Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting.

Objective: Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. This review is focused on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch: the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake).

Results And Conclusions: Emerging findings suggest that the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty acid-derived ketones, which serve to preserve muscle mass and function.

Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal.

Parkinson's disease (PD) is characterized by accumulations of toxic α-synuclein aggregates in vulnerable neuronal populations in the brainstem, midbrain, and cerebral cortex. Recent findings suggest that α-synuclein pathology can be propagated transneuronally, but the underlying molecular mechanisms are unknown. Advances in the genetics of rare early-onset familial PD indicate that increased production and/or reduced autophagic clearance of α-synuclein can cause PD.

How does hormesis impact biology, toxicology, and medicine?

Hormesis refers to adaptive responses of biological systems to moderate environmental or self-imposed challenges through which the system improves its functionality and/or tolerance to more severe challenges. The past two decades have witnessed an expanding recognition of the concept of hormesis, elucidation of its evolutionary foundations, and underlying cellular and molecular mechanisms, and practical applications to improve quality of life. To better inform future basic and applied research, we organized and re-evaluated recent hormesis-related findings with the intent of incorporating new knowledge of biological mechanisms, and providing fundamental insights into the biological, biomedical and risk assessment implications of hormesis.

Systolic orthostatic hypotension is related to lowered cognitive function: Findings from the Maine-Syracuse Longitudinal Study.

The aim of the present study was to examine the relationship between orthostatic changes in blood pressure (BP) and cognition, with consideration given to cardiovascular risk factors and lifestyle variables. The cross-sectional analysis included 961 community-dwelling participants of the Maine-Syracuse Longitudinal Study, for whom BP clinic measures (five sitting, five recumbent, and five standing) were obtained. Eighteen percent of participants had orthostatic hypotension (fall in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg upon standing) and 6% had orthostatic hypertension (rise in systolic BP ≥20 mm Hg).

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels).

Age-associated alterations in the levels of cytotoxic lipid molecular species and oxidative stress in the murine thymus are reduced by growth hormone treatment.

During age-associated thymic involution, thymocytes decrease and lipid-laden cells accumulate. However, if and how aging affects the thymic lipid profile is not well understood, nor is it known if the hormonal milieu modifies this process. Here we demonstrate a correlation between reduced thymocyte numbers and markers of inflammation and oxidative stress with age.

SASP regulation by noncoding RNA.

Noncoding RNAs (ncRNAs), including micro (mi)RNAs, long noncoding (lnc)RNAs, and circular (circ)RNAs, control specific gene expression programs by regulating transcriptional, post-transcriptional, and post-translational processes. Through their broad influence on protein expression and function, ncRNAs have been implicated in virtually all cellular processes such as proliferation, senescence, quiescence, differentiation, apoptosis, and the stress and immune responses. Senescence is a cellular phenotype associated with the physiologic decline of aging and with age-related pathologies.

eIF4E phosphorylation by MST1 reduces translation of a subset of mRNAs, but increases lncRNA translation.

Post-transcriptional gene regulation is an important step in eukaryotic gene expression. The last step to govern production of nascent peptides is during the process of mRNA translation. mRNA translation is controlled by many translation initiation factors that are susceptible to post-translational modifications.

LncRNA OIP5-AS1/cyrano suppresses GAK expression to control mitosis.

Some long noncoding RNAs (lncRNAs) can regulate gene expression programs, in turn affecting specific cellular processes. We sought to identify the mechanism through which the lncRNA OIP5-AS1, which is abundant in the cytoplasm, suppressed cell proliferation. Silencing of OIP5-AS1 in human cervical carcinoma HeLa cells triggered the appearance of many aberrant (monopolar, multipolar, misaligned) mitotic spindles.

WIG1 is crucial for AGO2-mediated ACOT7 mRNA silencing via miRNA-dependent and -independent mechanisms.

RNA-binding proteins (RBPs) are involved in mRNA splicing, maturation, transport, translation, storage and turnover. Here, we identified ACOT7 mRNA as a novel target of human WIG1. ACOT7 mRNA decay was triggered by the microRNA miR-9 in a WIG1-dependent manner via classic recruitment of Argonaute 2 (AGO2).

High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs.

High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively stable, their association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression programs. While exoribonuclease treatment is widely used to degrade linear RNAs and enrich circRNAs in RNA samples, it does not efficiently eliminate all linear RNAs.

Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategies have largely been focused on inhibiting the enzymes (β- and γ-secretases) that liberate Aβ from the amyloid precursor protein (APP). While evidence suggests that individuals who exercise regularly are at reduced risk for AD and studies of animal models demonstrate that running can ameliorate brain Aβ pathology and associated cognitive deficits, the underlying mechanisms are unknown.

AUF1 facilitates microRNA-mediated gene silencing.

Eukaryotic mRNA decay is tightly modulated by RNA-binding proteins (RBPs) and microRNAs (miRNAs). RBP AU-binding factor 1 (AUF1) has four isoforms resulting from alternative splicing and is critical for miRNA-mediated gene silencing with a distinct preference of target miRNAs. Previously, we have shown that AUF1 facilitates miRNA loading to Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex.

Whole-Body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor-Deficient Mice.

Whole-body vibration (WBV) has gained attention as a potential exercise mimetic, but direct comparisons with the metabolic effects of exercise are scarce. To determine whether WBV recapitulates the metabolic and osteogenic effects of physical activity, we exposed male wild-type (WT) and leptin receptor-deficient (db/db) mice to daily treadmill exercise (TE) or WBV for 3 months. Body weights were analyzed and compared with WT and db/db mice that remained sedentary.

Biopsychosocial Predictors of Fall Events Among Older African Americans.

This study identifies risk and protective factors for falls among older, community-dwelling African Americans. Drawing upon the biopsychosocial perspective, we conducted a series of sex- and age-adjusted multinomial logistic regression analyses to identify the correlates of fall events among older African Americans. Our sample consisted of 1,442 community-dwelling African Americans aged 65 and older, participating in the 2010-2012 rounds of the Health and Retirement Study.

TIA-1 RRM23 binding and recognition of target oligonucleotides.

TIA-1 (T-cell restricted intracellular antigen-1) is an RNA-binding protein involved in splicing and translational repression. It mainly interacts with RNA via its second and third RNA recognition motifs (RRMs), with specificity for U-rich sequences directed by RRM2. It has recently been shown that RRM3 also contributes to binding, with preferential binding for C-rich sequences.

RNA in extracellular vesicles.

Cells release a range of membrane-enclosed extracellular vesicles (EVs) into the environment. Among them, exosomes and microvesicles (collectively measuring 40-1000 nm in diameter) carry proteins, signaling lipids, and nucleic acids from donor cells to recipient cells, and thus have been proposed to serve as intercellular mediators of communication. EVs transport cellular materials in many physiologic processes, including differentiation, stem cell homeostasis, immune responses, and neuronal signaling.

Mitochondrial noncoding RNA transport.

Mitochondria are cytosolic organelles essential for generating energy and maintaining cell homeostasis. Despite their critical function, the handful of proteins expressed by the mitochondrial genome is insufficient to maintain mitochondrial structure or activity. Accordingly, mitochondrial metabolism is fully dependent on factors encoded by the nuclear DNA, including many proteins synthesized in the cytosol and imported into mitochondria via established mechanisms.

Hemodynamic Determinants of the Short-Term Blood Pressure Variability: Differential Roles of Arterial Stiffness and Wave Reflection.

Background: A high 24-hour ambulatory diastolic (DBP) but not systolic (SBP) blood pressure variability (BPV) is significantly predictive of long-term cardiovascular mortality in untreated hypertensive subjects, independent of office or 24-hour SBP. The present study was aimed to investigate hemodynamic factors that are independently associated with systolic and diastolic BPV from the 24-hour ambulatory blood pressure monitoring (ABPM).

Methods: A cohort of 624 normotensive and 633 untreated hypertensive participants with baseline ABPM was drawn from a community-based survey.

Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal.

Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute brain injuries and in neurodegenerative disorders. Membrane lipid peroxidation contributes to neuronal dysfunction and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that 4-hydroxynonenal (HNE), an aldehyde produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis.

Comorbid Parkinson's disease, falls and fractures in the 2010 National Emergency Department Sample.

Introduction: Parkinson's disease (PD) is a progressive, neurodegenerative disorder of multifactorial etiology affecting ∼1% of older adults. Research focused on linking PD to falls and bone fractures has been limited in Emergency Department (ED) settings, where most injuries are identified. We assessed whether injured U.

RT-qPCR Detection of Senescence-Associated Circular RNAs.

Primary cells that reach the end of their replicative potential, encounter sublethal stress, or experience the activation of certain oncogenes cease proliferation and enter a state of long-term growth arrest named senescence. The senescent process has been implicated in a variety of age-related diseases and also in the pathogenesis of cancer. Senescence is characterized by distinct changes in the types and levels of coding RNAs (mRNAs) as well as in the vast collective of regulatory noncoding (nc)RNAs, which includes microRNAs, long noncoding RNAs (lncRNAs), and circular (circRNAs).

Differential Associations of Socioeconomic Status With Global Brain Volumes and White Matter Lesions in African American and White Adults: the HANDLS SCAN Study.

Objective: The aim of the study was to examine interactive relations of race and socioeconomic status (SES) to magnetic resonance imaging (MRI)-assessed global brain outcomes with previously demonstrated prognostic significance for stroke, dementia, and mortality.

Methods: Participants were 147 African Americans (AAs) and whites (ages 33-71 years; 43% AA; 56% female; 26% below poverty) in the Healthy Aging in Neighborhoods of Diversity across the Life Span SCAN substudy. Cranial MRI was conducted using a 3.

The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons.

SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses.