ATR
Serine/threonine-protein kinase ATR (EC 2.7.11.1) (Ataxia telangiectasia and Rad3-related protein) (FRAP-related protein 1) [FRP1]
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REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
Keywords
- Rev1
- cell death
- chemotherapy
- senescence
- translesion synthesis
The chemical profiling of bloodstains is essential to link the suspect with the crime. The current study proposed a proof-of-concept methodology for the investigation of bloodstains by utilizing advanced ATR-FTIR spectroscopy coupled with new generation chemometric methods. Current study providesencouraging datato allow discrimination between human and animal blood though with small sample size. In this study, different models for the age estimation of human bloodstains are developed from the trained data sets of 1-175 days old bloodstains. The models such as curve estimation (CE), multiple linear regression (MLR), and partial least squares regressions (PLSR) are developed to determine the best prediction model for aged human bloodstains. The obtained results on the dating of bloodstains are very encouraging and also tested for unknown samples. The maximum dating errors are observed in the curve estimation models whereas, the other models MLR, PLSR show excellent age estimation of unknown bloodstains. These models represent an error of ~3 ± 1 days and ~4 ± 1 days in actual and estimated date, respectively, which is lowest ever reported so far. The present methodology is expected to provide a valuable insight into forensic society and hence, to the law enforcement community. The present methodology can further be explored for an ideal model by including all other external variables/factors and for more longer aging time.
Keywords
- Aging
- Bloodstains
- Chemometric
- Forensic chemistry
- MLR
- PLSR
The presence of water in lubricant oils is a parameter related to the lubricant deterioration, which can be indicative of a serious loss of tribological efficiency and, therefore, an increase in maintenance costs. Likewise, controlling the aging of the lubricant oil is a keynote issue to prevent damage on the lubricated surfaces (e.g. engine pieces). The combination of Attenuated Total Reflectance (ATR) techniques with Fourier-Transform Infrared Spectrometry (FTIR) result in an easy, simple, fast and non-destructive way for obtaining accurate information about the actual situation of a lubricant oil. The analysis of this ATR-FTIR information using Artificial Neural Networks (ANN) as well as Linear Discriminant Analysis (LDA) results in the proper classification of lubricant oils regarding the presence/absence of water, age and viscosity. The methodology proposed in this work describes procedures for identifying the deterioration degree of oils with as high as 100% success (aging week) or 97.7% (for viscosity and water presence).
Keywords
- ANN
- Artificial neural networks
- FTIR
- LDA
- Linear discriminant analysis
- Lubricant oil aging
DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.
Keywords
- ATM
- ATR
- DNA damage response inhibitor
- DNAPK
- HNSCC
- homologous recombination
- ionizing radiation
- kinase inhibitor
- radiosensitivity
- senescence
PVDF was prepared by compression molding, and its phase content/structure was assessed by WAXD, DSC, and FTIR-ATR spectroscopy. Next, PVDF samples were aged in bioethanol fuel at 60 °C or annealed in the same temperature by 30 ─ 180 days. Then, the influence of aging/annealing on thermal stability, thermal degradation kinetics, and lifetime of the PVDF was investigated by thermogravimetric analysis (TGA/DTG), as well as the structure was again examined. The crystallinity of ~41% (from WAXD) or ~49% (from DSC) were identified for unaged PVDF, without significant changes after aging or annealing. This PVDF presented not only one phase, but a mixture of [i]α[/i]-, [i]β[/i]- and [i]γ[/i]-phases, [i]α[/i]- and [i]β[/i]-phases with more highlighted vibrational bands. Thermal degradation kinetics was evaluated using the non-isothermal Ozawa-Flynn-Wall method. The activation energy ([i]E[/i] ) of thermal degradation was calculated for conversion levels of [i]α[/i] = 5 ─ 50% at constant heating rates (5, 10, 20, and 40 °C min ), [i]α[/i] = 10% was fixed for lifetime estimation. The results indicated that temperature alone does not affect the material, but its combination with bioethanol reduced the onset temperature and [i]E[/i] of primary thermal degradation. Additionally, the material lifetime decreased until about five decades ([i]T[/i] = 25 °C and 90 days of exposition) due to the fluid effect after aging.
Keywords
- Activation energy
- Aging
- Bioethanol fuel
- Kinetics analysis
- Lifetime prediction
- Materials chemistry
- Materials science
- Poly(vinylidene fluoride)
Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the [i]Chk1[/i] and/or [i]Rrm2[/i] genes, which we previously showed extend the lifespan of a progeroid ATR-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of [i]Chk1, Rrm2[/i] and [i]Chk1/Rrm2[/i] transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas- irrespective of their genetic background. Interestingly, a higher but not statistically significant percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of normal aging.
Keywords
- DNA damage
- aging
- cancer
- mouse models
- replication stress
[i]Objective[/i]. We examined whether prefrontal lobe EEG markers of slower brain rhythms, which are correlated with functional brain aging, can reliably reflect those of other brain lobes, as measured by a multichannel device. [i]Methods[/i]. EEG measurements were taken of 112 healthy individuals aged 20 to 69 years in the eyes-closed resting state. A 5-minute measurement was taken at 8 regions (Fp1, Fp2, F3, F4, T3, T4, O1, O2). Indices (median frequency [MDF], peak frequency [PF]) that quantitatively reflect the characteristics of EEG slowing, and traditional commonly used spectral indices (absolute powers as delta, theta, alpha, beta, and relative power as alpha-to-theta ratio [[[ATR]]]), were extracted from the EEG signals. For these indices, the differences between the prefrontal lobe and other areas were analyzed and the test-retest reproducibility was investigated. [i]Results[/i]. The EEG slowing indicators showed high conformity over all brain lobes and stable reproducibility. On the other hand, the typical EEG spectral indicators delta, theta, alpha, beta, and ATR differed between brain regions. [i]Conclusion[/i]. It was found that EEG slowing markers, which were used for assessing the aging or degeneration of brain functions, could be reliably extracted from a prefrontal EEG alone. [i]Significance[/i]. These findings suggest that EEG prefrontal markers may reflect markers of other brain regions when a multi-channel device is used. Thus, this method may constitute a low-cost, wearable, wireless, easily accessible, and noninvasive tool for neurological assessment that could be used in the early detection of cognitive decline and in the prevention of dementia.
Keywords
- EEG
- EEG slowing
- brain aging
- dominant frequency
- prefrontal
Chemical reaction of main polymer and additive with oxidative cleaning agents plays an important role in aging of polymeric membrane for water and wastewater treatment. As a green and powerful oxidant, hydrogen peroxide (H O ) can achieve good cleaning efficacy under alkaline condition, but its influence on membrane aging was poorly understood. In this study, degradation of polyethersulfone (PES) membrane due to H O exposure under alkaline condition (pH 9 and 11) was holistically investigated by humic acid (HA) filtration experiments and multiple membrane characterization techniques, with sodium hypochlorite (NaClO) aging examined as a comparison. Membrane permeability and HA retention rate was hardly changed by H O aging at an exposure dose of 500 g·h/L, whereas NaClO aging led to substantial increase of membrane permeability and significant decrease of retention ability. Meanwhile, H O aging slightly increased fouling propensity with HA filtration, while NaClO aging resulted in more serious fouling. ATR-FTIR and XPS analysis revealed much less degradation of PES and hydrophilic additive by H O than that by NaClO, and membrane morphology and surface properties were characterized to explain the variation of filtration performance. Overall, compared with cleaning with NaClO, membrane degradation can be minimized by cleaning with H O .
MeSH Terms
- Humic Substances
- Hydrogen Peroxide
- Hydrophobic and Hydrophilic Interactions
- Membranes, Artificial
- Polymers
- Sodium Hypochlorite
- Sulfones
- Ultrafiltration
Keywords
- chemical cleaning
- hydrogen peroxide (H2O2)
- membrane aging
- polyethersulfone (PES) ultrafiltration (UF) membrane
- sodium hypochlorite (NaClO)
Skin is the largest organ of the body, and is prone to be affected by external environmental factors. Skin aging is caused by both genetic and environmental factors. Furthermore, aging skin tissue is known to create a permissive tissue microenvironment that promotes the initiation, progression and resistance of cancer cells by promoting the senescence-associated secretory phenotype (SASP). Therefore, more attention should be paid to skin aging. In this review, we highlight the common Rel proteins and two activation pathways: the canonical activation pathway and the non-canonical activation pathway. Furthermore, we summarize the role of NF-κB in skin aging. The effects of UV on the skin results from the production of ROS. Excessive free radicals activate the NF-κB signaling pathway and MAPK signaling pathway, contributing to the activation of AP-1 and NF-κB. Then it increased the level of TNF-α and the expression of MMPs, which induce the degradation of ECM and accelerated skin aging. We also summarize some reported natural antioxidants and synthetic antioxidants which are related to NF-κB signals. On the other hand, NF-κB plays a key role in SASP. Upon senescence-inducing signals, ATM and ATR block p62-dependent autophagic degradation of GATA4, contributing to NF-κB activation and SASP induction.
MeSH Terms
- Animals
- Cellular Senescence
- Humans
- NF-kappa B
- Phenotype
- Signal Transduction
- Skin Aging
- Skin Neoplasms
Keywords
- NF-κB
- Senescence-associated secretory phenotype
- Skin aging
Skin aging affects personal image and health. α - lipoic acid (ALA), with excellent free radical scavenging capacity, was used in this research to prepare W/O emulsion. Considering the instability of ALA, ionic liquid strategy was adopted to heighten the solubility of ALA for dissolving in water phase. The mechanism of different ionic liquids (ILs) on skin retention of ALA was investigated by in vitro skin permeation experiment, emulsion quality characterization, rheological test, ATR - FTIR and molecular simulation. The results showed that ionic liquid strategy had a positive influence on the solubilization of ALA. Different ILs were different in skin retention and regulated by skin layers rather than drug release, in which ALA - triethanolamine (ALA - TEOA) presented the best affinity with both stratum corneum (SC) and viable epidermis and dermis (VED), while ALA - N - (2 - Hydroxyethyl) piperidine (ALA - HEPP) as well as ALA - N - (2 - hydroxyethyl) pyrrolidine (ALA - HEPR) showed affinity with either SC or VED respectively. Finally, the emulsion presented brilliant anti - aging efficacy. This study provided a new method of emulsion research and had great significance for the development of topical formulations.
MeSH Terms
- Administration, Cutaneous
- Animals
- Emulsions
- Hydroxyproline
- Ionic Liquids
- Male
- Rats, Wistar
- Skin
- Skin Absorption
- Skin Aging
- Thioctic Acid
- Ultraviolet Rays
Keywords
- Anti – aging efficacy
- Ionic liquids
- Skin retention
- Solubility
- Α – lipoic acid
Nitrogen-doped graphene oxide (GO), namely, NG, was prepared by o-phenylenediamine (OPD) grafting onto GO. The structure and morphology of NG were characterized by FITR, XRD, SEM, EDS, Raman spectroscopy, and TGA. OPD was linked to the GO surface by covalent bonds, and the absorption peak of the C=N bond in the phenazine structure was identified in the FITR spectra. The aging resistance properties of nitrile-butadiene rubber (NBR)-NG composites was investigated by mechanical testing, before and after aging. The resistance of the NBR/NG composites with the addition of 3 phr NG fillers was the highest. The aging mechanism was investigated by TGA-DSC, DMA, equilibrium swelling testing, and ATR-FTIR. The results showed that NG could effectively inhibit chain cross-linking in NBR.
Keywords
- aging resistance
- graphene oxide
- nitrile-butadiene rubber
- nitrogen-doped
Senescence increases the risks of inflammatory bowel diseases and colon cancer. Intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. However, the influence of aging on the functions of ISCs is largely unknown. The mutation rate is highest in the small and large intestines. Numerous types of naturally occurring DNA damage are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. This study investigated whether aging affects the DDR in mouse ISCs. Young (2-3-month-old) and old (> 19-month-old) Lgr5-EGFP-IRES-creERT2 mice were irradiated. The DDR in Lgr5-positive ISCs was compared between these mice by immunohistochemical analyses. Induction of DDR marker proteins (phosphorylated ATR and 53BP1), inflammatory factors (phosphorylated NF-κB and interleukin-6), and a mitochondrial biogenesis-associated gene (peroxisome proliferator-activated receptor-γ coactivator 1α) was lower in old ISCs than in young ISCs in vivo. The competence of the DDR in ISCs declines with age in vivo.
Keywords
- Aging
- DNA damage response
- Intestinal stem cell
To investigate how aging affects corneal geometry in Japanese adults, and the association between corneal geometry and astigmatism.We included 421 participants who had undergone systemic and ophthalmological examinations in 2015 in Funagata town, Yamagata, Japan. Corneal topographic data were obtained using anterior-segment optical coherence tomography (CASIA SS-1000). Astigmatism was evaluated using power vector analyses where J0 represents the power of the orthogonal astigmatism. Positive values of J0 indicate with-the-rule astigmatism, while negative values indicate against-the-rule (ATR) astigmatism.Regarding age-related variations in corneal geometry, the anterior elevations at axis 0° and 180° decreased, and those at axis 90° and 270° increased with increasing age in linear regression analyses, demonstrating horizontal steepening and vertical flattening of the corneal surface. There were no significant age-related variations in posterior elevations and pachymetry findings, including central corneal thickness. Regarding age-related variations in orthogonal astigmatism, the mean values of J0 and corneal J0 (cJ0) decreased by -0.014 and -0.015 per year of increase in age, indicating astigmatic shift toward ATR. Regarding the correlation between corneal geometry and astigmatism, the shift toward ATR was positively correlated with horizontal steepening and vertical flattening, in accordance with the age-related corneal variations. In addition, the posterior surface of the cornea also has an association with this shift to some extent.The results of our population-based study demonstrated that the age-related variation in astigmatism is associated with geometrical changes in the cornea, especially those in the anterior surface of the cornea.
MeSH Terms
- Aged
- Aging
- Astigmatism
- Cornea
- Corneal Pachymetry
- Corneal Topography
- Cross-Sectional Studies
- Female
- Humans
- Japan
- Male
- Middle Aged
- Tomography, Optical Coherence
To compare corneal astigmatism and shape between male and female eyes in relationship to age. Hayashi Eye Hospital, Fukuoka, Japan. Prospective case series. Eyes of men and women in 5 age groups (40 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 79 years, and ≥80 years) had videokeratographic evaluations using a Placido-Scheimpflug system. Corneal astigmatism decomposed to vertical-horizontal (J0) and oblique (J45) astigmatism components was compared between male and female eyes, and corneal shape changes were compared using videokeratography maps. The study comprised 1000 eyes (100 eyes of male patients and 100 eyes of female patients in each of the 5 age groups). The mean J0 of the total and anterior cornea were significantly smaller in male eyes than in female eyes in all age groups (P ≤ .0269) with no significant difference in the J45 between sexes, indicating greater against-the-rule (ATR) astigmatism in male eyes. The mean J0 of the posterior cornea did not differ significantly between sexes except in the 50 to 59 years group (P = .0105). The ATR astigmatic change per decade did not differ significantly between men and women. Videokeratography maps revealed that the total and anterior corneal shape changed to ATR astigmatism with age in both sexes, and that this ATR change began at a younger age in male eyes than in female eyes. The posterior corneal shape did not differ between sexes at any age. Against-the-rule corneal astigmatism was greater and the ATR astigmatic change with age began earlier in the male eyes than in the female eyes, suggesting that target astigmatism should be determined separately for men and women when performing astigmatism correction.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Astigmatism
- Cornea
- Corneal Topography
- Female
- Humans
- Male
- Middle Aged
- Prospective Studies
- Refraction, Ocular
- Sex Factors
- Visual Acuity
With the aim of improving the anti-aging properties of nitrile-butadiene rubber (NBR), a functional organic filler, namely LDH⁻SAS, prepared by intercalating 4-amino-benzenesulfonic acid monosodium salt (SAS) into layered double hydroxides (LDHs) through anion exchange, was added to nitrile-butadiene rubber (NBR), giving the NBR/LDH⁻SAS composites. Successful preparation of LDH⁻SAS was confirmed by XRD, TGA and FTIR. LDH⁻SAS was well dispersed in the NBR matrix, owing to its strong interaction with the nitrile group of NBR. The obtained NBR/LDH⁻SAS composites exhibited excellent thermo-oxidative aging resistance as shown by TGA-DSC. Further investigation by ATR-FTIR indicated that SAS can capture the radical groups, even during the aging process, which largely accounts for the improved aging resistance.
Keywords
- 4-Amino-benzenesulfonic acid monosodium salt (SAS)
- layered double hydroxides (LDHs)
- nitrile-butadiene rubber (NBR)
- thermal oxidative aging resistance properties
To study the protective effect of Wuzi Yanzong recipe on testicular DNA damage and apoptosis in natural ageing rats, SPF grade 16-month-old SD male rats were randomly divided into three groups: ageing model group, low and high dose Wuzi Yanzong recipe groups (WZ, 1， 4 g·kg⁻¹). In addition, 2-month-old SD rats were used as adult control group (10 rats in each group). The ageing model group and the adult control group were fed with normal diet for 4 months. Wuzi Yanzong groups received medicated feed for 4 months. After fasting for 12 hours, the rats were sacrificed. Then testis tissues were taken and weighed to calculate the testis index. The change of testicular tissue morphology was observed by HE staining. Expression and localization of DNA damage-associated protein ATR were observed by immunofluorescence. The expressions of DNA damage-related proteins γ-H2AX, Chk1, p-p53 and apoptosis-related proteins Bcl-2 and Bax in testes were detected by Western blot. The apoptosis of testis tissue in rats was detected by using TUNEL. The results showed that as compared with the youth control group, the protein expression levels of γ-H2AX, Chk1, p-p53 and Bax were significantly increased while Bcl-2 protein expression level was significantly decreased intestis tissues of ageing model group. Wuzi Yanzong recipe significantly decreased protein expression levels of γ-H2AX, Chk1, p-p53 and Bax and increased Bcl-2 protein expression level as well as Bcl-2/Bax ratio. Immunofluorescence results showed that Wuzi Yanzong recipe could significantly decrease the ageing-induced ATR, increase in testis tissues. TUNEL results showed that Wuzi Yanzong recipe could significantly attenuate the germ cell apoptosis in testicular tissues. All the above results suggest that Wuzi Yanzong recipe could protect the germ cell in testicular tissues of natural ageing rates from DNA damage and apoptosis, and the mechanism may be associated with regulating p53 signaling pathway.
MeSH Terms
- Aging
- Animals
- Apoptosis
- DNA Damage
- Drugs, Chinese Herbal
- Male
- Proto-Oncogene Proteins c-bcl-2
- Rats
- Rats, Sprague-Dawley
- Testis
Keywords
- DNA damage
- Wuzi Yanzong recipe
- apoptosis
- senescence
- testis
To describe the age-related changes in with-the-rule (WTR) and oblique keratometric astigmatism (KA), posterior corneal astigmatism (PCA) and total corneal astigmatism (TCA). We used a Pentacam HR (high-resolution) rotating Scheimpflug camera to determine the KA, PCA and TCA in the right eyes of 710 patients, aged from 20 to 88 years. The age-related changes along the vertical, horizontal and oblique meridians were analyzed with Naeser's polar value method in a cross-sectional study. In the whole group, all meridional astigmatic powers and polar values were stable in the age groups from 20 to 49 years, followed by a 1.0 dioptre (D) against-the-rule (ATR) change in KA and TCA, and a 0.12 D reduction in against-the-rule PCA. A nasal rotation of the steep meridian in KA and TCA was noted in the 70-88 years old. The PCA averaged approximately 0.25 D ATR in all age groups. Females displayed the same early astigmatic stability as in the whole group, while male eyes demonstrated a linear decay from 1.5 D WTR at 20 years to 0.5 D ATR astigmatism for the oldest patients. Corneal astigmatism is stable until the age of 50 years; thereafter both keratometric and total corneal astigmatism show a 0.25 D ATR change per 10 years. The average 0.25 D ATR PCA compensates the predominant keratometric WTR astigmatism in the younger patients and increases the TCA in the elderly with keratometric ATR astigmatism. The gender-based differences in age-related astigmatism require further studies.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Astigmatism
- Cornea
- Corneal Topography
- Cross-Sectional Studies
- Denmark
- Disease Progression
- Female
- Humans
- Incidence
- Male
- Middle Aged
- Refraction, Ocular
- Retrospective Studies
- Young Adult
Keywords
- age
- keratometry
- polar values
- posterior corneal astigmatism
- total corneal astigmatism
The influence of polymer aging, water pH, and aqueous Pb concentration on Pb deposition onto low density polyethylene (LDPE) was investigated. LDPE pellets were aged by ozonation at 85 °C. ATR-FTIR and X-ray photoelectron spectroscopy (XPS) analysis of aged LDPE surfaces showed that a variety of polar functional groups (>CO<, >CO, >COO) were formed during aging. These functional groups likely provided better nucleation sites for Pb(OH) deposition compared to new LDPE, which did not have these oxygen-containing functional groups. The type and amount of Pb species present on these surfaces were evaluated through XPS. The influence of exposure duration on Pb deposition onto LDPE was modeled using the pseudo-first-order equation. Distribution ratios of 251.5 for aged LDPE and 69.3 for new LDPE showed that Pb precipitates had greater affinity for the surface of aged LDPE compared to new LDPE. Aged LDPE had less Pb surface loading at pH 11 compared to loading at pH 7.8. Pb surface loading for aged LDPE changed linearly with aging duration (from 0.5-7.5 h). Pb surface loading on both new and aged LDPE increased linearly with increasing Pb initial concentration. Greater Pb precipitation rates were found for aged LDPE compared to new LDPE at both tested pH values.
Keywords
- Drinking water
- Lead
- Plastic pipes
- Polyethylene
- Polymer aging
Biological aging is a complex process dependent on the interplay of cell autonomous and tissue contextual changes which occur in response to cumulative molecular stress and manifest through adaptive transcriptional reprogramming. Here we describe a transcription factor (TF) meta-analysis of gene expression datasets accrued from 18 tissue sites collected at different biological ages and from 7 different in-vitro aging models. In-vitro aging platforms included replicative senescence and an energy restriction model in quiescence (ERiQ), in which ATP was transiently reduced. TF motifs in promoter regions of trimmed sets of target genes were scanned using JASPAR and TRANSFAC. TF signatures established a global mapping of agglomerating motifs with distinct clusters when ranked hierarchically. Remarkably, the ERiQ profile was shared with the majority of in-vivo aged tissues. Fitting motifs in a minimalistic protein-protein network allowed to probe for connectivity to distinct stress sensors. The DNA damage sensors ATM and ATR linked to the subnetwork associated with senescence. By contrast, the energy sensors PTEN and AMPK connected to the nodes in the ERiQ subnetwork. These data suggest that metabolic dysfunction may be linked to transcriptional patterns characteristic of many aged tissues and distinct from cumulative DNA damage associated with senescence.
MeSH Terms
- Aging
- Cluster Analysis
- Humans
- Promoter Regions, Genetic
- Protein Binding
- Transcription Factors
To investigate how age and other factors affect astigmatism in Japanese adults over a period of 5 years. We included 512 Japanese participants who had undergone systemic and ophthalmological examinations both in 2005-2007 and in 2010-2012 in Funagata town, Yamagata, Japan. Astigmatism was evaluated using power vector analyses, where J0 represents the power of orthogonal astigmatism. Positive values of J0 indicate with-the-rule astigmatism, whereas negative values indicate against-the-rule (ATR). In this cross-sectional investigation, J0 represented the power of orthogonal astigmatism, and multivariate regression revealed that both J0 and corneal J0 (cJ0) declined with increasing age (both P < 0.001). In a longitudinal investigation spanning 5 years, the mean amounts of change (Δ) in J0 and ΔcJ0 were -0.045 ± 0.308 and -0.072 ± 0.278, respectively. This confirmed an ATR shift with increasing age in most individuals. The age-divided distribution of the magnitude of differences indicated that older age was associated with a larger astigmatic change over a 5-year period in both the cornea and the entire eye. Using multivariate logistic regression, we observed that older age at baseline was a risk factor for low ΔJ0, indicating a large shift toward ATR astigmatism. We confirmed that a refractive and keratometric shift toward ATR astigmatism occurs with aging. Older age at baseline was also associated with a larger magnitude of astigmatic changes over the subsequent 5 years.
MeSH Terms
- Adult
- Aged
- Aging
- Astigmatism
- Cornea
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Japan
- Male
- Middle Aged
Renin-angiotensin (RAS) and nitric oxide (NO) systems and the balance and interaction between them are considered of primary importance in maintaining fluid and electrolyte homeostasis. It has been suggested that the effects of NO may be modulated at least in part by the angiotensin (Ang) II, yet the roles of angiotensin receptor type 1 (AT1R) and type 2 (AT2R) are not well understood. Even though both Ang II and NO are elevated at birth and during the newborn period, their contribution to the adaptation of the newborn to life after birth as well as their physiological roles during development are poorly understood. The aim of this study was to determine if NO regulation of renal function during postnatal maturation is modulated by Ang II through activation of AT1R or AT2R or both receptors. Glomerular and tubular effects of either AT1R selective antagonist ZD 7155, AT2R selective antagonist PD 123319, and both antagonists ZD 7155 plus PD 123319, were measured in 1- (N = 9) and 6-week-old (N = 13) conscious, chronically instrumented lambs before and after removal of endogenous NO with L-arginine analogue, L-NAME. Two-way analysis of variance (ANOVA) procedures for repeated measures over time with factors age and treatment were used to compare the effects of the treatments on several glomerular and tubular variables in both groups. This study showed that L-NAME infusion after pre-treatment with ATR antagonists did not alter glomerular function in 1- or 6-week-old lambs. NO effects on electrolytes handling along the nephron during postnatal development were modulated by Ang II through AT1R and AT2R in an age-dependent manner. Selective inhibition of AT1R and AT2R increased excretion of Na , K , and Cl in 6- but not in 1-week-old lambs. In 6-week-old lambs, urinary flow rate increased by 200%, free water clearance increased by 50%, and urine osmolality decreased by 40% after L-NAME was added to the pre-treatment with ZD 7155 plus PD 123319. When L-NAME was added either to ZD 7155 or PD 123319, the same trend in the alterations of these variables was observed, albeit to a lower degree. In conclusion, in conscious animals, during postnatal maturation, Ang II modulates the effects of NO on glomerular function, fluid, and electrolyte homeostasis through AT1Rs and AT2Rs in an age-dependent manner. Under physiological conditions, AT2Rs may potentiate the effects of AT1R, providing evidence of a crosstalk between ATRs in modulating NO effects on fluid and electrolyte homeostasis during postnatal maturation. This study provides new insights on the regulation of renal function during early postnatal development showing that, compared with later in life, newborns have impaired capacity to regulate glomerular function, water, and electrolyte balance.
MeSH Terms
- Aging
- Angiotensin II
- Angiotensin Receptor Antagonists
- Animals
- Female
- Male
- NG-Nitroarginine Methyl Ester
- Nephrons
- Nitric Oxide
- Receptors, Angiotensin
- Sheep
- Urodynamics
- Wakefulness
- Water-Electrolyte Balance
Keywords
- Angiotensin II
- Angiotensin receptor
- Development
- Electrolytes
- Newborn
- Nitric oxide
- Renal function
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability, and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here we show that young cycling HGPS fibroblasts exhibit chronic DNA damage, primarily in S phase, as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA, altering its distribution away from replicating DNA in HGPS cells, leading to γH2AX formation, ATR activation, and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress, and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.
MeSH Terms
- Cellular Senescence
- DNA Damage
- DNA Replication
- Fibroblasts
- Humans
- Lamin Type A
- Progeria
- Protein Precursors
- Telomerase
- Telomere
Keywords
- HGPS
- aging
- p53
- progerin
- senescence
- telomere
The changing demographics of Achilles tendon rupture (ATR) patients have not fully been investigated. However, there has been a general suspicion that this injury is occurring in an increasingly older population, in terms of mean age. The aim of this study was to objectively show an increase in age in Achilles tendon rupture patients over time. Published literature on Achilles tendon ruptures was searched for descriptive statistics on the demographics of patients in the studies, specifically mean and median age of Achilles tendon rupture patients, gender ratio, percentage of athletics-related injuries, percentage of smokers, and BMI. Linear regression analyses were performed to determine the trend of patient demographics over time. A Welch one-way ANOVA was carried out to identify any possible differences in data obtained from different types of studies. The patient demographics from 142 studies were recorded, with all ATR injuries occurring between the years 1953 and 2014. There was no significant difference in the mean age data reported by varying study types, i.e. randomized controlled trial, cohort study, case series, etc. (P=0.182). There was a statistically significant rise in mean age of ATR patients over time (P<0.0005). There was also a statistically significant drop in percentage of male ATR patients (P=0.02). There is no significant trend for percentage of athletics-related injuries, smoking or BMI. Since 1953 to present day, the mean age at which ATR occurs has been increasing by at least 0.721 years every five years. In the same time period, the percentage of female study patients with ATR injuries has also been increasing by at least 0.6% every five years. Level III; Retrospective cohort study.
MeSH Terms
- Achilles Tendon
- Age Distribution
- Aging
- Analysis of Variance
- Humans
- Incidence
- Rupture
- Sex Distribution
- Tendon Injuries
Keywords
- Achilles tendon rupture age
- Male/female ratio
Raman and FTIR (Fourier Transform Infra Red) spectroscopies provide information on the chemical structure of compounds through identification and analysis of functional groups. In the present study, both spectroscopic techniques were used for investigating the phospholipid - protein balance in blood serum of depressed subjects (major depressive disorder and bipolar disorder type I or II) taking also into account their age and gender. The obtained results were compared with those of healthy subjects. The Raman and FTIR (using ATR (Attenuated Total Reflectance) technique), spectra show that a correlation between the level of phospholipids and proteins exists. Indeed, in depressed subjects the quantity of phospholipids and proteins is lower, compared to healthy ones. The second derivative of FTIR spectra shows that phospholipids directly affect the structure of proteins and their functions. In all male depressed subjects a higher amount of phospholipids and proteins compared to female depressed subjects was measured, offering them faster recovery perspectives. Spectroscopy results show that the phospholipids' and proteins' levels are lower in depressed subjects from 41 to 65 compared to the age group between 20 and 40, independently from the gender. Consequently, this study shows that Raman and infrared spectroscopies might be applied as a diagnostic tool to evaluate the balance between phospholipids and proteins in blood serum as a potential biomarker in depressive disorders.
MeSH Terms
- Adult
- Aged
- Aging
- Bipolar Disorder
- Blood Proteins
- Case-Control Studies
- Depressive Disorder, Major
- Female
- Humans
- Male
- Middle Aged
- Phospholipids
- Pilot Projects
- Sex Characteristics
- Spectroscopy, Fourier Transform Infrared
- Spectrum Analysis, Raman
- Young Adult
Keywords
- Affective disorders
- Depression
- FTIR
- Phospholipid – protein balance
- Raman spectroscopy
- Serum markers
Aging is associated with progressive telomere shortening, resulting in the formation of dysfunctional telomeres that compromise tissue proliferation. However, dysfunctional telomeres can limit tumorigenesis by activating p53-dependent cellular senescence and apoptosis. While activation of both senescence and apoptosis is required for repress tumor formation, it is not clear which pathway is the major tumor suppressive pathway in vivo. In this study, we generated Eμ-myc; Pot1b(∆/∆) mouse to directly compare tumor formation under conditions in which either p53-dependent apoptosis or senescence is activated by telomeres devoid of the shelterin component Pot1b. We found that activation of p53-dependent apoptosis plays a more critical role in suppressing lymphoma formation than p53-dependent senescence. In addition, we found that telomeres in Pot1b(∆/∆) ; p53(-/-) mice activate an ATR-Chk1-dependent DNA damage response to initiate a robust p53-independent, p73-dependent apoptotic pathway that limited stem cell proliferation but suppressed B-cell lymphomagenesis. Our results demonstrate that in mouse models, both p53-dependent and p53-independent apoptosis are important to suppressing tumor formation.
MeSH Terms
- 3T3 Cells
- Animals
- Apoptosis
- B-Lymphocytes
- Carcinogenesis
- Cell Cycle Checkpoints
- Cell Differentiation
- Cell Proliferation
- Cellular Senescence
- DNA Damage
- DNA-Binding Proteins
- Gene Deletion
- Longevity
- Mice
- Sequence Analysis, DNA
- Telomere
- Tumor Protein p73
- Tumor Suppressor Protein p53
Keywords
- DNA damage
- apoptosis
- cellular senescence
- molecular biology of aging
- stem cells
- telomeres
To assess the relationship between age, corneal astigmatism, and ocular dimensions with reference to astigmatism correction during cataract surgery. In this cross-sectional study of right eyes of 2247 consecutive patients attending cataract surgery preassessment, data on patient demographics, axial length (AL), anterior chamber depth (ACD), and keratometric astigmatism were collected. Astigmatism was further analyzed as against-the-rule (ATR: steepest meridian 180±30°), with-the-rule (WTR: 90±30°), and oblique (OB: 30-60°or 120-150°). Mean age, AL, and ACD were 72.28±13.84 years, 23.99±1.85 mm and 3.08 ±0.52 mm, respectively. In all, 20.4% eyes had ≤0.50 diopters (D), 55.2% had 0.51-1.50 D, 7.9% had 2.01-3.00 D, and 3.7% eyes had >3.00 D of astigmatism. Overall, 44.2% of eyes had corneal astigmatism >1.00 D. Average astigmatism in age ranges 40-49, 50-59, 60-69, 70-79, 80-89, and 90 years were 0.82, 1.04, 1.04, 1.02, 1.15 and 2.01 D, respectively. The magnitude of preoperative astigmatism positively correlated with age (P<0.0001), with increasing and decreasing prevalence of ATR and WTR astigmatism, respectively, with advancing age. The magnitude of ATR astigmatism inversely correlates to AL (P<0.0001). ATR astigmatism is more prevalent with increasing magnitude of astigmatism (P<0.0001). A majority of patients for cataract surgery have astigmatism between 0.51 and 1.5 D. ATR astigmatism increases, whereas WTR decreases with age. ATR astigmatism inversely correlates to AL. With increasing age, the magnitude of astigmatism increases and ATR astigmatism becomes increasingly prevalent. The likelihood of a patient requiring astigmatic correction increases with age.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Anterior Chamber
- Astigmatism
- Axial Length, Eye
- Biometry
- Child
- Cornea
- Cross-Sectional Studies
- Female
- Humans
- Lens Implantation, Intraocular
- Male
- Middle Aged
- Phacoemulsification
- Retrospective Studies
Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Autophagy
- Brain
- Cell Cycle
- Cells, Cultured
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- DNA Damage
- Fibroblasts
- GATA4 Transcription Factor
- Gene Expression Profiling
- Humans
- Inflammation
- Interleukin-1alpha
- Mice
- Mice, Inbred C57BL
- MicroRNAs
- NF-kappa B
- Phenotype
- Promoter Regions, Genetic
- Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
- Tumor Suppressor Protein p53
To analyze the pattern of anterior corneal astigmatism before cataract surgery in Korean patients using power vector analysis and to assess the effect of aging on astigmatism. Seoul St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea. Cross-sectional retrospective study. The study evaluated eyes with cataract from May 1, 2009, to July 1, 2013. All eyes received a complete ophthalmologic examination and manual keratometer measurement (OM-4) preoperatively. Power vector J0 and linear regression analyses were used to assess the association between age and anterior corneal astigmatism. The study evaluated 2847 right eyes (2847 patients). The mean age of the patients was 66.64 years ± 12.06 (SD) (range 20 to 100 years); 64.2% of the patients were women. The corneal J0 vector values became progressively negative and trended toward against-the-rule (ATR) astigmatism with increasing age (for men, r = -0.388 and P < .001; for women, r = -0.348 and P < .001). The ATR shift occurred earlier in men than in women. The regression coefficient of J0 values analyzed by age was -0.014 in men and -0.015 in women (both P < .001). Anterior corneal astigmatism in Korean patients with cataract shifted with age from with-the-rule to ATR in both sexes. No author has a financial or proprietary interest in any material or method mentioned.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Astigmatism
- Cataract
- Cataract Extraction
- Cornea
- Cross-Sectional Studies
- Female
- Humans
- Male
- Middle Aged
- Preoperative Period
- Regression Analysis
- Republic of Korea
- Retrospective Studies
- Sex Factors
- Young Adult
The stem cell genomic stability forms the basis for robust tissue homeostasis, particularly in high-turnover tissues. For the genomic stability, DNA damage response (DDR) is essential. This study was focused on the role of two major DDR-related factors, ataxia telangiectasia-mutated (ATM) and ATM- and RAD3-related (ATR) kinases, in the maintenance of intestinal stem cells (ISCs) in the adultDrosophila midgut. We explored the role of ATM and ATR, utilizing immunostaining with an anti-pS/TQ antibody as an indicator of ATM/ATR activation, γ-irradiation as a DNA damage inducer, and the UAS/GAL4 system for cell type-specific knockdown of ATM, ATR, or both during adulthood. The results showed that the pS/TQ signals got stronger with age and after oxidative stress. The pS/TQ signals were found to be more dependent on ATR rather than on ATM in ISCs/enteroblasts (EBs). Furthermore, an ISC/EB-specific knockdown of ATR, ATM, or both decreased the number of ISCs and oxidative stress-induced ISC proliferation. The phenotypic changes that were caused by the ATR knockdown were more pronounced than those caused by the ATM knockdown; however, our data indicate that ATR and ATM are both needed for ISC maintenance and proliferation; ATR seems to play a bigger role than does ATM.
MeSH Terms
- Adult Stem Cells
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Drosophila
- Drosophila Proteins
- Immunohistochemistry
- Intestines
- Protein-Serine-Threonine Kinases
- Stem Cells
Keywords
- ATM/ATR
- DNA damage response
- Drosophila
- aging
- intestinal stem cell
Ambient temperature reduction (ATR) can extend the lifespan of organisms, but the underlying mechanism is poorly understood. In this study, cellular degradation activity was evaluated in the muscle of an annual fish (Nothobranchius rachovii) reared under high (30 °C), moderate (25 °C), and low (20 °C) ambient temperatures. The results showed the following: (i) the activity of the 20S proteasome and the expression of polyubiquitin aggregates increased with ATR, whereas 20S proteasome expression did not change; (ii) the expression of microtubule-associated protein 1 light chain 3-II (LC3-II) increased with ATR; (iii) the expression of lysosome-associated membrane protein type 2a (Lamp 2a) increased with ATR, whereas the expression of the 70-kD heat shock cognate protein (Hsc 70) decreased with ATR; (iv) lysosome activity increased with ATR, whereas the expression of lysosome-associated membrane protein type 1 (Lamp 1) did not change with ATR; and (v) the expression of molecular target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) as well as the p-mTOR/mTOR ratio did not change with ATR. These findings indicate that ATR activates cellular degradation activity, constituting part of the mechanism underlying the longevity-promoting effects of ATR in N. rachovii.
MeSH Terms
- Aging
- Animals
- Autophagy
- Cyprinodontiformes
- HSP70 Heat-Shock Proteins
- Lysosomes
- Microtubule-Associated Proteins
- Polyubiquitin
- Proteasome Endopeptidase Complex
- TOR Serine-Threonine Kinases
- Temperature
In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.
MeSH Terms
- Animals
- Cell Line
- Cell Survival
- Cells, Cultured
- Chromosome Breakage
- Chromosome Fragile Sites
- Enzyme Activation
- Fibroblasts
- Gene Dosage
- Humans
- Longevity
- Mice
- Nucleosides
- Protein-Serine-Threonine Kinases
- Ribonucleoside Diphosphate Reductase
- Survival Analysis
Keywords
- ATR
- RNR
- fragile site
- mouse models
- replication stress
Stem cell studies hold enormous potential for development of new therapies for tissue regeneration and repair. Bone marrow mesenchymal stem cells (BM-MSCs) can differentiate into a variety of non-hematopoietic tissues and contribute maintenance of healthy hematopoiesis by providing supportive cellular microenvironment into BM. Here, we investigated age-related differences in BM-MSCs by using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and FTIR imaging together with hierarchical clustering as a novel methods to clarify global alterations in the structure and function of macromolecules in characterized BM-MSCs of different aged donors. The results may contribute to identification of age-related new molecular marker(s) to determine the effects of donor age on MSCs. The spectral results reflected that there were significant increases in the concentration of saturated lipids, proteins, glycogen, and nucleic acids in children and adolescent group BM-MSCs when compared to the infants and early and mid adults. The concentration of mentioned macromolecules in adult (early and mid) BM-MSCs were significantly lower than the concentrations in the children and adolescents. These results were attributed to the increase in the proliferation activity in younger BM-MSCs. The distribution of macromolecules into the cells was shown as in the form of chemical maps by FTIR imaging, and the results are in agreement with the ATR-FTIR spectroscopy results. The cellular activity degree was determined by the thiazolyl blue tetrazolium bromide (MTT) proliferation assay to support ATR-FTIR spectroscopy results. BM-MSCs of five different age groups were discriminated by making the hierarchical cluster analysis where the spectral data according to alterations in structure and composition of macromolecules were considered.
MeSH Terms
- Adolescent
- Adult
- Aging
- Bone Marrow Cells
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Child
- Child, Preschool
- Female
- Hematopoietic Stem Cells
- Humans
- Infant
- Infant, Newborn
- Male
- Mesenchymal Stem Cells
- Middle Aged
- Multiprotein Complexes
- Spectroscopy, Fourier Transform Infrared
- Young Adult
Atrazine (ATR) is one of the most frequently detected pesticides in the U.S. water supply. This study aimed to investigate neurobehavioral and neurochemical effects of ATR in C57BL/6 mouse offspring and dams exposed to a relatively low (3 mg/l, estimated intake 1.4 mg/kg/day) concentration of ATR via the drinking water (DW) from gestational day 6 to postnatal day (PND) 23. Behavioral tests included open field, pole, grip strength, novel object recognition (NOR), forced swim, and marble burying tests. Maternal weight gain and offspring (PND21, 35, and 70) body or brain weights were not affected by ATR. However, ATR-treated dams exhibited decreased NOR performance and a trend toward hyperactivity. Juvenile offspring (PND35) from ATR-exposed dams were hyperactive (both sexes), spent less time swimming (males), and buried more marbles (females). In adult offspring (PND70), the only behavioral change was a sex-specific (females) decreased NOR performance by ATR. Neurochemically, a trend toward increased striatal dopamine (DA) in dams and a significant increase in juvenile offspring (both sexes) was observed. Additionally, ATR exposure decreased perirhinal cortex serotonin in the adult female offspring. These results suggest that perinatal DW exposure to ATR targets the nigrostriatal DA pathway in dams and, especially, juvenile offspring, alters dams' cognitive performance, induces sex-selective changes involving motor and emotional functions in juvenile offspring, and decreases cognitive ability of adult female offspring, with the latter possibly associated with altered perirhinal cortex serotonin homeostasis. Overall, ATR exposure during gestation and lactation may cause adverse nervous system effects to both offspring and dams.
MeSH Terms
- Aging
- Animals
- Atrazine
- Behavior, Animal
- Corpus Striatum
- Dopamine
- Drinking Water
- Female
- Gestational Age
- Lactation
- Male
- Mice, Inbred C57BL
- Pregnancy
- Prenatal Exposure Delayed Effects
- Sex Characteristics
- Water Pollutants, Chemical
Keywords
- atrazine
- behavior
- developmental neurotoxicity
- dopamine
- pesticides
The herbicide, atrazine (ATR), is used worldwide and its contamination in the environment has resulted in documented human exposure. It has also been shown that ATR results in dopaminergic neurotoxicity, however, few studies have investigated the long-term effects of ATR following in utero exposure. Therefore, we evaluated the effects of ATR exposure in Sprague Dawley rats during gestational on the offspring dopaminergic system development. Pregnant dams were treated with oral ATR at 0, 25, 50 mg/kg/day from gestational day 0 to postnatal day 1. In this study, we examined the hypothesis that ATR could cross the placental barrier and have long-term adverse effects on the synthesis, degradation and reuptake of DA in the brain. For this purpose,we examine the concentration of levodopa (L-DA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in stratum. The mRNA and protein expression of orphan nuclear hormone (Nurr1), tyrosine hydroxylase(TH), vesicular monoaminetransporter 2 (VMAT2), dopamine transporter (DAT), monoamine (MAO), and catechol-O-methyl transferase (COMT) in the midbrain were examined by fluorescence PCR and Western blot when the offspring reached six-month old or one year old .When measured 6 months post-treatment, the level of DA and expression of Nurr1, VMAT2, DAT and TH were reduced in the striatum and Substantia nigra, respectively.
MeSH Terms
- 3,4-Dihydroxyphenylacetic Acid
- Aging
- Animals
- Atrazine
- Corpus Striatum
- Dopamine
- Dopamine Plasma Membrane Transport Proteins
- Female
- Fetus
- Herbicides
- Homovanillic Acid
- Levodopa
- Maternal-Fetal Exchange
- Nuclear Receptor Subfamily 4, Group A, Member 2
- Pregnancy
- RNA, Messenger
- Rats, Sprague-Dawley
- Substantia Nigra
- Tyrosine 3-Monooxygenase
- Vesicular Monoamine Transport Proteins
Keywords
- Aging
- Atrazine
- Neurotoxicity
- Parkinson disease
CARF is an ARF-binding protein that has been shown to regulate the p53-p21-HDM2 pathway. CARF overexpression was shown to cause growth arrest of human cancer cells and premature senescence of normal cells through activation of the p53 pathway. Because replicative senescence involves permanent withdrawal from the cell cycle in response to DNA damage response-mediated signaling, in the present study we investigated the relationship between CARF and the cell cycle and whether it is involved in the DNA damage response. We demonstrate that the half-life of CARF protein is less than 60 min, and that in cycling cells CARF levels are highest in G2 and early prophase. Serially passaged normal human skin and stromal fibroblasts showed upregulation of CARF during replicative senescence. Induction of G1 growth arrest and senescence by a variety of drugs was associated with increase in CARF expression at the transcriptional and translational level and was seen to correlate with increase in DNA damage response and checkpoint proteins, ATM, ATR, CHK1, CHK2, γH2AX, p53 and p21. Induction of growth arrest by oncogenic RAS and shRNA-mediated knockdown of TRF2 in cancer cells also caused upregulation of CARF. We conclude that CARF is associated with DNA damage response and checkpoint signaling pathways.
MeSH Terms
- Antineoplastic Agents
- Apoptosis
- Apoptosis Regulatory Proteins
- Blotting, Western
- Cell Cycle Checkpoints
- Cell Cycle Proteins
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- DNA Damage
- Fibroblasts
- Fluorescent Antibody Technique
- Humans
- Neoplasms
- Promoter Regions, Genetic
- RNA, Messenger
- RNA, Small Interfering
- RNA-Binding Proteins
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Skin
- Stromal Cells
- Telomeric Repeat Binding Protein 2
Keywords
- CARF
- DNA damage response
- Mechanism
- Senescence
- Upregulation
Dysfunctional telomeres limit cellular proliferative capacity by activating the p53-p21- and p16(INK4a)-Rb-dependent DNA damage responses (DDRs). The p16(INK4a) tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo. While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16(INK4a) in response to telomere dysfunction remains unclear. Here, we generated protection of telomeres 1b p16-/- mice (Pot1bΔ/Δ;p16-/-) to address the function of p16(INK4a) in the setting of telomere dysfunction in vivo. We found that deletion of p16(INK4a) accelerated organ impairment and observed functional defects in highly proliferative organs, including the hematopoietic system, small intestine, and testes. Pot1bΔ/Δ;p16-/- hematopoietic cells exhibited increased telomere loss, increased chromosomal fusions, and telomere replication defects. p16(INK4a) deletion enhanced the activation of the ATR-dependent DDR in Pot1bΔ/Δ hematopoietic cells, leading to p53 stabilization, increased p21-dependent cell cycle arrest, and elevated p53-dependent apoptosis. In contrast to p16(INK4a), deletion of p21 did not activate ATR, rescued proliferative defects in Pot1bΔ/Δ hematopoietic cells, and significantly increased organismal lifespan. Our results provide experimental evidence that p16(INK4a) exerts protective functions in proliferative cells bearing dysfunctional telomeres.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Ataxia Telangiectasia Mutated Proteins
- Bone Marrow Transplantation
- Cell Proliferation
- Cells, Cultured
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- DNA Damage
- DNA Repair
- DNA-Binding Proteins
- Female
- Hematopoiesis
- Hematopoietic Stem Cells
- Intestine, Small
- Male
- Mice
- Mice, SCID
- Mice, Transgenic
- Protein Stability
- Sequence Deletion
- Spleen
- Telomere
- Telomere Homeostasis
- Tumor Suppressor Protein p53
ATR is highly conserved in all eukaryotes and functions as a cell-cycle nuclear checkpoint kinase. In mammals, ATR is essential whose complete absence results in early embryonic lethality and its hypomorphic mutation causes a complex disease known as Seckel syndrome. However, molecular mechanisms that cause a wide variety of symptoms including accelerated aging have remained unclear. Similarly, in the nematode Caenorhabditis elegans, a deletion mutant of ATR ortholog atl-1 appears to develop into normal adults, but their eggs do not hatch and die at early embryogenesis. Here we show that the parental worms of atl-1 defective mutant achieved longevity. Transcription levels of certain superoxide dismutase genes, sod-3 and -5 and enzymatic activity of superoxide dismutases significantly increased in the mutant. Furthermore, lipid peroxidation such as a formation of malondialdehyde was attenuated. Expressions of other genes regulated by DAF-16/FOXO transcription factor were also altered. In contrast, the mutant became hypersensitive to rotenone and ethidium bromide. Compared with the wild type the mitochondrial DNA copy number in the mutant was lesser and its proliferation is more severely inhibited in the presence of rotenone. These results suggest that C. elegans ATL-1 is involved not only in the nuclear checkpoint control but also in the mitochondrial maintenance, and its dysfunction activates mild oxidative stress response, resulting in an alteration of life span.
MeSH Terms
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Base Sequence
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- DNA Primers
- Enzyme Activation
- Lipid Peroxidation
- Longevity
- Malondialdehyde
- Mitochondria
- Mutation
- Polymerase Chain Reaction
- Superoxide Dismutase
- Transcription, Genetic
Keywords
- 4′,6-Diamino-2-phenylindole
- AT
- ATM
- ATR
- Ataxia telangiectasia
- Ataxia telangiectasia and Rad3 related protein
- Ataxia telangiectasia mutated
- DAF-16
- DAPI
- DMSO
- Dimethyl sulfoxide
- ETC.
- Electron transport chain
- EtBr
- Ethidium bromide
- Longevity
- MDA
- Malondialdehyde
- Mitochondrial DNA
- NGM
- Nematode growth medium
- ROS
- Reactive oxygen species
- Rotenone
- SOD
- Super oxide dismutase
- mtDNA
Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21(WAF1), p16(INK4A), phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16(INK4A) and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome.
MeSH Terms
- Actins
- Ataxia Telangiectasia Mutated Proteins
- Caveolin 1
- Cell Cycle Proteins
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Dwarfism
- Facies
- Fibroblasts
- Genes, p53
- Humans
- MAP Kinase Signaling System
- Microcephaly
- Mutation
- Protein Kinase Inhibitors
- Protein-Serine-Threonine Kinases
- RNA, Small Interfering
- Telomerase
- p38 Mitogen-Activated Protein Kinases
Keywords
- ATR
- Caveolin-1.
- Chromosome instability
- Fragile sites
- Premature aging
- Progeroid syndromes
- Replication stress
- Telomeres
- Werner syndrome
- p53
To characterize astigmatism as a function of age in a Hong Kong clinical population. All records from new clinical patients at a university optometry clinic in the year 2007 were used for the study. Only data from subjects with corrected visual acuity ≥6/9 in both eyes and with completed subjective refraction were analyzed. The subjects were divided into seven age groups by decade (i.e., 3 to 10 years, 11 to 20 years, …, >60 years). Refractive errors were decomposed into spherical-equivalent refractive error (M), J0, and J45 astigmatic components for analyses. Internal astigmatism was calculated by subtracting corneal astigmatism from refractive astigmatism (RA). Of the 2759 cases that fulfilled our selection criteria, 58.9% had myopia (M ≥-0.75 D) and 28.4% had RA (Cyl ≥ 1.00 D). The prevalence of RA increased from 17.8% in the 3 to 10 years age group to 38.1% in the 21 to 30 years age group. It then dipped to 25.8% in 41 to 50 years age group but increased again to 41.8% in the >60 years age group. Among the astigmats, almost all 3- to 10-year-old children (92.6%) had with-the-rule (WTR) astigmatism, but a majority of the elderly (>60 years) had against-the-rule (ATR) astigmatism (79.7%). For a subset of subjects who had both subjective refraction and keratometric readings (n = 883), RA was more strongly correlated with corneal (r = 0.35 to 0.74) than with internal astigmatism (r = 0.01 to 0.35). More importantly, the magnitudes of both refractive and corneal J0 were consistent with synchronized decrements (-0.15 and -0.14 D per 10 years, respectively) after the age of 30 years, indicating that the shift toward more ATR astigmatism was related to corneal change. In this Hong Kong Chinese clinical population, the prevalence rates of both myopia and astigmatism increased during the first three decades and shared a similar trend before the age of 50 years. The manifest astigmatism was mainly corneal in nature, bilaterally mirror symmetric in axis, and shifted from predominantly WTR to ATR with age.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Astigmatism
- Child
- Child, Preschool
- Disease Progression
- Female
- Follow-Up Studies
- Hong Kong
- Humans
- Male
- Middle Aged
- Population Surveillance
- Prevalence
- Prognosis
- Refraction, Ocular
- Retrospective Studies
- Young Adult
Old age and dyslipidemia increase the occurrence of atrial tachyarrhythmias (ATR). This study investigated the effect of age and hypercholesterolemia on the atrial substrates for ATR. Five 3-year-old rabbits fed standard chow were categorized into an old-age group, five 3-month-old rabbits fed high cholesterol chow were used as a hypercholesterolemia group, and five 3-month-old rabbits fed standard chow were controls. Effective refractory period, atrial vulnerability to ATR, expressions of connexin40 (Cx40) and connexin43 (Cx43), phosphorylated c-Jun N-terminal Kinase (P-JNK), and degree of fibrosis in the right (RA) and left (LA) atria were compared. Old-age and hypercholesterolemia rabbits were more vulnerable to ATR than the controls (18,628 ± 13,981 ms and 30,157 ± 39,548 ms vs 639 ± 325 ms, P < 0.05). Old-age rabbits had significantly decreased Cx40 expression in both atria (3.9-fold decrease in RA, P < 0.01 and 4.8-fold in LA, P < 0.01) and significantly decreased Cx43 in RA (14-fold, P < 0.01). Hypercholesterolemia rabbits had significantly decreased Cx40 expression in both atrial (18-fold decrease in RA, P < 0.01 and 17-fold in LA, P < 0.01) and significantly increased Cx43 expression in LA (five-fold increase, P < 0.01). Hypercholesterolemia, but not old-age rabbits, had greater expression of P-JNK in both atria (1.8-fold in RA and 2.3-fold in LA, P < 0.01). There were no significant group differences in ERP or degree of atrial fibrosis in both atria. ATR is more easily induced in the atria of old-age and hypercholesterolemia rabbits than younger rabbits with normal cholesterol levels. The age and hypercholesterolemia induced changes in gap junctions expression may have partially contributed to the higher atrial vulnerability to ATR.
MeSH Terms
- Aging
- Animals
- Atrial Fibrillation
- Heart Atria
- Heart Conduction System
- Hypercholesterolemia
- Male
- Rabbits
To investigate age-related trends in refractive, corneal, and internal astigmatism and to assess the association between internal astigmatism and lens opacity in an elderly Chinese population. A population-based study was conducted among 1360 inhabitants aged 65 years and older in Taipei, Taiwan. Participants underwent measurements of refraction, corneal dioptric power, and slit lamp biomicroscopy with lens grading. A total of 2084 eyes were included in power vector analyses of Cartesian astigmatism (J(0)) and oblique astigmatism (J(45)) components of refractive, corneal, and internal astigmatism. The crude prevalence of refractive astigmatism (defined as ≥0.75 diopters) was 73.0% based on the right eyes and 76.4% based on the left eyes. The vector values in both refractive J(0) and corneal J(0) tended to be more negative with increasing age (P < 0.001), indicating the trend toward against-the-rule (ATR) astigmatism. Corneal J(0) alone accounted for 54% of the variability in refractive J(0). Refractive J(45) increased with age in the right eyes (P < 0.001) and decreased slightly with age in the left eyes (P = 0.012). Cortical opacity was associated with internal J(0) (P = 0.025), but the association was weak. Astigmatism affects approximately three quarters of the Chinese population aged 65 years and older in Taiwan. With increasing age, the prevalence of astigmatism increases, and refractive and corneal astigmatism shift toward ATR. Continuous corneal changes appear to be responsible for the age trend in refractive astigmatism. The severity of lens opacity plays only a minor role in the change of internal astigmatism.
MeSH Terms
- Age Distribution
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Astigmatism
- Cataract
- Cornea
- Female
- Humans
- Male
- Prevalence
- Refraction, Ocular
- Sex Distribution
- Surveys and Questionnaires
- Taiwan
A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.
MeSH Terms
- Aging
- Animals
- Cellular Senescence
- DNA Damage
- Humans
- Lamins
- Progeria
- Signal Transduction
To study and analyze astigmatism and its characteristics in a cross-sectional study of schoolchildren from Dezful, Iran. In a cross-sectional study using random cluster sampling on 460 schools in Dezful (clusters), 39 clusters were selected. The study was conducted after coordinating with schools and obtaining written consent from students' parents. Cycloplegic refraction was done for primary and junior high school students and non-cycloplegic refraction was done for high school students. Astigmatism was defined as the cylinder power of 0.75 diopter (D) or more. Of 5726 selected students, 5544 (96.8%) participated in the study. The prevalence of astigmatism was 13.47% (95% confidence interval: 11.90 to 15.04) and was not significantly related to age and gender. Regarding axis, 45.76, 48.14, and 6.09% of astigmatic schoolchildren had with-the-rule (WTR), against-the-rule (ATR), and oblique astigmatism, respectively. An increase in age was accompanied by a decrease in the prevalence of WTR astigmatism and an increase in the prevalence of ATR astigmatism (p < 0.001). The association between astigmatism and myopia [odds ratio = 8.81] was stronger than its association with hyperopia (odds ratio = 3.81). Those with high values of spherical error had high values of cylindrical error, as well. Mean sphere in WTR, ATR, and oblique astigmatism was 1.93, 1.37, and 0.88 D, respectively (p < 0.001). The highest values of spherical refractive error were observed in WTR astigmatism group. The prevalence of ATR astigmatism was high in this study. It appears that the decrease in the prevalence of WTR and the increase in the prevalence of ATR astigmatism as a result of aging happened earlier in our study compared with other studies. Astigmatism was found to have a strong correlation with myopia, although individuals with high hyperopia also had high astigmatism. Individuals with high ametropia mostly had WTR astigmatism although the percentage of ATR astigmatism was high in those with low ametropia.
MeSH Terms
- Adolescent
- Age Distribution
- Aging
- Astigmatism
- Child
- Cluster Analysis
- Confidence Intervals
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Iran
- Male
- Odds Ratio
- Prevalence
- Prognosis
- Refraction, Ocular
- Retrospective Studies
- Sex Distribution
- Vision Tests
- Young Adult
Atrazine (ATR) is an herbicide that exerts negative reproductive effects. We examined the effects of vehicle or ATR (1, 5, 20 and 100mg/kg-d), administered to Sprague-Dawley rats on gestational days 14-21, once daily or divided into two doses per day, on female offspring reproductive indices. Offspring body weights at birth were reduced and mortality increased in the 100mg/kg-d group shortly after birth; by PND 21 there were no significant effects. Vaginal opening was delayed in this group, indicating delayed puberty. No significant differences in mammary gland development were apparent at PND 45, or estrous cyclicity through PND 272. There were no differences between dosing regimens. Lower ATR doses (0-20mg/kg-d) showed few effects in females prenatally exposed to ATR, while the high dose (100mg/kg-d) reduced offspring body weight and delayed vaginal opening. Nonetheless, it is unlikely that environmental exposure comparable to the high dose would be encountered.
MeSH Terms
- Animals
- Animals, Newborn
- Atrazine
- Body Weight
- Embryo Loss
- Estrous Cycle
- Female
- Growth and Development
- Herbicides
- Longevity
- Mammary Glands, Animal
- Maternal Exposure
- Rats
- Rats, Sprague-Dawley
- Reproduction
- Sexual Maturation
- Vagina
The Werner syndrome protein (WRN) is a member of the human RecQ family DNA helicases implicated in the maintenance of genome stability. Loss of WRN gives rise to the Werner syndrome, a genetic disease characterised by premature aging and cancer predisposition. WRN plays a crucial role in the response to replication stress and significantly contributes to the recovery of stalled replication forks, although how this function is regulated is not fully appreciated. There is a growing body of evidence that WRN accomplishes its task in close connection with the replication checkpoint. In eukaryotic cells, the replication checkpoint response, which involves both the ATR and ATM kinase activities, is deputed to the maintenance of fork integrity and re-establishment of fork progression. Our recent findings indicate that ATR and ATM modulate WRN function at defined steps of the response to replication fork arrest. This review focuses on the novel evidence of a functional relationship between WRN and the replication checkpoint and how this cross-talk might contribute to prevent genome instability, a common feature of senescent and cancer cells.
MeSH Terms
- Aging
- Ataxia Telangiectasia Mutated Proteins
- Binding Sites
- Cell Cycle Proteins
- DNA Replication
- DNA-Binding Proteins
- Exodeoxyribonucleases
- Genomic Instability
- Humans
- Models, Biological
- Neoplasms
- Phosphorylation
- Protein-Serine-Threonine Kinases
- RecQ Helicases
- Tumor Suppressor Proteins
- Werner Syndrome
- Werner Syndrome Helicase
The purpose of this work is to investigate the role of cellular stress-resistance mechanisms in the low-dose irradiation effects on Drosophila melanogaster lifespan. In males and females with the wild type Canton-S genotype the chronic low dose irradiation (40 cGy) induced the hormetic effect and radiation adaptive response to acute irradiation (30 Gy). The hormesis and radioadaptive responses were observed in flies with mutations in autophagy genes (atg7, atg8a) but absent in flies with mutations in FOXO, ATM, ATR, and p53 homologues. The hormetic effect was revealed in Sirt2 mutant males but not in females. On the contrary, the females but not males of JNK/ mutant strain showed adaptive response. The obtained results demonstrate the essential role of FOXO, SIRT1, JNK, ATM, ATR, and p53 genes in hormesis and radiation adaptive response of the whole organism.
MeSH Terms
- Adaptation, Physiological
- Animals
- Drosophila melanogaster
- Female
- Longevity
- Male
- Mutation
- Stress, Physiological
Replication comes with a price. The molecular gymnastics that occur on DNA during its duplication frequently derive to a wide spectrum of abnormalities which are still far from understood. These are brought together under the unifying term "replicative stress" (RS) which likely stands for large and unprotected regions of single-stranded DNA (ssDNA). In addition to RS, recombinogenic stretches of ssDNA are also formed at resected DNA double strand breaks (DSBs). Both situations converge on a ssDNA intermediate, which is the triggering signal for a damage situation. The cellular response in both cases is coordinated by a phosphorylation-based signaling cascade that starts with the activation of the ATR (ATM and Rad3-related) kinase. Given that ATR is essential for replicating cells, understanding the consequences of a defective ATR response for a mammalian organism has been limited until recent years. We here discuss on the topic and review the findings that connect ATR to ageing and cancer.
MeSH Terms
- Aging
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Checkpoint Kinase 1
- DNA Breaks, Double-Stranded
- DNA Repair
- DNA Replication
- DNA, Single-Stranded
- Models, Biological
- Neoplasms
- Phosphorylation
- Protein Kinases
- Protein-Serine-Threonine Kinases
- Signal Transduction
Members of the signal transducers and activators of transcription (STATs) family of proteins, which connect cytokine signaling to activation of transcription, are frequently activated in human cancers. Suppressors of cytokine signaling (SOCS) are transcriptional targets of activated STAT proteins that negatively control STAT signaling. SOCS1 expression is silenced in multiple human cancers suggesting a tumor suppressor role for this protein. However, SOCS1 not only regulates STAT signaling but can also localize to the nucleus and directly interact with the p53 tumor suppressor through its central SH2 domain. Furthermore, SOCS1 contributes to p53 activation and phosphorylation on serine 15 by forming a ternary complex with ATM or ATR. Through this mechanism SOCS1 regulates the process of oncogene-induced senescence, which is a very important tumor suppressor response. A mutant SOCS1 lacking the SOCS box cannot interact with ATM/ATR, stimulate p53 or induce the senescence phenotype, suggesting that the SOCS box recruits DNA damage activated kinases to its interaction partners bound to its SH2 domain. Proteomic analysis of SOCS1 interaction partners revealed other potential targets of SOCS1 in the DNA damage response. These newly discovered functions of SOCS1 help to explain the increased susceptibility of Socs1 null mice to develop cancer as well as their propensity to develop autoimmune diseases. Consistently, we found that mice lacking SOCS1 displayed defects in the regulation of p53 target genes including Mdm2, Pmp22, PUMA and Gadd45a. The involvement of SOCS1 in p53 activation and the DNA damage response defines a novel tumor suppressor pathway and intervention point for future cancer therapeutics.
MeSH Terms
- Aging
- Animals
- Cell Transformation, Neoplastic
- DNA Damage
- DNA-Binding Proteins
- Drug Design
- Genes, p53
- Humans
- Mice
- Oncogenes
- STAT Transcription Factors
- Suppressor of Cytokine Signaling Proteins
It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (p<0.01), and there was a significant decline both in the presenium with respect to middle age and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (p<0.01). AT2R expression was markedly increased in the senium (p<0.01). These results suggest that there are considerable variations in the expression levels of renal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Gene Expression Regulation, Developmental
- Kidney
- Male
- RNA, Messenger
- Rats
- Rats, Wistar
- Receptors, Adrenergic, alpha-1
- Receptors, Angiotensin
- Reverse Transcriptase Polymerase Chain Reaction
Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.
MeSH Terms
- Animals
- DNA Repair
- Genomic Instability
- Humans
- Lamin Type A
- Nuclear Proteins
- Progeria
- Protein Precursors
Keywords
- DNA damage responses
- DNA double strand breaks
- DNA repair
- Genome instability
- Hutchinson-Gilford progeria syndrome
- Lamin A
- XPA
- premature aging
Trp53 loss of function has previously been shown to rescue tissue maintenance and developmental defects resulting from DNA damage or DNA-repair gene mutations. Here, we report that p53 deficiency severely exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator Atr. Combined loss of Atr and p53 (Trp53(-/-)Atr(mKO)) led to severe defects in hair follicle regeneration, localized inflammation (Mac1( )Gr1( ) infiltrates), accelerated deterioration of the intestinal epithelium and synthetic lethality in adult mice. Tissue degeneration in Trp53(-/-)Atr(mKO) mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated frequency of these damaged cells in both progenitor and downstream compartments in Trp53(-/-)Atr(mKO) skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Together, our results indicate that the combined loss of Atr and Trp53 in adult mice leads to the accumulation of highly damaged cells, which, consequently, impose a barrier to regeneration from undamaged progenitors.
MeSH Terms
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Cell Death
- Hair Follicle
- Intestinal Mucosa
- Mice
- Mice, Knockout
- Protein-Serine-Threonine Kinases
- Regeneration
- Tumor Suppressor Protein p53
The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.
MeSH Terms
- Aging
- Animals
- Cell Cycle
- Cell Line
- Chromosome Fragility
- Cyclin-Dependent Kinase Inhibitor p21
- DNA Damage
- E2F1 Transcription Factor
- Epidermal Cells
- Epidermis
- Fibroblasts
- Gene Expression Regulation
- Hyperpigmentation
- Mice
- Mice, Knockout
- Mutation
- Neoplasm Proteins
- Neoplasms
- Protein Deficiency
- Skin Diseases
- Skin Neoplasms
- Stem Cells
- Telomere
- Telomeric Repeat Binding Protein 1
- Tumor Suppressor Protein p53
Previous reports of crosstalk between alpha(1)- adrenergic receptors (alpha(1)-AR) and angiotensin receptors (ATR) have pointed to the existence of physiological regulation between the sympathetic nervous system and the renin-angiotensin system at the receptor level. This regulation may have an important role in the control of blood pressure and may be modified in different cardiovascular pathologies. Aging is considered to be an independent cardiovascular risk factor. Nevertheless, neither the variation in physiological action or interaction of signal transduction between these two receptors as a result of aging has been established. To clarify these aspects, the interaction between alpha(1)-AR and ATR was evaluated. The inotropic response of alpha(1)-AR to agonists was assessed in the presence and absence of angiotensin II using the left atria of 3.5-, 12-, 18- and 24-month-old (young adult, middle aged, elderly and aged, respectively) male Wistar rats. In the four age groups of rat hearts, the activities of tyrosine kinase were measured when just the AT(1)R subtype was activated, or when both alpha(1)-AR and AT(1)R were activated. The activities of cytosolic phospholipase A(2) and the levels of cyclic GMP were investigated when just the AT(2)R subtype was activated, or when both alpha(1)-AR and AT(2)R were activated. No effect was found on the cumulative concentration-response curve for phenylephrine when AT(1)R was activated in 3.5- or 12-month-old rats. However, in 18- and 24-month-old rats, the maximum positive inotropic response and the negative logarithm of the effective 50% concentration increased markedly. No effect was found on the cumulative concentration response curve induced by phenylephrine when AT(2)R was activated. The activities of tyrosine kinase increased significantly in 3.5- and 12-month-old rats, but there was no difference in 18- and 24-month-old rats when alpha(1)-AR and AT(1)R were both activated compared with when just AT(1)R was activated. Cytosolic phospholipase A(2) activity and cyclic GMP levels decreased significantly when both alpha(1)-AR and AT(2)R were activated compared with when just AT(2)R was activated. In the isolated left atria of elderly and aged rats, the activation of AT(1)R enhanced the positive inotropic response induced by the activation of alpha(1)-AR. The activation of AT(2)R had no effect on the positive inotropic response induced by the activation of alpha(1)-AR. The action of alpha(1)-AR increased the signal transduction of AT(1)R in young-adult and middle-aged rat hearts but had no effect in elderly and aged hearts. The action of alpha(1)-AR had no effect on AT(2)R signal transduction.
MeSH Terms
- Age Factors
- Aging
- Angiotensin II
- Animals
- Male
- Myocardial Contraction
- Rats
- Rats, Wistar
- Receptor Cross-Talk
- Receptor, Angiotensin, Type 1
- Receptor, Angiotensin, Type 2
- Receptors, Adrenergic, alpha-1
- Renin-Angiotensin System
- Signal Transduction
- Sympathetic Nervous System
Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53.
MeSH Terms
- Abnormalities, Multiple
- Aging
- Alleles
- Animals
- Apoptosis
- Ataxia Telangiectasia Mutated Proteins
- Brain
- Cell Cycle Proteins
- DNA Damage
- DNA Repair
- DNA Replication
- DNA-Activated Protein Kinase
- DNA-Binding Proteins
- Disease Models, Animal
- Embryo, Mammalian
- Fibroblasts
- Humans
- Mice
- Nuclear Proteins
- Phenotype
- Progeria
- Protein Kinase Inhibitors
- Protein-Serine-Threonine Kinases
- Stress, Physiological
- Syndrome
- Tumor Suppressor Protein p53
The metabolism of dietary fatty acids in human has been measured so far using human blood cells and stable-isotope labeled fatty acids, however, no direct data was available for human peripheral tissues and other major organs. To realize the role of dietary fatty acids in human health and diseases, it would be eager to develop convenient and suitable method to monitor fatty acid metabolism in human. We have developed the measurement system in situ for human lip surface lipids using the Fourier transform infrared spectroscopy (FTIR) - attenuated total reflection (ATR) detection system with special adaptor to monitor metabolic changes of lipids in human body. As human lip surface lipids may not be much affected by skin sebum constituents and may be affected directly by the lipid constituents of diet, we could detect changes of FTIR-ATR spectra, especially at 3005 to approximately 3015 cm(-1), of lip surface polyunsaturated fatty acids in a duration time-dependent manner after intake of the docosahexaenoic acid (DHA)-containing triglyceride diet. The ingested DHA appeared on the lip surface and was detected by FTIR-ATR directly and non-invasively. It was found that the metabolic rates of DHA for male volunteer subjects with age 60s were much lower than those with age 20s. Lipid hydroperoxides were found in lip lipids which were extracted from the lip surface using a mixture of ethanol/ethylpropionate/iso-octane solvents, and were the highest in the content just before noon. The changes of lipid hydroperoxides were detected also in situ with FTIR-ATR at 968 cm(-1). The measurements of lip surface lipids with FTIR-ATR technique may advance the investigation of human lipid metabolism in situ non-invasively.
MeSH Terms
- Adult
- Aged
- Aging
- Analytic Sample Preparation Methods
- Docosahexaenoic Acids
- Eating
- Eicosapentaenoic Acid
- Fatty Acids
- Gas Chromatography-Mass Spectrometry
- Humans
- Lip
- Lipid Metabolism
- Lipid Peroxides
- Male
- Middle Aged
- Smoking
- Solvents
- Soybean Oil
- Spectroscopy, Fourier Transform Infrared
- Surface Properties
- Time Factors
- Young Adult
Structural and functional alterations in the senescent heart have been associated with an activated sympathetic nervous system and a regional cardiac renin-angiotensin system. To date, however, limited information related to their expression alteration during the whole procress of growth and development has been reported. To examine the expression of alpha(1)-adrenergic receptor (alpha(1)-AR) and angiotensin II receptor (ATR) subtypes in the left ventricle of hearts from young adult, middle-aged, presenescent and senescent rats. Semiquantitative reverse transcriptase polymerase chain reaction and Western blot were used to quantitate the messenger RNA and protein of alpha(1)-AR and ATR subtypes, respectively, in the left ventricles of three- (young adult), 12- (middle age), 18- (presenescent) and 24-month-old (senescent) Wistar rats. alpha(1A)-AR expression decreased gradually with age, and alpha(1D)-AR expression was repressed in middle age and presenescence, while the expression of alpha(1B)-AR remained unchanged during senescence. AT(1)R expression was unaffected by aging from young adulthood to presenescence, but exhibited a remarkable upregulation in senescence. There were no significant discrepancies of cardiac AT(2)R expression among the four age groups, but both messenger RNA and protein had a tendency to upregulate during aging. The results suggest that there are considerable changes of expression of cardiac alpha(1)-AR and ATR subtypes during growth and development. The change of cardiac alpha(1)-AR and ATR expression during aging is a protective response to senescence by keeping normal myocardial contractility, while the upregulation of AT(1)R and AT(2)R promotes age-related myocardium hypertrophy and cardiac remodelling.
MeSH Terms
- Age Factors
- Aging
- Animals
- Gene Expression Regulation, Developmental
- Heart Ventricles
- Hypertrophy, Left Ventricular
- Myocardium
- RNA, Messenger
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 1
- Receptors, Adrenergic, alpha-1
- Reverse Transcriptase Polymerase Chain Reaction
- Ventricular Remodeling
The cellular DNA damage response (DDR) entails the activation of ATM, ATR and/or DNA PK protein kinases that causes modifications of proteins including Chk1, Chk2 and 53BP1, aggregation of DDR proteins into foci, and activation of p53. The DDR is thought to be required for initiation and maintenance of cellular senescence. Potentially senescent cells with DNA damage foci occur in large numbers in vivo with many diseases, but, with the exception of mammalian dermis, there is little evidence for that with normal aging. After experimental induction of cellular senescence in the livers of juvenile mice, there was robust expression of DDR markers in hepatocytes at 1 week; however, by 7 weeks, activation of ATM/ATR kinase targets was limited, although cells with DNA damage foci were present. An analysis of hepatocytes of aged, 22-month-old mice, not experimentally exposed to genotoxins, showed limited activation of ATM/ATR targets, though high numbers of cells with DNA damage foci were found, similar to that seen many weeks after artificial senescence induction in young mice. Based on senescence heterochromatin and SA ss Gal assays of the 22-month-old mouse liver, more than 20% of hepatocytes were potentially senescent, though only some components of the DDR were enriched.
MeSH Terms
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Autoradiography
- Cell Cycle Proteins
- Cellular Senescence
- DNA Damage
- DNA-Binding Proteins
- Hepatocytes
- Immunohistochemistry
- Liver
- Mice
- Mice, Inbred C57BL
- Microscopy, Fluorescence
- Models, Biological
- Protein-Serine-Threonine Kinases
- Time Factors
- Tumor Suppressor Proteins
Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.
MeSH Terms
- Aging
- Animals
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Genes, Essential
- Mice
- Mice, Knockout
- Phenotype
- Protein-Serine-Threonine Kinases
- Stem Cells
Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.
MeSH Terms
- Animals
- Apoptosis
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Cell Proliferation
- Chromosomal Instability
- DNA Damage
- DNA, Single-Stranded
- Exodeoxyribonucleases
- Gamma Rays
- Gene Deletion
- Gene Fusion
- Genotype
- Intestinal Mucosa
- Longevity
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutagens
- Phenotype
- Protein-Serine-Threonine Kinases
- RNA
- Replication Protein A
- Signal Transduction
- Telomerase
- Telomere
- Thioguanine
Each year, 75 million pounds of the broadleaf herbicide atrazine (ATR) are applied to crops in the United States. Despite limited solubility, ATR is common in ground and surface water, making it of regulatory concern. ATR suppresses the immunomodulatory hormones prolactin (PRL) and the thyroid hormones (THs), with developmental exposure to ATR permanently disrupting PRL regulation. We hypothesized that ATR may cause developmental immunotoxicity through its disruption of PRL or THs. To test this hypothesis, pregnant Sprague-Dawley (SD) rats were exposed to 35-mg ATR/kg/d from gestational day (GD) 10 through postnatal day (PND) 23. Separate groups were exposed to bromocryptine (BCR) at 0.2 mg/kg/2x/day to induce hypoprolactinemia or to propylthiouracil (PTU) at 2 mg/kg/day to induce hypothyroidism. After the offspring reached immunologic maturity (at least 7 weeks old), the following immune functions were evaluated: natural killer (NK) cell function; delayed-type hypersensitivity (DTH) responses; phagocytic activity of peritoneal macrophages; and antibody response to sheep erythrocytes (SRBC). ATR decreased the primary antibody and DTH responses in male offspring only. Neither PTU nor BCR caused immunosuppression in any measured variable, although PTU increased phagocytosis by peritoneal macrophages. These results demonstrate that developmental exposure to ATR produced gender-specific changes in immune function in adult rats and suggest that immune changes associated with ATR are not mediated through the suppression of PRL or THs.
MeSH Terms
- Abnormalities, Drug-Induced
- Adjuvants, Immunologic
- Administration, Oral
- Animals
- Animals, Suckling
- Atrazine
- Body Weight
- Bromocriptine
- Congenital Hypothyroidism
- Female
- Herbicides
- Hypoproteinemia
- Hypothyroidism
- Immune System
- Immunity
- Lactation
- Longevity
- Organ Size
- Pregnancy
- Propylthiouracil
- Rats
- Rats, Sprague-Dawley
- Sex Factors
Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides, which elicit toxicity following biotransformation to the potent acetylcholinesterase inhibitors, paraoxon (PO) and chlorpyrifos oxon (CPO). Both oxons have also been shown to interact directly with muscarinic receptors coupled to inhibition of adenylyl cyclase. Immature animals are more sensitive than adults to the acute toxicity of PS and CPF but little is known regarding possible age-related differences in interactions between these toxicants and muscarinic receptors. We compared the inhibition of forskolin-stimulated cAMP formation by PO and CPO (1 nM-1 mM) in vitro in brain slices from 7-, 21-, and 90-day-old rats to the effects of well-known muscarinic agonists, carbachol and oxotremorine (100 microM). Both agonists inhibited cAMP formation in tissues from all age groups and both were more effective in adult and juvenile (20-26% inhibition) than in neonatal (12-13% inhibition) tissues. Atropine (10 microM) completely blocked agonist-induced inhibition in all cases. PO maximally inhibited (37-46%) cAMP formation similarly in tissues from all age groups, but atropine blocked those effects only partially and only in tissues from 7-day-old rats. CPO similarly inhibited cAMP formation across age groups (27-38%), but ATR was partially effective in tissues from all three age groups. Both oxons were markedly more potent in tissues from younger animals. We conclude that PO and CPO can directly inhibit cAMP formation through muscarinic receptor-dependent and independent mechanisms and that the developing nervous system may be more sensitive to these noncholinesterase actions.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Chlorpyrifos
- Colforsin
- Cyclic AMP
- Female
- In Vitro Techniques
- Male
- Paraoxon
- Pregnancy
- Rats
- Rats, Sprague-Dawley
In an effort to investigate neuromuscular changes with age, the isometric force-time curve of the Achilles tendon-tap reflex (ATR) was measured in 10 college age (M = 20.9 yr) and 10 healthy active old subjects (M = 74.3 yr). In an effort to investigate spinal interneuronal pathways, the tendon-jerk was also conditioned with a tap to the ipsilateral or contralateral patellar tendon. The conditioning stimulus preceded the ATR by 25, 40, 55, 70, 85, 100, 115, 130, or 145 ms. Three trials were elicited at each conditioning interval plus three unilateral trials, for 30 trials per experimental session. Results indicated that the force production of the unilateral Achilles tendon-tap reflex was significantly reduced and the half-relaxation times were significantly lengthened in the old subjects. Moreover, ipsilateral conditioning produced short-latency facilitation and long-latency inhibition to the triceps surae in young subjects, whereas the same conditioning produced only a delayed long-latency inhibition in the old subjects. Similarly, the contralateral conditioning produced short-latency facilitation in the young subjects, with no changes observed in the old subjects. It is concluded that unilateral Achilles tendon-tap responses are different for the two groups, and that the reflex recovery profiles for the two groups are different. Several neurophysiological mechanisms are proposed to contribute to these differences.
MeSH Terms
- Achilles Tendon
- Adult
- Aged
- Aging
- Conditioning, Classical
- Humans
- Leg
- Motor Neurons
- Muscles
- Neurophysiology
Change in physiologic corneal astigmatism due to aging was studied. A series of 868 cases (1,660 eyes) was evaluated. These eyes were divided into 6 groups by age; A) below 40 years, B) in the 40's, C) in the 50's, D) in the 60's, E) in the 70's, and F) over 80. Corneal astigmatism was examined with an autokeratometer. In Group A, 88.5% had with-the-rule astigmatism (WTR), whereas only 3.7% had against-the-rule astigmatism (ATR). The cylindrical diopter (CD) of WTR was 1.29 /- 0.73 D, which was significantly the largest among the groups. In Group C, WTR decreased to 55.9% and ATR increased to 22.9%. The CD of WTR also decreased to 0.85 /- 0.47 D. In Group E, WTR was 31.4% and ATR was 49.3%. The CD of ATR increased to 0.88 /- 0.70 D. In Group F, WTR was 19.9%, whereas ATR was 65.9%. The CD of ATR was 1.48 /- 0.88 D, which was the largest among the groups. As such, WTR was dominant at younger ages, and ATR increased with aging at older ages. The CD of WTR decreased, and ATR increased, with aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Astigmatism
- Cornea
- Female
- Humans
- Male
- Middle Aged
The genome electropherotyping technique was used in longitudinal surveys to detect group A rotavirus, rotaviruslike virus (RVLV), atypical rotavirus (ATR), and reovirus in intestinal contents or fecal specimens collected from turkeys in 10 commercial and 2 research station flocks. These viruses were detected in turkeys from 8 to 10 commercial flocks surveyed. Of 278 specimens collected from turkeys less then 29 days old in commercial flocks, 79 (28.4%) contained one or more viruses, whereas only 1 of 120 specimens collected from turkeys older than 28 days had virus. Viruses were detected in commercial turkeys between 3 and 35 days old, and over a third of the specimens collected from birds during their first week of life were positive for group A rotavirus. Between 8 and 28 days of age, commercial turkeys were infected with group A rotavirus, RVLV, ATR, and reovirus. ATR was the only virus detected in birds older than 28 days. Overall, group A rotavirus and RVLV were each detected in 39 specimens, and ATR was detected in 7 specimens; reovirus was detected in 2 specimens. Eight of the positive specimens contained two viruses. All 102 specimens collected from turkeys 1 to 56 days old in the two research station flocks were negative for virus.
MeSH Terms
- Aging
- Animals
- Electrophoresis, Polyacrylamide Gel
- Fluorescent Antibody Technique
- Genes, Viral
- Poultry Diseases
- RNA, Viral
- Rotavirus
- Rotavirus Infections
- Turkeys