Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques.

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6−7 months.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in , the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls ( = 7.

Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

The rhesus macaque () is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization.

An Emergent Integrated Aging Process Conserved Across Primates.

Aging is a complex process emerging from integrated physiological networks. Recent work using principal component analysis (PCA) of multisystem biomarkers proposed a novel fundamental physiological process, "integrated albunemia," which was consistent across human populations and more strongly associated with age and mortality risk than individual biomarkers. Here we tested for integrated albunemia and associations with age and mortality across six diverse nonhuman primate species and humans.

Conservation of physiological dysregulation signatures of aging across primates.

Two major goals in the current biology of aging are to identify general mechanisms underlying the aging process and to explain species differences in aging. Recent research in humans suggests that one important driver of aging is dysregulation, the progressive loss of homeostasis in complex biological networks. Yet, there is a lack of comparative data for this hypothesis, and we do not know whether dysregulation is widely associated with aging or how well signals of homeostasis are conserved.

Caloric Restriction and Healthy Life Span: Frail Phenotype of Nonhuman Primates in the Wisconsin National Primate Research Center Caloric Restriction Study.

Calorie restriction without malnutrition increases longevity and delays the onset of age-associated disorders in multiple species. Recently, greater emphasis has been placed on healthy life span and preventing frailty than on longevity. Here, we show the beneficial effect of long-term calorie restriction on frailty in later life in a nonhuman primate.

Caloric restriction improves health and survival of rhesus monkeys.

Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect.

Hyperinsulinemia/diabetes, hearing, and aging in the University of Wisconsin calorie restriction monkeys.

The purpose of this study was to determine the effects of hyperinsulinemia/Type 2 diabetes mellitus (HI-T2DM) on hearing impairment using rhesus monkeys to obtain control over diet and lifestyle factors that confound human studies. The study is a retrospective evaluation of rhesus monkeys from the Wisconsin National Primate Research Center (WNPRC) study on caloric restriction and aging. The research questions were the following: 1.

Measurement of 25-hydroxyvitamin D(2&3) and 1,25-dihydroxyvitamin D(2&3) by tandem mass spectrometry: A primate multispecies comparison.

Vitamin D metabolites are widely studied for their roles in bone health, immune functions, and other potential physiologic roles in humans. However, the optimal blood levels of vitamin D metabolites are still unclear. Various methods for measuring vitamin D metabolites have been used and recently liquid chromatography tandem mass spectroscopy (LC-MS/MS) has been adopted as the gold standard for vitamin D metabolite measurement.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys.

Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR's effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood.

Effect of age and calorie restriction on corpus callosal integrity in rhesus macaques: a fiber tractography study.

The rhesus macaque exhibits age-related brain changes similar to humans, making an excellent model of normal aging. Calorie restriction is a dietary intervention that reduces age-related comorbidities in short-lived animals, and its effects are still under study in rhesus macaques. Here, using deterministic fiber tracking method, we examined the effects of age and calorie restriction on a diffusion tensor imaging measure of white matter integrity, fractional anisotropy (FA), within white matter tracks traversing the anterior (genu) and posterior (splenium) corpus callosum in rhesus monkeys.

Development of a sensitive LC/MS/MS method for vitamin D metabolites: 1,25 Dihydroxyvitamin D2&3 measurement using a novel derivatization agent.

Active vitamin D metabolites 1,25-dihydroxyvitamin D2 [1,25-(OH)2-D2; derived from ergocalciferol] and D3 [1,25-(OH)2-D3; derived from cholecalciferol] are found in low levels in the circulation and require a very sensitive method for measurement. Radioimmunoassay (RIA) has been the method of choice, but it lacks the specificity needed to distinguish between 1,25-(OH)2-D2 and -D3, whereas liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods have the advantage of high specificity and sensitivity. Here, we compare a new derivative for ionizing 1,25-(OH)2-D to enhance the signal and provide the most sensitive assay for measuring vitamin D.

Toward more transparent and reproducible omics studies through a common metadata checklist and data publications.

Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies can only be realized through data harmonization, sharing, meta-analysis, and integrated research.

Toward More Transparent and Reproducible Omics Studies Through a Common Metadata Checklist and Data Publications.

Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies can only be realized through data harmonization, sharing, meta-analysis, and integrated research.

Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in rhesus monkeys.

Background: Short-term (<1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (>10 year) effect of CR on these parameters are lacking.

Objective: The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.

Design: Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.

Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study.

While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (∼30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis.

Brain volumetric and microstructural correlates of executive and motor performance in aged rhesus monkeys.

The aged rhesus macaque exhibits brain atrophy and behavioral deficits similar to normal aging in humans. Here we studied the association between cognitive and motor performance and anatomic and microstructural brain integrity measured with 3T magnetic resonance imaging in aged monkeys. About half of these animals were maintained on moderate calorie restriction (CR), the only intervention shown to delay the aging process in lower animals.

Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs.

Objective: To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs.

Animals: 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs.

Procedures: The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index.

A novel gene-environment interaction involved in endometriosis.

Objective: To establish a well-defined cohort for genetic epidemiology studies of endometriosis and conduct a pilot study to confirm validity using existing data associated with endometriosis.

Methods: Between January and May 2010, a nested cohort within a population-based biobank was established in Marshfield, Wisconsin, USA. The inclusion criteria were women who had laparoscopy or hysterectomy.

The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys.

Background: Activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclinical data on the use of the PPAR-γ agonist pioglitazone (Actos®; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates.

Calorie restriction and aging in nonhuman primates.

In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way.

Auditory function in rhesus monkeys: effects of aging and caloric restriction in the Wisconsin monkeys five years later.

Caloric restriction (CR) slows aging in many species and protects some animals from age-related hearing loss (ARHL), but the effect on humans is not yet known. Because rhesus monkeys are long-lived primates that are phylogenically closer to humans than other research animals are, they provide a better model for studying the effects of CR in aging and ARHL. Subjects were from the pool of 55 rhesus monkeys aged 15-28 years who had been in the Wisconsin study on CR and aging for 8-13.

High-quality genomic DNA extraction from formalin-fixed and paraffin-embedded samples deparaffinized using mineral oil.

Extracting DNA from formalin-fixed and paraffin-embedded (FFPE) tissue remains a challenge, despite numerous attempts to develop a more effective method. Polymerase chain reaction (PCR) success rates with DNA extracted using current methods remain low. We extracted DNA from 140 long-term archived FFPE samples using a simple but effective deparaffinization method, removing the wax with mineral oil, and a commercially available DNA extraction kit.