Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms.

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role.

Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice.

Background: Treatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products.

Mammalian Target of Rapamycin at the Crossroad Between Alzheimer's Disease and Diabetes.

Accumulating evidence suggests that Alzheimer's disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer's disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer's disease (Haaksma et al, PLoS One 12(5):e0177044, 2017).

Acute alcohol and cognition: Remembering what it causes us to forget.

Addiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders, it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry.

Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.

Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient.

Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc complex function.

Of the four separate PE biosynthetic pathways in eukaryotes, one occurs in the mitochondrial inner membrane (IM) and is executed by phosphatidylserine decarboxylase (Psd1). Deletion of Psd1 is lethal in mice and compromises mitochondrial function. We hypothesize that this reflects inefficient import of non-mitochondrial PE into the IM.

Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis.

Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood.

Tutorial on lipidomics.

The mainstream of lipidomics involves mass spectrometry-based, systematic, and large-scale studies of the structure, composition, and quantity of lipids in biological systems such as organs, cells, and body fluids. As increasingly more researchers in broad fields are beginning to pay attention to and actively learn about the lipidomic technology, some introduction on the topic is needed to help the newcomers to better understand the field. This tutorial seeks to introduce the basic knowledge about lipidomics and to provide readers with some core ideas and the most important approaches for studying the field.

Glycine supplementation extends lifespan of male and female mice.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program.

Rationale and Study Design of a Randomized Clinical Trial of Metformin to Prevent Frailty in Older Adults With Prediabetes.

Background: Frailty is a geriatric syndrome that leads to poor health outcomes with aging. Previous studies have demonstrated that insulin resistance and inflammation predict frailty onset. Metformin is a widely used, well-tolerated drug that improves insulin sensitivity and displays anti-inflammatory properties.

Review of Interventions for the Frailty Syndrome and the Role of Metformin as a Potential Pharmacologic Agent for Frailty Prevention.

Purpose: Frailty is a syndrome of vulnerability and physical decline with aging that increases risk for disability, hospitalizations, and death. To date, interventions for frailty have primarily focused on exercise and/or nutritional interventions, many of which show improvement in frailty-related characteristics, such as gait speed and lower extremity strength and function. The goal of this article was to review prior research studies investigating interventions for frailty and review the literature with regard to the role of insulin resistance and inflammation in the development of frailty.

Cardiolipin remodeling by ALCAT1 links mitochondrial dysfunction to Parkinson's diseases.

Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for membrane structure, respiration, dynamics, and mitophagy. Oxidative damage of CL by reactive oxygen species is implicated in the pathogenesis of Parkinson's disease (PD), but the underlying cause remains elusive. This work investigated the role of ALCAT1, an acyltransferase that catalyzes pathological remodeling of CL in various aging-related diseases, in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP).

Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis.

Background & Aims: Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases.

Genetically heterogeneous mice exhibit a female survival advantage that is age- and site-specific: Results from a large multi-site study.

The female survival advantage is a robust characteristic of human longevity. However, underlying mechanisms are not understood, and rodent models exhibiting a female advantage are lacking. Here, we report that the genetically heterogeneous (UM-HET3) mice used by the National Institute on Aging Interventions Testing Program (ITP) are such a model.

Models and Studies of Aging: Executive Summary of a Report from the U13 Conference Series.

The American Geriatrics Society convened a conference in Bethesda, Maryland, to explore models and studies of aging. This was the second of three conferences, supported by a U13 grant from the National Institute on Aging, to aid recipients of Grants for Early Medical/Surgical Specialists Transition to Aging Research (GEMSSTAR) in integrating geriatrics into their specialties. Recognizing that aging is the largest risk factor for multiple chronic diseases and age-related loss of resilience, the conference organizers focused scientific sessions on how targeting age-related mechanisms can delay, prevent, or reverse geriatric syndromes, age-related chronic diseases, and loss of resilience.

Acarbose improves health and lifespan in aging HET3 mice.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses.

Rapamycin and Alzheimer's disease: Time for a clinical trial?

The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer's disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer's disease. We argue that such clinical trials should be undertaken.

Cross-sectional comparison of health-span phenotypes in young versus geriatric marmosets.

The development of the marmoset as a translational model for healthspan and lifespan studies relies on the characterization of health parameters in young and geriatric marmosets. This cross-sectional study examined health phenotypes in marmosets for five domains of interest for human health and aging: mobility, cognition, metabolism, homeostasis, and immune function. Geriatric marmosets were found to have significant executive function impairment when compared to young animals.

Optimization of Differentiation of Nonhuman Primate Pluripotent Cells Using a Combinatorial Approach.

The directed differentiation of pluripotent stem cells to a desired lineage often involves complex and lengthy protocols. In order to study the requirements for differentiation in a systematic way, we present here methodology for an iterative approach using combinations of small molecules and biological factors. The factors are used in a cyclical process in which the best combination of factors and concentrations is selected in one round of testing, followed by a modification of the combination and subsequent rounds.

Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF-16 in C. elegans.

Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age-related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity.

Age-related changes in myelin of axons of the corpus callosum and cognitive decline in common marmosets.

Executive control is a higher-level cognitive function that involves a range of different processes that are involved in the planning, coordination, execution, and inhibition of responses. Many of the processes associated with executive control, such as response inhibition and mental flexibility, decline with age. Degeneration of white matter architecture is considered to be the one of the key factors underlying cognitive decline associated with aging.

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

Background: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.

Aging research using the common marmoset: Focus on aging interventions.

Traditional animal models have been used to make seminal discoveries in biomedical research including a better understanding of the biology of the aging process. However, translation of these findings from laboratory to clinical populations has likely been hindered due to fundamental biological and physiological differences between common laboratory animals and humans. Non-human primates (NHP) may serve as an effective bridge towards translation, and short-lived NHP like the common marmoset offer many advantages as models for aging research.