ARC
Activity-regulated cytoskeleton-associated protein (hArc) (Activity-regulated gene 3.1 protein homolog) (ARC/ARG3.1) (Arg3.1) [KIAA0278]
Publications[править]
Research showed that lanosterol can decrease protein aggregation in lens and reduce cataract formation. Lanosterol synthase (LSS) and 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) are the limiting enzymes in the process of synthesis of lanosterol. We demonstrate to investigate the association between functional single-nucleotide polymorphisms (SNPs) of [i]LSS[/i] and [i]HMGCR[/i] genes and age-related cataract (ARC) risks in Han Chinese population from Jiangsu Eye Study. This is a case-control study. We collected participants' venous blood for DNA genotyping and lens capsule samples for RNA. The SNPs of the genes were assayed with TaqMan RT-PCR genotyping. The quantitative RT-PCR was used to detect the [i]LSS[/i] mRNA levels of lens epithelial cells (LECs) in individuals. The chi-square test was used to compare differences between ARC groups and controls of each SNP and to calculate the odds ratio (OR). We found that [i]LSS[/i]-rs2968 of ARCs was different from controls ([i]p[/i] = 0.018), but the significance was lost after Bonferroni correction ([i]p[/i] = 0.072). We then further performed stratification analysis and found that [i]LSS[/i]-rs2968 A allele was associated with nuclear type of ARC risk in Chinese population ([i]p[/i] = 0.012, OR = 0.68). Consequently, we found that the mRNA expression of [i]LSS[/i] was lower in LECs of all subtypes of ARC group than that of control group ([i]p[/i] < 0.05). [i]LSS[/i]-rs2968 A allele might play a role in the formation and development of nuclear type of ARC risk in Chinese population.
MeSH Terms
- Aged
- Aging
- Alleles
- Cataract
- Female
- Gene Expression Regulation
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genotype
- Haplotypes
- Humans
- Hydroxymethylglutaryl CoA Reductases
- Intramolecular Transferases
- Lens, Crystalline
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
Keywords
- ARC
- HMGCR
- LSS
- SNPs
- lanosterol
Cow fertility decreases with age, but the hypothalamic pathomechanisms are not understood. Anti-Müllerian hormone (AMH) stimulates gonadotropin-releasing hormone (GnRH) neurons via AMH receptor type 2 ([[AMHR2]]), and most GnRH neurons in the preoptic area (POA), arcuate nucleus (ARC), and median eminence (ME) express AMH and [[AMHR2]]. Therefore, we hypothesized that both protein amounts would differ in the anterior hypothalamus (containing the POA) and posterior hypothalamus (containing the ARC and ME) between young post-pubertal heifers and old cows. Western blot analysis showed lower (P<0.05) expressions of AMH and [[AMHR2]] in the posterior hypothalamus, but not in the anterior hypothalamus, of old Japanese Black cows compared to young heifers. Therefore, AMH and [[AMHR2]] were decreased in the posterior hypothalami of old cows.
Keywords
- Müllerian inhibiting substance
- female reproductive senescence
- gonadotropin-releasing hormone neuron
- preoptic area
- ruminant
Age-related cataract (ARC) is the leading cause of visual impairment and blindness worldwide. The apoptosis of lens epithelial cells (LECs) induced by oxidative damage is a major contributing factor to ARC. Long noncoding RNAs (lncRNAs) play important roles in various biologic processes. We aimed to explore the role of glutathione peroxidase 3 (GPX3)-antisense (AS) in ARCs. We extracted total RNAs from transparent and age-matched cataractous human lenses and detected lncRNA expression profiles using high-throughput RNA sequencing. The expression of GPX3-AS and GPX3 was detected by quantitative real-time PCR (qRT-PCR). Apoptotic proteins were detected by western blot and immunofluorescence. We treated SRA01/04 cells with H O to mimic oxidative stress and induce cell apoptosis, which was analyzed by flow cytometry and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. The cell counting kit-8 (CCK-8) assay was used to detect the viability of SRA01/04 cells. The location of GPX3-AS was determined by fluorescence in situ hybridization (FISH) and cell nuclear and cytoplasmic RNA separation. The lncRNA GPX3-AS, which is located in the nuclei of LECs, was downregulated in cataractous human lenses compared with control lenses, and proapoptotic proteins were expressed at high levels in the anterior lens capsules of ARC tissues. An in vitro study suggested that GPX3-AS inhibited H O -induced SRA01/04 cell apoptosis. As GPX3-AS is transcribed from the AS strand of the GPX3 gene locus, we further revealed its regulatory role in GPX3 expression. GPX3-AS was positively correlated with GPX3 expression. In addition, GPX3-AS inhibited H O -induced SRA01/04 cell apoptosis by upregulating GPX3 expression. In summary, our study revealed that GPX3-AS downregulated the apoptosis of LECs via promoting GPX3 expression, implying a novel therapeutic target for ARCs.
MeSH Terms
- Aging
- Anterior Capsule of the Lens
- Apoptosis
- Cataract
- Cell Line
- Cell Nucleus
- Epithelial Cells
- Glutathione Peroxidase
- Humans
- Hydrogen Peroxide
- Lens, Crystalline
- RNA, Long Noncoding
- Up-Regulation
Oxidative stress-induced toxicity plays a major role in ocular diseases such as retinal degeneration, age-related cataract (ARC) formation and macular dystrophy. In this study, we explored the possible role of resveratrol (RSV) at the different dose levels (10, 20 and 40 mg/kg/day, ip) in an experimental model of naphthalene (1 g/kg/day, po)-induced age-related cataracts. Morphological changes in the eyes of the rats in two groups, the RSV and the ARC groups, were monitored weekly, and biochemical parameters in the lenses were assessed after completion of the experimental work. A comparison between the rats in the two groups showed that treatments at RSV doses of 20 and 40 mg/kg/day significantly retarded lenticular opacity, restored antioxidants (CAT, SOD, GPX, GSH), Ca ATPase function, and protein contents, and reduced lipid peroxidation in the lenses of the animals in the RSV group. The treatment with resveratrol at a dose of 10 mg/kg/day did not show any anti-cataractogenic effects. Based on the results of our investigation, we conclude that supplemental doses of resveratrol at 40 mg/kg/day effectively prevent cataract formation associated with the aging via increased soluble protein contents and Ca homeostasis, apart from the antioxidant restoration. The results demonstrate that RSV treatment may be considered as a promising preventive or supplemental measure for delaying and/or preventing the formation of ARCs.
MeSH Terms
- Animals
- Cataract
- Dose-Response Relationship, Drug
- Male
- Naphthalenes
- Rats
- Rats, Sprague-Dawley
- Resveratrol
Keywords
- age-related cataracts
- aging
- oxidative stress
- resveratrol
Age-related cataract (ARC) is caused by the exposure of the lens to UVB which promotes oxidative damage and cell death. This study aimed to explore the role of lncRNA H19 in oxidative damage repair in early ARC. lncRNAs sequencing technique was used to identify different lncRNAs in the lens of early ARC patients. Human lens epithelial cells (HLECs) were exposed to ultraviolet irradiation; and 8-OHdG ELISA, Cell counting kit 8 (CCK8), EDU, flow cytometry and TUNEL assays were used to detect DNA damage, cell viability, proliferation and apoptosis. Luciferase assay was used to examine the interaction among H19, miR-29a and thymine DNA glycosylase (TDG) 3'UTR. We found that lncRNA H19 and TDG were highly expressed while miR-29a was down-regulated in the three types of early ARC and HLECs exposed to ultraviolet irradiation, compared to respective controls. lncRNA H19 knockdown aggravated oxidative damage, reduced cell viability and proliferation, and promoted apoptosis in HLECs, while lncRNA H19 overexpression led to opposite effects in HLECs. Mechanistically, miR-29a bound TDG 3'UTR to repress TDG expression. lncRNA H19 up-regulated the expression of TDG by repressing miR-29a because it acted as ceRNA through sponging miR-29a. In conclusion, the interaction among lncRNA H19, miR-29a and TDG is involved in early ARC. lncRNA H19 could be a useful marker of early ARC and oxidative damage repair pathway of lncRNA H19/miR-29a/TDG may be a promising target for the treatment of ARC.
MeSH Terms
- Aging
- Apoptosis
- Cataract
- Cell Line
- Cell Proliferation
- Cell Survival
- Epithelial Cells
- Gene Expression Regulation
- Humans
- Lens, Crystalline
- MicroRNAs
- Oxidative Stress
- RNA, Long Noncoding
- Signal Transduction
- Thymine DNA Glycosylase
- Ultraviolet Rays
Keywords
- TDG
- early age-related cataract
- lncRNA H19
- miRNA-29a
Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53. In lens epithelial cell (HLE B-3) senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1. Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.
MeSH Terms
- Aging
- Antibodies
- Cataract
- Cell Line
- Cellular Senescence
- Epithelial Cells
- Gene Expression Regulation
- Gene Silencing
- Humans
- Laminin
- Lens Capsule, Crystalline
- Matrix Metalloproteinase 9
- Transforming Growth Factor beta1
- Tumor Suppressor Protein p53
- p38 Mitogen-Activated Protein Kinases
Keywords
- age-related cataract
- anterior lens capsule
- basement membrane
- human lens epithelial cell
- laminin α4
- senescence
Existing studies suggest that dietary vitamins and carotenoids might be associated with a reduced risk of age-related cataract (ARC), although a quantitative summary of these associations is lacking. The aim of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) and cohort studies of dietary vitamin and carotenoid intake and ARC risk. The MEDLINE, EMBASE, ISI Web of Science, and Cochrane Library databases were searched from inception to June 2018. The adjusted RRs and corresponding 95% CIs for the associations of interest in each study were extracted to calculate pooled estimates. Dose-response relations were assessed with the use of generalized least-squares trend estimation. We included 8 RCTs and 12 cohort studies in the meta-analysis. Most vitamins and carotenoids were significantly associated with reduced risk of ARC in the cohort studies, including vitamin A (RR: 0.81; 95% CI: 0.71, 0.92; P = 0.001), vitamin C (RR: 0.80; 95% CI: 0.72, 0.88; P < 0.001), vitamin E (RR: 0.90; 95% CI: 0.80, 1.00; P = 0.049), β-carotene (RR: 0.90; 95% CI: 0.83, 0.99; P = 0.023), and lutein or zeaxanthin (RR: 0.81; 95% CI: 0.75, 0.89; P < 0.001). In RCTs, vitamin E (RR: 0.97; 95% CI: 0.91, 1.03; P = 0.262) or β-carotene (RR: 0.99; 95% CI: 0.92, 1.07; P = 0.820) intervention did not reduce the risk of ARC significantly compared with the placebo group. Further dose-response analysis indicated that in cohort studies the risk of ARC significantly decreased by 26% for every 10-mg/d increase in lutein or zeaxanthin intake (RR: 0.74; 95% CI: 0.67, 0.80; P < 0.001), by 18% for each 500-mg/d increase in vitamin C intake (RR: 0.82; 95% CI: 0.74, 0.91; P < 0.001), by 8% for each 5-mg/d increase in β-carotene intake (RR: 0.92; 95% CI: 0.88, 0.96; P < 0.001), and by 6% for every 5 mg/d increase in vitamin A intake (RR: 0.94; 95% CI: 0.90, 0.98; P < 0.001). Higher consumption of certain vitamins and carotenoids was associated with a significant decreased risk of ARC in cohort studies, but evidence from RCTs is less clear.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Ascorbic Acid
- Carotenoids
- Cataract
- Diet
- Dietary Supplements
- Female
- Humans
- MEDLINE
- Male
- Middle Aged
- Randomized Controlled Trials as Topic
- Risk Factors
- Vitamin A
- Vitamin E
- Vitamins
- beta Carotene
The gap junction protein alpha 8 (GJA8) gene has been widely studied in human congenital cataracts. However, little is known about its relationship with age-related cataract (ARC). In this study, three GJA8-tagged single nucleotide polymorphisms related to an increased ARC risk were identified: rs2132397 for general ARC under both dominant and additive models; rs7541950 for general ARC under both recessive and additive models; and rs6657114 for cortical cataract under the recessive model. To uncover the underlying mechanisms, this study also sought to explore whether GJA8 is involved in the autophagy process in human lens epithelial cells. The results showed that GJA8 may participate in autophagy to maintain the intracellular environment, which may be a novel mechanism for cataract formation induced by GJA8. In conclusion, this study identified the genetic susceptibility of GJA8 polymorphisms on ARC and provides new clues for fully understanding the pathological mechanism of GJA8 variants in affecting lens opacity.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amino Acid Sequence
- Autophagy
- Cataract
- Connexins
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Pedigree
- Polymorphism, Single Nucleotide
DNA oxidative damage repair is strongly involved in the pathogenesis of age-related cataract (ARC). The sequence variants of in coding region of DNA repair genes have been shown to be associated with ARC. It is known that single nucleotide polymorphisms (SNPs) in the 3'-terminal untranslated region (3'-UTR) can alter the gene expression by binding with microRNAs (miRNAs). We hypothesize that SNP(s) in miRNA binding site of certain DNA oxidative damage repair genes might associate with ARC risk. We examined 10 miRNA binding SNPs in 3'-UTR of 7 oxidative damage genes and revealed the XPC- rs2229090 C allele was associated with nuclear type of ARC (ARNC) risk in Chinese population. The individuals with the variant G allele (CG and GG) of XPC- rs2229090 had higher XPC mRNA expression compared to individuals carrying CC genotype. The in vitro assay showed that luciferase reporter gene expression can be down regulated by hsa-miR-589-5p in cells transfected with rs2229090 C allele compared to G allele. These results suggested that the C allele of XPC-2229090 increase the risk with ARNC. The mechanism underlying might be due to the stronger interation of the C allele with hsa-miR-589-5p, resulting in lower XPC expression and DNA repair capability than the individuals carring G allele in lens.
MeSH Terms
- 3' Untranslated Regions
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Case-Control Studies
- Cataract
- DNA Repair
- DNA-Binding Proteins
- Disease Susceptibility
- Female
- Gene Expression Regulation
- Humans
- Male
- MicroRNAs
- Middle Aged
- Odds Ratio
- RNA Interference
The aim of the study is to analyse correlations between age-related cataract (ARC), serum selenium levels and glutathione peroxidase gene 1 and 4 (GPX-1 and GPX-4). A total sample of 275 participants were enrolled into the study: group A, 94 subjects elligible for ARC surgery, and group B, 181 volunteers without ocular symptoms, gender-, age-, and smoking- status and volume-matched at 1:2 with subjects in group A. All participants (n=275) were divided according to the Lens Opacities Classification System III (LOCS III) into: 1) study group (subjects with clinically significant cataract; N≥3 or C≥3 or P≥2), 2) control group (controls with clinically non-significant cataract; N<3 and C<3 and P<2). The single nucleotide polymorphisms of GPX-1 and GPX-4 were assessed using Real Time PCR. Serum selenium levels were assayed using Inductively Coupled Plasma Mass Spectrometry. Low selenium levels significantly predicted any age-related cataract (OR 7.969; p<.01), nuclear cataract (OR 12.823; p<.01) and cortical cataract (OR 3.31; p<.01). There was no significant effect of gender, age, SNP GPX-1 and SNP GPX-4 on the prevalence of age-related nuclear, cortical and posterior sub-capsular cataract. Serum selenium levels of 75-85 µg/L were associated with the lowest prevalence of ARC. Due to a confirmed association between serum selenium levels and age-related cataract, low serum selenium levels may constitute a potential risk factor of age-related cataract.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cataract
- Genotype
- Glutathione Peroxidase
- Humans
- Middle Aged
- Phospholipid Hydroperoxide Glutathione Peroxidase
- Polymorphism, Single Nucleotide
- Selenium
- Sex Factors
Keywords
- LOCS III
- SNP
- age-related cataract
- glutathione peroxidase
- selenium
- single nucleotide polymorphism
Tributyltin (TBT), an antifouling agent found in boat paints, is a common contaminant of marine and freshwater ecosystems. It is rapidly absorbed by organic materials and accumulated in many aquatic animals. Human exposure may depend on ingestion of contaminated food or by indirect exposure from household items containing organotin compounds. TBT is defined as an endocrine disruptor compound (EDC) because it binds to androgen receptors. Moreover, it is also included on the list of metabolic disruptors. The brain is a known target of TBT and this compound interferes with the orexigenic system, inducing a strong decrease in NPY expression in the hypothalamus. In the present experiment, we investigated the effect of a chronic treatment with TBT on the mouse anorexigenic system in both sexes, to look at the pro-opiomelanocortin (POMC) expression in the paraventricular (PVN), dorsomedial (DMN), ventromedial (VMN), and arcuate (ARC) hypothalamic nuclei. The results show a sexually dimorphic effect of TBT on both systems. TBT induced a significant decrease of POMC-positive structures only in female mice in DMN, ARC, and in PVN for both sexes. Apparently, these results show that TBT may interfere with the anorexigenic system in hypothalamic areas involved in the control of food intake, by inhibiting POMC in a sexually dimorphic way. In conclusion, in addition to having a direct effect on fat tissue, the effects of TBT as metabolic disruptor, may be due to gender-specific actions on both orexigenic and anorexigenic hypothalamic systems.
MeSH Terms
- Adiposity
- Aging
- Animals
- Female
- Hypothalamus
- Male
- Mice
- Pro-Opiomelanocortin
- Sex Characteristics
- Trialkyltin Compounds
- Weight Gain
Keywords
- EDCs
- Hypothalamus
- Pro-opiomelanocortin
- Sex differences
- TBT
This study aimed to determine the effect of exercise training on cognitive functioning, and hippocampal PGC-1α, FNDC5, BDNF, and other cognition-related gene and protein expression in rats. Rats were divided into 4 groups based on age [3 months (young) vs. 20 months (aged)] and training status (control vs. exercise training). The rats that exercised voluntarily performed exercise training for 90 days, and then all the rats underwent several methods of behavioral assessment. Locomotor activity and spatial memory were lower but anxiety scores were higher in the aged control rats, than in the young control, young exercised, and aged exercised rats (P < 0.05). Hippocampal BDNF, FNDC5, PGC-1α, mTOR, ARC, cF-OS, ERK, SIRT, and FOXO expressions were lower, but NF-κB expressions were higher in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). Similarly, hippocampal BDNF and FNDC5 protein expression were lower in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). These findings show that aging-induced cognitive dysfunction is associated with a decrease in hippocampal expression of PGC-1α, FNDC5, and BDNF, and that exercise training might improve cognitive functioning via activation of these genes and proteins.
MeSH Terms
- Accessory Atrioventricular Bundle
- Aging
- Animals
- Anxiety
- Body Weight
- Brain-Derived Neurotrophic Factor
- Cognitive Dysfunction
- Exploratory Behavior
- Female
- Fibronectins
- Hippocampus
- Locomotion
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Physical Conditioning, Animal
- Rats
- Signal Transduction
- Spatial Memory
Keywords
- Aging
- BDNF
- Cognition
- Exercise
- FNDC5
- Irisin
Epidemiological reports and studies using rodent models indicate that early exposure to nutrient and/or hormonal challenges can reprogram metabolism at adulthood. Hypothalamic arcuate nucleus (ARC) integrates peripheral and central signals to adequately regulate energy homeostasis. microRNAs (miRNAs) participate in the control of gene expression of large regulatory networks including many signaling pathways involved in epigenetics regulations. Here, we have characterized and compared the miRNA population of ARC of adult male rats continuously exposed to a balanced metabolic environment to the one of adult male rats exposed to an unbalanced high-fat/high-carbohydrate/moderate-protein metabolic environment during the perinatal period and/or at adulthood that consequently displayed hyperinsulinemia and/or hyperleptinemia. We identified more than 400 miRNA species in ARC of adult male rats. By comparing the miRNA content of six biological replicates in each of the four perinatal/adult environments/rat groups, we identified the 10 miRNAs specified by clusters miR-96/182/183, miR-141/200c, and miR-200a/200b/429 as miRNAs of systematic and uncommonly high variation of expression. This uncommon variation of expression may underlie high individual differences in aging disease susceptibilities. By comparing the miRNA content of the adult ARC between the rat groups, we showed that the miRNA population was not affected by the unbalanced adult environment while, in contrast, the expression of 11 miRNAs was repeatedly impacted by the perinatal unbalanced environment. Our data revealed a miRNA response of adult ARC to early metabolic environmental challenge.
Keywords
- Illumina sequencing
- aging
- brain
- metabolic environment
- metabolic programming
- miRNA expression
- miRNome
To evaluate the changes in β-amyloid (Aβ) expression in age-related cataract (ARC) lens epithelia and the effect of Aβ on oxidative damage in human lens epithelial cells (HLECs). Specimens of lens epithelia and aqueous humor were obtained from 255 cataract surgery patients and 48 healthy donor eyes. The ARC samples were divided into four groups according to the Lens Opacities Classification System III, with increasing severity from Group I to Group IV. The HLECs were cultured under healthy or oxidative conditions with or without Aβ pretreatment. Western blot, immunofluorescence, real-time PCR, and enzyme-linked immunosorbent assay were performed to detect Aβ and β-amyloid precursor protein (APP) expression. β-secretase activity was analyzed in lens epithelia and HLECs. The effect of Aβ on the viability of HLECs under oxidative conditions was investigated using a cell viability assay. Compared with the healthy group, the Aβ 1-42 expression levels in lens epithelia and Aβ 1-40 expression levels in aqueous humor decreased in Groups I, II, and III (p<0.05) but were unchanged in Group IV. In contrast, APP expression levels increased in Groups I, II, and III (p<0.05) compared with those in the healthy group but were unchanged in Group IV. H O -treated HLECs exhibited decreased amounts of Aβ 1-42 and increased amounts of APP. β-secretase activity decreased in the lens epithelia of all four subgroups of ARCs compared with that in the lens epithelia of healthy subjects and decreased in H O -treated HLECs. Furthermore, treatment with nanomolar concentrations (0.2 nM to 10 nM) of Aβ could protect cell viability from oxidative damage. Aβ and APP expression levels exhibited differential changes during the development of ARC, indicating active feedback of this protein processing. Decreased expression of physiologically generated Aβ in the early and mid-stages of ARC development might be one of the potential mechanisms accelerating oxidative stress in HLECs during cataractogenesis.
MeSH Terms
- Aging
- Amyloid Precursor Protein Secretases
- Amyloid beta-Peptides
- Aqueous Humor
- Blotting, Western
- Cataract
- Cell Survival
- Cells, Cultured
- Enzyme-Linked Immunosorbent Assay
- Epithelial Cells
- Female
- Fluorescent Antibody Technique, Indirect
- Humans
- Hydrogen Peroxide
- Lens, Crystalline
- Male
- Middle Aged
- Oxidants
- Oxidative Stress
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age-related disease. We previously reported that 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α-E2 acts through pro-opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α-E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently.
MeSH Terms
- Animals
- Arcuate Nucleus of Hypothalamus
- Behavior, Animal
- Eating
- Estradiol
- Feeding Behavior
- Hypothalamus
- Leptin
- Mice, Transgenic
- Neurons
- Obesity
- Pro-Opiomelanocortin
Keywords
- 17α-estradiol
- aging
- food intake
- hypothalamus
- obesity
- pro-opiomelanocortin
Augmented apoptotic signaling can result in degradation of skeletal muscle proteins and loss of myonuclei, ultimately contributing to muscle atrophy and contractile dysfunction. Apoptosis repressor with caspase recruitment domain (ARC) is an anti-apoptotic protein highly expressed in skeletal muscle. Here we examined the role of ARC on age-related skeletal muscle apoptosis and wasting by utilizing an ARC-deficient mouse model. Aged mice displayed a number of morphological, phenotypic, and contractile alterations in both soleus and plantaris muscle with aging. Although no differences were found in proteolytic enzyme activity, ARC protein decreased while several anti-apoptotic proteins (e.g., BCL2, BCLXL, HSP70, and XIAP) and the release of mitochondrial housed protein (i.e., SMAC, AIF) increased in aged muscle. Importantly, ARC KO mice had low muscle weights and fewer fibers in soleus, with 2-year-old ARC KO mice displaying lower mitochondrial BCL2 protein along with augmented release of CYTC and SMAC in red/oxidative muscle. Overall, these results indicate that aged skeletal muscle undergoes atrophy as well as contractile and fiber type composition alterations despite an increase in anti-apoptotic protein expression. Although some mitochondrial-specific apoptotic alterations occurred in skeletal muscle due to ARC ablation over the lifespan, our data suggest that ARC may not have a large influence during skeletal muscle aging.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Apoptosis Regulatory Proteins
- Caspase Activation and Recruitment Domain
- Caspases
- Cellular Senescence
- Mice
- Muscle Proteins
- Muscle, Skeletal
- Signal Transduction
Age-related cataract (ARC) is a major cause of blindness. Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are non-protein-coding transcripts >200 nucleotides in length. LncRNAs are involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Furthermore, the dysregulation of lncRNAs causes a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders and various cancers. However, the role of lncRNA in cataract remains unclear. Therefore, in the present study, lens anterior capsular membrane was collected from normal subjects and patients with ARC and total RNA was extracted. High-throughput sequencing was applied to detect differentially expressed lncRNAs and mRNAs. The analysis identified a total of 42,556 candidate differentially expressed mRNAs (27,447 15,109) and a total of 7,041 candidate differentially expressed lncRNAs (4,146 2,895). Through bioinformatics analysis, the significant differential expression of novel lincRNA was observed and its possible molecular mechanism was explored. Reverse transcription-quantitative polymerase chain reaction was used to validate the different expression levels of selected lncRNAs. These findings may lead to the development of novel strategies for genetic diagnosis and gene therapy.
MeSH Terms
- Aging
- Cataract
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Genetic Therapy
- High-Throughput Nucleotide Sequencing
- Humans
- Male
- RNA, Long Noncoding
- RNA, Messenger
PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called PAK1 has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan. Moreover, PAK1-deficient mutant of C. elegans lives longer than the wild-type by 60%, clearly indicating that PAK1 is not only an oncogenic but also ageing kinase. Thus, in theory, both anti-oncogenic and longevity-promoting activities are among the "intrinsic" properties or criteria of "clinically useful" PAK1-blockers. There are a variety of PAK1-blocking natural products such as propolis and curcumin which indeed extend the healthy lifespan of small animals such as C. elegans by inducing the autophagy. Recently, we managed to synthesize a series of potent water-soluble and highly cell-permeable triazolyl esters of COOH-bearing PAK1-blockers such as Ketorolac, ARC (artepillin C) and CA (caffeic acid) via "Click Chemistry" that boosts their anti-cancer activity over 500-fold, mainly by increasing their cell-permeability, and one of them called 15K indeed extends the lifespan of C. elegans. In this mini-review we shall discuss both synthetic and natural PAK1-blockers, some of which would be potentially useful for cancer therapy with least side effect (rather promoting the longevity as well).
MeSH Terms
- Animals
- Antineoplastic Agents
- Click Chemistry
- Drug Discovery
- Humans
- Longevity
- Neoplasms
- Protein Kinase Inhibitors
- p21-Activated Kinases
Keywords
- C. elegans
- Cancer
- Click Chemistry
- Longevity
- PAK1
- Propolis
The hypothalamic arcuate nucleus (ARC) represents a major component of the neuroendocrine reproductive axis and plays an important role in controlling the onset of puberty as well as age-associated reproductive senescence. Although significant gene expression changes have been observed in the ARC during sexual maturation, it is unclear what changes occur during aging, especially in males. Therefore, in the present study, we profiled the expression of reproduction-related genes in the ARC of young and old male rhesus macaques, as well as old males that had received 6 months of hormone supplementation (HS) in the form of daily testosterone and dehydroepiandrosterone; we also compared morning vs night ARC gene expression in the old males. Using Affymetrix gene microarrays, we found little evidence for age-associated expression changes for genes associated with the neuroendocrine reproductive axis, whereas using qRT-PCR, we detected a similar age-associated decrease in [i]PGR[/i] (progesterone receptor) that we previously observed in postmenopausal females. We also detected a sex-steroid-dependent and age-associated decrease in androgen receptor ([i]AR[/i]) expression, with highest [i]AR[/i] levels being expressed at night (i.e., coinciding with the natural peak in daily testosterone secretion). Finally, unlike previous observations made in females, we did not find a significant age-associated increase in [i]KISS1[/i] (Kisspeptin) or [i]TAC3[/i] (Neurokinin B) expression in the ARC of males, most likely because the attenuation of circulating sex-steroid levels in the males was much less than that in postmenopausal females. Taken together, the data highlight some similarities and differences in ARC gene expression between aged male and female nonhuman primates.
MeSH Terms
- Age Factors
- Aging
- Androgens
- Animals
- Arcuate Nucleus of Hypothalamus
- Gene Expression Regulation, Developmental
- Macaca mulatta
- Male
- Real-Time Polymerase Chain Reaction
Keywords
- aging
- androgen receptor
- circadian rhythms
- reproduction
- testosterone
The objective was to compare effects of anti-GnRH immunization (immunocastration) versus surgical castration on hypothalamic-pituitary function in boars. Thirty-six boars were randomly divided into three groups (n = 12/group): control, surgically castrated, or immunized against GnRH at 10 wk of age (boostered 8 wk later). Compared to intact boars, immunocastration reduced (P < 0.05) serum concentrations of LH, FSH, testosterone and inhibin B and caused severe testicular atrophy, whereas surgical castration increased (P < 0.05) serum concentrations of LH and FSH. Both immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis, with decreased (P < 0.05) mRNA expressions of GnRH, GnRH up-stream gatekeeper genes kiss1 and its receptor (GPR54), and androgen receptor in the hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), as well as GnRH content in the median eminence. Inconsistently, mRNA expressions of gonadotropin-inhibitory hormone (GnIH) in ARC and AVPV as well as its receptor (GPR147) in pituitary were selectively reduced (P < 0.05), but mRNA expressions of estrogen receptor alpha and aromatase (CPY17A1) in pituitary were selectively increased (P < 0.05) in surgical castrates. In response to selectively attenuated suppressive signaling from GnIH and testosterone, mRNA expressions of GnRH receptor (GnRHR), LH-β and FSH-β in pituitary were increased (P < 0.05) in surgical castrates, whereas these pituitary gene expressions were decreased (P < 0.05) in immunocastrates, due to loss of hypothalamic GnRH signaling. We concluded that immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis due to a testosterone deficiency disrupting testosterone-Kisspeptin-GPR54-GnRH signaling pathways. Furthermore, selectively attenuated GnIH and testosterone signaling in the pituitary increased gonadotropin production in surgical castrates.
MeSH Terms
- Aging
- Animals
- Antibodies
- Case-Control Studies
- Feedback, Physiological
- Gonadotropin-Releasing Hormone
- Hypothalamo-Hypophyseal System
- Male
- Orchiectomy
- Organ Size
- Pituitary Gland
- RNA, Messenger
- Receptors, LHRH
- Receptors, Neuropeptide
- Swine
- Testis
- Vaccines, Contraceptive
Keywords
- Boar
- GnIH
- GnRH
- Immunocastration
- Reproductive axis
- Surgical castration
To identify distinct temporal likelihoods of age-related comorbidity (ARC) diagnoses: cardiovascular diseases (CVD), cancer, depression, dementia, and frailty-related diseases (FRD) in older men with type 2 diabetes (T2D) but ARC naïve initially, and assess the heterogeneous effects of metformin on ARCs and mortality. We identified a clinical cohort of male veterans in the United States who were ≥65years old with T2D and free from ARCs during 2002-2003. ARC diagnoses during 2004-2012 were analyzed using latent class modeling adjusted for confounders. The cohort consisted of 41,204 T2D men with age 74.6±5.8years, HbA1c 6.5±0.97%, and 8393 (20.4%) metformin users. Four ARC classes were identified. 'Healthy Class' (53.6%): metformin reduced likelihoods of all ARCs (from 0.14% in dementia to 6.1% in CVD). 'High Cancer Risk Class' (11.6%): metformin reduced likelihoods of CVD (13.3%), cancer (45.5%), depression (5.0%), and FRD (13.7%). 'High CVD Risk Class' (17.4%): metformin reduced likelihoods of CVD (48.6%), cancer (3.2%), depression (2.8%), and FRD (6.3%). 'High Frailty Risk Class' (17.2%): metformin reduced likelihoods of CVD (18.8%), cancer (3.9%), dementia (3.8%), depression (15.6%), and FRD (23.8%). Metformin slowed ARC development in old men with T2D, and these effects varied by ARC phenotype.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cardiovascular Diseases
- Cohort Studies
- Comorbidity
- Dementia
- Depression
- Diabetes Mellitus, Type 2
- Drug Resistance
- Electronic Health Records
- Frail Elderly
- Humans
- Hypoglycemic Agents
- Longitudinal Studies
- Male
- Metformin
- Mortality
- Neoplasms
- Prevalence
- Risk
- United States
- United States Department of Veterans Affairs
- Veterans Health
Keywords
- Comorbidity
- Frailty
- Metformin
- Mortality
- Type 2 diabetes
The formation and development of age-related cataract (ARC) has been demonstrated to have the involvement of defective DNA repair in lens epithelial cells (LECs). This study aimed to investigate DNA repair genes expression in human lens cortex collected from age-related cortical cataract (ARCC) and controls during surgery. The expression levels of the genes were evaluated by xx genes microarray analysis. The results were further confirmed by Quantitative Real-Time PCR (qRT-PCR). The mRNA levels of 7 genes decreased and 4 genes out of 92 genes increased in lens cortex of ARCCs compared with controls with the fold change >1.5. Using Comet assay, we found the DNA breaks in the LECs of ARCCs were obviously severer than that of controls. The present data provide a global perspective on expression of DNA repair genes that may contribute to cataract pathogenesis. The DNA damage and repair pathway might be an effective target to delay the onset of ARC.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Case-Control Studies
- Cataract
- Comet Assay
- DNA Damage
- DNA Repair
- Epithelial Cells
- Female
- Gene Expression Regulation
- Humans
- Male
- Microarray Analysis
- Middle Aged
- Oxidative Stress
- RNA, Messenger
Keywords
- Age-related cataract
- Comet assay
- DNA repair gene
- Lens cortex
- Lens fiber cell
Kisspeptin neurons in the arcuate nucleus (ARC) regulate prolactin secretion, and are in physical contact with tuberoinfundibular dopaminergic (TIDA) neurons, which inhibit prolactin secretion. Prolactin levels in the blood are increased with advancing age in rats; therefore, we investigated the interactions with TIDA neurons and kisspeptin neurons in aged female rats (24 months of age), relative to those of young adult female rats (9-10 weeks of age). Plasma prolactin levels in the aged rats were significantly higher than those of young adult rats. Tyrosine hydroxylase (TH)-immunoreactive (ir) cell bodies and kisspeptin-ir nerve fibers were found in the dorsomedial ARC of both groups. The number of TH-ir cell bodies in the dorsomedial ARC did not differ significantly between groups. Additionally, no significant differences in the number of TH-ir cells in contact with kisspeptin-ir fibers was observed between groups. However, the number of kisspeptin-ir or [i]Kiss1[/i] mRNA-expressing cells in the ARC was significantly reduced in the aged rats compared with that of the young rats. These results suggest that the contacts between TIDA neurons and kisspeptin neurons are maintained after reproductive senescence, while production of kisspeptin in the ARC decreases significantly during aging.
Keywords
- aging
- dopamine
- kisspeptin
- prolactin
- tyrosine hydroxylase
Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet-induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12). Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age-related variations in anorexigenic but not hypermetabolic leptin effects. High-fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats. Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data also raise the possibility that chronic diet-induced obesity promotes responsiveness to centrally applied leptin at least concerning anorexigenic effects.
MeSH Terms
- Aging
- Animals
- Anorexia
- Body Temperature
- Body Weight
- Diet, High-Fat
- Eating
- Energy Metabolism
- Feeding Behavior
- Gene Expression
- Leptin
- Male
- Obesity
- Rats
- Rats, Wistar
- Receptors, Leptin
- Suppressor of Cytokine Signaling 3 Protein
Keywords
- Aging
- Body temperature
- Food intake
- Leptin
- Leptin receptor (Ob-Rb)
- Metabolic rate
- Obesity
- Rat
- Suppressor of cytokine signaling 3 (SOCS3)
In the present study, we examined whether and by what mechanisms dexmedetomidine (DMED) prevents the development of systemic inflammation (SI)-induced cognitive dysfunction in aged rats. Animals received a single intraperitoneal (i.p.) injection of either 5.0 mg/kg lipopolysaccharide (LPS) or vehicle. LPS-treated rats were further divided into three groups: early DMED, late DMED, or midazolam (MDZ) treatment (n = 12 each). Seven days after LPS injection, cognitive function was evaluated using a novel object recognition task, followed by measurement of hippocampal levels of proinflammatory cytokines and Toll-like receptor 4 (TLR-4) expression. For ex vivo experiments, microglia were isolated from the hippocampus for assessment of cytokine response to LPS. LPS-treated rats showed memory deficits, hippocampal neuroinflammation, and TLR-4 upregulation as compared to saline-treated animals. However, early DMED treatment was able to attenuate these SI-induced neurocognitive changes, whereas no benefits were observed in the MDZ and late DMED treatment groups. In ex vivo experiments, early DMED treatment prevented the development of SI-induced excessive microglial hyperactivation, which was blocked by the nonspecific α -adrenergic receptor (AR) antagonist atipamezole or the specific α -AR antagonist BRL-44408, but not by the specific α -AR antagonist [[ARC]]-239. On the other hand, neither DMED nor MDZ had a direct effect on LPS-induced release of pro-inflammatory cytokines from hippocampal microglia at clinically relevant concentrations. Our findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α -AR signaling pathway.
MeSH Terms
- Aging
- Animals
- Cognitive Dysfunction
- Dexmedetomidine
- Hippocampus
- Hypnotics and Sedatives
- Imidazoles
- Inflammation
- Isoindoles
- Isoquinolines
- Lipopolysaccharides
- Male
- Memory Disorders
- Neuroprotective Agents
- Piperazines
- Rats
- Signal Transduction
Keywords
- Cognitive function
- Dexmedetomidine
- Microglia
- Neuroinflammation
Glutathione S-Transferase Mu 3 (GSTM3) protects the lens from oxidative stress that contributes to age-related cataract (ARC) formation. We examined the expression and epigenetics of GSTM3 in lens epithelial cells (LECs) and lens cortex of ARC, and investigated the potential role of molecular changes in ARC pathogenesis. This study included 120 ARCs and 40 controls. Expression of GSTM3, DNA methylation, and histone modification were assessed by quantificational real-time PCR, Western blot, bisulfite-sequencing PCR, pyrosequencing, and chromatin immunoprecipitation assay. Human lens epithelial (HLE) cell lines, SRA01/04 and HLEB3, were served as an in vitro model to observe the relationship between epigenetic status and GSTM3 expression. Potential transcription factors binding to GSTM3 promoter were detected by electrophoretic mobility shift assay. Expression of GSTM3 decreased in ARC lens tissues compared to that in the controls, which correlated with the hypermethylation of GSTM3 promoter. Lower level of GSTM3 was detected in HLEB3 than in SRA01/04, while HLEB3 displayed hypermethylation of GSTM3 and SRA01/04 did not. Compared to SRA01/04, HLEB3 displayed lower acetylated H3 and higher trimethylated H3K9 levels. After treatment with DNA methyltransferase inhibitor or histone deacetylase inhibitor, HLEB3 had an increased GSTM3 expression. Methylation of GSTM3 promoter abrogated the potential transcription factor binding. The GSTM3 expression declined in hydrogen peroxide-treated HLE cell lines. Expression of GSTM3 might be regulated by epigenetic changes in lens tissue. Hypermethylation in GSTM3 promoter and altered histone modification might have a role in the ARC formation. The results provided a potential strategy of ARC management by manipulating epigenetic changes.
MeSH Terms
- Aging
- Cataract
- Cells, Cultured
- DNA
- DNA Methylation
- Epigenomics
- Female
- Gene Expression Regulation
- Glutathione Transferase
- Humans
- Lens Cortex, Crystalline
- Male
- Middle Aged
- Oxidative Stress
- Promoter Regions, Genetic
- Real-Time Polymerase Chain Reaction
Reactive oxygen species caused by oxidative stress are considered as an important risk factor in the pathogenesis of age-related cataract (ARC). In addition, it has been shown that DNA damage has a potential role in the pathogenesis of cataract. In this study, background DNA damage, oxidative stress-induced DNA damage, and repair of nuclear and mitochondrial DNA of peripheral blood mononuclear cells (PBMCs) of ARC patients were investigated. The study population included 30 age-matched and sex-matched controls with 30 ARC patients aged 50 years and older. Acute oxidative stress was induced by 200 µM H O . The DNA damage was determined using gene-specific quantitative PCR-based assay in DNA extracted from PBMCs, both at basal condition and after (0, 6, and 20 h) acute oxidative stress. Background level of mitochondrial DNA frequency was higher in cataract patients. The present study revealed that, for the first time, both nDNA and mtDNA of cataract patients were sensitive to the oxidative stress in comparison with healthy individuals. It was found that oxidative DNA damage in PBMCs was almost all repaired within 20 h. Also, time-dependent repair of nDNA and mtDNA damage was not different between cataract patients and healthy individuals. Our findings clearly demonstrate that both nDNA and mtDNA in cataract patients are susceptible to oxidative DNA damage and background level of mitochondrial DNA damage was higher. Also, these results suggest that oxidative DNA damage accumulation (especially mtDNA damage) can play a crucial role in pathogenesis of cataract.
MeSH Terms
- Aging
- Cataract
- Cell Nucleus
- DNA
- DNA Damage
- DNA Repair
- DNA, Mitochondrial
- Female
- Humans
- Hydrogen Peroxide
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Oxidative Stress
- Reactive Oxygen Species
- Real-Time Polymerase Chain Reaction
Keywords
- Age-related cataract
- DNA damage
- QPCR
- oxidative DNA repair
- oxidative stress
The aging of lens progenitor cell has been repeatedly proposed to play a key role in age-related cataracts (ARCs), but the mechanism is far from being understood. The present study aims to investigate the relationship between aging of lens progenitor/epithelial cells and the 4 subtypes of ARCs in humans.Lens capsules, which were collected from ARC patients during surgery, were divided into 3 groups according to the age of patients (50-60, 60-80, and >80 years). The expressions of lens progenitor cell-related markers Sox2, Abcg2, and Ki67 were first examined in human lens epithelial cells (HLECs) in situ. Then, the percentage of senescent and SA-β-gal HLECs isolated from lens capsules were quantified. Finally, the potential relationships between the percentage of senescent (and SA-β-gal) HLECs and the severity of ARCs were analyzed.Ki67, Sox2, and Abcg2 HLECs in lens capsules were clearly more abundant in young people than in patients older than 50 years, and they were almost absent in patients older than 60 years. The percentage of primary HLECs with aging morphology increased with age, consistent with the results of SA-β-gal primary HLECs. Only cortical cataract classification was found to be strongly related to the percentage of SA-β-gal and senescent HLECs.Our study gave the initial evidence on the dynamical change of lens stem/progenitor cells in human lens capsule with age and suggested that lens progenitor/epithelial cell aging is important in the severity of cortical cataracts.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apoptosis
- Cataract
- Cell Proliferation
- Cells, Cultured
- Disease Progression
- Epithelial Cells
- Female
- Humans
- Lens Capsule, Crystalline
- Lens, Crystalline
- Male
- Middle Aged
- Retrospective Studies
- Severity of Illness Index
In our previous research, the formation and development of age-related cataract (ARC) is associated with DNA hypermethylation of some genes in lens epithelial cells (LECs). This study aimed to investigate the expression profile of DNA methylation- and transcriptional repression-associated genes in LECs of ARC. The expression levels of the genes were first evaluated by microarray analysis. The results were further confirmed by Quantitative Real-Time PCR (qRT-PCR) and Western blot assay. The mRNA and protein levels of 5 genes increased in LECs of ARCs compared with the controls. These data provided a global perspective on expression of DNA methylation- and transcriptional repression-associated genes. The study supports the notion that the epigenetic modification of macromolecules in LECs might contribute to ARC pathogenesis.
MeSH Terms
- Aged
- Aging
- Case-Control Studies
- Cataract
- DNA Methylation
- Epithelial Cells
- Female
- Gene Expression Profiling
- Humans
- Lens, Crystalline
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Reproducibility of Results
- Transcription, Genetic
Keywords
- Age-related cataract
- DNA methylation
- Epigenetics
- Lens epithelial cells
- mRNA array
To study the prevalence of age-related cataract (ARC), cataract surgery, and visual outcomes in a Chinese adult population in Taizhou, China. A population-based, cross-sectional study was conducted using a random cluster sampling method. We evaluated 10,234 eligible subjects 45 years or older (response rate 78.1%) in the Taizhou Eye Study. We conducted a detailed eye examination in all participants, including presenting visual acuity (PVA), best-corrected visual acuity (BCVA), slit-lamp assessment of lens opacities using the Lens Opacities Classification System III (LOCS III), and fundus examination. The standardized prevalences of cortical, nuclear, and posterior subcapsular cataract (PSC) were 28.6%, 24.3%, and 4.4%, respectively, and combined nuclear and cortical cataract was the most common cataract type (40.0%). According to the US visual impairment (VI) criteria and World Health Organization VI criteria, 40.6% and 21.8% of PSC participants had binocular VI, respectively; these values were higher than the VI rates in cortical and nuclear cataract (all P < 0.001). Of 148 patients (3.5%) who had cataract surgeries, 41.2% had PVA <20/63, and 19.6% had PVA <20/200. The main causes of poor visual outcome after cataract surgery were ocular comorbidities (41.3%), uncorrected refractive error (30.0%), surgical complications (15.0%), and posterior capsular opacification (PCO; 13.7%). The high prevalence of cataract and high rate of VI from ARC in the adult Chinese population remains a severe public health problem. Cataract surgery remains insufficient in mainland China and poor visual outcomes were frequent. Surgical complications and PCO were important avoidable causes that attributed to poor visual outcomes after cataract surgeries.
MeSH Terms
- Age Distribution
- Aged
- Aged, 80 and over
- Aging
- Cataract
- Cataract Extraction
- China
- Cluster Analysis
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Male
- Middle Aged
- Population Surveillance
- Prevalence
- Retrospective Studies
- Rural Population
- Sex Distribution
- Visual Acuity
CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Binding Sites
- Case-Control Studies
- Cataract
- Cell Line
- Crystallins
- Early Growth Response Transcription Factors
- Female
- Genotype
- Haplotypes
- Humans
- Kruppel-Like Transcription Factors
- Linkage Disequilibrium
- Male
- Middle Aged
- Odds Ratio
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Protein Binding
- RNA Interference
- RNA, Small Interfering
- Transcription, Genetic
Silent information regulator T1 (SIRT1), a member of the sirtuin family, has a preventive role in various ocular diseases. We evaluated the relations between the aqueous humor level of SIRT1 and age, sex, systemic diseases, the severity of lens opacity, and other factors. This study was conducted at a university teaching hospital in Tokyo, Japan. This study was designed based on the consecutive case series. Aqueous humor samples were obtained from 29 eyes of the 21 consecutive patients undergoing surgery for age-related cataract (ARC). SIRT1 levels were determined by enzyme-linked immunosorbent assay. Aqueous humor levels of SIRT1 showed a positive correlation with visual acuity (logarithm of the minimum angle of resolution) and with the severity of nuclear cataract (r=0.32 and 0.30, respectively, P<0.05). However, only visual acuity was correlated with SIRT1 according to the stepwise multiple regression analysis (P<0.05). These findings suggest that SIRT1 may have an effect on the formation of ARC, acting as a defensive factor against ARC.
Keywords
- SIRT1
- cataract surgery
- ocular aging
- oxidative stress
- resveratrol
- sirtuin
Oxidative stress has been implicated in the pathophysiology of glaucoma, cataract, and many degenerative diseases. The purpose of this study is to evaluate the systemic oxidative stress in black-African patients diagnosed with primary glaucoma or age-related cataract (ARC) and compare these indices to normal control patients and between the two conditions. This was a descriptive cross-sectional study of consecutive recruited subjects attending a tertiary care facility. One hundred adults were enrolled and sub-grouped into: Normal controls (n = 20), patients with primary glaucoma (n = 40), and patients with cataract (n = 40). The data were collected on patient demographics and clinical information. Ten milliliters of the venous blood was taken from each subject for the evaluation of serum biochemical indices of oxidative stress. Laboratory measurements of enzymatic and nonenzymic anti-oxidants, as well as lipid peroxidation, were conducted using established and validated spectrophotometric methods. The systemic oxidative stress was measured by the serum levels of anti-oxidant enzymes and lipid peroxidation, and compared between the groups and to a control group of patients. Statistically, significantly reduced serum levels of glutathione, glutathione-S-transferase, superoxide dismutase, catalase, and ascorbic acid were found in the patients with glaucoma or cataract when compared with controls (P < 0.05 for all). Differences in serum lipid peroxidation levels across or between the groups were nonsignificant. Serum protein levels were significantly higher among the subjects with cataract or glaucoma than in controls. Our results concur with findings in Caucasian study cohorts. This indicates that in black-Africans, primary glaucoma, and ARC are associated with increased systemic oxidative stress. This supports the existing evidence on the role of oxidative stress in these ocular disorders and reinforces the rationale for the use of anti-oxidants in the management and possible prevention of these conditions.
MeSH Terms
- Adult
- African Continental Ancestry Group
- Aged
- Aging
- Catalase
- Cataract
- Cross-Sectional Studies
- Female
- Glaucoma, Open-Angle
- Glutathione
- Glutathione Transferase
- Humans
- Lipid Peroxidation
- Male
- Middle Aged
- Oxidative Stress
- Oxidoreductases
- Superoxide Dismutase
Keywords
- Anti-oxidants
- Cataract
- Glaucoma
- Oxidative Stress
Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by affecting MTHFR enzyme activity and tHcy levels.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Case-Control Studies
- Cataract
- Female
- Genetic Predisposition to Disease
- Haplotypes
- Homocysteine
- Humans
- Male
- Methylenetetrahydrofolate Reductase (NADPH2)
- Middle Aged
- Polymorphism, Single Nucleotide
- Vitamin B 12
- Vitamin B 6
Epidemiological evidence suggests that diets rich in flavonoids may reduce the risk of developing age-related cataract (ARC). Flavonoids are widely distributed in foods of plant origin, and the objective of this study was to evaluate retrospectively the association between the intakes of the five flavonoid subclasses and the risk of ARC. A population-based case-control study (249 cases and 66 controls) was carried out in Heilongjiang province, which is located in the northeast of China, and where intakes and availability of fresh vegetables and fruits can be limited. Dietary data gathered by food-frequency questionnaire (FFQ) were used to calculate flavonoid intake. Adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression. No linear associations between risk of developing ARC and intakes of total dietary flavonoids, anthocyanidins, flavon-3-ol, flavanone, total flavones or total flavonols were found, but quercetin and isorhamnetin intake was inversely associated with ARC risk (OR 11.78, 95% CI: 1.62-85.84, p<0.05, and OR 6.99, 95% CI: 1.12-43.44, p<0.05, quartile 4 vs. quartile 1, respectively). As quercetin is contained in many plant foods and isorhamnetin in very few foods, we concluded that higher quercetin intake may be an important dietary factor in the reduction of the risk of ARC.
Keywords
- crystal aging
- diet
- epidemiology
- food-frequency questionnaire
- quercetin
Oral submucous fibrosis (OSMF) is a pre-malignant condition that is strongly associated with the areca nut alkaloids, arecoline (ARC) and arecaidine (ARD). The condition is characterised by the presence of senescent fibroblasts in the subepithelial mesenchyme which have the potential to promote malignancy in the neighbouring epithelial cells. We tested the hypothesis that areca nut alkaloids induce senescence in oral fibroblasts and promote the secretion of invasion-promoting transforming growth factor β (TGF-β) and matrix metalloproteinase-2 (MMP-2). Two oral fibroblast lines were treated for 48h with ARC and ARD. Senescence-associated β-galactosidase (SA-βGal) activity, Ki67 (cycling cells), large 53BP1 foci (irreparable DNA strand breaks) and p16(INK) (4A) (late senescence) were used as markers of cellular senescence and were quantified using indirect immunofluorescence and the ImageJ program. TGF-β and MMP-2 levels were measured using ELISA. Statistical analyses were performed with the two-tailed unpaired t-test where n = 3 and the Wilcoxon-Mann-Whitney test where n = 6. ARC (100 and 300 μM) and ARD (30 and 100 μM) significantly (P < 0.05) induced fibroblast senescence, as determined by the increased expression of SA-βGal, 53BP1 staining and CDKN2A/p16(INK) (4A) ; there was also a non-significant reduction in Ki67 staining. Treated cells also showed a three- fivefold increase in TGF-β and a small non-significant increase in MMP-2. Areca nut alkaloids induce senescence in oral fibroblasts and promote increased secretion of TGF-β and perhaps MMP-2 that may create a tissue environment thought to be critical in the progression of OSMF to malignancy.
MeSH Terms
- Areca
- Arecoline
- Cell Cycle
- Cell Line
- Cellular Senescence
- DNA Damage
- Disease Progression
- Fibroblasts
- Humans
- Matrix Metalloproteinase 2
- Mouth Neoplasms
- Oral Submucous Fibrosis
- Transforming Growth Factor beta
- Tumor Suppressor p53-Binding Protein 1
- beta-Galactosidase
Keywords
- alkaloid
- areca nut
- fibroblast
- matrix metalloproteinase
- senescence
- transforming growth factor beta
To study the relationship between outdoor activity and risk of age-related cataract (ARC) in a rural population of Taizhou Eye Study (phrase 1 report). A population-based, cross-sectional study of 2006 eligible rural adults (≥45 years old) from Taizhou Eye Study was conducted from Jul. to Sep. 2012. Participants underwent detailed ophthalmologic examinations including uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp and fundus examinations as well as questionnaires about previous outdoor activity and sunlight protection methods. ARC was recorded by LOCSⅢ classification system. The prevalence of cortical, nuclear and posterior subcapsular cataract were assessed separately for the risk factors and its association with outdoor activity. Of all 2006 eligible participants, 883 (44.0%) adults were diagnosed with ARC. The prevalence rates of cortical, nuclear and posterior subcapsular cataract per person were 41.4%, 30.4% and 1.5%, respectively. Women had a higher tendency of nuclear and cortical cataract than men (OR = 1.559, 95% CI 1.204-2.019 and OR = 1.862, 95% CI 1.456-2.380, respectively). Adults with high myopia had a higher prevalence of nuclear cataract than adults without that (OR = 2.528, 95% CI 1.055-6.062). Multivariable logistic regression revealed that age was risk factor of nuclear (OR = 1.190, 95% CI 1.167-1.213) and cortical (OR = 1.203, 95% CI 1.181-1.226) cataract; eyes with fundus diseases was risk factor of posterior subcapsular cataract (OR = 6.529, 95% CI 2.512-16.970). Outdoor activity was an independent risk factor of cortical cataract (OR = 1.043, 95% CI 1.004-1.083). The risk of cortical cataract increased 4.3% (95% CI 0.4%-8.3%) when outdoor activity time increased every one hour. Furthermore, the risk of cortical cataract increased 1.1% (95% CI 0.1%-2.0%) when cumulative UV-B exposure time increased every one year. Outdoor activity was an independent risk factor for cortical cataract, but was not risk factor for nuclear and posterior subcapsular cataract. The risk of cortical cataract increased 4.3% when outdoor activity time increased every one hour. In addition, the risk of cortical cataract increased 1.1% (95% CI 0.1%-2.0%) when cumulative UV-B exposure time increased every one year.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cataract
- China
- Female
- Humans
- Male
- Middle Aged
- Radiation Exposure
- Risk Factors
- Rural Population
- Ultraviolet Rays
To determine the mRNA and protein expression, and methylation levels of the Klotho in lens epithelial cells (LECs) of normal transparent lenses and age-related cataracts (ARCs), and to explore the role of epigenetic changes of the Klotho gene in regulating the development of ARCs. A total of 90 subjects were divided into three groups: a young adult group with normal transparent lenses aging from18 to30 years, a middle-aged group with ARC aging from 40 to 49 years, and an elderly group with ARC aging from 67 to 85 years. The LECs were collected through curvilinear capsulorhexis. The mRNA expression of the Klotho gene was determined using the reverse transcription polymerase chain reaction (RT-PCR). Protein expression of the Klotho gene in LECs was detected using immunohistochemical (IHC) staining. The methylation specific polymerase chain reaction (MSP) was used to detect the methylation level of the target gene. Decreased mRNA expression of the Klotho gene was reversely correlated with age. IHC results showed that the Klotho was mainly expressed in the cell membrane and cytoplasm of LECs. It was strongly positive in the young adult group (100.0%), with even distribution; weakly positive in the middle-aged group (36.7%), with expression distributed 4-5 mm away from the center of the anterior lens capsule; and negative in the elderly group (0.0%). MSP results showed that the Klotho gene was highly methylated in the elderly group (93.3%) and weakly methylated (56.7%) in the middle-aged group, but barely methylated in the young adult group (3.3%). Klotho were positively expressed in the LECs of normal individuals at the mRNA and protein level. Its promoter showed increased methylation as age increased, resulting in Klotho gene silencing as well as down-regulated expression or no expression of the Klotho protein. These epigenetic changes could affect the biological activities of LECs, which provided the basis for further studies of the association between the Klotho gene and ARC.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cataract
- Down-Regulation
- Epigenesis, Genetic
- Female
- Gene Silencing
- Glucuronidase
- Humans
- Lens, Crystalline
- Male
- Middle Aged
- Promoter Regions, Genetic
- RNA, Messenger
- Young Adult
Age-related cataract (ARC) is the leading cause of visual disability and reversible blindness all over the world. The different expressions of GST isozymes among animals may explain the variations in the cataract formation caused by oxidative stress. In this study, we evaluated the distribution of GST gene polymorphisms in ARC patients and the possible associations between the presence of ARC and GST gene polymorphisms. The epidemiological data was collected by a standard questionnaire and blood samples were obtained from 130 ARC patients and 159 healthy controls. Data about smoking habits of the groups was recorded. Real-time polymerase chain reaction-based methods were used to detect genetic polymorphisms. The GSTM 1 null genotype was found to carry an increased risk for developing ARC (OR: 1.84, 95% CI: 1.13-2.99). The frequency of the GSTT 1 null genotype was not significantly different among the ARC patients and the controls (OR: 1.0, 95% CI: 0.64-1.6). The GSTP 1 Val/Val genotype was also not significantly different among the ARC patients and control groups (OR: 1.06, 95% CI: 0.50-2.23). GSTM 1 null genotype was highly frequent in non-smokers (OR: 3.25, 95% CI: 1.66-6.35) and moderately frequent in smokers (OR: 2.50, 95% CI: 1.28-4.86). Also, carrying the combined genotypes of GSTM 1 null, GSTT 1 and GSTP 1 105-Val allele was seen to have an increased risk of developing ARC (OR: 2.91, 95% CI: 1.31-6.44). This data may provide evidence that GSTM 1 gene polymorphisms may be associated with genetic susceptibility to develop ARC. Larger studies are warranted to verify these findings.
MeSH Terms
- Aged
- Aging
- Alleles
- Case-Control Studies
- Cataract
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Genotype
- Glutathione S-Transferase pi
- Glutathione Transferase
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
- Risk Factors
- Smoking
The development of age-related cataract (ARC) is associated with DNA damage of the lens epithelial cells (LECs). This study aimed to investigate the expression level of DNA repair genes in LECs of ARC and examine whether any altered expression observed could result from DNA methylation of the promoter region of the genes. The expression levels of DNA repair genes were evaluated by microarray analysis. The results were further confirmed by qRT-PCR. DNA methylation of genes with altered expression was determined by bisulfite-specific (BSP) PCR. The mRNA levels of 10 DNA repair genes were decreased and the level of 1 DNA repair gene was increased in LECs of ARC patients compared with controls. The promoter region of the MGMT gene was hypermethylated in ARC tissue compared to controls. The data provide evidence that altered expression of DNA repair genes is associated with pathogenesis of ARC. DNA methylation of MGMT may regulate the expression of the gene and be involved in the development of ARC.
MeSH Terms
- Aging
- Case-Control Studies
- Cataract
- CpG Islands
- DNA Methylation
- DNA Repair
- Epithelium
- Female
- Gene Expression Profiling
- Humans
- Lens, Crystalline
- Male
- Microarray Analysis
Keywords
- Age-related cataract
- DNA methylation
- DNA repair
The hypothalamus plays a key role in mediating the effects of estrogen on many physiological functions, including reproduction, metabolism, and thermoregulation. We have previously observed marked estrogen-dependent gene expression changes within the hypothalamus of rhesus macaques during aging, especially in the KNDy neurons of the arcuate-median eminence (ARC-ME) that produce kisspeptin, neurokinin B, and dynorphin A. Little is known, however, about the mechanisms involved in mediating the feedback from estrogen onto these neurons. We used quantitative real-time PCR to profile age- and estrogen-dependent gene expression changes in the rhesus macaque hypothalamus. Our focus was on genes that encode steroid receptors (ESR1, ESR2, PGR, and AR) and on enzymes that contribute to the local synthesis of 17β-estradiol (E2; STS, HSD3B1/2, HSD17B5, and CYP19A). In addition, we used RT(2) Profiler™ PCR Arrays to profile a larger set of genes that are integral to hypothalamic function. KISS1, KISS1R, TAC3, and NPY2R mRNA levels increased in surgically menopausal (ovariectomized) old females relative to age-matched ovariectomized animals that received E2 hormone therapy. In contrast, PGR, HSD17B, GNRH2, SLC6A3, KISS1, TAC3, and NPY2R mRNA levels increased after E2 supplementation. The rhesus macaque ARC-ME expresses many genes that are responsive to changes in circulating estrogen levels, even during old age, and these may contribute to causing the normal and pathophysiological changes that occur during menopause.
MeSH Terms
- Aging
- Animals
- Arcuate Nucleus of Hypothalamus
- Estradiol
- Female
- Gene Expression
- Macaca mulatta
- Menopause
- Ovariectomy
- Receptors, Steroid
We conducted a meta-analysis to evaluate the relationship between vitamin E and age-related cataract (ARC). The fixed- or random-effect model was selected based on heterogeneity. Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was evaluated using Begg's test. The dose-response relationship was assessed by a restricted cubic spline model. Relevant studies were identified by a search of PubMed and the Cochrane Library to May 2014, without language restrictions. Studies involved samples of people of all ages. Dietary vitamin E intake, dietary and supplemental vitamin E intake, and high serum tocopherol levels were significantly associated with decreased risk of ARC, the pooled relative risk was 0·73 (95% CI 0·58, 0·92), 0·86 (95% CI 0·75, 0·99) and 0·77 (95% CI 0·66, 0·91), respectively. Supplemental vitamin E intake was non-significantly associated with ARC risk (relative risk=0·92; 95% CI 0·78, 1·07). The findings from dose-response analysis showed evidence of a non-linear association between dietary vitamin E intake and ARC. The risk of ARC decreased with dietary vitamin E intake from 7 mg/d (relative risk=0·94; 95% CI 0·90, 0·97). The findings of the meta-analysis indicated that dietary vitamin E intake, dietary and supplemental vitamin E intake, and high level of serum tocopherol might be significantly associated with reduced ARC risk.
MeSH Terms
- Aging
- Antioxidants
- Cataract
- Diet
- Dietary Supplements
- Humans
- Tocopherols
- Vitamin E
- Vitamins
Keywords
- Age-related cataract
- Meta-analysis
- Serum tocopherol
- Vitamin E
Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge.
MeSH Terms
- Aging
- Animals
- Cognition
- Cytoskeletal Proteins
- Hippocampus
- In Situ Hybridization
- Learning
- Male
- Nerve Tissue Proteins
- Protein Biosynthesis
- Rats
- Rats, Long-Evans
- Transcription, Genetic
Keywords
- Immediate-early gene
- Memory
- Plasticity
- Synapse
DNA repair gene (XPD and XRCC1) polymorphisms have been considered as risk factors for the development of age-related cataract (ARC). To confirm the association between DNA repair gene (XPD and XRCC1) polymorphisms and the risk of ARC, a meta-analysis was conducted. A search was made of published literature from Institute for Scientific Information (ISI) Web of Knowledge, PubMed, Google Scholar, China National Knowledge Infrastructure (CNKI), and Wanfang Data. In addition, all studies evaluating the association between DNA repair genes (XPD and XRCC1) polymorphisms and the risk for ARC were included in our analysis. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated by using fixed- or random-effects model. The Egger's test was used to check the publication bias. Six studies on XRCC1 Arg399Gln (1,300 cases, 1,222 controls) and five studies on XPD Lys751Gln (1,092 cases, 1,061 controls) were included. For the XPD Lys751Gln (A/C) SNP, the overall analysis demonstrated that the CC genotype showed a significant association with a decreased risk for ARC compared with the AA genotype (OR = 0.59, 95 % CI, 0.38-0.92, P = 0.019). Similarly, the CC genotype showed a significant association with a decreased risk for ARC compared with the (AA AC) genotype (OR = 0.65, 95 % CI, 0.43-0.98, P = 0.040). Subgroup analysis showed that the association between the CC genotype and decreased risk for ARC is statistically significant in Caucasians (OR = 0.41, 95 % CI, 0.24-0.73, P = 0.002) but not in Asians (OR = 1.06, 95 % CI, 0.51-2.19, P = 0.877). For the XRCC1 Arg399Gln (G/A) SNP, the overall analysis demonstrated that the A allele showed a significant association with an increased risk for ARC compared with the G allele (OR = 1.16, 95 % CI, 1.03-1.31, P = 0.015). Subgroup analyses exhibited that the association between the A allele and the risk for ARC was statistically significant in Asians (OR = 1.23, 95 % CI, 1.07-1.41, P = 0.003) but not in Caucasians (OR = 0.94, 95 % CI, 0.73-1.22, P = 0.660). Compared with the GG genotype, the GA genotype showed a significant association with an increased risk for ARC in Asians (OR = 1.32, 95 % CI, 1.08-1.61, P = 0.006) but not in Caucasians (OR = 0.58, 95 % CI, 0.27-1.26, P = 0.171). The Egger's test did not reveal an obvious publication bias among the included studies. Our meta-analysis suggested that the CC genotype of XPD Lys751Gln (A/C) SNP seemed to portend a decreased risk for ARC in Caucasian populations but not in Asian populations. The A allele and GA genotype of XRCC1 Arg399Gln (G/A) SNP might increase risk for ARC in Asian populations but not in Caucasian populations. More researches with larger and more different ethnic populations on this issue are therefore necessary.
MeSH Terms
- Aging
- Case-Control Studies
- Cataract
- DNA Repair
- DNA-Binding Proteins
- Genetic Predisposition to Disease
- Genotype
- Humans
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- Polymorphism, Single Nucleotide
- X-ray Repair Cross Complementing Protein 1
- Xeroderma Pigmentosum Group D Protein
The role of the hypothalamus in female reproductive senescence is unclear. Here we identified novel molecular neuroendocrine changes during the natural progression from regular reproductive cycles to acyclicity in middle-aged female rats, comparable with the perimenopausal progression in women. Expression of 48 neuroendocrine genes was quantified within three hypothalamic regions: the anteroventral periventricular nucleus, the site of steroid positive feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback and pulsatile GnRH release; and the median eminence (ME), the site of GnRH secretion. Surprisingly, the majority of changes occurred in the ARC and ME, with few effects in anteroventral periventricular nucleus. The overall pattern was increased mRNA levels with chronological age and decreases with reproductive cycle status in middle-aged rats. Affected genes included transcription factors (Stat5b, Arnt, Ahr), sex steroid hormone receptors (Esr1, Esr2, Pgr, Ar), steroidogenic enzymes (Sts, Hsd17b8), growth factors (Igf1, Tgfa), and neuropeptides (Kiss1, Tac2, Gnrh1). Bionetwork analysis revealed region-specific correlations between genes and hormones. Immunohistochemical analyses of kisspeptin and estrogen receptor-α in the ARC demonstrated age-related decreases in kisspeptin cell numbers as well as kisspeptin-estrogen receptor-α dual-labeled cells. Taken together, these results identify unexpectedly strong roles for the ME and ARC during reproductive decline and highlight fundamental differences between middle-aged rats with regular cycles and all other groups. Our data provide evidence of decreased excitatory stimulation and altered hormone feedback with aging and suggest novel neuroendocrine pathways that warrant future study. Furthermore, these changes may impact other neuroendocrine systems that undergo functional declines with age.
MeSH Terms
- Aging
- Animals
- Female
- Gene Expression Regulation, Developmental
- Humans
- Hypothalamus
- Rats
- Rats, Sprague-Dawley
- Reproduction
To evaluate the changes of oxidative DNA damage (in the form of 8-OHdG) and three key DNA base-excision repair (BER) proteins, human 8-oxoguanine DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease 1 (APE1) and DNA polymerase β (Pol β), in lens epithelium cells (LECs), cortex and nucleus of lenses with age-related cataract (ARC) and age-matched controls. A total of 90 patients with ARC and 21 control subjects were enrolled. The samples included the anterior lens capsules (mainly composed of LECs) and various portions of lens. An ELISA assay was used to assess the 8-OHdG levels of genomic DNA extracted. Immunofluorescence and Western blot were used to analyze the localization and quantification of three BER proteins, respectively. The 8-OHdG levels in lenses with ARC were higher than those of controls, and were not different among ARC subtypes. The 8-OHdG levels were the highest in the nucleus, followed by the LECs and cortex. The repair proteins were predominantly detected in the cellular nuclei of the LECs and superficial cortical cells. In the LECs, the protein levels of the three BER enzymes were higher in ARC than in controls. In the cortex, a downward trend of the levels of three BER enzymes was found with the increasing opaque degrees. In the nucleus, no enzymes were detected. Our findings indicate that the oxidative DNA damage increases in lenses with ARC, and the three BER enzymes compensatively increase in the LECs, while decreasing in the opaque cortex. The results suggest that the oxidative DNA damage may be related ARC and the alteration of DNA repair enzyme levels in ARC is associated with the location and opaque degrees of lens.
MeSH Terms
- 8-Hydroxy-2'-Deoxyguanosine
- Aged
- Aging
- Blotting, Western
- Cataract
- DNA Damage
- DNA Glycosylases
- DNA Polymerase beta
- DNA Repair
- DNA-(Apurinic or Apyrimidinic Site) Lyase
- Deoxyguanosine
- Enzyme-Linked Immunosorbent Assay
- Female
- Fluorescent Antibody Technique, Indirect
- Gene Expression Regulation
- Humans
- Lens, Crystalline
- Male
- Oxidative Stress
Keywords
- 8-OHdG
- APE1
- DNA damage
- DNA repair
- Pol β
- age-related cataract
- hOGG1
To analyze the association of the polymorphisms of xeroderma pigmentosum complementation group D (XPD) and 8-oxoguanine glycosylase-1 (OGG1) genes with the risk of age-related cataract (ARC) in an Egyptian population. This case-control study included 150 patients with ARC and 50 controls. Genotyping of XPD Asp³¹²Asn was performed by amplification refractory mutation system PCR assay and genotyping of OGG1 Ser³²⁶Cys was carried out by PCR including confronting two-pair primers. The Asn/Asn genotype of XPD gene was significantly associated with increased risk of ARC (odds ratio [OR] = 2.74, 95% confidence interval [CI] = 1.01-7.43, p = 0.04) and cortical cataract (OR = 5.06, 95% CI = 1.70-15.05, p = 0.002). The Asn³¹² allele was significantly associated with an increased risk of ARC (OR = 1.75, 95% CI 1.06-2.89, p = 0.03) and cortical cataract (OR = 2.81, 95% CI = 1.56-5.08, p<0.001). The OGG1 Cys/Cys genotype frequency was significantly higher in ARC (OR = 4.13, 95% CI = 0.93-18.21, p = 0.04) and the Cys(³²⁶ allele (OR = 1.85, 95% CI = 1.07-3.20, p = 0.03). Moreover, the Cys/Cys genotype of the OGG1 gene was significantly higher in cortical cataract (OR = 6.00, 95% CI = 1.24-28.99, p = 0.01) and the Cys³²⁶ allele was also significantly associated with cortical cataract (OR = 2.45, 95% CI = 1.30-4.63, p = 0.005). The results suggest that the Asn/Asn genotype and Asn³¹² allele of XPD polymorphism, as well as the Cys/Cys genotype and Cys³²⁶ allele of the OGG1 polymorphism, may be associated with increased risk of the development of ARC, particularly the cortical type, in the Egyptian population.
MeSH Terms
- Aged
- Aging
- Alleles
- Case-Control Studies
- Cataract
- DNA Glycosylases
- DNA Repair
- Demography
- Egypt
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- Xeroderma Pigmentosum Group D Protein
Steroid hormone receptors are widely and heterogeneously expressed in the brain, and are regulated by age and gonadal hormones. Our goal was to quantify effects of aging, long-term estradiol (E2 ) treatment, and their interactions, on expression of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα) and progesterone receptor (PR) immunoreactivity in two hypothalamic regions, the arcuate (ARC) and the periventricular area (PERI) of rhesus monkeys as a model of menopause and hormone replacement. Ovariectomized (OVX) rhesus macaques were young (∼ 11 years) or aged (∼ 25 years), given oil (vehicle) or E2 every 3 weeks for 2 years. Immunohistochemistry and stereologic analysis of ERα, PR, and GPER was performed. More effects were detected for GPER than the other two receptors. Specifically, GPER cell density in the ARC and PERI, and the percent of GPER-immunoreactive cells in the PERI, were greater in aged than in young monkeys. In addition, we mapped the qualitative distribution of GPER in the monkey hypothalamus and nearby regions. For ERα, E2 treated monkeys tended to have higher cell density than vehicle monkeys in the ARC. The percent of PR density in the PERI tended to be higher in E2 than vehicle monkeys of both ages. This study shows that the aged hypothalamus maintains expression of hormone receptors with age, and that long-term cyclic E2 treatment has few effects on their expression, although GPER was affected more than ERα or PR. This result is surprising in light of evidence for E2 regulation of the receptors studied here, and differences may be due to the selected regions, long-term nature of E2 treatment, among other possibilities.
MeSH Terms
- Aging
- Animals
- Drug Administration Schedule
- Estradiol
- Estrogen Receptor alpha
- Estrogens
- Female
- Immunohistochemistry
- Macaca mulatta
- Receptors, G-Protein-Coupled
- Receptors, Progesterone
To examine whether polymorphisms in the RNA granule component tudor domain-containing protein 7 (TDRD7) gene are associated with susceptibility to age-related cataract (ARC) in a Han Chinese population. Patients with ARC, and age-, sex- and ethnically-matched healthy control subjects were enrolled in the study. Five single nucleotide polymorphisms (SNPs) within the TDRD7 gene, rs1462091, rs11793735, rs10981985, rs2045732 and rs1462089, were genotyped using a SNaPshot® Multiplex Kit. The study included 271 control subjects and 218 patients with ARC. The rs10981985 SNP was associated with ARC in dominant (odds ratio [OR] 0.561, 95% confidence interval [CI] 0.388, 0.809) and allele dose (OR 0.619, 95% CI 0.455, 0.841) genetic models. The rs10981985 A allele frequency was lower in patients with cortical ARC than in control subjects (OR 0.502, 95% CI 0.315, 0.801). The rs10981985 polymorphism was significantly associated with cortical ARC in a dominant genetic model (OR 0.431, 95% CI 0.251, 0.740). The present study suggests that the rs10981985 G → A variant within the TDRD7 gene may protect against cortical ARC in a Han Chinese population.
MeSH Terms
- Aged
- Aging
- Base Sequence
- Case-Control Studies
- Cataract
- China
- DNA Primers
- Ethnic Groups
- Female
- Humans
- Male
- Middle Aged
- Polymerase Chain Reaction
- Polymorphism, Single Nucleotide
- RNA
- Ribonucleoproteins
Keywords
- Age-related cataract
- RNA granules
- single nucleotide polymorphism
- tudor domain-containing protein 7
Lutein and zeaxanthin are thought to have beneficial effects on protecting the lens against cataract formation, but findings from epidemiologic studies have been inconsistent. We aimed to conduct a meta-analysis of prospective cohort studies to examine the association between dietary lutein and zeaxanthin intake and risk of age-related cataract (ARC). We systematically searched MEDLINE, EMBASE, Web of Science, and Cochrane Library databases up to March 2013. Reference lists from retrieved articles were also reviewed. The adjusted relative risks (RRs) from each study were extracted to calculate a pooled estimate with its 95 % confidence interval (CI). The dose-response relationships were assessed by using generalized least-squares trend estimation. Six prospective cohort studies were identified involving 4,416 cases and 41,999 participants. For the comparison between the highest and the lowest categories of dietary lutein and zeaxanthin intake, significant inverse association were found for nuclear cataract (RR: 0.75; 95 % CI: 0.65, 0.85), but not for cortical cataract (RR: 0.85; 95 % CI: 0.53, 1.17) and for posterior subcapsular cataract (RR: 0.77; 95 % CI: 0.40, 1.13). Dose-response analysis showed that every 300 μg/d increment in dietary lutein and zeaxanthin intake was associated with a 3 %, 1 %, or 3 % reduction in the risk of nuclear cataract (RR: 0.97; 95 % CI: 0.94, 0.99), cortical cataract (RR: 0.99; 95 % CI: 0.95, 1.02), or posterior subcapsular cataract (RR: 0.97; 95 % CI: 0.93, 1.01) respectively. Dietary lutein and zeaxanthin intake is associated with a reduced risk of ARC, especially nuclear cataract in a dose-response manner, indicating a beneficial effect of lutein and zeaxanthin in ARC prevention.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cataract
- Cohort Studies
- Databases, Factual
- Diet
- Dose-Response Relationship, Drug
- Feeding Behavior
- Female
- Humans
- Lutein
- Male
- Middle Aged
- Prospective Studies
- Risk Factors
- Xanthophylls
- Zeaxanthins
Augmented renal clearance (ARC) is a new phenomenon in patients' pathophysiology without universally accepted aetiology and with various incidence rates most often described in critically ill patients in the Intensive Care Unit (ICU). The objective of this retrospective observational comparative study was to estimate the incidence rate of ARC in patients with different medical conditions employing steady state trough vancomycin serum concentrations (VSCss) for analysis. All patients tested for VCSss during two years (2010-2011) in a tertiary level hospital were analysed and 77 VSCs were eligible for analysis: 38 (50%) and 39 cases were assigned to the ARC (eCrClCG (creatinine clearance, estimated by Cockcroft-Gault) > 130 mL/min) and the control groups (eCrClCG in the range 90-130 mL/min) respectively. Patients' age, mechanical ventilation and haemodynamically unstable status had significant association with ARC occurrence (P < 0.05). Majority of ARC patients (11 patients (61 %)) were managed in non-ICU settings. ARC event showed statistically significant higher risk for under dosage (RR (relative risk for subtherapeutic VSCss), 1.84; 95% CI, 1.23\x962.74; P = 0.011), and the correlation between different thresholds (eCrClCG >130 mL/min, ≥140 mL/min and ≥150 mL/min) for ARC and VSCss allows to predict decrease of VSCss in case of eCrClCG ≥150 mL/min: every increase of eCrClCG by 40 mL/min predicts clinically relevant decrease of VSCss by 1 mmol/L (1.49 mg/mL). ARC cases lead to the doubled risk of subtherapeutic VSC, and this phenomenon is a significant event in patients in any hospital department. Investigation of medical patients' status relevant to this phenomenon needs to be continued.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Anti-Bacterial Agents
- Female
- Hemodynamics
- Humans
- Kidney
- Linear Models
- Lithuania
- Male
- Middle Aged
- ROC Curve
- Respiration, Artificial
- Retrospective Studies
- Risk Factors
- Sex Characteristics
- Vancomycin
- Young Adult
Keywords
- augmented renal clearance
- creatinine clearance
- non-ICU settings
- subtherapeutic concentration
- vancomycin
Age-related cataract (ARC) is a complex multifactorial disorder, including genetic and environmental factors. Ezrin (EZR), a member of the ezrin/radixin/moesin (ERM) protein family, plays a crucial role in the development of the lens as a plasma membrane-cytoskeleton linker. We conducted this study to investigate the role of genetic variations of ezrin and the relationship between single nucleotide polymorphisms (SNPs) in EZR and susceptibility to ARC in a Chinese population. A total of 205 sporadic age-related cataract patients and 218 unrelated random healthy controls participated in our study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of EZR were sequenced after being amplified with polymerase chain reaction. The functional consequences of the mutations were analyzed using PolyPhen2. SNP statistical analysis was performed using SNPstats. We found three novel variations in 205 patients. None presented in the 218 controls, including c.441C>G, c.924G>C, and c.1503G>A. PolyPhen2 predicted that the c.924G>C mutation probably had pathogenicity. Compared with the healthy controls, the rs5881286 -/GT genotype and - allele frequencies (p=0.0012; odds ratio [OR]=3.37; 95% confidence interval [CI]=1.70-6.70; p=3.96e-5; χ(2)=18.98, respectively), rs2242318 T/C genotype and C allele frequencies (p=0.0045; OR=3.40; 95% CI=1.70-6.79; p=8.82e-6; χ(2)=21.86, respectively), and rs144581330 A/G genotype and G allele frequencies (p=0.0472; OR=14.46; 95% CI=1.29-162.43; p=0.0244, χ(2)=6.99, respectively) were higher in the patients with age-related cataract. SNP rs144581330 in exon 2 was also predicted to be probably damaging by PolyPhen2. Haplotype association including the - allele of rs5881286, C allele of rs2242318, and A allele of rs144581330 exhibited significantly higher distribution in the patients with ARC (p=8.0e-4; OR=3.38; 95% CI=1.66-6.87). This study suggests that the genetic variations and SNPs in the gene EZR possibly contribute to the development of age-related cataracts in the Chinese population.
MeSH Terms
- Aged
- Aging
- Animals
- Base Sequence
- Cataract
- Computer Simulation
- Conserved Sequence
- Cytoskeletal Proteins
- DNA Mutational Analysis
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genome, Human
- Haplotypes
- Humans
- Linkage Disequilibrium
- Male
- Middle Aged
- Molecular Sequence Data
- Mutation
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Software
- Species Specificity
Polychlorinated biphenyls (PCBs) are industrial contaminants and known endocrine-disrupting chemicals. Previous work has shown that gestational exposure to PCBs cause changes in reproductive neuroendocrine processes. Here we extended work farther down the life spectrum and tested the hypothesis that early life exposure to Aroclor 1221 (A1221), a mixture of primarily estrogenic PCBs, results in sexually dimorphic aging-associated alterations to reproductive parameters in rats, and gene expression changes in hypothalamic nuclei that regulate reproductive function. Pregnant Sprague Dawley rats were injected on gestational days 16 and 18 with vehicle (dimethylsulfoxide), A1221 (1 mg/kg), or estradiol benzoate (50 μg/kg). Developmental parameters, estrous cyclicity (females), and timing of reproductive senescence were monitored in the offspring through 9 months of age. Expression of 48 genes was measured in 3 hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV), arcuate nucleus (ARC), and median eminence (females only) by real-time RT-PCR. Serum LH, testosterone, and estradiol were assayed in the same animals. In males, A1221 had no effects; however, prenatal estradiol benzoate increased serum estradiol, gene expression in the AVPV (1 gene), and ARC (2 genes) compared with controls. In females, estrous cycles were longer in the A1221-exposed females throughout the life cycle. Gene expression was not affected in the AVPV, but significant changes were caused by A1221 in the ARC and median eminence as a function of cycling status. Bionetwork analysis demonstrated fundamental differences in physiology and gene expression between cycling and acyclic females independent of treatment. Thus, gestational exposure to biologically relevant levels of estrogenic endocrine-disrupting chemicals has sexually dimorphic effects, with an altered transition to reproductive aging in female rats but relatively little effect in males.
MeSH Terms
- Aging
- Animals
- Arcuate Nucleus of Hypothalamus
- Aroclors
- Body Weight
- Endocrine Disruptors
- Environmental Pollutants
- Estradiol
- Estrous Cycle
- Female
- Gene Expression
- Gestational Age
- Hypothalamus
- Luteinizing Hormone
- Male
- Median Eminence
- Midline Thalamic Nuclei
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
- Rats, Sprague-Dawley
- Reproduction
- Reverse Transcriptase Polymerase Chain Reaction
- Sex Factors
DNA damage is critical in the pathogenesis of age-related cataract (ARC). This study examined the association of copy number variations (CNVs) of DNA repair genes with susceptibility to ARC in the Han Chinese. Study participants were from the population-based Jiangsu Eye Study, which includes 780 ARC patients and 525 controls. DNA was extracted from blood for copy number (CN) assays using RT-PCR. The Comet assay was to assess DNA damage in peripheral lymphocytes. Novel CNV was detected in WRN. Initial analyses found that CN = 3 for WRN had an increased risk of ARC (odds ratio [OR] = 1.88, P = 0.02); CN = 1 for HSF4 had an increased risk of ARC (OR = 4.09, P = 0.004). CN = 3 for WRN was associated with nuclear and posterior subcapsular cataract (OR = 2.06, P = 0.02; OR = 3.72, P = 0.02). CN = 1 for HSF4 was associated with nuclear and posterior subcapsular cataract (OR = 5.73, P = 0.001; OR = 6.80, P = 0.01). The combination WRN and HSF4 CNVs markedly increased the risk of ARC; the OR was increased from 2.63 by HSF4 alone to 6.80 by combined WRN and HSF4 CNVs. However, after multiple testing correction, only HSF4 CNV was associated with ARC overall and with nuclear and posterior subcapsular cataract as well. The DNA damage in lymphocytes from ARC patients was significantly higher when compared to normal controls. HSF4 and WRN CNVs might be involved in ARC pathogenesis in the Han Chinese. These findings suggest the importance of DNA repair in ARC susceptibility and distinct risk factors in ARC subtypes.
MeSH Terms
- Aged
- Aging
- Asian Continental Ancestry Group
- Cataract
- China
- Comet Assay
- DNA
- DNA Copy Number Variations
- DNA-Binding Proteins
- Exodeoxyribonucleases
- Female
- Genetic Predisposition to Disease
- Genotype
- Heat Shock Transcription Factors
- Humans
- Male
- Odds Ratio
- RecQ Helicases
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factors
- Werner Syndrome Helicase
Age-related cataract (ARC) is one of the most common causes of severe visual impairment among the elderly worldwide with four subtypes, such as cortical, nuclear, subcapsular, and mixed types. DNA damage and malfunction of DNA repair are believed to contribute to the pathogenesis of ARC. This study examined the associations of 18 single nucleotide polymorphisms (SNPs) in four DNA repair genes (BLM, WRN, [[ERCC6]], and OGG1) with ARC in Han Chinese from the Jiangsu Eye Study, a population-based epidemiologic study. We also determined the possible functional consequence of the SNPs to DNA damage. Eighteen SNPs in four DNA repair genes were genotyped in 789 ARC patients and 531 normal controls from the Jiangsu Eye Study. The Comet assay was to assess the extent of DNA damage in peripheral lymphocytes of selected subjects. The results show that WRN-rs11574311 was initially associated with ARC in general, cortical, and mixed cataracts (P = 0.003, odds ratio [OR] = 1.49; P = 0.001, OR = 1.68; and P < 0.0001, OR = 2.08), BLM-rs1063147 with nuclear cataract (P = 0.03, OR = 1.31), WRN-rs2725383 with cortical cataract (P = 0.01, OR = 1.49), and WRN-rs4733220 and WRN-rs2725338 with mixed cataract (P = 0.04, OR = 0.74; P = 0.003, OR = 0.60). However, the significances of some of the above-cited associations disappeared after multiple testing corrections. WRN-rs11574311 remains associated with cortical and mixed cataract and WRN-rs2725338 with mixed cataract after multiple testing correction. We did not find any correlation between DNA damage of peripheral lymphocytes and SNP types. We concluded that WRN genes might be involved in ARC pathogenesis in the Han Chinese population. The associations were ARC subtype specific. These findings stress the importance of detailed phenotyping in ARC subtypes, which may be associated with different risk factors and disease mechanisms.
MeSH Terms
- Adult
- Aged
- Aging
- Asian Continental Ancestry Group
- Cataract
- China
- Comet Assay
- DNA Damage
- DNA Glycosylases
- DNA Helicases
- DNA Repair
- DNA Repair Enzymes
- Exodeoxyribonucleases
- Female
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Lymphocytes
- Male
- Middle Aged
- Poly-ADP-Ribose Binding Proteins
- Polymorphism, Single Nucleotide
- RecQ Helicases
- Risk Factors
- Werner Syndrome Helicase