Subtyping Social Determinants of Health in : Network Analysis and Visualization Approach.

Background: Social determinants of health (SDoH), such as financial resources and housing stability, account for between 30-55% of people's health outcomes. While many studies have identified strong associations among specific SDoH and health outcomes, most people experience multiple SDoH that impact their daily lives. Analysis of this complexity requires the integration of personal, clinical, social, and environmental information from a large cohort of individuals that have been traditionally underrepresented in research, which is only recently being made available through the research program.

Patient Engagement and Attitudes Toward Using the Electronic Medical Record for Medical Research: The 2015 Greater Plains Collaborative Health and Medical Research Family Survey.

Background: Electronic health records (EHRs) are ubiquitous. Yet little is known about the use of EHRs for prospective research purposes, and even less is known about patient perspectives regarding the use of their EHR for research.

Objective: This paper reports results from the initial obesity project from the Greater Plains Collaborative that is part of the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network (PCORNet).

A System for an Accountable Data Analysis Process in R.

Efficiently producing transparent analyses may be difficult for beginners or tedious for the experienced. This implies a need for computing systems and environments that can efficiently satisfy reproducibility and accountability standards. To this end, we have developed a system, R package, and R Shiny application called adapr (Accountable Data Analysis Process in R) that is built on the principle of accountable units.

Estimate risk difference and number needed to treat in survival analysis.

The hazard ratio (HR) is a measure of instantaneous relative risk of an increase in one unit of the covariate of interest, which is widely reported in clinical researches involving time-to-event data. However, the measure fails to capture absolute risk reduction. Other measures such as number needed to treat (NNT) and risk difference (RD) provide another perspective on the effectiveness of an intervention, and can facilitate clinical decision making.

DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans.

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan.

Liver specific expression of Cu/ZnSOD extends the lifespan of Sod1 null mice.

Genetic ablation of CuZn-superoxide dismutase (Sod1) in mice (Sod1(-/-) mice) leads to shortened lifespan with a dramatic increase in hepatocellular carcinoma and accelerated aging phenotypes, including early onset sarcopenia. To study the tissue specific effects of oxidative stress in the Sod1(-/-) mice, we generated mice that only express the human SOD1 gene specifically in the liver of Sod1(-/-) mice (Sod1(-/-)/hSOD1(alb) mice). Expression of hSOD1 in the liver of Sod1(-/-) mice improved liver function, reduced oxidative damage in liver, and partially restored the expression of several genes involved in tumorigenesis, which are abnormally expressed in the livers of the Sod1(-/-) mice.

Mitochondrial metabolites extend lifespan.

Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long-lived respiratory mutants generate elevated amounts of α-ketoacids. These compounds are structurally related to α-ketoglutarate, suggesting they may be biologically relevant.

Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice.

Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.

Background: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models.

Short-term rapamycin treatment in mice has few effects on the transcriptome of white adipose tissue compared to dietary restriction.

Rapamycin, a drug that has been shown to increase lifespan in mice, inhibits the target of rapamycin (TOR) pathway, a major pathway that regulates cell growth and energy status. It has been hypothesized that rapamycin and dietary restriction (DR) extend lifespan through similar mechanisms/pathways. Using microarray analysis, we compared the transcriptome of white adipose tissue from mice fed rapamycin or DR-diet for 6 months.

Negative elongation factor controls energy homeostasis in cardiomyocytes.

Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress.

Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome.

Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis.

Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver.

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups.

Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice.

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing.

Rapamycin extends life and health in C57BL/6 mice.

Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later.

Dietary restriction attenuates the accelerated aging phenotype of Sod1(-/-) mice.

Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the antiaging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1(-/-) mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1(-/-) mice 30%, returning it to that of wild-type, control mice fed ad libitum.

Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors.

Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice.

Probing the relationship between insulin sensitivity and longevity using genetically modified mice.

Interference in insulin and/or insulin-like growth factor 1 (IGF-1) signaling can extend invertebrate life span, and interference in IGF-1 signaling can extend murine life span. Whether interference with murine insulin signaling, which can be diabetogenic and pathological, is also life-extending is controversial. We therefore measured life span in 3 murine strains genetically modified to reduce or increase insulin sensitivity.

Profiling the anaerobic response of C. elegans using GC-MS.

The nematode Caenorhabditis elegans is a model organism that has seen extensive use over the last four decades in multiple areas of investigation. In this study we explore the response of the nematode Caenorhabditis elegans to acute anoxia using gas-chromatography mass-spectrometry (GC-MS). We focus on the readily-accessible worm exometabolome to show that C.

Rapamycin selectively alters serum chemistry in diabetic mice.

The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed.

Effects of diet on synaptic vesicle release in dynactin complex mutants: a mechanism for improved vitality during motor disease.

Synaptic dysfunction is considered the primary substrate for the functional declines observed within the nervous system during age-related neurodegenerative disease. Dietary restriction (DR), which extends lifespan in numerous species, has been shown to have beneficial effects on many neurodegenerative disease models. Existing data sets suggest that the effects of DR during disease include the amelioration of synaptic dysfunction but evidence of the beneficial effects of diet on the synapse is lacking.

Does reduced IGF-1R signaling in Igf1r+/- mice alter aging?

Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo-insufficiency of the IGF-1 receptor (Igf1r(+/-)) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r(+/-) mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r(+/-) mice show reduced IGF-1 signaling.

PGC-1α protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model.

Introduction: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We sought to determine whether peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) would have a beneficial effect on this disease.

Methods: PGC-1α transgenic mice were crossed with SOD1 mutant G93A DL mice.

Thioredoxin 1 overexpression extends mainly the earlier part of life span in mice.

We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)(+/0)]. The Tg(TRX1)(+/0) mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)(+/0) mice compared with wild-type littermates.

Dietary restriction but not rapamycin extends disease onset and survival of the H46R/H48Q mouse model of ALS.

Dietary restriction (DR) and rapamycin (Rapa) have been shown to increase the lifespan of a variety of organisms leading to the speculation that these interventions increase lifespan through related mechanisms. However, both these interventions have a detrimental effect in the G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). Our previous work indicated that different ALS SOD1 mutant mouse models differ in disease pathogenesis; therefore in this study we measured the effect of DR and Rapa in a second ALS mutant mouse model (the H46R/H48Q mutant).