-life liver disease in offspring, especially in males. This may be due to impaired cytochrome P450 (CYP) enzyme activity driven by an altered maternal-fetal hormonal milieu. MO increases fetal cortisol concentrations that may increase CYP activity; however, glucocorticoid receptor (GR)-mediated signaling can be modulated by alternative GR isoform expression. We hypothesized that MO induces sex-specific changes in GR isoform expression and localization that contribute to reduced hepatic CYP activity. METHODS: Nonpregnant, nulliparous female baboons were assigned to either an ad libitum control diet or a high-fat, high-energy diet (HF-HED) at 9 months pre pregnancy. At 165 days' gestation (term = 180 days), fetal liver samples were collected (n = 6/sex/group). CYP activity was quantified using functional assays, and GR was measured using quantitative RT-PCR and Western blot. RESULTS: CYP3A activity was reduced in the HF-HED group, whereas CYP2B6 activity was reduced in HF-HED males only. Total GR expression was increased in the HF-HED group. Relative nuclear expression of the antagonistic GR isoform GRß was increased in HF-HED males only. CONCLUSIONS: Reduced CYP activity in HF-HED males may be driven in part by dampened hepatic-specific glucocorticoid signaling via altered GR isoform expression. These findings highlight targetable mechanisms that may reduce later-life sex-specific disease risk.
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The consumption of high fat-high energy diets (HF-HEDs) continues to rise worldwide and parallels the rise in maternal obesity (MO) that predisposes offspring to cardiometabolic disorders. Although the underlying mechanisms are unclear, thyroid hormones (TH) modulate cardiac maturation in utero. Therefore, we aimed to determine the impact of a high fat-high energy diet (HF-HED) on the hormonal, metabolic and contractility profile of the non-human primate (NHP) fetal heart. At â¼9 months preconception, female baboons (Papio hamadryas) were randomly assigned to either a control diet or HF-HED. At 165 days gestational age (term = 184 days), fetuses were delivered by Caesarean section under anaesthesia, humanely killed, and left ventricular cardiac tissue (Control (n = 6 female, 6 male); HF-HED (n = 6 F, 6 M)) was collected. Maternal HF-HED decreased the concentration of active cardiac TH (i.e. triiodothyronine (T3)), and type 1 iodothyronine deiodinase (DIO1) mRNA expression. Maternal HF-HED decreased the abundance of cardiac markers of insulin-mediated glucose uptake phosphorylated insulin receptor substrate 1 (Ser789) and glucose transporter 4, and increased protein abundance of key oxidative phosphorylation complexes (I, III, IV) and mitochondrial abundance in both sexes. Maternal HF-HED alters cardiac TH status, which may induce early signs of cardiac insulin resistance. This may increase the risk of cardiometabolic disorders in later life in offspring born to these pregnancies. KEY POINTS: Babies born to mothers who consume a high fat-high energy diet (HF-HED) prior to and during pregnancy are predisposed to an increased risk of cardiometabolic disorders across the life course. Maternal HF-HED prior to and during pregnancy decreased thyroid hormone triiodothyronine (T3) concentrations and type 1 iodothyronine deiodinase DIO1 mRNA expression in the non-human primate fetal heart. Maternal HF-HED decreased markers of insulin-dependent glucose uptake, phosphorylated insulin receptor substrate 1 and glucose transporter 4 in the fetal heart. Maternal HF-HED increased mitochondrial abundance and mitochondrial OXPHOS complex I, III and IV in the fetal heart. Fetuses from HF-HED pregnancies are predisposed to cardiometabolic disorders that may be mediated by changes in T3, placing them on a poor lifetime cardiovascular health trajectory.
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Dieta Hiperlipídica , Coração Fetal , Animais , Feminino , Gravidez , Dieta Hiperlipídica/efeitos adversos , Coração Fetal/metabolismo , Masculino , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/sangue , Fenômenos Fisiológicos da Nutrição Materna , Papio hamadryas/metabolismoRESUMO
Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid ß-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms.
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There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Accurate measures of chronological aging are essential for inferences into genetic, demographic, and physiological variables driving differences in NHP lifespan within and between species. Understanding NHP lifespans is relevant to public health because unraveling the demographic, molecular, and clinical bases of health across the life course in translationally relevant NHP species is fundamentally important to the study of human aging. Data from more than 110,000 captive individual NHP were contributed by 15 major research institutions to generate sex-specific Kaplan-Meier survival curves using uniform methods in 12 translational aging models: Callithrix jacchus (common marmoset), Chlorocebus aethiops sabaeus (vervet/African green), Macaca fascicularis (cynomolgus macaque), M. fuscata (Japanese macaque), M. mulatta (rhesus macaque), M. nemestrina (pigtail macaque), M. radiata (bonnet macaque), Pan troglodytes spp. (chimpanzee), Papio hamadryas spp. (baboon), Plecturocebus cupreus (coppery titi monkey), Saguinus oedipus (cotton-top tamarin), and Saimiri spp. (squirrel monkey). After employing strict inclusion criteria, primary analysis results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. For the primary analyses, we report ages of 25th, 50th, 75th, and 85th percentiles of survival, maximum observed ages, rates of survivorship, and sex-based differences captured by quantile regression models and Kolmogorov-Smirnov tests. Our findings show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan. Captive NHP used in research are typically euthanized for humane welfare reasons before their natural end of life, often after diagnosis of their first major disease requiring long-term treatment with reduced quality of life (e.g., endometriosis, cancer, osteoarthritis). Supporting the idea that these data are capturing healthspan, for several species typical age at onset of chronic disease is similar to the median lifespan estimates. This data resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. The results clarify the relationships among NHP ages and will provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of the expected survival rates of NHP assigned to studies, providing a metric for comparisons in future studies, and contributing to our understanding of the factors that drive lifespan differences within and among species.
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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.
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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.
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Envelhecimento , Astrócitos , Metabolismo Energético , Fibroblastos , Hepatócitos , Papio , Animais , Fibroblastos/metabolismo , Astrócitos/metabolismo , Feminino , Masculino , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Metabolismo Energético/fisiologia , Hepatócitos/metabolismo , Mitocôndrias/metabolismo , Células CultivadasRESUMO
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.
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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.
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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.
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Disfunção Cognitiva , Multiômica , Humanos , Animais , Feminino , Envelhecimento/psicologia , Transdução de Sinais/genética , Córtex Pré-Frontal/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismoRESUMO
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.
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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.
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Obesidade Materna , Humanos , Animais , Masculino , Feminino , Gravidez , Desmame , Obesidade/metabolismo , Dieta , Músculo Esquelético/metabolismo , Fígado/metabolismo , Estilo de Vida , PuberdadeRESUMO
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.
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Envelhecimento , Pesquisa Biomédica , Animais , Callithrix , Macaca , Papio , PrimatasRESUMO
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.
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Envelhecimento , Velocidade de Caminhada , Animais , Feminino , Masculino , PapioRESUMO
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.
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Capilares , Retardo do Crescimento Fetal , Papio/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Feminino , Masculino , Desnutrição , Fenômenos Fisiológicos da Nutrição Materna , Mucosa Bucal/irrigação sanguínea , Mucosa Bucal/patologia , GravidezRESUMO
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.
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Envelhecimento , Sistema Hipotálamo-Hipofisário/metabolismo , Estado Nutricional , Animais , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Desnutrição , Gravidez , PrimatasRESUMO
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.
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Biologia do Desenvolvimento/métodos , Modelos Animais de Doenças , Macaca/fisiologia , Papio/fisiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Biologia do Desenvolvimento/normas , Biologia do Desenvolvimento/tendências , Feminino , Desenvolvimento Fetal , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reprodutibilidade dos Testes , Projetos de Pesquisa/normas , Projetos de Pesquisa/tendências , Tamanho da Amostra , Fatores SexuaisRESUMO
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.
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Peso Corporal , Dieta Hiperlipídica , Lactação/fisiologia , Papio/fisiologia , Gravidez/fisiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Feminino , Masculino , FenótipoRESUMO
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.
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Hormônio Adrenocorticotrópico/sangue , Hidrocortisona/sangue , Obesidade Materna/complicações , Papio , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos/fisiologia , Feminino , Feto/fisiopatologia , Fenótipo , Gravidez , SoroRESUMO
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.