FAS
Tumor necrosis factor receptor superfamily member 6 precursor (Apo-1 antigen) (Apoptosis-mediating surface antigen FAS) (FASLG receptor) (CD95 antigen) [APT1] [FAS1] [TNFRSF6]
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Mesenchymal stem cells (MSCs) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair MSC function. However, little is currently known about how aged MSCs affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of MSC function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα) MSCs, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of MSC function showed that the expression of surface antigen markers for MSCs (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged MSCs were significantly declined compared to those of young MSCs. Moreover, a significantly higher proportion of aged MSCs were positive for the senescence-associated β galactosidase activity. Importantly, aged MSCs presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged MSCs to induce T cell apoptosis in co-cultures compared with young MSCs. In summary, this is the first study showing that aging-induced impairment of MSC function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration.
Keywords
- aging
- bone resorption
- immunomodulation
- mesenchymal stem cell
- periodontitis
- tissue destruction
Obesity and hyperlipidemia are independent risk factors of chronic kidney disease (CKD). In mice, diet induced obesity accelerates lipogenesis, lipid accumulation, and injury in kidneys. Expression of adenoviral protein, E4orf1, improves glucose clearance and reduces endogenous insulin secretion to glucose challenge in mice. Therefore, in this pilot study, we examined, if enhanced glycemic control in HFD fed E4orf1 transgenic (E4orf1-Tg) mice, will reduce renal lipogenesis and lipid accumulation. In two separate experiments, E4orf1-Tg mice were fed 60% (kcal) high-fat diet (HFD) supplemented with doxycycline for 10-weeks or 20-weeks along with wild-type (C57BL6/J) or E4orf1-non-transgenic (E4orf1-non-Tg) control mice, respectively. Protein expression of Fatty Acid Synthase (FAS) and Acetyl-CoA Carboxylase (ACC), accumulation of triglyceride (TG) along with mRNA levels of lipid metabolism and injury markers were determined in kidneys. Renal expression of FAS and ACC, and TG content was significantly reduced in E4orf1-Tg mice compared to controls. E4orf1-Tg mice show significant increase in genes involved in mitochondrial fatty acid oxidation and oxidative stress compared to wild-type mice after 10-weeks of HFD. However, mice exposed to 20-weeks of HFD, show no difference in gene expression. E4orf1 expression reduces lipid synthesis and accumulation in kidneys despite HFD, which may be due to attenuation of hyperinsulinemia by E4orf1.
Keywords
- Aging
- CKD
- Diabetes
- Diet
- E4orf1
- FA synthesis
- Hyperinsulinemia
- Insulin
- Lipid metabolism
- Obesity
To identify age-related changes in maximum tongue pressure (MTP), it is necessary to determine individual biological age. The fitness age score (FAS) is used to calculate the biological age, based on the one-leg standing time with eyes open, vertical jump height, grip strength, functional reach, and 10-m walk time. The study included 112 community-dwelling elderly adults (42 males and 70 females). We investigated MTP, FAS, and body mass index (BMI) at baseline and 5 years later. MTP was determined with a pressure measurement device. A significant reduction in MTP, FAS, and BMI in both male and female subjects was observed at 5 years. A negative correlation between change in MTP and baseline MTP was observed, but there was no correlation between MTP change and baseline FAS, BMI, and change in FAS and BMI. Age-related decline in MTP might be associated with high MTP, reflecting decreased reserve. Additionally, age-related decline in tongue function might be different from that of physical function.
Keywords
- Aging
- Biological age
- Elderly
- Physical function
- Tongue pressure
We have recently reported that epigallocatechin gallate (EGCG) could extend lifespan in healthy rats. This study aimed to investigate the effects and mechanisms of a high dose of EGCG in extending the lifespan of obese rats. Ninety adult male Wistar rats were randomly divided into the control (NC), high-fat (HF) and EGCG groups. Serum glucose and lipids, inflammation and oxidative stress were dynamically determined from adulthood to death, and the transcriptome and proteome of the liver were also examined. The median lifespans of the NC, HF and EGCG groups were 693, 599 and 683 days, respectively, and EGCG delayed death by 84 days in obese rats. EGCG improved serum glucose and lipids and reduced inflammation and oxidative stress associated with aging in obese rats induced by a high-fat diet. EGCG also significantly decreased the levels of total free fatty acids (FFAs), SFAs and the n-6/n-3 ratio but significantly increased the n-3 FFAs related to longevity. The joint study of the transcriptome and proteome in liver found that EGCG exerted its effects mainly by regulating the suppression of hydrogen peroxide and oxygen species metabolism, suppression of oxidative stress, activation of fatty acid transport and oxidation and cholesterol metabolism. EGCG significantly increased the protein expression of FOXO1, Sirt1, CAT, FABP1, GSTA2, ACSL1 and CPT2 but significantly decreased NF-κB, ACC1 and FAS protein levels in the livers of rats. All the results indicate that EGCG extends lifespan by improving FFA metabolism and reducing the levels of inflammatory and oxidative stress in obese rats.
Keywords
- EGCG
- free fatty acid
- high-fat dietary
- lifespan
- proteomics
- transcriptome
The cell resistance to apoptosis can be related to the activity of cytokine-dependent signaling. So, the aim of the work is to investigate the mechanisms of cytokine-dependent FAS/TNF-mediated regulation of apoptosis of neurosecretory cells in the physiological and pathological (overexpression of the oncogene HER-2/Neu) aging. HER2/Neu transgenic accelerated aged mice of different ages and wild type FVB/N were examined. The apoptosis level of neurons in hypothalamic sections (supraoptic and paraventricular nuclei) (TUNEL) and expression of caspase-8, CD178 (FASL), FAS, FADD, TRADD (Western blotting) was determined. Participation of the proinflammatory component in the aging process is shown. FAS, adapter proteins associated with the death domain (FADD and TRADD), caspase-8 expression is activated in hypothalamus in FVB/N mice (wild type) during aging, and it correlates with an increase in the apoptosis level. HER-2/Neu expression leads to the extrinsic apoptotic pathway suppression. In this case, the reception of an apoptotic signal (FAS-receptor expression) and its further transmission (expression of FADD and TRADD) is suppressed. However, in young transgenic mice, increased expression of TRADD can activate one of the survival ways - NF-κB, ERK or PI3K-AKT cascade. Thus, the HER-2/Neu tyrosine kinase receptor plays a role in the mechanism of cell resistance to age-dependent apoptosis, and the FAS/TNF-signaling pathway is one of the targets of HER-2/Neu.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Female
- Hypothalamus
- Mice
- Mice, Transgenic
- Signal Transduction
- Tumor Necrosis Factor-alpha
- fas Receptor
Keywords
- FAS-, TNF-dependent pathways
- aging
- apoptosis
- hypothalamus
- neurons
The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.
Keywords
- MDM2
- Senescence
- USP7
- apoptosis
- p53
- senolytics
Recent studies have found vitamin D deficiency promotes fat deposition into the hepatocytes, thus contributing to the development of nonalcoholic fatty liver disease (NAFLD), which is a hepatic manifestation of metabolic syndrome. This study aimed to investigate the potential effects of vitamin D on NAFLD with the involvement of the p53 pathway. Initially, an in vivo high-fat diet (HFD)-induced NAFLD mouse model was established. Then the HFD-induced NAFLD mice were treated with vitamin D. Next, the serum levels of TNF-α, GSH-px and malondialdehyde (MDA) were assessed using ELISA and ROS content was evaluated by flow cytometry, followed by the measurement of expression of Duox1, Duox2, SOD1, SOD2, PRDX1 I, ACC, SREBP1c, MTTP, PPARα, p53, p21 and p16 using RT-qPCR and Western blot analysis. Positive expression of FAS and FASL proteins was measured using immunohistochemistry. TUNEL and Senescence-associated β-galactosidase (SA-β-Gal) staining were subsequently conducted to assess the senescence and apoptosis of hepatocytes. HFD-induced mice treated with vitamin D presented with significantly increased GSH-px levels, as well as protein expression of SOD1, SOD2, PRDX1, MTTP and PPARα, but decreased MDA and ROS levels, expression of Duox1, Duox2, ACC, SREBP1c, p53, p21 and p16, positive expression of FAS and FASL proteins as well as impaired senescence and apoptosis of hepatocytes. Active vitamin D supplementation could potentially impede hepatocyte senescence and apoptosis via suppression of the p53 pathway, thus preventing the progression of NAFLD. Our study provides available evidence on the potential clinical utility of vitamin D supplementation in NAFLD.
MeSH Terms
- Animals
- Apoptosis
- Cellular Senescence
- Diet, High-Fat
- Dietary Supplements
- Fas Ligand Protein
- Hepatocytes
- Metabolic Networks and Pathways
- Mice, Knockout
- Non-alcoholic Fatty Liver Disease
- Oxidative Stress
- Proteins
- Steroid Hydroxylases
- Tumor Suppressor Protein p53
- Vitamin D
- fas Receptor
Keywords
- Active vitamin D
- Apoptosis
- Nonalcoholic fatty liver disease
- Oxidative stress
- Senescence
- p53 pathway
Estimated glomerular filtration rate (eGFR) equations can be inaccurate when applied to elderly patients. Newly, the full-age-spectrum (FAS) equation was developed for use in elderly patients. We compared the available eGFR equations in elderly Chinese patients with mGFRs < 60 mL/min/1.73 m . Measured glomerular filtration rates (mGFRs) were obtained using Tc-DTPA (diethylene-triamine-pentaacetic acid) scans, 220 patients ≥ 80 years with mGFRs < 60 mL/min/1.73 m were enrolled. Serum creatinine (SCr) levels were measured simultaneously, and eGFRs based on SCr were calculated using four formulas: the modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI-SCr), Berlin initiative study (BIS1), and the FAS-SCr equations. All the equations tended to overestimate GFR. The FAS-SCr equation provided the least bias (1.84), the highest proportion of eGFR within 30% of mGFR (P30, 72.7%), the bias and P30 of the BIS1 equation were 3.45 and 72.3%, respectively. In patients with mGFRs of 30-60 mL/min/1.73 m , the BIS1 and FAS-SCr equations demonstrated better performances than the MDRD and CKD-EPI-SCr equations. While in patients with mGFR < 30 mL/min/1.73 m , the accuracy of all equations was poor. In older patients with mGFRs of 30-60 mL/min/1.73 m , the BIS1 and the FAS-SCr equations exhibited good performance, none of the equations based on SCr were suitable for older subjects with mGFRs < 30 mL/min/1.73 m . The BIS1 and FAS-SCr equations may be optimal for older patients with moderately reduced kidney function.
MeSH Terms
- Aged, 80 and over
- Aging
- Algorithms
- China
- Creatinine
- Female
- Glomerular Filtration Rate
- Humans
- Male
- Renal Insufficiency, Chronic
Keywords
- Elderly patients
- Equation
- Glomerular filtration rate
- Serum creatinine
Methionine (Met) is one of the most important amino acids in fish feed. The effects of dietary Met on lipid deposition in fish varied a lot among different studies. The present study was aimed at investigating the effects of dietary Met supplementation on the lipid accumulation in tiger puffer, which have a unique lipid storage pattern. Crystalline L-Met was supplemented to a low-fishmeal control diet to obtain two experimental diets with a low (1.1% of dry weight, L-MET) or high Met level (1.6% of dry weight, H-MET). A 67-day feeding trial was conducted with juvenile tiger puffer (average initial weight, 13.83 g). Each diet was fed to triplicate tanks (30 fish in each tank). The results showed that the total lipid contents in whole-body and liver significantly increased with increasing dietary Met levels. The hepatosomatic index, weight gain, and total bile acid content in serum showed similar patterns in response to dietary Met treatments, while the lipid content in muscle was not affected. The hepatic contents of 18-carbon fatty acids were elevated by dietary Met supplementation. The Hepatic mRNA expression of lipogenetic gene such as FAS, GPAT, PPARγ, ACLY, and SCD1 was down-regulated, while the gene expression of lipolytic genes ACOX1 and HSL, as well as that of ApoB100, were up-regulated by increasing dietary Met levels. The hepatic lipidomics of experimental fish was also analyzed. In conclusion, increasing dietary Met levels (0.61%, 1.10%, and 1.60%) increased the hepatic lipid accumulation in tiger puffer. The mechanisms involved warrant further studies.
MeSH Terms
- Aging
- Animals
- Diet
- Dietary Supplements
- Fatty Acids
- Lipid Metabolism
- Liver
- Methionine
- Takifugu
Keywords
- Diet
- Lipid
- Methionine
- Takifugu rubripes
We used a sub-sample from the Older Australian Twins Study to estimate the heritability of performance on three tests of language ability: Boston Naming Test (BNT), Letter/Phonemic Fluency (FAS) and Category/Semantic Fluency (CFT) Tests. After adjusting for age, sex, education, mood, and global cognition (GC), heritability estimates obtained for the three tests were 0.35, 0.59, and 0.20, respectively. Multivariate analyses showed that the genetic correlation were high for BNT and CFT (0.61), but low for BNT and FAS (0.17), and for FAS and CFT (0.28). Genetic modelling with Cholesky decomposition indicated that the covariation between the three measures could be explained by a common genetic factor. Environmental correlations between the language ability measures were low, and there were considerable specific environmental influences for each measure. Future longitudinal studies with language performance and neuroimaging data can further our understanding of genetic and environmental factors involved in the process of cognitive aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Australia
- Environment
- Female
- Humans
- Inheritance Patterns
- Language
- Male
- Models, Genetic
- Multivariate Analysis
- Phenotype
- Phonetics
- Semantics
- Twins
Keywords
- Aging
- Genetic
- Heritability
- Language ability
- Twins
Sheldrake is a duck breed widely used for its meat and eggs. In this study, the quantities of abdominal fat, sebum, intramuscular fat and liver fat, meat quality (pH, cooking loss, drip loss, and shear force), and expression and activity of several enzymes at different ages were determined. The results showed that the fat content increased (P < 0.05) during the aging process (90 d, 180 d, 270 d, and 360 d). Fatty acid synthase (FAS) and malic enzyme (ME) were chosen to represent the activity of lipid biosynthesis in Sheldrake ducks. The quantitative real-time PCR and enzymic activity data showed that the expression of both FAS and ME were generally up-regulated along with aging. Based on these results, the individual ducks were selected at 180 d and 360 d for analyzing the changes of serum lipid levels and related enzymic activities in liver. The contents of triglycerides (TG), total cholesterol (TCH), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in serum were found not significantly different (P > 0.05). However, we thought that the variation of TG/HDL (P < 0.05) might explain the increased fat deposition. Moreover, the activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were both detected significantly up-regulated at 360 d (P < 0.05). The meat quality results of breast muscles indicated that pH, cooking loss, drip loss, and shear force values could all be affected by aging. Considering these results, we concluded that the best quality of Sheldrake duck meat occurs between 180 d and 270 d. These results might provide useful information for Sheldrake cultivation and research on lipid metabolism.
MeSH Terms
- Abdominal Fat
- Aging
- Animals
- Ducks
- Female
- Lipids
- Liver
- Male
- Meat
- Pectoralis Muscles
- Subcutaneous Fat
Executive functions (EFs) regulate human behavior and allow individuals to interact and act in the world. EFs are sensitive to sociodemographic variables such as age, which promotes their decline, and to others that can exert a neuroprotective effect. To assess the predictive role of education, occupation and family income on decline in executive functions among a sample with a wide age range. A total of 925 participants aged 18-89 years with 1-28 years' education were submitted to assessment of executive functions using the Card Sorting Test (CST), Phonemic Verbal Fluency (FAS) Task and Semantic Verbal Fluency (SVF) Task. Data on income, occupation and educational level were collected for the sample. The data were analyzed using Linear Regression, as well as Pearson's and Spearman's Correlation. Age showed a significant negative correlation (p<0.001) with performance on the CST, FAS and SVF, whereas education, income and occupation were positively associated (p<0.001) with the tasks applied. After application of the multivariate linear regression model, a significant positive relationship with the FAS was maintained only for education (p<0.001) and income (p<0.001). The negative relationship of age (p<0.001) and positive relationship of both education (p<0.001) and income (p<0.001and p=0.003) were evident on the CST and SVF. Educational level and income positively influenced participants' results on executive function tests, attenuating expected decline for age. However, no relationship was found between occupation and the cognitive variables investigated.
Keywords
- aging
- executive function
- socioeconomic factors
In aging populations with an ever-growing burden of risk factors such as obesity, diabetes, and hypertension, chronic kidney disease (CKD) is on the rise. However, little is known about its exact prevalence among elderly adults, and often albuminuria is not included in the definition of CKD. Moreover, novel equations for the estimated glomerular filtration rate (eGFR) have recently emerged, which have not been applied comprehensively to older adults. Data on CKD awareness among the elderly are sparse. To determine the prevalence of CKD among older adults by eGFR and albumin/creatinine ratio (ACR), compare the performance of 6 established and novel eGFR formulas, explore risk factors, and determine the awareness of CKD in a large cohort of community-dwelling elderly from Germany. A total of 1,628 subjects from the Berlin Aging Study II (BASE-II) were included in this analysis (mean age 68.7 years; 51.2% female). Extensive cross-sectional data on sociodemographics, lifestyle, medication, and diagnoses were inquired during structured interviews and a medical examination, and blood and urine parameters were measured. In all, 77.1% of the subjects had hypertension, 12.4% had diabetes, and 18.3% were obese. The prevalence of CKD strongly depended on the eGFR equations used: 25.4% (full age spectrum [[[FAS]]] equation), 24.6% (Berlin Initiative Study), 23.1% (Lund-Malmö revised), 19.3% (Cockcroft-Gault), 16.4% (Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI]), and 14.7% (Modification of Diet in Renal Disease [MDRD]). Of the subjects with an eGFRFAS <60 mL/min/1.73 m2 and/or an ACR >30 mg/g, only 3.9% were aware of having CKD. Polypharmacy, age, BMI, coronary artery disease, non-HDL cholesterol, and female sex were independently associated with CKD. CKD is prevalent among older adults in Germany, but awareness is low. The FAS equation detects higher rates of CKD than MDRD and CKD-EPI, which are most widely used at present. Also, when CKD is defined based on eGFR and albuminuria, considerably more people are identified than by eGFR alone. Finally, polypharmacy is associated with an increased risk for CKD in the elderly.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Albuminuria
- Berlin
- Cross-Sectional Studies
- Female
- Glomerular Filtration Rate
- Humans
- Male
- Middle Aged
- Polypharmacy
- Prevalence
- Renal Insufficiency, Chronic
- Risk Factors
Verbal fluency (VF) tasks are widely used in neuropsychological evaluations, as a measure of executive/semantic dysfunction. The revised criteria for Alzheimer's disease (AD) diagnosis (National Institute on Aging and the Alzheimer Association, 2011) incorporating biomarkers has increased the interest in finding algorithms that combine neuropsychological and biomarkers features to better predict conversion from mild cognitive impairment (MCI) to AD. Our aim was to compare the most frequently used VF categories to determine which best discriminated cognitively healthy elderly from MCI patients, and whether cerebrospinal fluid (CSF) biomarkers levels (Aβ42, P-tau, T-tau, and Aβ42/P-tau) correlated with patient's performance in MCI. We studied 37 cognitively healthy elderly and 30 MCI patients in five VF tasks (animal, fruits, means of transportation, FAS-COWA, and verbs); 23 controls and 19 MCI patients had their CSF biomarkers for AD determined. MCI group performed worse than controls in all VF tasks (p < 0.0001). The cut-off scores were: 14 (animals) (AUC = 0.794), 12 (fruits and means of transportation) (AUC = 0.740 and 0.719, respectively), 41 (FAS) (AUC = 0.744), and 11 (verbs) (AUC = 0.700). The model "animal plus FAS-COWA" was the best to discriminate both groups (AUC = 0.833) (all p < 0.05). MCI produced fewer words than controls in the second-half of the task for all categories (p < 0.001). T-tau levels were negatively correlated to animal fluency (r = -0.485, p = 0.035), and showed a trend for negative correlation with fruits fluency (r = -0.4429, p = 0.057). Animal fluency alone and combined to FAS-COWA was slightly superior in discriminating controls from MCI (p < 0.001), and correlated to T-tau levels.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Biomarkers
- Brazil
- Cognitive Dysfunction
- Female
- Humans
- Male
- Middle Aged
- Neuropsychological Tests
- Semantics
- tau Proteins
Keywords
- CSF
- aging
- biomarkers
- mild cognitive impairment
- verbal fluency
Normal kidney function or, more specifically, normal glomerular filtration rate (GFR) in men and women and its decline with age is still much debated today. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has gender (and race) multiplication factors, accounts for a decline that starts at very young age and assumes that the mean GFR is as high as 120-130 ml/min/1.73 m2 from a young age. The full age spectrum (FAS) estimated mean GFR is about 107 ml/min/1.73 m2 at a young age and remains constant until the age of 40 years and then starts to decline both in men and women. The aim of this research study was to give more insight into 'normal' GFR levels and the physiological decrease of kidney function with age and to use a meta-analysis to evaluate the mathematical construction of the FAS and the CKD-EPI equation. We conducted a meta-analysis of published GFR measurements in healthy Caucasian living potential kidney donors (n = 5,482, 46.8% men). Only publications dating from 2000 were selected to avoid the possible influence of body surface area changes in the last decades on the indexed GFR, expressed in ml/min/1.73 m2. We found that the mean GFR ≈ 107 ml/min/1.73 m2 up to the age of 40 years, but renal decline begins beyond 40 years. No evidence could be found for any difference between men and women in the separate age groups. The current meta-analysis supports the mathematical form of the FAS equation, which matches the age/sex dependency of measured GFR for healthy potential living kidney donors.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- European Continental Ancestry Group
- Female
- Glomerular Filtration Rate
- Humans
- Kidney Transplantation
- Living Donors
- Male
- Middle Aged
- Models, Biological
- Reference Values
- Sex Characteristics
- Young Adult
To estimate the life expectancy and specify the causes of death among people with fetal alcohol syndrome (FAS). Included were all patients recorded in Alberta provincial databases of inpatients, outpatients, or practitioner claims from 2003 to 2012. People with FAS were identified by ICD-9 code 760.71 and ICD-10 codes Q86.0 and P04.3, and were linked to the Vital Statistics Death Registry to get information about mortality. Life expectancy was estimated by using the life table template developed in the United Kingdom, which is recommended for estimating life expectancy in small areas or populations. The life expectancy at birth of people with FAS was 34 years (95% confidence interval: 31 to 37 years), which was about 42% of that of the general population. The leading causes of death for people with FAS were "external causes" (44%), which include suicide (15%), accidents (14%), poisoning by illegal drugs or alcohol (7%), and other external causes (7%). Other common causes of death were diseases of the nervous and respiratory systems (8% each), diseases of the digestive system (7%), congenital malformations (7%), mental and behavioural disorders (4%), and diseases of the circulatory system (4%). The life expectancy of people with FAS is considerably lower than that of the general population. As the cause of FAS is known and preventable, more attention devoted to the prevention of FAS is urgently needed.
MeSH Terms
- Adolescent
- Adult
- Aged
- Alberta
- Cause of Death
- Child
- Child, Preschool
- Cohort Studies
- Female
- Fetal Alcohol Spectrum Disorders
- Humans
- Infant
- Infant, Newborn
- Life Expectancy
- Male
- Middle Aged
- Retrospective Studies
- Young Adult
Elderly HIV-1 infected individuals progress to AIDS more frequently and rapidly than people becoming infected at a young age. To identify possible reasons for these differences in clinical progression, we performed comprehensive phenotypic analyses of CD4 T cells from uninfected young and elderly individuals, and examined their susceptibility to HIV-1 infection and programmed death. Peripheral blood mononuclear cells (PBMCs) from older people contain an increased percentage of central memory and Th17 CD4 T cells that are main target cells of HIV-1 and strongly reduced proportions of naïve T cells that are poorly susceptible to HIV-1. Unstimulated T cells from elderly individuals expressed higher levels of activation markers, death receptors, and the viral CXCR4 co-receptor than those from young individuals but responded poorly to stimulation. CD4 T cells from older individuals were highly susceptible to CXCR4- and CCR5-tropic HIV-1 infection but produced significantly lower quantities of infectious virus than cells from young individuals because they were highly prone to apoptosis and thus presumably had a very short life span. The increased susceptibility of T cells from the elderly to HIV-1 infection correlated directly with CXCR4 and inversely with CD4 expression. The levels of apoptosis correlated with the cell surface expression of FAS but not with the expression of programmed death receptor 1 (PD1) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Increased levels of activated and highly susceptible HIV-1 target cells, reduced CD4 and enhanced CXCR4 cell surface expression, together with the high susceptibility to FAS-induced programmed cell death may contribute to the rapid CD4 T cell depletion and accelerated clinical course of infection in elderly HIV-1-infected individuals.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Apoptosis
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Female
- HIV Infections
- HIV-1
- Humans
- Immunologic Memory
- Leukocytes, Mononuclear
- Male
- Membrane Glycoproteins
- Middle Aged
- Programmed Cell Death 1 Receptor
- Receptors, CXCR4
- Signal Transduction
- Young Adult
- fas Receptor
Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1 after tumor onset in p53(-/-) mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53(-/-) mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53(-/-) thymic lymphoma inhibits Skp2 expression and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.
MeSH Terms
- Animals
- Apoptosis
- Cell Line, Tumor
- Fas Ligand Protein
- Humans
- Longevity
- Lymphoma
- Mice
- Proto-Oncogene Proteins c-akt
- S-Phase Kinase-Associated Proteins
- Thymocytes
- Tumor Suppressor Protein p53
Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr/lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-κB (NF-κB) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-κB family members NF-κB1, NF-κB2 and c-REL in the various autoimmune pathologies of Fas(lpr/lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr/lpr) mice. Interestingly, compared with the Fas(lpr/lpr) animals, Fas(lpr/lpr)nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr/lpr)nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-κB1. These findings demonstrate that different NF-κB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr/lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.
MeSH Terms
- Animals
- Autoantibodies
- Chemokines
- Dermatitis
- Forkhead Transcription Factors
- Genotype
- Hypergammaglobulinemia
- Immune Tolerance
- Leukocytes
- Longevity
- Lupus Erythematosus, Systemic
- Lymphatic Diseases
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Mutant Strains
- NF-kappa B p50 Subunit
- NF-kappa B p52 Subunit
- Organ Specificity
- Proto-Oncogene Proteins c-rel
- Splenomegaly
- Transcription Factors
- fas Receptor
Although the heterogeneity of white adipose tissue (WAT) in different anatomical sites is a well-known phenomenon, there are scarce data on aging-associated metabolic alterations in various WAT depots. We used the model of fasting and refeeding to analyze the effect of aging on the activity of key lipogenic enzymes in retroperitoneal (rWAT), epididymal (eWAT), and subcutaneous (sWAT) adipose tissue depots. 5- and 24-month-old male Wistar rats were fasted for 48 h or were fasted for 2 days and subsequently refed for 2 or 4 days. Control animals had ad libitum access to chow. Samples obtained from three WAT deposits were analyzed for the enzymatic activities of ATP citrate lyase (ACL), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PD). Concentrations of lipids and proteins were measured in the blood serum. Fasting for 2 days decreased the concentration of free fatty acids only in the young rats. The basal activities of ACL and FAS were lower in eWAT than in rWAT and sWAT of the young rats. In the young rats, fasting did not change ACL and FAS activities in any of the studied depots. Refeeding increased these activities more quickly in rWAT than in eWAT, while in sWAT no induction was observed. ACL and FAS activities were manifold lower in all WAT depots of the old than in those of the young rats. In the old animals fasting had no effect on ACL activity in any depot and decreased FAS activity only in sWAT. After 4 days of refeeding, FAS activity increased in rWAT and sWAT, but no change in ACL activity occurred. G6PD activity in the young rats was lower by 40% in eWAT than in rWAT. The induction of the enzyme by refeeding occurred faster in rWAT than in eWAT, while in sWAT no change in G6PD activity was observed. G6PD activity did not change with aging. Fasting of the old rats decreased G6PD activity in rWAT and sWAT. Refeeding failed to induce the enzyme in these depots, whereas in eWAT G6PD activity increased by 76% after 4 days of refeeding. Fasting and refeeding revealed WAT depot-specific, age-related changes of the activities of lipogenic enzymes.
MeSH Terms
- ATP Citrate (pro-S)-Lyase
- Adipose Tissue, White
- Aging
- Animals
- Body Weight
- Eating
- Fasting
- Fatty Acid Synthase, Type I
- Glucosephosphate Dehydrogenase
- Lipids
- Lipogenesis
- Male
- Rats
- Rats, Wistar
- Tissue Distribution
The metabolic effects of short-term calorie restriction (SCR) and subsequent refeeding were compared in different white adipose tissue (WAT) depots of young (5-month old) and old (24-month) male Wistar rats. The animals were subjected to a 40% calorie restricted diet (i.e. 40% lower food supply than of control rats) for 30 days, and then re-fed for 0, 2, or 4 days. WAT samples from perirenal (pWAT), epididymal (eWAT), and subcutaneous (sWAT) depots were analysed for the enzymatic activities of ATP-citrate lyase (ACL), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PD). The total WAT mass almost doubled in old rats, however, aging did not alter the relative proportions of the major regional fat depots. Serum leptin concentration was prominently higher in old rats, in which SCR resulted in less suppression of leptin level than in young animals, whereas refeeding increased leptin concentration in young, but not old, rats. In young rats refeeding elevated leptin gene expression only in pWAT, while in old rats the expression was induced first in eWAT, and later in pWAT. A prominent age-related decrease of ACL and FAS activities, but not of G6PD activity, was found in all the studied WAT depots. In young control rats, ACL activity was highest in pWAT, FAS activity was similar in all WAT depots, and G6PD activity was lowest in eWAT. In old rats, the enzymatic activities were lower in eWAT than in the other depots. The patterns of response to SCR and refeeding varied by age and WAT location. SCR stimulated ACL activity in pWAT but not in other depots of young rats, while FAS activity in pWAT and sWAT did not change in young and decreased in the old animals. Among the studied depots, pWAT was most responsive to refeeding in both age groups. In conclusion, SCR in old rats, as compared to the young, may be accompanied by reduced 'rebound effect' upon returning to unrestricted diet.
MeSH Terms
- ATP Citrate (pro-S)-Lyase
- Adipose Tissue, White
- Aging
- Animals
- Caloric Restriction
- Fatty Acid Synthases
- Glucosephosphate Dehydrogenase
- Leptin
- Lipids
- Male
- Rats
- Rats, Wistar
The senescent endothelial cells show various phenotypes which can increase the incidence of inflammatory cardiovascular diseases, but the fundamental basis for such phenotypic changes of senescing cells remains to be elucidated. This study was undertaken to find transmembrane receptors that might be highly expressed in senescent endothelial cells and play a key role in cell death signal transduction. Comparison of mRNA expression in young and senescent human umbilical vein endothelial cells, using a cDNA microarray method, provided a list of transmembrane receptors including the FAS receptor (tumor necrosis factor receptor superfamily member 6) whose expression levels were significantly increased by cellular senescence. Additional studies focused on FAS demonstrated that a high expression of FAS receptor in senescent endothelial cells is responsible for the susceptibility to apoptotic cell death, as the siRNA-mediated suppression of FAS expression in senescent cells prevented the cell death, and overexpression of exogenous FAS in young cells increased cell death. We also verified that FAS expression level was closely associated with the activation of caspase-3 and caspase-9 involved in apoptosis. The senescence-induced transmembrane receptors including the FAS receptor may provide novel therapeutic targets to prevent cardiovascular diseases.
MeSH Terms
- Apoptosis
- Cardiovascular Diseases
- Caspase 3
- Caspase 9
- Cell Survival
- Cellular Senescence
- Gene Expression Profiling
- Gene Expression Regulation
- Human Umbilical Vein Endothelial Cells
- Humans
- Oligonucleotide Array Sequence Analysis
- Phenotype
- Plasmids
- RNA, Small Interfering
- Tumor Necrosis Factor-alpha
- fas Receptor
Keywords
- Cell death
- EGFP
- Endothelial cells
- FAS
- FAS receptor
- GAPDH
- HUVECs
- LSS
- NO
- NOS3
- RT-PCR
- Senescence
- TNF
- enhanced green fluorescent protein
- glyceraldehyde 3-phosphate dehydrogenase
- human umbilical vein endothelial cells
- laminar shear stress
- nitric oxide
- nitric oxide synthase 3
- reverse transcriptase-polymerase chain reaction
- siRNA
- small interfering RNA
- tumor necrosis factor
- tumor necrosis factor receptor superfamily member 6
Fetal alcohol syndrome (FAS) is a leading cause of neurodevelopmental impairments (NDIs) in developed countries. Sensory deficits can play a major role in NDI, yet few studies have investigated the effects of prenatal alcohol exposure on sensory function. In addition, there is a paucity of information on the lifelong effects of prenatal alcohol exposure. Thus, we sought to investigate the effects of prenatal alcohol exposure on auditory function across the life span in an animal model. Based on prior findings with prenatal alcohol exposure and other forms of adverse prenatal environments, we hypothesized that animals prenatally exposed to alcohol would show an age-dependent pattern of (i) hearing and neurological abnormalities as postweanling pups, (ii) a substantial dissipation of such abnormalities in young adulthood, and (iii) a resurgence of such abnormalities in middle-aged adulthood. Pregnant rats were randomly assigned to an untreated control (CON), a pair-fed control (PFC), or an alcohol-treated (ALC) group. The ALC dams were gavaged with 6 mg/kg alcohol daily from gestation day (GD) 6 to 21. The PFC dams were gavaged daily from GD6 to GD21 with an isocaloric and isovolumetric water-based solution of maltose-dextrins and pair-fed to the ALC dams. The CON dams were the untreated group to which the ALC and CON groups were compared. Hearing and neurological functions in the offspring were assessed with the auditory brainstem response (ABR) at the postnatal ages of 22, 220, and 520 days. In accord with our hypothesis, ABR abnormalities were first observed in the postweanling pups, largely dissipated in young adulthood, and then resurged in middle-aged adulthood. This age-related pattern suggests that the ALC pups had a developmental delay that dissipated in young adulthood and an enhanced age-related deterioration that occurred in middle-aged adulthood. Such a pattern is consistent with the fetal programming hypothesis of adult-onset diseases (the Barker hypothesis). Our findings have important clinical implications for the assessment and management of (i) childhood hearing disorders and their comorbidities (i.e., speech-and-language, learning, and attention deficit disorders) and (ii) enhanced age-related hearing and neurological degeneration in middle-aged adulthood that can result from prenatal alcohol exposure. We recommend hearing evaluation be a part of any long-term follow-up for FAS patients and patients exposed to any adverse prenatal environment.
MeSH Terms
- Acoustic Stimulation
- Age Factors
- Animals
- Animals, Newborn
- Ethanol
- Evoked Potentials, Auditory, Brain Stem
- Female
- Fetal Alcohol Spectrum Disorders
- Longevity
- Male
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
- Rats, Sprague-Dawley
There is dramatic slowing of GnRH pulse frequency during sleep in the early follicular phase of the menstrual cycle, but it is unknown whether this represents a primary effect of sleep or is dependent upon the sex steroid environment. Our objective was to determine 1) whether sleep affects GnRH pulse frequency in postmenopausal women (PMW) in whom gonadal hormones are low and 2) whether this relationship changes with aging. Studies were performed in the Clinical Research Center of an academic medical center. Subjects included healthy PMW, 45-55 (n = 8) and 70-80 (n = 6) years old. Subjects were studied during one night of polysomnographic-recorded sleep and one night of monitored wake during which blood was sampled every 5 min for 8 h. Pulsatile secretion of free α-subunit (FAS), a marker of GnRH secretion, was assessed. There were no differences in sleep macroarchitecture or sleep efficiency [75 ± 12% (mean ± sd)] between older and younger PMW. The FAS interpulse interval was longer during sleep than nighttime wake in all women (60.5 ± 4.3 vs. 52.0 ± 2.8 min, P = 0.03) with a similar effect in the two groups. FAS pulse amplitude did not differ between sleep and wake periods (474.8 ± 36.7 vs. 478.2 ± 36.5 ng/liter, P = 0.9). Sleep is associated with a significant decline in GnRH pulse frequency in both older and younger PMW. Its persistence in PMW reinforces the important connection between sleep and GnRH secretion.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Circadian Rhythm
- Estradiol
- Female
- Follicle Stimulating Hormone
- Follicular Phase
- Gonadal Steroid Hormones
- Gonadotropin-Releasing Hormone
- Humans
- Luteinizing Hormone
- Middle Aged
- Postmenopause
- Progesterone
- Sleep
A standardized method for assessing the physical fitness of elderly adults has not yet been established. In this study, we developed an index of physical fitness age (fitness age score, FAS) for older Japanese adults and investigated sex differences based on the estimated FAS. Healthy elderly adults (52 men, 70 women) who underwent physical fitness tests once yearly for 7 years between 2002 and 2008 were included in this study. The age of the participants at the beginning of this study ranged from 60.0 to 83.0 years. The physical fitness tests consisted of 13 items to measure balance, agility, flexibility, muscle strength, and endurance. Three criteria were used to evaluate fitness markers of aging: (1) significant cross-sectional correlation with age; (2) significant longitudinal change with age consistent with the cross-sectional correlation; and (3) significant stability of individual differences. We developed an equation to assess individual FAS values using the first principal component derived from principal component analysis. Five candidate fitness markers of aging (10-m walking time, functional reach, one leg stand with eyes open, vertical jump and grip strength) were selected from the 13 physical fitness tests. Individual FAS was predicted from these five fitness markers using a principal component model. Individual FAS showed high longitudinal stability for age-related changes. This investigation of the longitudinal changes of individual FAS revealed that women had relatively lower physical fitness compared with men, but their rate of physical fitness aging was slower than that of men.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Cross-Sectional Studies
- Female
- Geriatric Assessment
- Hand Strength
- Health Status Indicators
- Humans
- Japan
- Longitudinal Studies
- Male
- Middle Aged
- Muscle Strength
- Physical Endurance
- Physical Fitness
- Postural Balance
- Range of Motion, Articular
- Sex Distribution
- Walking
Prefrontal cortical lobe function is related to social behavior in humans. We investigated whether performance on tests of prefrontal cortical function was associated with social vulnerability. Associations with non-frontal cognitive function were investigated for comparison. 1216 participants aged 70 of the Canadian Study of Health and Aging-2 screening examination, who also underwent detailed neuropsychological testing, comprised the study sample. Performance on WAIS-R abstraction, WAIS-R comprehension, Trails B, FAS and category verbal fluency, Block construction, Token Test and Wechsler Memory Scale Information Subset was tested in relation to the participant's level of social vulnerability using regression models adjusted for age, education, sex, frailty, MMSE score, diagnosis of depression, and use of psychoactive medications. Social vulnerability was measured by an index comprising many social problems or "deficits". The most socially vulnerable group had worse performance on FAS verbal fluency, generating 4.1 fewer words (95% CI: 1.8-6.4, p<0.001) than those in the least socially vulnerable group; those with intermediate social vulnerability generated 2.6 fewer words (95% CI: 0.4-4.8, p = 0.02). Social vulnerability was also associated, though less strongly, with category verbal fluency. The most socially vulnerable people had impaired performance on the Trails B, taking 37 seconds longer (95% CI: 11-63, p = 0.005). These results were independent of age, education, sex, frailty, MMSE score, depression, and psychoactive medications. Social vulnerability was not associated with performance on WAIS-R abstraction, WAIS-R comprehension, Block Design, Token Test or Wechsler Memory Scale tests. High social vulnerability was associated with impaired performance on verbal fluency and set shifting but not with common sense judgment, abstraction, long-term memory, constructional ability, or language comprehension. The association between social functioning and the cognitive functions subserved by prefrontal cortex warrants further study.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Canada
- Chi-Square Distribution
- Cognition Disorders
- Female
- Humans
- Male
- Neuropsychological Tests
- Prefrontal Cortex
- Social Behavior
- Wechsler Scales
Alcohol exposure during pregnancy may cause fetal alcohol syndrome (FAS), characterized by impaired cognitive functions. Neurogenesis occurs in the adult hippocampus and is functionally associated with learning, memory, and mood disorders. However, whether early postnatal exposure to alcohol impairs neurogenesis and through which mechanisms it occurs is poorly understood. Here, we report that a single episode of alcohol exposure in postnatal day 7 (P7) decreases neurogenesis in the adult hippocampus. Furthermore, we demonstrate a co-localization of glial fibrillar acidic protein, nestin, and vimentin with activated caspase-3 12 h after ethanol treatment. Finally, we show that the number of primary neurospheres derived from the hippocampi of alcohol-exposed mice is reduced compared to controls. These findings suggest that alcohol exposure in postnatal mice reduces the pool of neural stem/progenitor cells in the DG, and subsequently results in a decrease of adult neurogenesis. This may explain certain aspects of impaired hippocampal functions in FAS.
MeSH Terms
- Aging
- Alcohol-Induced Disorders, Nervous System
- Animals
- Animals, Newborn
- Caspase 3
- Cell Differentiation
- Cells, Cultured
- Central Nervous System Depressants
- Drug Administration Schedule
- Ethanol
- Glial Fibrillary Acidic Protein
- Hippocampus
- Intermediate Filament Proteins
- Memory Disorders
- Mice
- Nerve Tissue Proteins
- Nestin
- Neurons
- Spheroids, Cellular
- Stem Cells
- Time
- Vimentin
The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low-protein (LP) diet, targeted to early (LPE), mid-(LPM), or late (LPL) pregnancy, or throughout gestation (LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP-exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP-programmed hypertriglyceridemia and insulin resistance. All LP-exposed groups exhibited histological evidence of hepatic steatosis and were found to have two- to threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age-related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPARgamma, and PPARalpha and their respective downstream target genes ACC1, FAS, L-PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPARgamma and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome-like phenotype that develops only with senescence. The data implicate altered expression of SREBP-1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
- Body Weight
- Diet, Protein-Restricted
- Fatty Liver
- Female
- Hypertriglyceridemia
- Insulin Resistance
- Lipid Metabolism
- Liver
- Muscle, Skeletal
- Organ Size
- PPAR alpha
- PPAR gamma
- Pregnancy
- Prenatal Exposure Delayed Effects
- RNA, Messenger
- Rats
- Rats, Wistar
- Sterol Regulatory Element Binding Protein 1
- Time Factors
- Triglycerides
Patients with schizophrenia demonstrate impaired verbal fluency, but no studies have examined the underlying cognitive mechanisms (e.g., clustering and switching) associated with impaired fluency among middle-aged and older, non-institutionalized patients. Using Troyer et al.'s [Troyer, A.K., Moscovitch, M., Winocur, G., 1997. Clustering and switching as two components of verbal fluency: evidence from younger and older healthy adults. Neuropsychology 11 (1), 138-146] conceptual model, we examined clustering and switching on verbal fluency tasks among 163 middle-aged and older outpatients with schizophrenia and 92 age comparable healthy comparison (HC) participants. The patients produced significantly fewer total words than HC participants on both the letter ("F", "A", "S") and Animal fluency conditions. With regard to clustering, patients were similar to HC participants on both FAS and Animal fluency tasks. However, significantly fewer switches between lexical-semantic categories were observed among patients with schizophrenia on both conditions relative to HC participants. A small, but statistically significant association was found between number of switches on the Animal fluency task and severity of negative symptoms. The absence of a difference in mean cluster size between the patient and HC groups suggests intact lexical-semantic stores among middle-aged and older outpatients with schizophrenia. Differences in switching between patients and HC participants may be driven by several cognitive impairments associated with schizophrenia. Further delineation of the cognitive mechanisms of the observed lexical-semantic switching deficits in schizophrenia should be a focus of future research.
MeSH Terms
- Age Factors
- Aged
- Aging
- Ambulatory Care
- Cognition Disorders
- Demography
- Humans
- Middle Aged
- Neuropsychological Tests
- Schizophrenia
- Severity of Illness Index
- Speech Disorders
- Verbal Behavior
Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. In the present study we tested the possibility that prenatal exposure to a high level of inflammatory factors may increase the risk for neurodegeneration in aging. The effect of systemic maternal inflammation (MI), induced by lipopolysaccharide (LPS) on offspring brain aging, was examined in 8 month old (adult) and 20 month old (aged) offspring mice. A significant effect of age was found in the distance and velocity of exploration in the open field in both groups. In addition, MI aged offspring covered longer distances and enter frequently to the center of the field compared with the aged control group. Although only little difference was found in the aged MI offspring compared with the control offspring, the overall profile of behavior of these mice differs from that of the control group, as detected by clustering analysis. The expression of the death-associated protein FAS-ligand and the amount of apoptotic cell death were examined in the brains of aged offspring. Similar levels of FAS-ligand expression and parallel density of apoptotic cells were detected in the brains of aged mice of control and MI groups. Altogether, moderate systemic MI was not found to increase the risk for cell death in the aged offspring; limited effect was found in mice profile of behavior.
MeSH Terms
- Age Factors
- Aging
- Analysis of Variance
- Animals
- Animals, Newborn
- Behavior, Animal
- Brain
- Cell Death
- Cytokines
- Exploratory Behavior
- Fas Ligand Protein
- Female
- Gestational Age
- Immunohistochemistry
- Inflammation
- Learning
- Lipopolysaccharides
- Mice
- Motor Activity
- Pregnancy
- Pregnancy Complications
- Prenatal Exposure Delayed Effects
Prenatal alcohol exposure produces anatomical and behavioral abnormalities associated with fetal alcohol syndrome (FAS). Animal FAS models have demonstrated temporal windows of vulnerability in the developing cerebellum, with substantial ethanol (EtOH)-mediated apoptotic activation during these periods. In rodents, the cerebellum is most sensitive to EtOH on postnatal days 4 to 6 (P4 to P6). At slightly later ages (P7 and later), this region is less vulnerable to EtOH. The present study investigated EtOH effects on mechanisms related to activities of Bad, a proapoptotic member of the Bcl-2 gene family, to further characterize processes underlying these disparate EtOH sensitivities. In healthy cells, Bad is retained in the cytosol by association with 14-3-3, a primarily cytosolic protein. Bad promotes apoptosis by disassociating from 14-3-3 and sequestering Bcl-xL through heterodimerization. This dimerization prevents the neutralizing association of Bcl-xL with Bax, freeing Bax to perform in a prodeath manner. Caspase-dependent cleavage of Bad to a 15-kDa fragment increases its proapoptogenic capacity. Two hours following EtOH exposure of P4 and P7 animals via inhalation, we determined how exposure affects intracellular localization and proteolytic cleavage of Bad and expression of cerebellar 14-3-3, using subcellular fractionation and Western blot techniques. Ethanol effects on interactions between Bad and 14-3-3 or Bcl-xL at the more vulnerable and less vulnerable ages were determined using an enzyme-linked immunosorbent assay-based technique to detect native protein-protein interactions. At P4, EtOH increased mitochondrial localization of Bad, expression of a 15-kDa fragment recognized by Bad antibody, and formation of Bad:Bcl-xL complexes. At that more vulnerable age, EtOH also decreased formation of Bad:14-3-3 complexes. At P7, EtOH increased Bad:14-3-3 complexes and reduced Bad:Bcl-xL complexes. Cytosolic 14-3-3 remained unchanged by EtOH at P4 and P7. Ethanol-induced alterations of Bad-related mechanisms at P4 favor a prodeath response. EtOH does not influence these same mechanisms in a manner that promotes cell death at P7. Divergent Bad-related responses at these 2 developmental ages likely contribute to their differential EtOH vulnerability.
MeSH Terms
- 14-3-3 Proteins
- Aging
- Animals
- Animals, Newborn
- Blotting, Western
- Cell Fractionation
- Cerebellum
- Enzyme-Linked Immunosorbent Assay
- Ethanol
- Female
- Male
- Mitochondria
- Peptide Fragments
- Rats
- Rats, Long-Evans
- bcl-Associated Death Protein
- bcl-X Protein
The aim of this pilot study was to assess any trends related to the timing of initiation, and duration, of hormone therapy (HT) use on cognitive function to facilitate the design and power calculations for a future large cohort study entitled Research into Memory, Brain function and Estrogen Replacement (REMEMBER). A total of 428 women aged older than 60 years were recruited from a computer-generated random selection of Adelaide households. Demographic and lifestyle characteristics, and HT use history were recorded and confirmed. The Center for Epidemiological Studies-Depression score was used to assess mood. Cognitive tests were administered measuring global cognition (Mini-Mental State Examination), attention and concentration (Trail Making Test Parts A and B), verbal learning and memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list immediate and delayed recall), and verbal expression (letter fluency [[[FAS]]], category fluency [Animals], and the Boston Naming Test [short form]). Analyses were adjusted for age, education, mood, body mass index, smoking, alcohol intake, and history of cerebrovascular disease. HT use was defined as the use of systemic HT for at least 1 year. Early initiation of HT use was defined as commencement of HT before age 56 years for women with a uterus and ovaries, or within 5 years of a hysterectomy and bilateral oophorectomy. Late initiation of HT use was defined as HT commencing after these times. Early initiators of HT performed better than late initiators on the Mini-Mental State Examination (P = 0.04) and were faster than never users on the Trail Making Test Part A (P = 0.02). Women aged 70-79 years who initiated HT early performed better on the FAS test than never users (P = 0.0008). Late initiators performed worse than never users on the Mini-Mental State Examination (P = 0.09), and on the FAS test in the 60-69 year (P = 0.06) and 80 years and older (P = 0.095) age groups. However, late initiators performed better than never users on the FAS test in the 70-79 year age group (P = 0.015). HT users of less than 11 years (P = 0.09), HT users of more than 11 years (P = 0.04), and estrogen-only users (P = 0.024) performed faster than never users on the Trail Making Test Part A. Combined estrogen plus progestin users performed better than never users on the Boston Naming Test short form (P = 0.07). For some cognitive domains, early initiation of HT from around menopause may be beneficial, and initiation of HT in late menopause may be detrimental. The timing of the initiation of HT seems critical. To fully test these hypotheses and to further examine these trends by route and type of HT regimen in this population, a study size of 2,500 women would be required.
MeSH Terms
- Affect
- Aged
- Aging
- Alcohol Drinking
- Attention
- Australia
- Body Mass Index
- Cognition
- Cohort Studies
- Educational Status
- Estrogen Replacement Therapy
- Female
- Humans
- Hysterectomy
- Memory
- Middle Aged
- Ovariectomy
- Pilot Projects
- Progestins
- Time Factors
Sterol regulatory element binding protein (SREBP)-1 is a membrane-bound transcription factor that regulates the expression of several genes involved in cellular fatty acid synthesis in the peripheral tissues, including liver. Although SREBP-1 is expressed in brain, little is known about its function. The aim of the present study was to clarify the characteristics of SREBP-1 mRNA expression in rat brain under various nutritional and hormonal conditions. In genetically obese (fa/fa) Zucker rats, expression of SREBP-1 mRNA was greater in liver than in hypothalamus or cerebrum compared to the lean littermates of these rats. Fasting for 45 h and refeeding for 3 h did not affect expression in brains of Wistar rats of SREBP-1 mRNA or the mRNAs of lipogenic enzymes that are targets of SREBP-1, i.e., fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). Infusion of 2.0 mIU insulin or 3.0 microg leptin into the third cerebroventricle did not affect SREBP-1 mRNA expression in either hypothalamus or cerebrum. SREBP-1 mRNA expression in brains of transgenic mice that overexpressed leptin did not differ from that of wild-type mice. However, we observed a unique age-related alteration in SREBP-1 mRNA expression in brains of Sprague-Dawley rats. Specifically, SREBP-1 mRNA expression increased between 1 and 20 months of age, while there was no such change in the expression of FAS or ACC. This raises the possibility that increased SREBP-1 expression secondary to aging-related decline of polyunsaturated fatty acid (PUFA) might compensate for the reduction of FAS expression in brain. These findings suggest that the expression of SREBP-1 and downstream lipogenic enzymes in brain is probably not regulated by peripheral nutritional conditions or humoral factors. Aging-related changes in SREBP-1 mRNA expression may be involved in developmental changes in brain lipid metabolism.
MeSH Terms
- Acetyl-CoA Carboxylase
- Age Factors
- Aging
- Animals
- Blotting, Northern
- Body Weight
- Brain
- Fasting
- Fatty Acids
- Gene Expression
- Gene Expression Regulation
- Insulin
- Leptin
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Rats, Zucker
- Sterol Regulatory Element Binding Protein 1
Aging is associated with a decrease in gonadotropin levels in postmenopausal women (PMW) and is also associated with alterations in a number of circadian rhythms. The goals of this study were to determine the presence of circadian rhythms of gonadotropins and glycoprotein free alpha-subunit (FAS) in young and old PMW. Healthy, euthyroid PMW, ages 45 to 55 years (n = 11) and 70 to 80 years (n = 11), were admitted in the morning to start a 24-h constant routine of light, temperature, position, and activity. Subjects remained awake and semirecumbent for the duration of the study and were fed hourly snacks, and activity was monitored continuously. Blood was sampled every 5 min for two 8-h periods corresponding to the estimated acrophase and nadir of the temperature rhythm. Luteinizing hormone (LH) and FAS were measured in all samples and follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and cortisol in 20-min serum pools. Mean LH (p < 0.001), FSH (p < 0.002), and FAS (p < 0.002) were lower in older compared with younger PMW. Day/night differences in cortisol and TSH (p < 0.001) were present in all subjects. However, there were no day/night differences in LH in younger or older PMW or in FSH in younger or older PMW. There were no day/night differences in mean FAS in younger or older PMW or in FAS pulse frequency or amplitude. Thus, in controlled studies in which differences in cortisol and TSH were demonstrated, there were no day/night differences in LH, FSH, or FAS in PMW. These studies suggest that despite evidence of intact circadian rhythms of cortisol and TSH, gonadotropin secretion does not appear to follow a circadian pattern in PMW. Thus, the age-related decline in gonadotropin secretion in PMW is not associated with a dampening of circadian rhythmicity. The absence of day/night differences in FAS suggests that GnRH plays a more prominent role in FAS regulation than does thyrotropin-releasing hormone in PMW.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Circadian Rhythm
- Female
- Follicle Stimulating Hormone
- Glycoprotein Hormones, alpha Subunit
- Gonadotropins
- Humans
- Hydrocortisone
- Luteinizing Hormone
- Middle Aged
- Postmenopause
- Thyrotropin
Aging is associated with a significant reduction of lipogenic enzyme gene expression and lipogenesis in white adipose tissue (WAT). The age-related increase of lep gene expression could be, in part, responsible for these changes. Considering that sterol regulatory element binding protein 1c (SREBP-1c) plays an important role in regulation of lipogenic enzyme gene expression, it is likely that the age-related decrease of WAT lipogenic potential could be a consequence of the inhibition of SREBP-1c gene expression by leptin. We determined whether the increase of lep gene expression would account for the age-related decrease in SREBP-1c and its direct target, main lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), by assaying the messenger RNA (mRNA) levels of SREBP-1c, FAS, ACC, and leptin in WAT of 2-month-old (young) and 20-month-old (old) rats. Leptin mRNA level was much higher in the old animals, whereas in contrast, old rats displayed much lower mRNA levels of SREBP-1c and lipogenic enzymes. Moreover, experimentally increased plasma leptin concentration in young rats to the value observed in old rats resulted in the decrease of SREBP-1c, FAS, and ACC mRNA levels in WAT. Thus, the increase of lep gene expression could, in part, account for the reduced SREBP-1c gene expression and, consequently, the diminished lipogenic activity in WAT of old animals.
MeSH Terms
- Acetyl-CoA Carboxylase
- Adipose Tissue
- Aging
- Animals
- CCAAT-Enhancer-Binding Proteins
- DNA-Binding Proteins
- Fatty Acid Synthases
- Gene Expression Regulation, Enzymologic
- Leptin
- Male
- RNA, Messenger
- Rats
- Rats, Wistar
- Sterol Regulatory Element Binding Protein 1
- Transcription Factors
Oxidative stress has been proposed as a possible mechanism underlying nervous system deficits associated with Fetal Alcohol Syndrome (FAS). Current research suggests that antioxidant therapy may afford some level of protection against the teratogenic effects of alcohol. This study examined the effectiveness of antioxidant treatment in alleviating biochemical, neuroanatomical, and behavioral effects of neonatal alcohol exposure. Neonatal rats were administered alcohol (5.25 g/kg) by intragastric intubation on postnatal days 7, 8, and 9. A subset of alcohol-exposed pups were co-administered a high dose of Vitamin E (2 g/kg, or 71.9 IU/g). Controls consisted of a non-treated group, a group given the administration procedure only, and a group given the administration procedure plus the Vitamin E dose. Ethanol-exposed animals showed impaired spatial navigation in the Morris water maze, a decreased number of hippocampal CA1 pyramidal cells, and higher protein carbonyl formation in the hippocampus than controls. Vitamin E treatment alleviated the increase in protein carbonyls and the reduction in CA1 pyramidal cells seen in the ethanol-exposed group. However, the treatment did not improve spatial learning in the ethanol-exposed animals. These results suggest that while oxidative stress-related neurodegeneration may be a contributing factor in FAS, the antioxidant protection against alcohol-induced oxidative stress and neuronal cell loss in the rat hippocampus does not appear to be sufficient to prevent the behavioral impairments associated with FAS. Our findings underscore the complexity of the pathogenesis of behavioral deficits in FAS and suggest that additional mechanisms beyond oxidative damage of hippocampal neurons also contribute to the disorder.
MeSH Terms
- Administration, Oral
- Age Factors
- Aging
- Animals
- Animals, Newborn
- Apoptosis
- Dose-Response Relationship, Drug
- Drug Interactions
- Ethanol
- Female
- Hippocampus
- Male
- Maze Learning
- Neurons
- Oxidative Stress
- Rats
- Rats, Long-Evans
- Vitamin E
Ageing in rats is associated with significant reduction of lipogenic enzymes genes expression and the rate of fatty acids synthesis in white adipose tissue. Since resistance to insulin and/or triiodothyronine is not directly related to reduction in lipogenic enzymes activity in white adipose tissue of old rats, we have proposed recently that the age-related increase in leptin gene expression and high serum leptin concentration could, at least partly, account for the down regulation of lipogenic enzymes gene expression. To test this hypothesis, in this paper we experimentally (by single intraperitoneal injection of recombinant leptin) increased plasma leptin concentration in young rats to the level observed in old animals, and we examined its effect on fatty acids synthase (FAS) gene expression in white adipose tissue. The results presented in this paper indicate that leptin administration to young rats, in amount that cause the increase in serum leptin concentration to that found in old rats, significantly decreased the white adipose tissue FAS gene expression. We propose, therefore, that leptin could play a causative role in the down-regulation of lipogenic enzyme gene expression observed with ageing.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Blotting, Northern
- Fatty Acid Synthases
- Gene Expression
- Leptin
- Male
- Rats
- Rats, Wistar
We have previously demonstrated in alveolar macrophages that aging is associated with a decline in lipopolysaccharide-induced tumor necrosis factor-alpha production. The purpose of the present study was to investigate the immunotoxicological consequences of this defective activation in an experimental model of acute silicosis. Young (3 months old) and old (>18 months old) rats were intratracheally instilled with silica or saline as control. In young animals, as expected, silica induced a significant increase in bronchoalveolar lavage fluid of tumor necrosis factor-alpha, lactate dehydrogenase, and cell numbers, which correlated with increased collagen deposition and silicotic nodule formations. On the contrary, in old rats, no changes in bronchoalveolar lavage fluid or lung parameters were observed, indicating that senescent rats are resistant to the acute effects of silica. These in vivo results were confirmed in vitro, where silica-induced tumor necrosis factor-alpha release was drastically reduced in alveolar macrophages obtained from old animals. This could be explained with a defective protein kinase C betaII translocation in aged macrophages, due to decreased expression of its anchoring protein RACK-1. Furthermore, a decrease in FAS-L expression and silica-induced apoptosis in old macrophages was observed, supporting the idea that age-associated alterations in signal transduction pathways contribute to decreased sensitivity to silica-induced acute lung fibrosis in old animals.
MeSH Terms
- Acute Disease
- Aging
- Animals
- Apoptosis
- Bronchoalveolar Lavage Fluid
- Cell Membrane
- Cytosol
- Disease Models, Animal
- Fas Ligand Protein
- L-Lactate Dehydrogenase
- Lung
- Macrophages, Alveolar
- Male
- Membrane Glycoproteins
- Protein Kinase C
- Protein Kinase C beta
- Rats
- Rats, Sprague-Dawley
- Receptors for Activated C Kinase
- Receptors, Cell Surface
- Silicon Dioxide
- Silicosis
- Tumor Necrosis Factor-alpha
The prefrontal temporal cortical network (PFTCN) is a crucial part of a widely distributed neural network which has been shown (a) to subserve language function; (b) to modulate the cognitive circuits that are linked with work production; and (c) to organise thinking and develop word-search strategies. Dysfunction of the PFTCN has been reported in very early states of the dementing process. However, the functional state of the PFTCN during ageing in healthy volunteers remains unclear. Therefore, in this study, we investigated the effects of ageing, total years of education and use of caffeine and nicotine on Controlled Word Association Test (COWA) performance, a measure of PFTCN function. All subjects were mentally and physically healthy based on self-report and history, and were free of any medication at the time of the test. The COWA (also known as the Verbal Fluency Test or the FAS test) was used to investigate the functional state of the PFTCN. The total score is presented as the sum of all acceptable words generated. Multiple regression analysis was used to analyse the data. COWA scores did not correlate with caffeine or nicotine intake. However, there was a significant linear relationship between total years of education and COWA scores. Age-related changes were noted. A significant quadratic trend was observed in which subjects at both extremes of the age spectrum demonstrated poorer COWA performance. Due to limitations of our data, findings are suggestive of this trend in females but inconclusive vis a vis a possible ageing-related effect for males. These results might suggest that normal ageing-related changes as they involve the PFTCN are observed in females and, pending further studies, may differentially affect males and females. Furthermore, demographic variables such as education must be taken into account in studies in which the COWA is used. However, further studies are required in order to investigate the functional state of the PFTCN in dementia-related disorders.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aging
- Female
- Humans
- Male
- Middle Aged
- Nerve Net
- Prefrontal Cortex
- Regression Analysis
- Socioeconomic Factors
- Word Association Tests
Fetal alcohol syndrome (FAS) is often associated with cardiac hypertrophy and impaired ventricular function in a manner similar to postnatal chronic alcohol ingestion. Chronic alcoholism has been shown to lead to hypomagnesemia, and dietary Mg2 supplementation was shown to ameliorate ethanol- induced cardiovascular dysfunction such as hypertension. However, the role of gestational Mg2 supplementation on FAS-related cardiac dysfunction is unknown. This study was conducted to examine the influence of gestational dietary Mg2 supplementation on prenatal ethanol exposure-induced cardiac contractile response at the ventricular myocyte level. Timed-pregnancy female rats were fed from gestation day 2 with liquid diets containing 0.13 g/L Mg2 supplemented with ethanol (36%) or additional Mg2 (0.52 g/L), or both. The pups were maintained on standard rat chow through adulthood, and ventricular myocytes were isolated and stimulated to contract at 0.5 Hz. Mechanical properties were evaluated using an IonOptix soft-edge system, and intracellular Ca2 transients were measured as changes in fura-2 fluorescence intensity (Delta FFI). Offspring from all groups displayed similar growth curves. Myocytes from the ethanol group exhibited reduced cell length, enhanced peak shortening (PS), and shortened time to 90% relengthening (TR90) associated with a normal Delta FFI and time to PS (TPS). Mg2 reverted the prenatal ethanol-induced alteration in PS and maximal velocity of relengthening. However, it shortened TPS and TR90, and altered the Delta FFI, as well as Ca2 decay rate by itself. Additionally, myocytes from the ethanol group exhibited impaired responsiveness to increased extracellular Ca2 or stimulating frequency, which were restored by gestational Mg2 supplementation. These data suggest that although gestational Mg2 supplementation may be beneficial to certain cardiac contractile dysfunctions in offspring of alcoholic mothers, caution must be taken, as Mg2 supplementation affects cell mechanics itself.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Body Weight
- Calcium Signaling
- Central Nervous System Depressants
- Diet
- Electric Stimulation
- Ethanol
- Female
- Heart Ventricles
- Magnesium
- Myocardial Contraction
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
There is now evidence for alterations in the neuroendocrine control of the reproductive axis with aging, but its sensitivity to gonadal steroid negative feedback remains controversial. To examine the independent effect of age and gonadal steroid negative feedback, younger (45-55 yr; n = 7) and older (70-80 yr; n = 6) postmenopausal women (PMW) were studied at baseline on no HRT, after 1 month of transdermal estrogen (50 microg/d; E) and again after a further month of E and 7 d of transvaginal progesterone (P) (100 mg bid; E P). At each admission, blood was sampled every 5 min for 8 h for measurement of gonadotropin free alpha-subunit (FAS), which was used as a marker of GnRH pulse frequency. LH and FSH were measured in pooled samples. Midfollicular and midluteal phase levels of E2 and P were achieved during the E and E P treatments and were not different between younger and older PMW. There was a negative feedback effect of E and E P on mean LH (P < 0.0001) and an additional effect of age (P < 0.003), with older women having lower values throughout. Mean FSH was also decreased with E and E P (P < 0.0001) and was consistently lower in the older women (P < 0.05). Mean FAS levels decreased with hormonal treatment (P < 0.0001) and age (P < 0.001), but the effect of hormonal treatment was attenuated in the older group (P < 0.005). FAS pulse frequency was unchanged with addition of E, but dramatically decreased with E P (P < 0.002). Both hormonal replacement (P < 0.05) and age (P < 0.005) decreased FAS pulse amplitude, an effect that was attributable entirely to E as there was no additional change with E P. These studies indicate that: 1) both age and gonadal steroids independently decrease mean LH, FSH, and FAS in PMW; 2) responsiveness to steroid negative feedback on FAS is attenuated with aging in absolute but not relative terms, whereas the effect on mean levels of LH and FSH is clearly preserved; and 3) FAS pulse frequency is unchanged with E2 administration but decreases dramatically with addition of P in both old and young PMW.
MeSH Terms
- Aged
- Aging
- Estradiol
- Feedback
- Female
- Follicle Stimulating Hormone
- Glycoprotein Hormones, alpha Subunit
- Humans
- Luteinizing Hormone
- Middle Aged
- Postmenopause
- Progesterone
The expression of fatty acid synthase (FAS) in rat and mouse sciatic nerves during postnatal development was investigated. FAS activity was not sensitive to the nutritional status of the animals. During development, the specific activity of FAS was low in rat and mouse nerves immediately after birth. Then, there was a steady increase in the activity (8- to 10-fold) which reached a maximal level around postnatal day 11, plateaued till day 32, and decreased to reach 30% of the maximum at day 80. A similar developmental profile was obtained when the amount of FAS protein was quantified, thus suggesting that the variations in activity observed during sciatic nerve development are mainly due to variations in FAS protein content. Northern blot analysis showed that the mRNA levels for FAS parallels those of the ceramide galactosyl transferase (CGT) during mouse sciatic nerve development and in a rat demyelination-nerve regeneration model. In addition, we measured FAS expression in the sciatic nerves of the trembler mutant, which is a mouse model of PNS dysmyelination. In 20-day-old trembler nerves, FAS specific activity, protein amount and mRNA levels represented only 25% of the normal values. Altogether, our data indicate that FAS expression is linked to the PNS myelination process, and that the main regulation occurs at the level of the gene expression.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Brain
- Demyelinating Diseases
- Disease Models, Animal
- Fatty Acid Synthases
- Galactosyltransferases
- Gene Expression Regulation, Enzymologic
- Liver
- Malonyl Coenzyme A
- Membrane Lipids
- Mice
- Mice, Neurologic Mutants
- Myelin Sheath
- N-Acylsphingosine Galactosyltransferase
- Nerve Regeneration
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Schwann Cells
- Sciatic Nerve
- Up-Regulation
- Wallerian Degeneration
{{medline-entry |title=COWAT metanorms across age, education, and gender. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11686651 |abstract=Norms for the Controlled Oral Word Association Test (COWAT; Benton