Protein synthesis in slowed aging: insights into shared characteristics of long-lived mouse models

2014 Spring.The following dissertation describes a series of experiments with the overall aim to understand the role that changes in protein synthesis have in slowed aging. The specific aims of the three sets of experiments were 1) to determine if chronic administration of the mTORC1 inhibitor rapamycin to mice increases proteostatic mechanisms in skeletal muscle, heart, and liver; 2) to determine if an underdeveloped anterior pituitary, caused by deletion of the Pit-1 gene in mice, increases proteostatic mechanisms in skeletal muscle, heart, and liver of long-lived Snell dwarf mice; 3) and to determine if transient nutrient restriction during the suckling period in mice (i.e. crowded litter), increases proteostatic mechanisms in skeletal muscle, heart, and liver later in life. In Experiment #1 we found that mitochondrial proteins were preferentially synthesized in skeletal muscle and that global protein synthesis in the heart was maintained despite reduced cellular proliferation and mTORC1 activity in mice fed rapamycin compared to normal diet controls. Originally we determined that these data were indicative of an improved somatic maintenance of skeletal muscle mitochondria and the heart proteome. Since we could not account for changes to other energetic processes (e.g. metabolism), we reasoned that our data was more consistent with proteostasis, a component of somatic maintenance. In Experiment #2 we developed a novel method for assessing proteostasis and determined that Snell dwarf mice had an increase in proteostatic mechanisms across sub-cellular fractions within skeletal muscle and heart compared control mice, despite differential rates of protein synthesis in the face of decreased mTORC1. Together with our previous investigations into rapamycin fed and caloric restriction models of long-life we concluded that increased proteostatic mechanisms may be a shared characteristic of models of slowed aging. In Experiment #3 we demonstrate that the crowded litter mouse transitions from growth to maintenance as it ages. Furthermore, in the crowded litter mouse, we demonstrate that proteostasis is not dependent upon decreased mTORC1. Our results indicate that decreased mTORC1 does not necessarily correlate to decreases in protein synthesis across all sub-cellular fractions. Discerning which proteins and the mechanism(s) of how specific proteins can be preferentially synthesized despite decreases in protein synthesis in other fractions and decreased mTORC1, may give further insight into characteristics of slowed aging. Further, we demonstrate that increases in proteostasic mechanisms are a shared characteristic of multiple unique models of slowed aging and therefore, provides a basis for future work aimed at slowing the aging process

Epidemiology of Myocardial Infarction

Coronary heart disease (CHD) is the leading cause of morbidity and mortality throughout the world. The most common form of CHD is the myocardial infarction. It is responsible for over 15% of mortality each year, among the vast majority of people suffering from non-ST-segment elevation myocardial infarction (NSTEMI) than ST-segment elevation myocardial infarction (STEMI). The prevalence of myocardial infarction (MI) is higher in men in all age-specific groups than women. Although the incidence of MI is decreased in the industrialized nations partly because of improved health systems and implementation of effective public health strategies, nevertheless the rates are surging in the developing countries such as South Asia, parts of Latin America, and Eastern Europe. The modifiable risk factors represent over 90% of the risk for acute MI. The risk factors such as dyslipidemia, smoking, psychosocial stressors, diabetes mellitus, hypertension, obesity, alcohol consumption, physical inactivity, and a diet low in fruits and vegetables were strongly associated with acute MI

Nutritional Condition and Physiological Stress Levels of Elk in the Black Hills, South Dakota

Percent of body fat and physiological stress are important correlates to wildlife demographics. We studied winter percent of body fat and physiological stress levels for a declining elk (Cervus canadensis nelsoni) population in South Dakota, 2011–2013. We obtained percent of winter body fat, pregnancy status, lactation status, and physiological stress data from 58 adult females (2+ years old). We compared physiological stress level data from 2011 with data collected from this same herd when elk densities were much higher (1995–1997). Our objectives were to determine percent of body fat during winter, examine if winter body fat was correlated with pregnancy and lactation status, and quantify and compare physiological stress hormone values from elk in the mid-1990s. Probability of being pregnant increased with higher winter nutritional condition, or percent of body fat; whereas females with a higher probability of previously lactating were lower in winter body fat. Mean fecal glucocorticoid metabolite (FGM) levels in 2011 (mean = 47.78 ng/g, SE = 2.37) were higher during summer compared to data collected in 1995–1997 (mean = 34.21 ng/g, SE = 3.71); however, mean FGM levels during winter did not differ between the two time periods. Although summer levels of FGM have significantly increased since the mid-1990s, we caution against any interpretation of increased FGM levels on elk fitness, as it may not infer biological significance. Mean winter percent of body fat of elk was lower when compared to other populations in the west but this difference does not appear to be limiting vital rates and population growth for this elk herd. We recommend future research focus on summer/autumn data collection to provide a more comprehensive understanding of percent of body fat for elk in our region

Characteristics of successful puma kill sites of elk in the Black Hills, South Dakota

Elk Cervus canadensis nelsoni in the Black Hills, South Dakota, have been declining since 2006 and there is concern by resource managers and hunters that puma Puma concolor predation may be contributing to declining herds. We evaluated characteristics at sites where puma successfully killed elk in the Black Hills of South Dakota. We evaluated characteristics at coarse (79-ha plots) and fine (0.2-ha plot) scales across the landscape. Our primary objective was to obtain a better understanding of vegetation and terrain characteristics that may have facilitated greater susceptibility of elk to predation by puma. We evaluated effects of road density, terrain heterogeneity, probability of elk use, and vegetation variables at 62 puma kill sites of elk and 186 random sites to identify key landscape attributes where elk were killed by puma. Elk were killed by puma in high use areas. Elk were also killed in areas that had greater amounts of edge and intermediate ruggedness at the coarse scale. Further, elk were killed in areas with greater small tree density and woody debris at the fine scale. High germination rates of ponderosa pine trees are unique to the Black Hills and provide dense patches of cover for puma. We hypothesize that cover from small trees and woody debris provided conditions where puma could stalk elk in areas with optimal security cover for elk. We suggest managers implement vegetation management practices that reduce small tree density and woody debris in areas with greater density of meadow—forest edge if they are interested in potentially diminishing hiding cover for puma in elk high use areas

Effects of radiotransmitters on fecal glucocorticoid metabolite levels of three-toed box turtles in captivity

The increased use of radio-telemetry for studying movement, resource selection, and population demographics in reptiles necessitates closer examination of the assumption that radiotransmitter attachment does not bias study results. We determined the effects of radiotransmitter attachment on fecal glucocorticoid metabolite levels of wild three-toed box turtles (Terrapene carolina triunguis) in captivity. During May 2002 we captured 11 adult three-toed box turtles in central Missouri. We housed turtles in individual pens in a semi-natural outdoor setting. We radio-tagged 6 turtles, and the remaining 5 turtles served as controls. We captured and handled all turtles similarly during treatments. We collected feces daily prior to attachment (14 June–05 July 2002), while transmitters were attached (06 July–02 August 2002), and after transmitters were removed (03 August–24 August 2002). We conducted a standard assay validation and found that the assay accurately and precisely quantified fecal glucocorticoid metabolites of box turtles. We did not find a significant effect of radiotransmitter attachment on fecal glucocorticoid metabolite levels of three-toed box turtles (F1, 9 =0.404, P=0.541). Fecal glucocorticoid metabolite levels of control and treatment turtles increased significantly during the study (F2,166=7.874, P= 0.001), but there was no treatment:period interaction (F2,166 = 0.856, P = 0.427). Additionally, we did not find a significant relationship between glucocorticoid metabolite levels and time in captivity (r2=0.01, F1,179=2.89, P=0.091) or maximum daily temperature (r2\u3c0.01, F1,179=0.301, P=0.584). Our results suggested that radiotransmitter attachment did not significantly increase fecal glucocorticoid metabolite levels in adult three-toed box turtles; however, we conducted our study in captivity and sample sizes were small. Thus, more research is needed to assess potential effects of radiotransmitters on turtles in the wild. We believe this study is the first to validate the use of fecal glucocorticoid metabolite measures for reptiles, which might prove useful in other research studies

Treating Type 2 Diabetes with Therapeutic Carbohydrate Restriction

This chapter gives clinicians the tools to use therapeutic carbohydrate restriction as a dietary intervention for type 2 diabetes patients. The chapter is divided into three section, each addressing a different aspect of therapeutic carbohydrate restriction (TCR). Section 1 delves into the background of carbohydrate restriction, nutrition physiology, the three levels of therapeutic carbohydrate restriction physiological, and metabolic rationale for using TCR to treat the symptoms of type 2 diabetes. Section two explains how to start TCR in a patient population. It goes over which patients are good candidates for TCR and which ones should be approached with caution when implementing this dietary change and explains the importance of baseline assessments. Section three spells out how to administer and manage TCR in a clinical setting. It covers behavior change support, patient education on TCR principles, medication adjustments during the early stages of the intervention, and anticipating and treating common side effects

Can a Point-of-Care Troponin I Assay be as Good as a Central Laboratory Assay? A MIDAS Investigation.

BACKGROUND: We aimed to compare the diagnostic accuracy of the Alere Triage Cardio3 Tropinin I (TnI) assay (Alere, Inc., USA) and the PathFast cTnI-II (Mitsubishi Chemical Medience Corporation, Japan) against the central laboratory assay Singulex Erenna TnI assay (Singulex, USA). METHODS: Using the Markers in the Diagnosis of Acute Coronary Syndromes (MIDAS) study population, we evaluated the ability of three different assays to identify patients with acute myocardial infarction (AMI). The MIDAS dataset, described elsewhere, is a prospective multicenter dataset of emergency department (ED) patients with suspected acute coronary syndrome (ACS) and a planned objective myocardial perfusion evaluation. Myocardial infarction (MI) was diagnosed by central adjudication. RESULTS: The C-statistic with 95% confidence intervals (CI) for diagnosing MI by using a common population (n=241) was 0.95 (0.91-0.99), 0.95 (0.91-0.99), and 0.93 (0.89-0.97) for the Triage, Singulex, and PathFast assays, respectively. Of samples with detectable troponin, the absolute values had high Pearson (R(P)) and Spearman (R(S)) correlations and were R(P)=0.94 and R(S)=0.94 for Triage vs Singulex, R(P)=0.93 and R(S)=0.85 for Triage vs PathFast, and R(P)=0.89 and R(S)=0.73 for PathFast vs Singulex. CONCLUSIONS: In a single comparative population of ED patients with suspected ACS, the Triage Cardio3 TnI, PathFast, and Singulex TnI assays provided similar diagnostic performance for MI

Political Expression and Action on Social Media:Exploring the Relationship Between Lower- and Higher-Threshold Political Activities Among Twitter Users in Italy

Scholars and commentators have debated whether lower‐threshold forms of political engagement on social media should be treated as being conducive to higher‐threshold modes of political participation or a diversion from them. Drawing on an original survey of a representative sample of Italians who discussed the 2013 election on Twitter, we demonstrate that the more respondents acquire political information via social media and express themselves politically on these platforms, the more they are likely to contact politicians via e‐mail, campaign for parties and candidates using social media, and attend offline events to which they were invited online. These results suggest that lower‐threshold forms of political engagement on social media do not distract from higher‐threshold activities, but are strongly associated with them