Obstructive sleep apnea (OSA) is a common clinical disorder and is linked to health-related morbidity. Positive airway pressure (PAP) reverses OSA-related hypoxia, yet less than half of patients are adherent to PAP treatment. Insulin-like growth factor 1 (IGF-1) is a neuropeptide that promotes neuronal growth and is essential for normal brain development. IGF-1 is reduced in OSA and may relate to improvement in symptoms following PAP treatment. This relationship has not yet been determined in a young cohort of patients with OSA. This was a prospective, observational study of 58 males, diagnosed with OSA. Auto-titrating PAP (APAP) was used as the treatment intervention. Adherence with APAP was objectively measured, as well as changes in the apnea-hypopnea index (AHI). I collected blood samples to determine changes in concentrations of IGF-1 and compiled clinical data regarding APAP usage and treatment responses. I then assessed these changes through one-way analysis of variance (ANOVA) analysis. There were 58 participants, all males, mean age 36.2±7.7, BMI 31.4±3.7, apnea-hypopnea index 19.1±19.2. There were no clinical differences between the APAP adherent and non-adherent groups. APAP adherence was achieved in 23 (39.7%); their usage of 5.7±0.9 hours was elevated compared to non-adherent patients at 1.1±1.8 hours (p< 0.001). IGF-1 concentrations at baseline were similar between APAP adherent and APAP non-adherent participants; however, at follow-up, adherent participants had concentrations of IGF-1 that were significantly higher than non-adherent participants (p <0.01). Young adult males with OSA who are adherent with APAP have increases in IGF-1 which could lead to improvements in brain functioning and overall quality of life. IGF-1 is a potential biomarker of adequate treatment of OSA and could be used to help in the assessment of proper treatment.

Pancreatic islets are comprised of ß cells that secrete insulin in response to glucose to maintain glucose homeostasis. The renin-angiotensin system is a regulatory hormone system active in many organs. Angiotensin (1-7) (Ang(1-7)), a product of the renin-angiotensin system, enhances glucose-stimulated insulin secretion (GSIS) in a rat model of type 2 diabetes. Since Ang(1-7) is cleaved into angiotensin (1-4) (Ang(1-4)) by neprilysin (NEP), an enzyme present in islets, it remains unknown whether Ang(1-7) or Ang(1-4) is responsible for enhancing GSIS. We sought to determine whether under normal conditions, absence of NEP attenuates the ability of Ang(1-7) to promote GSIS, and whether Ang(1-4) per se enhances GSIS. We cultured Wild-type or NEP deficient mouse islets for 48 hours in the absence (vehicle) or presence of 1 nM Ang(1-7) or 1 nM Ang(1-4) (4-7 experiments). We then measured insulin secretion in response to 2.8 mM (basal) and 20 mM (GSIS) glucose. Ang(1-7) enhanced GSIS in wild-type islets [Ang(1-7) 93.4±10.0 vs. Vehicle 59.0±6.8 pM/5 islets/h; p<0.05] but failed to do so in Nep deficient islets [Ang(1-7) 135.4±17.4 vs. Vehicle 145.1±23.1 pM/5 islets/h; p>0.05]. Ang(1-4) also enhanced GSIS in wild-type islets [Ang(1-7) 105.3±17.5 vs. Vehicle 44.9±9.5 pM/5 islets/h; p<0.05], while neither Ang(1-7) nor Ang(1-4) significantly altered basal insulin secretion from islets of either genotype. In conclusion, NEP is required for the increase in GSIS mediated by Ang(1-7), suggesting that a NEP-derived cleavage product of Ang(1-7) is responsible for its beneficial effects on ß-cell function. The enhancement of GSIS by Ang(1-4) supports this notion, suggesting that Ang(1-4) may be a novel therapeutic approach to improve GSIS in type 2 diabetes.

Circadian rhythms such as the sleep-wake cycle and rhythms of hormonal release are regulated by biological clocks within the brain. Because these clocks have a period of about 24 hours, they need to be synchronized (or entrained) to the solar day by 24-h cyclic environmental input. Although the light-dark cycle is typically the strongest synchronizer, several studies have shown that the restriction of food access to a few hours a day can act as a stronger synchronizer than light. Under these conditions the suprachiasmatic nucleus (SCN) of the hypothalamus, which contains the master circadian oscillator that regulates circadian rhythms, stops regulating the timing of rest and activity. This regulation is instead achieved by other circadian oscillators entrained by restricted food access, allowing rodents to anticipate a predictable daily mealtime. The location of these food-entrainable oscillators (FEOs) in the brain remains unknown. To identify the putative location of the FEO, we divided the rats under a normal 12:12 light-dark cycle into 3 groups: Group 1 had access to food 2 hours during the day, group 2 had access to food 2 hours during the night, and group 3 had access to food 2 hours during the day the night. I carried out in situ hybridizations targeted to the clock genes PER2 and BMAL1, whose circadian expression is essential to sustain a normal circadian rhythmicity. To quantify the mRNA levels for each gene, I then exposed the brain slices hybridized with radioactive probes specific to each gene to X-ray-sensitive films and measured the optical densities within the dorsomedial hypothalamus and the SCN. The results show that the temporal pattern of expression of Bmal1 and Per2 mRNAs within both the SCN and the DMH are affected by the feeding schedule in opposite ways, suggesting that the DMH may contain an FEO.

Tyrosinemia Type II is a genetic disorder caused by a mutation in the enzyme tyrosine aminotransferase (TAT), which leads to an elevated level of tyrosine in the blood. If untreated, individuals with tyrosinemia develop life-threatening clinical symptoms that include an increased tendency to bleed, damage to the nervous system, damage to the eyes, and organ failure. Unexpectedly, mutation of TAT in the nematode Caenorhabditis elegans results in animals that are long lived in comparison with wild-type (WT) worms. This study aims to elucidate the cellular mechanism and workings of TAT in the mitochondria, its role in the pathology of the disease, and its possible links with aging in C. elegans. Thus far, we have developed a simple method to measure the CO2 output of the worms and shown that the TAT mutant’s metabolism is about 50% compared to WT. This significant decrease in CO2 output was matched comparable to a strain deficient for mitochondrial Cytochrome C Oxidase, which served as a positive control. Cytochrome C Oxidase, or Electron Transport Chain Complex IV, is one of the three complexes that create the proton gradient inside the mitochondrial matrix upon accepting electrons. Notably, mutation of the gene acting downstream to TAT in the tyrosine degradation pathway, which causes Tyrosinemia Type III in people, or any other mutation in tyrosine metabolism that we have tested, causes no significant change in CO2 output of C. elegans. Furthermore, through our preliminary metabolomics assay we have identified three metabolites that are accumulated to extremely high levels in comparison to positive and negative controls. The future steps will include determining whether these metabolites play a direct role in the effects of TAT mutation on mitochondrial function and aging.

Aging research depends on the use of model organisms to test hypotheses about the biological mechanisms common to many organisms. One commonly used model organism is the roundworm Caenorhabditis elegans. Unlike homeothermic mammals, C. elegans are poikilotherms, and as a result of a variable internal temperature, they also exhibit variable longevity based on the ambient temperature. Under standard laboratory conditions, C. elegans are commonly grown in incubators ranging between 15°C and 25°C, and lifespan varies inversely with temperature; worms live longer at colder temperatures. Our recent data show that the relationship between temperature and aging has a genetic component. By measuring the lifespan of worm strains with mutations in genes found in established aging pathways, we have identified mutations that have opposing effects on lifespan at different temperatures. For example, utilizing lifespan assays I have conducted, we have found worm strains that live longer than controls at high or low temperature, but not both, as well as strains that are short-lived at specific temperatures. These experiments suggest there may be overlapping but distinct mechanisms driving aging at different temperatures, and we are developing hypotheses to explain the temperature-dependent mechanisms of aging. Thus far, our data are consistent with the hypothesis that genes that contribute to protein homeostasis promote longevity at higher temperatures, whereas genes that limit effects of toxic compounds (both internally and externally produced) promote longevity at low temperatures. Understanding the temperature-dependent mechanisms of aging in C. elegans will advance the aging research field by extending knowledge on a widely used model organism and by testing how the mechanisms of aging and disease may be conserved in homeotherms. We hope our results will suggest how and why many genetic longevity pathways are conserved from worms to mammals despite drastically different life histories.