Enhancing and Extending Biological Performance and Resilience.

Human performance, endurance, and resilience have biological limits that are genetically and epigenetically predetermined but perhaps not yet optimized. There are few systematic, rigorous studies on how to raise these limits and reach the true maxima. Achieving this goal might accelerate translation of the theoretical concepts of conditioning, hormesis, and stress adaptation into technological advancements.

GRSF1 suppresses cell senescence.

A prominent phenotype triggered by the loss of mitochondrial homeostasis is cellular senescence, characterized by cessation of growth and a senescence-associated secretory phenotype (SASP). We identified the G-rich RNA sequence-binding factor 1 (GRSF1) as a major mitochondrial protein implicated in this response. GRSF1 levels declined in senescent cells through reduced protein stability, and lowering GRSF1 abundance caused mitochondrial stress leading to elevated production of superoxide, increased DNA damage foci, and diminished cell proliferation.

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice.

Alzheimer's disease (AD) is characterized by progressive cognitive impairment and by extensive neuronal loss associated with extracellular amyloid β-peptide (Aβ) plaques and intraneuronal tau pathology in temporal and parietal lobes. AD patients are at increased risk for epileptic seizures, and data from experimental models of AD suggest that aberrant neuronal network activity occurs early in the disease process before cognitive deficits and neuronal degeneration. The contributions of Aβ and/or tau pathologies to dysregulation of neuronal network activity are unclear.

SCAMP4 enhances the senescent cell secretome.

The senescence-associated secretory phenotype (SASP) is a major trait of senescent cells, but the molecular regulators of SASP factor secretion are poorly understood. Mass spectrometry analysis revealed that secretory carrier membrane protein 4 (SCAMP4) levels were strikingly elevated on the surface of senescent cells compared with proliferating cells. Interestingly, silencing SCAMP4 in senescent fibroblasts reduced the secretion of SASP factors, including interleukin 6 (IL6), IL8, growth differentiation factor 15 (GDF-15), C-X-C motif chemokine ligand 1 (CXCL1), and IL7, while, conversely, SCAMP4 overexpression in proliferating fibroblasts increased SASP factor secretion.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States.

During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer's and Parkinson's diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging.

The Ultrastructure, Spatial Distribution, and Osmium Tetroxide Binding of Lipofuscin and Melanosomes in Aging Monkey Retinal Epithelium.

Purpose: To examine the ultrastructure of lipofuscin bodies and melanosomes in retinal epithelium of elderly rhesus monkeys and determines changes in their number and morphology as a function of retinal eccentricity.

Methods: Electron microscopy was used to describe and quantify two major organelles in elderly monkey retinal epithelium, lipofuscin bodies and melanosomes, at different retinal loci extending from the macula to the peri-macula, equator, periphery and ora serrata. Osmium tetroxide was used to distinguish lipofuscin bodies from melanosomes.

Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA through Interaction with MicroRNA 29b.

The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown.

The Biology and Therapeutic Implications of Tumor Dormancy and Reactivation.

Advancements in the early detection of cancer coupled with improved surgery, radiotherapy, and adjuvant therapy led to substantial increase in patient survival. Nevertheless, cancer metastasis is the leading cause of death in several cancer patients. The majority of these deaths are associated with metastatic relapse kinetics after a variable period of clinical remission.

Stress granules counteract senescence by sequestration of PAI-1.

Cellular senescence is a physiological response by which an organism halts the proliferation of potentially harmful and damaged cells. However, the accumulation of senescent cells over time can become deleterious leading to diseases and physiological decline. Our data reveal a novel interplay between senescence and the stress response that affects both the progression of senescence and the behavior of senescent cells.

Notch signaling and neuronal death in stroke.

Ischemic stroke is a leading cause of morbidity and death, with the outcome largely determined by the amount of hypoxia-related neuronal death in the affected brain regions. Cerebral ischemia and hypoxia activate the Notch1 signaling pathway and four prominent interacting pathways (NF-κB, p53, HIF-1α and Pin1) that converge on a conserved DNA-associated nuclear multi-protein complex, which controls the expression of genes that can determine the fate of neurons. When neurons experience a moderate level of ischemic insult, the nuclear multi-protein complex up-regulates adaptive stress response genes encoding proteins that promote neuronal survival, but when ischemia is more severe the nuclear multi-protein complex induces genes encoding proteins that trigger and execute a neuronal death program.

Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability.

Gene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post-transcription, and post-translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear.

A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3'UTR mechanism.

Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBPβ through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBPβ activation is inhibited by G/U-rich elements (GREs) in its 3'UTR. This mechanism, termed "3'UTR regulation of protein activity" (UPA), maintains C/EBPβ in a low-activity state in tumor cells and thus facilitates senescence bypass.

Deficiency of Toll-like receptors 2, 3 or 4 extends life expectancy in Huntington's disease mice.

Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by progressive striatal and cortical atrophy, has been strongly linked with neuroinflammation. Toll-like receptors, a family of innate immune receptors, are a major pathway for neuroinflammation with pleiotropic effects on neuronal plasticity and neurodevelopment. We assessed whether deficiency for TLRs 2, 3 or 4 affects life expectancy in the N171-82Q mouse model of HD.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain.

Objective: Brain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case-control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD-related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.

Methods: J-modulated Point-Resolved Spectroscopy (J-PRESS) and Prior-Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.

Cytoplasmic functions of long noncoding RNAs.

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides found throughout the cell that lack protein-coding function. Their functions are closely linked to their interaction with RNA-binding proteins (RBPs) and nucleic acids. Nuclear lncRNAs have been studied extensively, revealing complexes with structural and regulatory roles that enable gene organization and control transcription.

Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis.

Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknown. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels.

Noncoding RNAs in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs for preventing and treating AD, no effective therapies are available as yet, posing a growing burden at the personal, medical, and socioeconomic levels. AD is characterized by the production and aggregation of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP), the presence of hyperphosphorylated microtubule-associated protein Tau (MAPT), and chronic inflammation leading to neuronal loss.

Analysis of Circular RNAs Using the Web Tool CircInteractome.

Circular RNAs (circRNAs) are generated through nonlinear back splicing, during which the 5' and 3' ends are covalently joined. Consequently, the lack of free ends makes them very stable compared to their counterpart linear RNAs. By selectively interacting with microRNAs and RNA-binding proteins (RBPs), circRNAs have been shown to influence gene expression programs.

Intermittent metabolic switching, neuroplasticity and brain health.

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease.

Combination Therapy with Low-Dose IVIG and a C1-esterase Inhibitor Ameliorates Brain Damage and Functional Deficits in Experimental Ischemic Stroke.

Acute ischemic stroke causes a high rate of deaths and permanent neurological deficits in survivors. Current interventional treatment, in the form of enzymatic thrombolysis, benefits only a small percentage of patients. Brain ischemia triggers mobilization of innate immunity, specifically the complement system and Toll-like receptors (TLRs), ultimately leading to an exaggerated inflammatory response.

Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes.