Late‐life time‐restricted feeding and exercise differentially alter healthspan in obesity

Aging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time‐restricted feeding (TRF) benefit multiple health parameters when initiated in early life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet‐induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.     

Lipophilic ionophore complexes as superoxide dismutase mimetics

A wide range of metal ion complexes exhibit superoxide dismutase like activities as detected by inhibition of nitroblue tetrazolium reduction. Mn(II) and Cu(II) complexes of EDTA, EHPG, and EGTA exhibit SOD like activities commensurate with many of the purpose-built SOD mimics. Here, we report analogous lipophilic chelators that localise metal ions (Cu(II), Mn(II), and Fe(III)) in the lipid membranes and lipoproteins to protect them from superoxide mediated oxidative damage. Spectroscopic titrations and Jobs method confirm that both 1:1 and 2:1 metal ion monensin complexes form. The cupric complexes are the most active exhibiting IC(50) values of 0.09 and 0.18 microM for 2Cu(II)-monensin and Cu(II)-monensin, respectively, for superoxide destruction. In addition, the IC(50) value for Mn(II)-monensin is 0.31 microM. In conclusion, Mn(II) and Cu(II) complexes of the ionophore monensin exhibit considerable superoxide scavenging activities and represent a novel class of catalytic antioxidants for the protection of lipid structures.     

Social behavior of Matschie's tree kangaroos (Dendrolagus matschiei) and its implications for captive management

Social behavior was studied in four (one male and three females) adult, captivebred Matschie's tree kangaroos (Dendrolagus matschiei) over a 124 day span in a large, naturalistic exhibit at the Woodland Park Zoological Gardens, Seattle, WA. A relatively high rate of social interaction occurred (15.2 per hour), over half of which consisted of approaches and nose contacts. The male initiated 54.1% of all social behaviors. Females tended to respond aggressively toward the male (avoid, bite, cuff, or swipe). The male initiated more affiliative behaviors and the females initiated more agonistic behaviors toward both the male and other females. A clear-cut dominance hierarchy could not be determined; reversals (i.e., cases in which the “subordinate” supplanted the “dominant”) occurred 43% of the time overall. Non-aggressive contact behavior consisted primarily of olfactory examination (nose contact). Allogrooming was extremely rare. The high level of agonism and lack of consistent association among individuals suggests that this species may be solitary in the wild. Two joeys were found dead on the floor during the course of the study, and based on previous findings, infanticide or behavioral stress was suspected to be the cause. Successful reproduction did not occur until females were isolated by removing other conspecifics from the enclosure.     

Rapid determination of vapA/vapB genotype in Rhodococcus equi using a differential polymerase chain reaction method

Rhodococcus equi is a facultative pathogen of foals. Infection causes an often fatal pulmonary pneumonia. The organism has also been isolated from pigs, cattle, humans and the environment. Equine virulence has a high positive correlation with the expression of a 17.4 kD polypeptide of unknown function, VapA, the product of the plasmid-encoded vapA gene. More recently an isogene of vapA, referred to as vapB and encoding an 18.2 kDa polypeptide, has been identified among pig and human isolates. The two genes share > 80% sequence identity, yet their host strains apparently exhibit different pathogenicity profiles (for example by reference to virulence in mouse model system and host specificity). In this study, a polymerase chain reaction (PCR) technique was developed that permits the selective amplification of vapA and vapB. Using this technique the distribution of the two genes among 35 randomly selected isolates of Rhodococcus equi from various animal and environmental sources was determined. Using this technique the genotype of each isolate could be unambiguously assigned as vapA+, vapB+ or vap- (i.e., scoring negative for both vapA and vapB). No isolate scored positive for both vapA and vapB. 100% of equine isolates scored vapA+, confirming the status of vapA as a reliable marker of equine virulence. All three genotypes were found among human isolates; porcine isolates scored either vapB+ or vap- and no vapA+ isolates were present in this sample. Rigorous statistical analysis using the Fisher Exact test confirmed that the high frequency of vapA+ among equine isolates is significant; however the sample size was too small to draw statistically significant conclusions regarding the distribution of genotypes among within other animal groups.     

Randomized single oral dose phase 1 study of safety,tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects

BackgroundUV-4 (N-(9’-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions.Methodology/Principal findingsHere we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT02061358","term_id":"NCT02061358"}}NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5–1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses.Conclusions/SignificanceUV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported and no subjects were withdrawn from the study due to treatment-emergent adverse events. These data suggest that therapeutically relevant drug levels of UV-4 can be safely administered to humans and support further clinical development of UV-4 hydrochloride or other candidate antivirals in the iminosugar class.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02061358","term_id":"NCT02061358"}}NCT02061358 https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02061358","term_id":"NCT02061358"}}NCT02061358.