REST
RE1-silencing transcription factor (Neural-restrictive silencer factor) (X2 box repressor) [NRSF] [XBR]
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In rodents, well characterized neurogenic niches of the adult brain, such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus, support the maintenance of neural/stem progenitor cells (NSPCs) and the production of new neurons throughout the lifespan. The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation. At the same time, it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli. A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging, injury or disease. At the core of the molecular mechanisms regulating neurogenesis, several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues. Here, we focus on REST, Egr1 and Dbx2 and their roles in adult neurogenesis, especially in the subventricular zone. We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche. We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain. Finally, we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis.
Keywords
- adult neurogenesis
- aging
- extracellular signaling
- gene regulation
- neural stem/progenitor cells
- transcription factors
Providing plausible strategies for brain aging protection should be a critical concern for countries with large elderly populations including Japan. Age-related cognitive impairments and movement disorders, such as Alzheimer's and Parkinson's diseases, are caused by neurodegeneration that primarily initiates in the hippocampus and the midbrain substantia nigra, respectively. Neurons are postmitotic, and therefore, the accuracy of cellular metabolism should be crucial for maintaining neural functions throughout their life. Thus accuracy of protein synthesis is a critical concern in discussing mechanisms of aging. The essence of the so-called "error catastrophe theory" of aging was on the fidelity of ribosomal translation and/or aminoacylation of tRNA. There is evidence that reduced protein synthesis accuracy results in neurodegeneration. Similarly, reduced proteostasis via autophagy and proteasomes in aging is crucial for protein quality control and well documented as a risk for aging. In both neurodegeneration and protein quality controls, various proteins are involved in their regulation, but recent evidence suggests that repressor element-1 silencing transcription factor (REST) could be a master regulatory protein that is crucial for orchestrating the neural protecting events in human brain aging. REST is induced in the aged brain, and protects neurons against oxidative stress and protein toxicity. Interestingly, REST is identical with neuron-restrictive silencer factor (NRSF), the master regulator of neural development. Thus NRSF/REST play important roles in both neurogenesis and neurodegeneration. In this review, I summarize the interesting scientific crossover, and discuss the potential use of NRSF/REST as a pharmaceutical target for controlling aging, particularly in relation to brain aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Brain
- Gene Expression
- Gene Expression Regulation, Developmental
- Humans
- Neurodegenerative Diseases
- Protein Biosynthesis
- Repressor Proteins
- Ribosomes
Keywords
- aging
- brain
- gene expression
- neurodegeneration
- ribosome
- translational fidelity
Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of REST on cognitive impairment of diabetes was explored for the first time. It was found that the expression of REST in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased REST/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Blood Glucose
- Body Weight
- Brain
- Brain-Derived Neurotrophic Factor
- Cognitive Dysfunction
- Diabetes Mellitus, Experimental
- Exploratory Behavior
- Male
- Memory Disorders
- Mice
- Palmitic Acid
- Repressor Proteins
- Social Behavior
- Spatial Memory
- Stearic Acids
Keywords
- 9-PAHSA
- BDNF
- Diabetes mellitus
- REST
Reduced levels of neural activity are associated with a longer life span in the nematode [i]Caenorhabditis elegans[/i] and in mice. Augmented neural activity is associated with a shorter life span. Recent studies show that levels of repressor element 1-silencing transcription factor (REST) increase with normal aging in mice and humans, and reduce neuronal excitation. In [i]C. elegans,[/i] increased expression of [i]spr-4[/i], a functional REST homologue, increased the worm life span and is required for classical life span increase mediated by reduced DAF-2/insulin-IGF-1 and increased DAF-16. Preliminary evidence shows that REST and FOXO1, a DAF-16, homologue increase during mammalian aging, and that REST activity is needed for the age-related FOXO1 increase. On the contrary, REST is activated in epilepsy and plays a role in the pathogenesis of Huntington's disease. A simple unifying hypothesis suggests that REST is a "goldilocks-effect factor": too little REST promotes excitotoxic activity, which in turn leads to neurodegenerative diseases such as Alzheimer's. Appropriate increased levels of REST maintain the excitation/inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of REST beyond this are toxic as neurons become dysfunctional due to loss of a neuronal phenotype.
MeSH Terms
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Homeostasis
- Longevity
- Repressor Proteins
- Signal Transduction
Keywords
- life span
- neuronal activity
- neurotoxicity
The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST.
MeSH Terms
- Aging
- Animals
- Brain
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- DNA-Binding Proteins
- Forkhead Transcription Factors
- Humans
- Longevity
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Neurons
- RNA Interference
- RNA-Binding Proteins
- Repressor Proteins
- Transcription Factors
In heart period (HP) variability (HPV) recordings the percentage of negative HP variations tends to be greater than that of positive ones and this pattern is referred to as HPV asymmetry (HPVA). HPVA has been studied in several experimental conditions in healthy and pathological populations, but its origin is unclear. The baroreflex (BR) exhibits an asymmetric behavior as well given that it reacts more importantly to positive than negative arterial pressure (AP) variations. We tested the hypothesis that the BR asymmetry (BRA) is a HPVA determinant over spontaneous fluctuations of HP and systolic AP (SAP). We studied 100 healthy subjects (age from 21 to 70 yr, 54 men) comprising 20 subjects in each age decade. Electrocardiogram and noninvasive AP were recorded for 15 min at rest in supine position (REST) and during active standing (STAND). The HPVA was evaluated via Porta's index and Guzik's index, while the BRA was assessed as the difference, and normalized difference, between BR sensitivities computed over positive and negative SAP variations via the sequence method applied to HP and SAP variability. HPVA significantly increased during STAND and decreased progressively with age. BRA was not significantly detected both at REST and during STAND. However, we found a significant positive association between BRA and HPVA markers during STAND persisting even within the age groups. This study supports the use of HPVA indexes as descriptors of BRA and identified a challenge soliciting the BR response like STAND to maximize the association between HPVA and BRA markers.
MeSH Terms
- Adult
- Aged
- Arterial Pressure
- Baroreflex
- Female
- Heart
- Heart Rate
- Humans
- Male
- Middle Aged
- Young Adult
Keywords
- aging
- autonomic nervous system
- baroreflex sensitivity
- cardiovascular control
- heart rate variability
- postural challenge
Pterostilbene (Pt; trans-3,5-dimethoxy-4'-hydroxystilbene) is a natural phenol found in blueberries and grapevines. It shows remarkable biomedical activities similar to those of resveratrol. Its high bioavailability is a major advantage for possible biomedical applications. The goal of the study was to evaluate the effects of chronic pterostilbene administration on cognitive performance in aged rats with mild cognitive impairment. 18-month-old animals were subjected to behavioral tests to establish the "baseline", then divided into treatment and control groups. The former were chronically fed Pt (22.5 mg/kg-day) for 20 consecutive days. At the end of this period all animals were tested again and sacrificed. The dentate gyrus, the hippocampus and the prefrontal and perirhinal cortices were then collected, and RT-qPCR and/or Western blot analyses were performed on a few transcripts/proteins involved in synaptic remodeling. Mitochondrial content was also assessed. Pt administration improved performance in behavioral tests and positively affected memory consolidation. We found increased levels of REST, PSD-95 and mitochondrial porin1 in the dentate gyrus and a positive correlation between T-maze test score and levels of cAMP responsive element binding protein (CREB) phosphorylation. These results underscore the therapeutic potential of Pt supplementation for age-related cognitive decline.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- CREB-Binding Protein
- Cognition
- Cognitive Dysfunction
- Dentate Gyrus
- Disks Large Homolog 4 Protein
- Maze Learning
- Rats
- Repressor Proteins
- Stilbenes
Keywords
- Aging
- Cognitive decline
- Object in context
- Object recognition
- Pterostilbene
- Synaptic plasticity
- T-maze
Probabilistic causality (PC) is a framework for checking that the occurrence of a cause raises the probability of the effect by comparing the probability of the effect conditioned and unconditioned to the cause. Even though it is less frequently utilized with respect to the more traditional model-based Wiener-Granger causality (WGC) that is based on the predictability improvement of an effect resulting from the inclusion of the presumed cause in the multivariate linear regression model, PC has the advantage of being model-free. The aim of the study is to apply the PC framework to assess the evolution of cardiac baroreflex control with age from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and to compare it to the more common WGC approach. We studied 100 healthy humans (54 males, age: 21-70 years, 20 subjects for each 10 years bin). HP and SAP were extracted on a beat-to-beat basis from 5 min recordings of electrocardiogram and plethysmographic arterial pressure at rest in supine position (REST) and during active standing (STAND) under spontaneous breathing. The WGC ratio (WGCR) was computed as the log ratio of the prediction error variance of the autoregressive model on HP to that on HP with exogenous SAP. The PC ratio (PCR) was computed as the probability of observing an HP ramp given an associated parallel SAP variation divided by the probability of observing an HP ramp. The WGCR and PCR suggested the gradual impairment of cardiac baroreflex with age, especially during STAND. Moreover, they were significantly associated both at REST and during STAND but the degree of the PCR-WGCR association was weak. PC can be effectively exploited to assess modification of the cardiovascular control during senescence even though a limited agreement was observed with WGC.
MeSH Terms
- Adult
- Aged
- Aging
- Baroreflex
- Electrocardiography
- Female
- Humans
- Male
- Middle Aged
- Models, Cardiovascular
- Models, Statistical
- Plethysmography
- Posture
- Rest
- Young Adult
The antagonistic pleiotropy theory hypothesizes that evolutionary adaptations maximizing the fitness in early age increase disease burden after reproduction. This theory remains largely untested at the molecular level. Here, we analyzed enhancer evolution in primates to investigate the relationships between aging-related diseases and enhancers acquired after the human-chimpanzee divergence. We report a 5-fold increased evolutionary rate of enhancers that are activated in neural tissues, leading to fixation of ∼100 human-specific enhancers potentially under adaptation. These enhancers show prognostic expression levels and correlations with driver genes in cancer, and their nearby genes are enriched in known loci associated with aging-related diseases. Using CRISPR/Cas9, we further functionally validated an enhancer on chr8p23.1 as activator counteracting REST, a master regulator known to be a transcriptional suppressor of Alzheimer disease. Our results suggest an evolutionary origin of aging-related diseases: the side effects of human-specific, neural-tissue expressed enhancers. Thus, adaptive molecular changes in human macroevolution may introduce vulnerabilities to disease development in modern populations.
MeSH Terms
- Adaptation, Biological
- Aging
- Animals
- Biological Evolution
- CRISPR-Cas Systems
- Enhancer Elements, Genetic
- Evolution, Molecular
- Genome, Human
- Hominidae
- Humans
- Neurons
- Pan troglodytes
- Phylogeny
- Primates
Keywords
- Alzheimer disease
- REST
- adaptive change
- cancer genes
- enhancer regulation
- human evolution
- trade-offs
{{medline-entry |title=Influence of age and gender on the phase and strength of the relation between heart period and systolic blood pressure spontaneous fluctuations. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29212671 |abstract=Aging affects baroreflex regulation. The effect of senescence on baroreflex control was assessed from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) through the HP-SAP gain, while the HP-SAP phase and strength are usually disregarded. This study checks whether the HP-SAP phase and strength, as estimated, respectively, via the phase of the HP-SAP cross spectrum (Ph ) and squared coherence function (K ), vary with age in healthy individuals and trends are gender-dependent. We evaluated 110 healthy volunteers (55 males) divided into five age subgroups (21-30, 31-40, 41-50, 51-60, and 61-70 yr). Each subgroup was formed by 22 subjects (11 males). HP series was extracted from electrocardiogram and SAP from finger arterial pressure at supine resting (REST) and during active standing (STAND). Ph and K functions were sampled in low-frequency (LF, from 0.04 to 0.15 Hz) and in high-frequency (HF, above 0.15 Hz) bands. Both at REST and during STAND Ph (LF) showed a negative correlation with age regardless of gender even though values were more negative in women. This trend was shown to be compatible with a progressive increase of the baroreflex latency with age. At REST K (LF) decreased with age regardless of gender, but during STAND the high values of K (LF) were more preserved in men than women. At REST and during STAND the association of Ph (HF) and K (HF) with age was absent. The findings points to a greater instability of baroreflex control with age that seems to affect to a greater extent women than men. NEW