Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease.

Objective: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.

Methods: Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches.

TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51.

DNA damage tolerance (DDT) and homologous recombination (HR) stabilize replication forks (RFs). RAD18/UBC13/three prime repair exonuclease 2 (TREX2)-mediated proliferating cell nuclear antigen (PCNA) ubiquitination is central to DDT, an error-prone lesion bypass pathway. RAD51 is the recombinase for HR.

A Lipidomics View of Circadian Biology.

Lipidomics approaches provide quantitative characterization of hundreds of lipid species from biological samples. Recent studies highlight the value of these methods in studying circadian biology, and their potential goes far beyond studying lipid metabolism per se. For example, lipidomics analyses of subcellular compartments can be used to determine daily rhythmicity of different organelles and their intracellular dynamics.

Development of a Geropathology Grading Platform for nonhuman primates.

A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist.

The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression.

A repertoire of T cells with diverse antigen receptors is selected in the thymus. However, detailed mechanisms underlying this thymic positive selection are not clear. Here we show that the CCR4-NOT complex limits expression of specific genes through deadenylation of mRNA poly(A) tails, enabling positive selection.

Assessing acceptability and patient experience of a behavioral lifestyle intervention using fitbit technology in older adults to manage type 2 diabetes amid COVID-19 pandemic: A focus group study.

Type 2 diabetes (T2D) contributes to reduced quality of life in older adults, especially in those with comorbidities such as being overweight or obese. Personal fitness technology (Fitbit ®) has the potential to improve the management of T2D. Using a semi-structured interview guide, focus groups were conducted to explore participants' acceptability and experiences following a behavioral lifestyle intervention that integrated Fitbit in overweight/obese older adults with T2D amid the COVID-19 pandemic which began during the time of this study.

Axon Injury-Induced Autophagy Activation Is Impaired in a Model of Tauopathy.

Autophagy is a conserved pathway that plays a key role in cell homeostasis in normal settings, as well as abnormal and stress conditions. Autophagy dysfunction is found in various neurodegenerative diseases, although it remains unclear whether autophagy impairment is a contributor or consequence of neurodegeneration. Axonal injury is an acute neuronal stress that triggers autophagic responses in an age-dependent manner.

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation.

A geriatrics walking clinic improves hemoglobin A1c and timed gait in older veterans with type 2 diabetes.

Over one quarter of older adults in the U.S. has diabetes; and, physical activity is important for the promotion of healthy aging in this population.

Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes.

Diabetic neuropathy is a major complication of diabetes. Current treatment options alleviate pain but do not stop the progression of the disease. At present, there are no approved disease-modifying therapies.

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only.

Rapamycin Extends Life Span in Apc Colon Cancer FAP Model.

Background: We previously showed that lifelong rapamycin treatment of short-lived Apc mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. Apc mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (Apc-DSS model).

Materials And Methods: We asked, what effect would pretreatment of Apc mice with chronic rapamycin prior to DSS exposure have on survival and colonic neoplasia?

Results: Forty-two ppm enteric formulation of rapamycin diet exacerbated the temporary weight loss associated with DSS treatment in both sexes.

A randomized controlled trial of a home-based exercise program on prognostic biomarkers in men with prostate cancer: A study protocol.

Background: Herein, we propose a novel RCT study to collect preliminary data on the impact of a 24-week home-based exercise program that can improve prognosis, physical function, and quality of life (QoL) in men with prostate cancer (PCa). This study will provide data on the feasibility of conducting a home-based exercise study and pilot data on the impact of exercise on circulating concentrations of biomarkers reported in the literature to be beneficial for the prognostication of PCa.

Methods/design: Thirty male patients, clinically-diagnosed with prostate cancer under active surveillance, will be recruited to participate in a 2-arm, 24-week home-based program Random allocation to each arm - intervention, and control - will be performed in a 1:1 ratio.

is associated with longevity independent of Alzheimer's disease.

Although the ε2 allele of apolipoprotein E () benefits longevity, its mechanism is not understood. The protective effects of the 2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound effects on longevity. Herein, we showed that the association between and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models.

Leptin Receptors in RIP-Cre Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice.

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified.

Primary neuron and astrocyte cultures from postnatal Callithrix jacchus: a non-human primate in vitro model for research in neuroscience, nervous system aging, and neurological diseases of aging.

The ability to generate in vitro cultures of neuronal cells has been instrumental in advancing our understanding of the nervous system. Rodent models have been the principal source of brain cells used in primary cultures for over a century, providing insights that are widely applicable to human diseases. However, therapeutic agents that showed benefit in rodent models, particularly those pertaining to aging and age-associated dementias, have frequently failed in clinical trials.

RECOGNITION AND AVOIDANCE OF ION SOURCE-GENERATED ARTIFACTS IN LIPIDOMICS ANALYSIS.

Lipid research is attracting more and more attention as various key roles and novel biological functions of lipids have been demonstrated and discovered in the organism. Mass spectrometry (MS)-based lipidomics approaches are the most powerful and effective tools for analysis of cellular lipidomes with very high sensitivity and specificity. However, the artifacts generated from in-source fragmentation are always present in all kinds of ion sources, even soft ionization techniques (i.

Canagliflozin extends life span in genetically heterogeneous male but not female mice.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death.

Sexual trauma uniquely associated with eating disorders: A replication study.

Extensive research supports the contention that trauma exposure is a nonspecific risk factor for the development of eating disorders (EDs). Limited research has investigated the relative association of diverse types of traumatic events with EDs in the same statistical model. In a recent exception, Breland et al.

Docosahexaenoic Acid (DHA) Supplementation Alters Phospholipid Species and Lipid Peroxidation Products in Adult Mouse Brain, Heart, and Plasma.

The abundance of docosahexaenoic acid (DHA) in phospholipids in the brain and retina has generated interest to search for its role in mediating neurological functions. Besides the source of many oxylipins with pro-resolving properties, DHA also undergoes peroxidation, producing 4-hydroxyhexenal (4-HHE), although its function remains elusive. Despite wide dietary consumption, whether supplementation of DHA may alter the peroxidation products and their relationship to phospholipid species in brain and other body organs have not been explored sufficiently.

Analysis of monohexosyl alkyl (alkenyl)-acyl glycerol in brain samples by shotgun lipidomics.

Lipid species possess very different structures, leading to their very diversified cellular functions in biological systems. Lipidomics represents a powerful technology for deep analysis of hundreds to thousands of intact lipid molecular species. In the current study, a cluster of unknown ion peaks was displayed when we profiled cerebroside species in rat spinal cord samples by neutral loss scan of 162 Da in the positive ion mode using a multi-dimensional mass spectrometry-based shotgun lipidomics strategy.

Generation of Lung and Thyroid Tissues from Embryonic Stem Cells Using Blastocyst Complementation.

The regeneration and replacement of lung cells or tissues from induced pluripotent stem cell- or embryonic stem cell-derived cells represent future therapies for life-threatening pulmonary disorders but are limited by technical challenges to produce highly differentiated cells able to maintain lung function. Functional lung tissue-containing airways, alveoli, vasculature, and stroma have never been produced via directed differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells. We sought to produce all tissue components of the lung from bronchi to alveoli by embryo complementation.

Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer's disease.

Clinical studies show that cerebral amyloid angiopathy (CAA) associated with Alzheimer's disease (AD) and arterial hypertension are independent risk factors for cerebral microhemorrhages (CMHs). To test the hypothesis that amyloid pathology and hypertension interact to promote the development of CMHs, we induced hypertension in the Tg2576 mouse model of AD and respective controls by treatment with angiotensin II (Ang II) and the NO synthesis inhibitor L-NAME. The number, size, localization, and neurological consequences (gait alterations) of CMHs were compared.

A Detergent-Free Method for Preparation of Lipid Rafts for the Shotgun Lipidomics Study.

Lipid rafts are microdomains on plasma membrane that contain high levels of cholesterol and sphingolipids. Because of the detergent-resistant property of lipid rafts, lipid rafts isolated by methods that use detergents frequently yield different results. Artifacts can also be introduced through the use of detergents.