C3
Complement C3 precursor (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1) [Contains: Complement C3 beta chain; C3-beta-c (C3bc); Complement C3 alpha chain; C3a anaphylatoxin; Acylation stimulating protein (ASP) (C3adesArg); Complement C3b alpha' chain; Complement C3c alpha' chain fragment 1; Complement C3dg fragment; Complement C3g fragment; Complement C3d fragment; Complement C3f fragment; Complement C3c alpha' chain fragment 2] [CPAMD1]
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Although abdominal obesity plays a fundamental role in the onset of immune and inflammatory reactions leading to cardiac abnormalities and premature mortality, the potential association between periumbilical fat and longevity mediated by the antibody-complement system and/or cardiac structure and function remains unclear. To address this issue, we collected biochemical and morphological data from 419 centenarians and 491 non-centenarian oldest-old individuals from the China Hainan Centenarian Cohort Study. Centenarians had lower waist circumference (WC), periumbilical fat thickness (PFT), serum complement C3 level, right atrium end-systolic diameter (RAESD), left atrium end-systolic diameter (LAESD), and left ventricular end-diastolic diameter (LVEDD) than non-centenarians (P<0.05 for all comparisons). WC, PFT, complement C3 levels, RAESD, LAESD, and LVEDD were inversely associated with centenarians (P<0.05 for all variables). Complement C3 level, LAESD, and LVEDD were positively associated with PFT and WC (P<0.05 for all variables). RAESD was positively associated with WC and complement C3 level (P<0.05 for both variables). Centenarians had less periumbilical fat, a weaker complement system, and smaller cardiac structure than non-centenarians. Importantly, periumbilical fat was inversely associated with longevity mediated by complement C3 and cardiac structure. This study suggests that successful aging can be promoted by increased efforts to prevent abdominal obesity.
Keywords
- abdominal obesity
- cardiac structure
- complement C3
- longevity
- periumbilical fat
Complement C3 (C3) has been shown to be involved in the aging process. However, the role of C3 in kidney aging has not been fully elucidated. This study aimed to investigate the effect of C3 on senescence related kidney disorders in mice. Two-, 8-, and 16-month-old C3-deficient male mice (KO) (n = 6) and age-, gender-, and strain- matched wild type (WT) C57BL/6 mice (n = 6) were selected to represent young, middle-aged and aging mice. Renal, blood and urine samples were collected. Hematoxylin-eosin (HE), Masson, and immunohistochemistry (IHC) staining as well as ELISA and Western blotting were used to explore the mechanisms involved in renal aging. The level of C3 was upregulated during aging in WT mice. The glomerular sclerosis index and tubulointerstitial fibrosis index were increased significantly in WT mice during aging. Renal function was not significantly different between the young and aged groups. Compared with those in WT mice, the levels of inflammation and fibrosis were decreased, while the expression of CD31 was significantly increased in the KO group. Our data demonstrated that age-related changes in renal structure occur earlier than functional changes and that complement C3 is involved in aging-related kidney disorder.
MeSH Terms
- Aging
- Animals
- Complement C3
- Inflammation
- Kidney
- Kidney Diseases
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
Keywords
- Complement component 3
- Kidney disorder
- Senescence
Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 (TLR4), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to TLR4 and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity [i]in vivo[/i]. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.
Keywords
- aging
- desialylation
- galectin-3
- microglia
- neurodegeneration
- phagocytosis
- sialic acid
There is increasing recognition of the significance of chronic, low-level inflammation in older adults, or "inflammaging." Innate immune responses and host-bacterial interactions are recognized as key factors in inflammaging. Inflammatory cytokine IL-6, and complement protein C1q have been identified as biomarkers for the development of frailty and aging-related diseases. Older adults are also susceptible to infections with serotypes of [i]Streptococcus pneumoniae[/i] that bind ficolin-2, a component of the lectin complement pathway, and low ficolin-2 levels could possibly be involved in such susceptibility. The aim of our study was to evaluate complement pathway components and biomarkers for inflammaging among older adults in order to investigate potential innate immune mechanisms that may account for susceptibility to infections in this population. We compared inflammatory markers, as well as components/activity of the classical and lectin complement pathways between healthy older and younger adults. We hypothesized that older adults would have higher levels of inflammatory markers and C1q, and lower levels of lectin pathway components. Older (≥70 years old) and younger (19-54 years old) adults without significant smoking history or chronic medical conditions were eligible for participation. Inflammatory markers (IL-6, TNF-α, CRP), classical complement pathway activity (CH50) and protein levels (C1q, C3, C4), and lectin pathway (MBL levels/activity, CL-L1, MASP-1/2/3, MAp44, MAp19, and H/M/L-ficolin) were compared between groups. Older adults had significantly higher mean levels of IL-6 and TNF-α. There were no significant differences in lectin pathway components between older and younger adults. Unexpectedly, mean C1q was significantly higher in the younger group in both unadjusted and adjusted analyses. There was also a significant association between race and C1q levels, but this association did not completely account for the observed differences between age groups. We did not observe deficiencies in lectin pathway components to account for increased susceptibility to ficolin-binding serotypes of [i]S. pneumoniae[/i]. Elevated levels of inflammatory cytokines in older adults are suggestive of inflammaging. However, the observed age and race-associated changes in C1q have not been previously reported in the populations included in our study. These findings are relevant to the investigation of C1q in aging-related pathology, and for its proposed role as a biomarker for frailty and disease.
Keywords
- Aging
- Complement system
- Elderly
- Immune
- Inflammation
- Lectin
Aging globally effects cellular and organismal metabolism across a range of mammalian species, including humans and rabbits. Rabbits (Oryctolagus cuniculus are an attractive model system of aging due to their genetic similarity with humans and their short lifespans. This model can be used to understand metabolic changes in aging especially in major organs such as liver where we detected pronounced variations in fat metabolism, mitochondrial dysfunction, and protein degradation. Such changes in the liver are consistent across several mammalian species however in rabbits the downstream effects of these changes have not yet been explored. We have applied proteomics to study changes in the liver proteins from young, middle, and old age rabbits using a multiplexing cPILOT strategy. This resulted in the identification of 2,586 liver proteins, among which 45 proteins had significant p < 0.05) changes with aging. Seven proteins were differentially-expressed at all ages and include fatty acid binding protein, aldehyde dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl CoA dehydrogenase, apolipoprotein C3, peroxisomal sarcosine oxidase, adhesion G-protein coupled receptor, and glutamate ionotropic receptor kinate. Insights to how alterations in metabolism affect protein expression in liver have been gained and demonstrate the utility of rabbit as a model of aging.
Keywords
- Aging
- Enhanced multiplexing
- Liver
- Metabolism
- Oryctolagus cuniculus
- Proteomics
- Rabbit
- cPILOT
Sialic acid-binding Ig-like lectin (Siglec) receptors are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated the impact of reduced sialylation in the brain of mice heterozygous for the enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE /-) that is essential for sialic acid biosynthesis. We demonstrate that GNE /- mice have hyposialylation in different brain regions, less synapses in the hippocampus and reduced microglial arborization already at 6 months followed by increased loss of neurons at 12 months. A transcriptomic analysis revealed no pro-inflammatory changes indicating an innate homeostatic immune process leading to the removal of synapses and neurons in GNE /- mice during aging. Crossbreeding with complement C3-deficient mice rescued the earlier onset of neuronal and synaptic loss as well as the changes in microglial arborization. Thus, sialic acids of the glycocalyx contribute to brain homeostasis and act as a recognition system for the innate immune system in the brain.
MeSH Terms
- Aging
- Animals
- Brain
- Homeostasis
- Immunity, Innate
- Mice, Transgenic
- Neurons
- Racemases and Epimerases
- Sialic Acid Binding Immunoglobulin-like Lectins
- Sialic Acids
- Synapses
Keywords
- Aging
- GNE
- Glycocalyx
- Microglia
- Neurodegeneration
- Neuroinflammation
- Sialic acid
To analyze experimental data on the effect of various polyphenolic compounds on lifespan of mice, we approximated survival curves with the Gompertz model in its minimal form, which does not account for the heterogeneity of samples and the age-independent mortality. The plots of regressions of log0 (logarithm of the initial mortality) on (the rate of aging) in series of control samples were used to assess the deviations of vectors directed from control to experimental data from the slopes of the control regressions. The analysis of published data suggests that resveratrol, polyphenol-containing grape skin extract, metformin, tocopherol, and the antioxidant SkQ1 do not produce changes beyond those possible upon comparing of different samples of a control population. The effect of the polyphenolic composition BP-C3 on female SHR mice is unique in being associated with a significant decrease in the rate of aging. The effect may be partly contributed to by the antioxidant properties of BP-C3. Its antioxidant capacity determined in vitro is comparable with that of established antioxidants, such as dihydroquercetin. Its effects in vivo include the ability to ameliorate reduction in the peroxide-decomposing activity of RBC lysates from male BALB/c mice treated with 5-fluorouracil.
MeSH Terms
- Animals
- Antioxidants
- Female
- Longevity
- Male
- Mice
- Mice, Inbred BALB C
- Polyphenols
- Survival Analysis
Keywords
- BP-C3
- Gompertz model
- SkQ1
- aging
- herbal extracts
- lifespan
- metformin
- polyphenols
- resveratrol
- tocopherol
In response to changes in brain micro-environment caused by aging, microglia could polarize into proinflammatory M1 phenotype and anti-inflammatory M2 phenotype. Besides, astroglia could polarize into A1 phenotype, exhibiting neurotoxicity, or A2 phenotype, showing neuroprotection. This study aimed to investigate the change of glial cells and dopaminergic (DA) neuron in midbrain with age. Two-, 6-, 18- and 28- months old rat brains were collected. The DA neurons were detected using anti-TH and anti-DAT antibodies. The expressions of astroglia markers (glial fibrillary acidic protein, GFAP), microglia markers (ionized calcium binding adaptor molecule 1, Iba-1), M1 markers (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), M2 markers (arginase 1 (Arg1) and IL-10), A1 markers (lipocalin-2 (Lcn2) and complement C3 (C3), A2 markers (brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were examined by real time RT-PCR and Western Blotting. DA neuron expressions decreased in 18-, 28- months old rat brains. In addition, microglia and astroglia have different degrees of activation with age. Besides, M1 markers (TNF-α and IL-1β) increased and M2 markers (Arg1 and IL-10) decreased in aged rats. Furthermore, A2 markers (BDNF and GDNF) decreased and A1 markers (Lcn2 and C3) increased in aged rats. Age induced DA neuron loss and influenced midbrain glial cells phenotypic polarization, which might account for the occurrence and pathogenesis of Parkinson's diseases.
MeSH Terms
- Aging
- Animals
- Arginase
- Astrocytes
- Brain-Derived Neurotrophic Factor
- Complement C3
- Dopaminergic Neurons
- Glial Cell Line-Derived Neurotrophic Factor
- Glial Fibrillary Acidic Protein
- Interleukin-10
- Interleukin-1beta
- Lipocalin-2
- Male
- Microglia
- Rats
- Rats, Wistar
- Tumor Necrosis Factor-alpha
Keywords
- Age
- Astroglia phenotype
- Microglia phenotype
- Parkinson's diseases
Lipopolysaccharides (LPS) and salinity are important variables in aquatic environments. High concentration of LPS and large changes in salinity seriously threat the survival of a variety of organisms, including fish. To reveal the effects of salinity and LPS on a fish immune response, we measured the immune-related parameters (total leukocyte count, total serum protein, albumin and globulin concentrations, complement C3 concentration, and lysozyme activity) and genes (the expressions of TNF-α, IL-1β, and SOCS1-3 at the mRNA and protein levels) of juvenile Takifugu fasciatus exposed to phosphate buffered saline (PBS) or LPS (25 μg mL ) under different salinities (0, 15, and 30 ppt) for 24 h. Changes in key immunological indicators suggested that the LPS challenge induced considerable damage to T. fasciatus, whereas an increase in salinity mitigated the harmful effects. Moreover, although the immune responses in blood and other selected tissues (gill and kidney) were suppressed with an increase in salinity, the increased response in liver in saltwater enabled T. fasciatus to conquer large salinity variation during migration. The appropriate addition of salts appeared to be a sensible strategy to mitigate LPS-induced toxicity in the aquaculture of T. fasciatus.
MeSH Terms
- Aging
- Albumins
- Animals
- Blood Proteins
- Complement C3
- Cytokines
- Environmental Exposure
- Gene Expression Regulation
- Gills
- Globulins
- Muramidase
- RNA, Messenger
- Salinity
- Salt Tolerance
- Takifugu
- Water
Keywords
- Immune response
- Lipopolysaccharides
- Salinity
- Takifugu fasciatus
Features of the immune response to injection of suspension of bacteria (Pseudomonas aeruginosa and Escherichia coli) in young (3 months) and old (20 months) Wistar rats at 3, 5 and 7 days after infection were investigated. The dynamics of the content of circulating immune complexes (CEC), complement C3 fragments, and the activity of oxygen-dependent and oxygen-independent phagocytosis were determined. It was shown that infection was accompanied by a multiple increase in the content of circulating immune complexes in young and, especially, in old animals. It remained at a high level from the 3d to the 7th day of the development of pathology in young animals, while they content decreased to 7 days in old animals. On the background of the development of the infectious process, the content of complement C3 fragments decreased in young animals, and it increased in old animals, in the case of infection with P. aeruginosa and E. coli. The activity of oxygen-dependent and oxygen-independent phagocytosis decreased in different ways in young and old animals on the background of infections, i.e. the ratio of the forms of phagocytosis in old and young animals was different. Old animals were not inferior to the young in terms of the ability of the immune system to respond to the presence of an infectious agent. So they used a different strategy for forming the immune response.
MeSH Terms
- Aging
- Animals
- Escherichia coli
- Phagocytosis
- Pseudomonas aeruginosa
- Rats
- Rats, Wistar
Keywords
- aging
- circulating immune complexes
- infection with P. aeruginosa and E. coli
- phagocytic activity
The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. The typical aging process goes along with microglial changes and mild neuronal loss, but the exact contribution of TREM2 is still unclear. Aged TREM2 knock-out mice showed decreased age-related neuronal loss in the substantia nigra and the hippocampus. Transcriptomic analysis of the brains of 24 months old TREM2 knock-out mice revealed 211 differentially expressed genes mostly downregulated and associated with complement activation and oxidative stress response pathways. Consistently, 24 months old TREM2 knock-out mice showed lower transcription of microglial (Aif1 and Tmem119), oxidative stress markers (Inos, Cyba, and Cybb) and complement components (C1qa, C1qb, C1qc, C3, C4b, Itgam, and Itgb2), decreased microglial numbers and expression of the microglial activation marker Cd68, as well as accumulation of oxidized lipids. Cultured microglia of TREM2 knock-out mice showed reduced phagocytosis and oxidative burst. Thus, microglial TREM2 contributes to age-related microglial changes, phagocytic oxidative burst, and loss of neurons with possible detrimental effects during physiological aging.
MeSH Terms
- Age Factors
- Aging
- Animals
- Hippocampus
- Membrane Glycoproteins
- Mice
- Mice, Knockout
- Microglia
- Neurons
- Oxidative Stress
- Phagocytosis
- Receptors, Immunologic
- Substantia Nigra
Keywords
- TREM2
- aging
- microglia
- neurodegeneration
- oxidative stress
The complement system is essential for an adequate immune response. Much attention has been given to the role of complement in disease. However, to better understand complement in pathology, it is crucial to first analyze this system under different physiological conditions. The aim of the present study was therefore to investigate the inter-individual variation in complement activity and the influences of age and sex. Complement levels and functional activity were determined in 120 healthy volunteers, 60 women, 60 men, age range 20-69 year. Serum functional activity of the classical pathway (CP), lectin pathway activated by mannan (MBL-LP) and alternative pathway (AP) was measured in sera, using deposition of C5b-9 as readout. In addition, levels of C1q, MBL, MASP-1, MASP-2, ficolin-2, ficolin-3, C2, C4, C3, C5, C6, C7, C8, C9, factor B, factor D, properdin, C1-inhibitor and C4b-binding protein, were determined. Age- and sex-related differences were evaluated. Significantly lower AP activity was found in females compared to males. Further analysis of the AP revealed lower C3 and properdin levels in females, while factor D concentrations were higher. MBL-LP activity was not influenced by sex, but MBL and ficolin-3 levels were significantly lower in females compared to males. There were no significant differences in CP activity or CP components between females and males, nevertheless females had significantly lower levels of the terminal components. The CP and AP activity was significantly higher in the elderly, in contrast to MBL-LP activity. Moreover, C1-inhibitor, C5, C8, and C9 increased with age in contrast to a decrease of factor D and C3 levels. In-depth analysis of the functional activity assays revealed that MBL-LP activity was predominantly dependent on MBL and MASP-2 concentration, whereas CP activity relied on C2, C1-inhibitor and C5 levels. AP activity was strongly and directly associated with levels of C3, factor B and C5. This study demonstrated significant sex and age-related differences in complement levels and functionality in the healthy population. Therefore, age and sex analysis should be taken into consideration when discussing complement-related pathologies and subsequent complement-targeted therapies.
MeSH Terms
- Adult
- Aged
- Aging
- Complement Activation
- Complement System Proteins
- European Continental Ancestry Group
- Female
- Humans
- Male
- Middle Aged
- Sex Characteristics
Keywords
- complement
- gender
- health
- innate imunity
- sex and age
Traumatic brain injury (TBI) is of particular concern for the aging community since there is both increased incidence of TBI and decreased functional recovery in this population. In addition, TBI is the strongest environmental risk factor for development of Alzheimer's disease and other dementia-related neurodegenerative disorders. Critical changes that affect cognition take place over time following the initial insult. Our previous work identified immune system activation as a key contributor to cognitive deficits observed in aged animals. Using a focal contusion model in the current study, we demonstrate a brain lesion and cavitation formation, as well as prolonged blood⁻brain barrier breakdown. These changes were associated with a prolonged inflammatory response, characterized by increased microglial cell number and phagocytic activity 30 days post injury, corresponding to significant memory deficits. We next aimed to identify the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals, and measured increases in complement initiation components C1q, C3, and CR3, which are known to regulate microglial⁻synapse interactions. Specifically, we found significant accumulation of C1q on synapses within the hippocampus, which was paralleled by synapse loss 30 days post injury. We used genetic and pharmacological approaches to determine the mechanistic role of complement initiation on cognitive loss in aging animals after TBI. Notably, both genetic and pharmacological blockade of the complement pathway prevented memory deficits in aged injured animals. Thus, therapeutically targeting early components of the complement cascade represents a significant avenue for possible clinical intervention following TBI in the aging population.
MeSH Terms
- Aging
- Animals
- Blood-Brain Barrier
- Brain
- Brain Injuries, Traumatic
- Cell Count
- Chronic Disease
- Complement System Proteins
- Contusions
- Disease Progression
- Female
- Magnetic Resonance Imaging
- Male
- Memory Disorders
- Mice, Inbred C57BL
- Microglia
- Models, Biological
- Phagocytosis
- Synapses
Keywords
- C1q
- complement
- microglia
- synapse
- traumatic brain injury
Dialdehyde cellulose (DAC) derived from α-cellulose by periodate oxidation was solubilized and utilized as a suitable crosslinking agent for poly(vinyl alcohol) (PVA). The crosslinking occurs between reactive aldehyde groups of DAC on the C2 and C3 carbons of anhydroglucose unit and hydroxyl groups on PVA backbone in the presence of acidic catalyst. Two catalyst systems based on diluted hydrochloric or sulfuric acid were tested. Their influence on the PVA/DAC network has been investigated by solid-state C NMR, XRD analysis and in the terms of network parameters and mechanical properties. Because DAC undergoes structural changes and decays with time, the role of DAC solution age (1, 14 and 28 days old) on material properties of formed PVA/DAC samples was studied as well. Outlined, even after 28 days after solution preparation, DAC exhibited the capability to act as an efficient crosslinker for PVA. The resulting material properties of PVA/DAC hydrogels were found to be dependent on the molecular weight of solubilized DAC closely related to its age and the choice of catalyst system. Furthermore, the DAC potential for PVA crosslinking was investigated in a broad concentration range. Besides, the DAC crosslinking efficiency was also compared to that of common crosslinking agent glutaraldehyde. The results showed different network topology of prepared hydrogels and exceptional crosslinking potential of DAC in comparison to glutaraldehyde, which is most likely related to DAC macromolecular character.
Keywords
- Aging
- Crosslinking
- Dialdehyde cellulose
- Glutaraldehyde
- Network parameters
- Poly(vinyl alcohol)
In the study, 130 honey bee colonies fed with different levels (5, 20, and 100 liters/colony) of various industrial commercial sugars, including High-Fructose Corn 85 (Fructose-85), High-Fructose Corn 55 (Fructose-55), Glucose Monohydrate (Glucose), Bee feed, and Sucrose syrups, for 2 mo were compared with colonies fed with no sugar (control) in terms of their colony development of worker bee population, hive weight, wax production, wintering ability, foraging behavior, and lifespan of worker bee. Utilization of industrial sugars by honey bee colonies showed differences in terms of colony performance and behavior parameters. Honey bees did not use Glucose heavily, resulting in 4% increase in worker bee loss in winter and 46% decrease in marked worker bee numbers over time when compared to the control. Sucrose syrup had a positive effect on wintering ability, wax production, and hive weight. While Sucrose had a positive effect (3-4%) on wintering ability, the 100 liters/colony sugar syrups of all other sugars had negative effects (6-15%). Sugars containing high levels of monosaccharide were not used effectively by honey bee colonies, whereas the sugars containing fructose and glucose at rates of 40 and 30% (Bee feed and Fructose-55), were utilized effectively. The lifespan of worker bees decreased over time in the 100 liters/colony of all sugars syrup. In conclusion, except Glucose, other industrial sugars can be used for promoting colonies at the beginning of the season (in spring). Industrial sugars except sucrose should not be used in order to meet carbohydrate needs of the colonies in winter.
MeSH Terms
- Animals
- Beekeeping
- Bees
- Behavior, Animal
- Dietary Sugars
- Longevity
- Seasons
Age-related para-inflammation in the retina-choroidal interface is featured by low-levels of complement activation and subretinal macrophage accumulation. This study aimed to understand how complement expression in macrophages is regulated by retinal pigment epithelium (RPE). Bone marrow-derived macrophages (BMDMs) and RPE cells were cultured from 8-10 weeks old C57BL/6J mice. The BMDMs were co-cultured with normal RPE, or oxidized photoreceptor outer segment (oxPOS) or TNF-α pre-treated RPE, or apoptotic RPE, or RPE-choroid eyecups. Macrophages were then isolated and processed for real-time RT-PCR. The expression of complement inhibitor C1INH in BMDMs was significantly upregulated by RPE and RPE-choroid eyecups. The eyecups also upregulated CFH, CD59a, and Crry in BMDMs. oxPOS pre-treated RPE upregulated C1qb but down-regulated C3 expression in BMDMs. TNF-α pre-treated RPE enhanced C1INH and CFB expression. When BMDMs were treated with apoptotic RPE, the expression of C1qb, CFH, and CD59a was reduced, whereas the expression of C3, CFB and C1INH was increased. Our results suggest that RPE can modulate macrophages complement expression at the retina-choroidal interface even under aging or oxidative conditions. However, during inflammation, they may promote the alternative pathway of complement activation through down-regulating CFH and CD59a and upregulating CFB and C3.
MeSH Terms
- Animals
- Cattle
- Cells, Cultured
- Coculture Techniques
- Complement C1 Inhibitor Protein
- Epithelial Cells
- Macrophages
- Mice
- Photoreceptor Cells, Vertebrate
- Retinal Pigment Epithelium
- Tumor Necrosis Factor-alpha
- Up-Regulation
Keywords
- aging
- complement
- macrophages
- retinal pigment epithelial cells
- subretinal immune privilege
Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein (APP) is cleaved by α-secretase, generating soluble α-amyloid precursor protein (sAPPα), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-β-peptide (Aβ) of either 40 or 42 residues are generated by increased activity of β- and γ-secretase. These proteins amalgamate in specific regions of the brain, which disrupts neuronal functions and leads to cognitive impairment. Human umbilical cord blood cells (HUCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases, including AD. Our most recent work studied the impact of umbilical cord blood serum (CBS) on modulation of sAPPα production. Heat-sensitive CBS significantly promoted sAPPα production, indicating that heat-sensitive factor(s) play(s) a role in this process. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to determine the molecular source of α-secretase in purified CBS and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of C1 complex (C1q, C1r, and C1s) and alpha-2-macroglobulin showed significantly greater levels in purified α-CBS fraction (α-CBSF) compared with the AgBS fraction (AgBSF). Specifically, C1 markedly increased sAPPα and alpha-carboxyl-terminal fragment (α-CTF) production in a dose-dependent fashion, whereas C1q alone only minimally increased and C3 did not increase sAPPα production in the absence of sera. Furthermore, C1q markedly increased sAPPα and α-CTF, while decreasing Aβ, in CHO/APPwt cells cultured in the presence of whole sera. These results confirm our initial assumption that APP α-secretase activity in human blood serum is mediated by complement C1, opening a potential therapeutic modality for the future of AD.
MeSH Terms
- Aged
- Aging
- Amyloid Precursor Protein Secretases
- Amyloid beta-Peptides
- Animals
- CHO Cells
- Complement C1
- Complement C3b
- Cricetinae
- Cricetulus
- Fetal Blood
- Hot Temperature
- Humans
- Mice
- Proteomics
Keywords
- Alzheimer’s Disease
- Aβ
- amyloid precursor protein
- complement C1 complex
- complement system
- cord blood serum
- human umbilical cord blood cell
- soluble α-amyloid precursor protein
Numerous changes occur in the old myocardium which finally cause lower cardiac output and, therefore, circulatory dysfunction. In order to identify an age-related gene expression pattern, we analyzed left ventricular myocardium of adult (6 months) and old (24 months) mice by use of whole genome expression arrays. About 2.3% of genes expressed above the median value of all genes were differentially expressed in old hearts. Nearly all of them were upregulated. After application of defined exclusion criteria, 98 genes were selected for a more detailed analysis. About one third of the 98 genes codes for factors involved in the immune reaction, such as chemokines (CCLs 6, 8, 9), proteins of the S100 family (S100s 4, 8, 9, 10, 11), complement components (C1qa, C1qb, C1qc, C3, C4b), bacteria/virus-induced genes (lysozyme 1/2, interferon-activated genes), and pro-inflammatory caspases (Casp1, Casp4, Casp12). Predominantly, genes coding for factors of the immune reaction were simultaneously upregulated in the kidneys and lungs of old mice, thereby emphasizing the pivotal role of immune cells in tissue aging. In conclusion, myocardial aging is mainly associated with an altered expression pattern of molecules involved in the immune reaction.
MeSH Terms
- Aging
- Animals
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Heart
- Immune System
- Kidney
- Male
- Mice, Inbred C57BL
- Myocardium
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger
Keywords
- Age
- Gene expression
- Mouse
- Myocardium
The extracellular matrix (ECM) plays a vital role in maintaining normal tissue function. Collagens are major components of the ECM and there is a tight equilibrium between degradation and formation of these proteins ensuring tissue health and homeostasis. As a consequence of tissue turnover, small collagen fragments are released into the circulation, which act as important biomarkers in the study of certain tissue-related remodeling factors in health and disease. The aim of this study was to establish an age-related collagen turnover profile of the main collagens of the interstitial matrix (type I and III collagen) and basement membrane (type IV collagen) in healthy men and women. By using well-characterized competitive ELISA-assays, we assessed specific fragments of degraded (C1M, C3M, C4M) and formed (PINP, Pro-C3, P4NP7S) type I, III and IV collagen in serum from 617 healthy men and women ranging in ages from 22 to 86. Subjects were divided into 5-year age groups according to their sex and age. Groups were compared using Kruskal-Wallis adjusted for Dunn's multiple comparisons test and Mann-Whitney t-test. Age-specific changes in collagen turnover was most profound for type I collagen. PINP levels decreased in men with advancing age, whereas in women, the level decreased in early adulthood followed by an increase around the age of menopause (age 40-60). Sex-specific changes in type I, III and IV collagen turnover was present at the age around menopause (age 40-60) with women having an increased turnover. In summary, collagen turnover is affected by age and sex with the interstitial matrix and the basement membrane being differently regulated. The observed changes needs to be accounted for when measuring ECM related biomarkers in clinical studies.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Basement Membrane
- Collagen
- Extracellular Matrix
- Female
- Humans
- Male
- Middle Aged
- Pregnancy
- Sex Characteristics
Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl-insoluble fractions reveal a pattern of phospho-tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen in AD. Phosphoproteomics of dissected vulnerable regions identifies an increase of phosphorylation marks in a large number of proteins in ARTAG compared with controls. GFAP, aquaporin 4, several serine-threonine kinases, microtubule associated proteins and other neuronal proteins are among the differentially phosphorylated proteins in ARTAG thus suggesting a hyper-phosphorylation background that affects several molecules, including many kinases and proteins from several cell compartments and various cell types. Finally, present results show for the first time that tau seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type mice of sarkosyl-insoluble fractions enriched in hyper-phosphorylated tau from selected ARTAG cases. These findings show astrocytes as crucial players of tau seeding in tauopathies.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Astrocytes
- Corpus Callosum
- Female
- Fornix, Brain
- Glial Fibrillary Acidic Protein
- Hippocampus
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Oligodendroglia
- Phosphorylation
- Superoxide Dismutase
- Tauopathies
- White Matter
- tau Proteins
Keywords
- ARTAG
- kinases
- phosphorylation
- seeding
- tau
- thorn-shaped astrocytes
Progranulin (PGRN) is a multi-functional growth factor that mediates cell proliferation, survival, migration, tumorigenesis, wound healing, development, and anti-inflammation activity. A novel alternatively spliced transcript from the short-form PGRN1 gene encoding a novel, secreted GRN peptide composed of 20-a.a. signal peptide and 41-a.a. GRN named GRN-41 was identified to be abundantly expressed in immune-related organs including spleen, head kidney, and intestine of Mozambique tilapia. The expression of GRN-41 and PGRN1 were further induced in the spleen of tilapia challenged with Vibrio vulnificus at 3 h post infection (hpi) and 6 hpi, respectively. In this study, we established three transgenic zebrafish lines expressing the secreted GRN-41, GRN-A and PGRN1 of Mozambique tilapia specifically in muscle. The relative percent of survival (RPS) was enhanced in adult transgenic zebrafish expressing tilapia GRN-41 (68%), GRN-A (32%) and PGRN1 (36%) compared with control transgenic zebrafish expressing AcGFP after challenge with V. vulnificus. It indicates tilapia GRN-41 is a potent peptide against V. vulnificus infection. The secreted tilapia GRN-41 can induce the expression of innate immune response-related genes, such as TNFa, TNFb, IL-8, IL-1β, IL-6, IL-26, IL-21, IL-10, complement C3, lysozyme (Lyz) and the hepatic antimicrobial peptide hepcidin (HAMP), in adult transgenic zebrafish without V. vulnificus infection. The tilapia GRN-41 peptide can enhance the innate immune response by further elevating TNFb, IL-1β, IL-8, IL-6, and HAMP expression in early responsive time to the V. vulnificus challenge in transgenic zebrafish. Our results suggest that the novel GRN-41 peptide generated from alternative splicing of the tilapia PGRN1 gene is a potent peptide that defends against V. vulnificus in the transgenic zebrafish model by modulation of innate immunity.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Female
- Fish Diseases
- Fish Proteins
- Immunity, Innate
- Intercellular Signaling Peptides and Proteins
- Longevity
- Male
- Progranulins
- Tilapia
- Vibrio Infections
- Vibrio vulnificus
- Zebrafish
Keywords
- Alternative splicing
- Granulin
- Innate immunity
- Progranulin
- Tilapia
- Transgenic zebrafish
- Vibrio
As prevention trials for Alzheimer's disease move into asymptomatic populations, identifying older individuals who manifest the earliest cognitive signs of Alzheimer's disease is critical. Computerized cognitive testing has the potential to replace current gold standard paper and pencil measures and may be a more efficient means of assessing cognition. However, more empirical evidence about the comparability of novel computerized batteries to paper and pencil measures is required. To determine whether two computerized IPad batteries, the NIH Toolbox Cognition Battery and Cogstate-C3, similarly predict subtle cognitive impairment identified using the Preclinical Alzheimer Cognitive Composite (PACC). A pilot sample of 50 clinically normal older adults (Mage=68.5 years±7.6, 45% non-Caucasian) completed the PACC assessment, and the NIH Toolbox and Cogstate-C3 at research centers of Massachusetts General and Brigham and Women's Hospitals. Participants made 3-4 in-clinic visits, receiving the PACC first, then the NIH Toolbox, and finally the Cogstate-C3.>= 0.5SD), versus subtle cognitive impairment (<0.5SD). Composites for each computerized battery were created using principle components analysis, and compared with the PACC using non-parametric Spearman correlations. Logistic regression analyses were used to determine which composite was best able to classify subtle cognitive impairment from typical performance. The NIH Toolbox formed one composite and exhibited the strongest within-battery alignment, while the Cogstate-C3 formed two distinct composites (Learning-Memory and Processing Speed-Attention). The NIH Toolbox and C3 Learning-Memory composites exhibited positive correlations with the PACC (ρ=0.49, p<0.001; ρ=0.58, p<0.001, respectively), but not the C3 Processing Speed-Attention composite, ρ=-0.18, p=0.22. The C3 Learning-Memory was the only composite that classified subtle cognitive impairment, and demonstrated the greatest sensitivity (62%) and specificity (81%) for that subtle cognitive impairment. Preliminary findings suggest that the NIH Toolbox has the advantage of showing the strongest overall clustering and alignment with standardized paper-and-pencil tasks. By contrast, Learning-Memory tasks within the Cogstate-C3 battery have the greatest potential to identify cross-sectional, subtle cognitive impairment as defined by the PACC.
MeSH Terms
- Aged
- Clinical Trials as Topic
- Cognition
- Cognitive Dysfunction
- Computers, Handheld
- Diagnosis, Computer-Assisted
- Humans
- Logistic Models
- Neuropsychological Tests
- Pilot Projects
- Principal Component Analysis
- Sensitivity and Specificity
Keywords
- Cognition
- aging
- computerized testing
- neuropsychology
Red blood cells (RBCs) have a well-defined lifespan, indicating a mechanism by which senescent cells of a certain age are removed from circulation. However, the specifics by which senescent cells are recognized and removed are poorly understood. There are multiple competing hypotheses for this process, perhaps the most commonly cited is that senescent RBCs expose neoantigens [or senescent antigen(s)] that are then recognized by naturally occurring antibodies, which opsonize the senescent cells and result in clearance from circulation. While there are a large volume of published data to indicate that older RBCs accumulate increased levels of antibody on their surface, to the best of our knowledge, the causal role of such antibodies in clearance has not been rigorously assessed. In the current report, we demonstrate that RBC lifespan and clearance patterns are not altered in mice deficient in antibodies, in C3 protein, or missing both. These data demonstrate that neither antibody nor C3 is required for clearance of senescent RBCs, and questions if they are even involved, in a murine model of RBC lifespan.
Keywords
- antibodies
- complement C3
- naturally occurring antibodies
- red blood cell clearance
- red blood cell lifespan
- senescent antigen
Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent studies have suggested that alterations in the gut microbiota, referred to as dysbiosis, are associated with MS. However, it is still largely unknown how gut dysbiosis affects the onset and progression of CNS autoimmunity. In this study, we investigated the effects of age and gut dysbiosis on the development of CNS autoimmunity in humanized transgenic mice expressing the MS-associated MHC class II (MHC-II) gene, HLA-DR2a, and T-cell receptor (TCR) genes specific for MBP87-99/DR2a that were derived from an MS patient. We show here that the induction of gut dysbiosis triggers the development of spontaneous experimental autoimmune encephalomyelitis (EAE) during adolescence and early young adulthood, while an increase in immunological tolerance with aging suppresses disease onset after late young adulthood in mice. Furthermore, gut dysbiosis induces the expression of complement C3 and production of the anaphylatoxin C3a, and down-regulates the expression of the [i]Foxp3[/i] gene and anergy-related E3 ubiquitin ligase genes. Consequently, gut dysbiosis was able to trigger the development of encephalitogenic T cells and promote the induction of EAE during the age window of young adulthood.
MeSH Terms
- Animals
- Autoimmunity
- Central Nervous System
- Complement C3a
- Down-Regulation
- Dysbiosis
- Encephalomyelitis, Autoimmune, Experimental
- Forkhead Transcription Factors
- Gastrointestinal Microbiome
- Genes, MHC Class II
- HLA-DR2 Antigen
- Humans
- Immune Tolerance
- Mice
- Mice, Transgenic
- Multiple Sclerosis
- Receptors, Antigen, T-Cell
- T-Lymphocytes
- Ubiquitin-Protein Ligases
Keywords
- aging
- complement
- dysbiosis
- immune tolerance
- multiple sclerosis
Increasing of anthropogenic electromagnetic fields in aquatic environments has been recently become the core of attention. In this study, the effect of extremely low-frequency electromagnetic fields (50 Hz) on immune status and metabolic markers of common carp fingerling was assessed. The fish were exposed to extremely low-frequency electromagnetic fields at four intensities of 0.1, 0.5, 1, and 2 mT only once for 2 h; then, they were reared for 60 days. Results showed that the levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) and alkaline phosphatase (ALP) were increased with an increase in the electromagnetic field intensity on 15 and 60 days post exposure. A significant increase was obtained in these enzyme levels in all the tested intensities compared to the control one (p < 0.05), with a maximum value measured in 2-mT trail. Conversely, with an increasing in the electromagnetic intensity, the levels of C3, C4, and lysozyme were reduced in all the treated groups in comparison with the control group (p < 0.05). The results suggested a significant impact of electromagnetic on fish immunophysiological functions. Therefore, it is required to have serious attention in aquatic ecosystems.
MeSH Terms
- Aging
- Alanine Transaminase
- Alkaline Phosphatase
- Animals
- Aspartate Aminotransferases
- Carps
- Dose-Response Relationship, Radiation
- Electromagnetic Fields
Keywords
- Cyprinus carpio
- Electromagnetic fields
- Metabolic enzymes
- Nonspecific immunity
Leaf senescence is a long developmental process important for nutrient management and for source to sink remobilization. Constituents of the mesophyll cells are progressively degraded to provide nutrients to the rest of the plant. Up to now, studies on leaf senescence have not paid much attention to the role of the different leaf tissues. In the present study, we dissected leaf laminae from the midvein to perform metabolite profiling. The laminae mesophyll cells are the source of nutrients, and in C3 plants they contain Rubisco as the most important nitrogen storage pool. Veins, rich in vasculature, are the place where all the nutrients are translocated, and sometimes interconverted, before being exported through the phloem or the xylem. The different metabolic changes we observed in laminae and midvein with ageing support the idea that the senescence programme in these two tissues is different. Important accumulations of metabolites in the midvein suggest that nutrient translocations from source leaves to sinks are mainly controlled at this level. Carbon and nitrogen long-distance molecules such as fructose, glucose, aspartate, and asparagine were more abundant in the midvein than in laminae. In contrast, sucrose, glutamate, and aspartate were more abundant in laminae. The concentrations of tricarboxylic acid (TCA) compounds were also lower in the midvein than in laminae. Since nitrogen remobilization increased under low nitrate supply, plants were grown under two nitrate concentrations. The results revealed that the senescence-related differences were mostly similar under low and high nitrate conditions except for some pathways such as the TCA cycle.
MeSH Terms
- Aging
- Brassica napus
- Metabolome
- Metabolomics
- Nitrates
- Plant Leaves
Keywords
- Leaf senescence
- metabolomics
- phloem
- source–sink relationship
Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d-Allulose (d-Alu), the C3-epimer of d-fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d-Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d-Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d-Alu did not reduce the food intake of wild-type C. elegans. To explore the mechanisms of the d-Alu longevity effect, we examined the lifespan of d-Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16, sir-2.1, aak-2, and skn-1. As a result, d-Alu increased the lifespan of the daf-16, sir-2.1, and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d-Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d-Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic.
MeSH Terms
- AMP-Activated Protein Kinases
- Animals
- Biomimetic Materials
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Caloric Restriction
- Catalase
- Eating
- Fructose
- Genes, Helminth
- Longevity
- Mutation
- Oxidative Stress
- Protein-Serine-Threonine Kinases
- Receptors, Nicotinic
- Stereoisomerism
- Superoxide Dismutase
Keywords
- Caenorhabditis elegans
- Dietary restriction
- Dietary restriction mimetic
- Lifespan
- d-Allulose
The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker-4HNE-and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Autophagy
- Biomarkers
- Complement C3
- Disease Models, Animal
- Down-Regulation
- Female
- Gene Expression Profiling
- Mice, Inbred C57BL
- Oxidative Stress
- Protein Folding
- Retina
- Up-Regulation
Pattern onset VEPs do not always show distinct C1-C2-C3 peaks and troughs. Our purpose was to study changes in pattern onset VEP with age to determine when the illustrated ISCEV standard onset VEP waveform can be reliably recorded. We recorded pattern onset VEPs from an Oz electrode referred to mid-frontal electrode according to ISCEV standards by presenting checks of 60' and 15' side length in a 15° field. Twenty-four adults aged 20-63 years participated. Amplitudes and latencies were collated. Pattern onset adult VEP shapes were compared to the waveform published in the ISCEV VEP standard and to paediatric pattern onset VEP waveforms recorded from 16 infants aged 7 months. The shape of the pattern onset VEP changed gradually with age. The C1-C2-C3 morphology of the ISCEV standard pattern onset VEP becomes apparent consistently after 40 years to 60' check stimulation. As age increases a negative trough, C2 is more frequently seen; however, the broad positive peak which characterises infant onset VEPs may still be recorded at 20 years. The group median measurements of onset VEPs to 60' were C1 7 µV@ 88 ms (range 67-110 ms), C2 9 µV@109 ms (range 89-158 ms) and C3 13 µV@121-246 ms. To smaller 15' checks, peak latencies were earlier and C2 became more obvious. The group median measures of onset VEPs to 15' were C1 2 µV@69 ms (55-108 ms), C2 10 µV@90 ms (77-145 ms) and C3 14 µV@122 ms (99-200 ms). The ISCEV standard onset VEP best describes the waveform configuration and latency of the onset VEP produced by 60' checks in adults of more than 40 years of age. The onset VEP waveform produced by 15' checks is distinguished by more prominent negative C2 and earlier C1 and C2 latencies.
MeSH Terms
- Adult
- Aging
- Cross-Sectional Studies
- Electrophysiology
- Evoked Potentials, Visual
- Female
- Humans
- Infant
- Male
- Middle Aged
- Ophthalmology
- Retrospective Studies
- Societies, Medical
- Young Adult
Keywords
- Age
- Check size
- ISCEV standard VEP waveform
- Pattern onset VEP
- Waveform maturation
The complement cascade not only is an innate immune response that enables removal of pathogens but also plays an important role in microglia-mediated synaptic refinement during brain development. Complement C3 is elevated in Alzheimer's disease (AD), colocalizing with neuritic plaques, and appears to contribute to clearance of Aβ by microglia in the brain. Previously, we reported that C3-deficient C57BL/6 mice were protected against age-related and region-specific loss of hippocampal synapses and cognitive decline during normal aging. Furthermore, blocking complement and downstream iC3b/CR3 signaling rescued synapses from Aβ-induced loss in young AD mice before amyloid plaques had accumulated. We assessed the effects of C3 deficiency in aged, plaque-rich APPswe/PS1dE9 transgenic mice (APP/PS1;[i]C3[/i] KO). We examined the effects of C3 deficiency on cognition, Aβ plaque deposition, and plaque-related neuropathology at later AD stages in these mice. We found that 16-month-old APP/PS1;[i]C3[/i] KO mice performed better on a learning and memory task than did APP/PS1 mice, despite having more cerebral Aβ plaques. Aged APP/PS1;[i]C3[/i] KO mice also had fewer microglia and astrocytes localized within the center of hippocampal Aβ plaques compared to APP/PS1 mice. Several proinflammatory cytokines in the brain were reduced in APP/PS1;[i]C3[/i] KO mice, consistent with an altered microglial phenotype. C3 deficiency also protected APP/PS1 mice against age-dependent loss of synapses and neurons. Our study suggests that complement C3 or downstream complement activation fragments may play an important role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains of APP/PS1 mice.
MeSH Terms
- Aging
- Amyloid beta-Protein Precursor
- Animals
- Astrocytes
- Cognitive Dysfunction
- Complement C3
- Cytokines
- Gliosis
- Hippocampus
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Degeneration
- Plaque, Amyloid
- Presenilin-1
- Solubility
- Synapses
The lack of high-throughput methods to analyze the adipose tissue protein composition limits our understanding of the protein networks responsible for age and diet related metabolic response. We have developed an approach using multiple-dimension liquid chromatography tandem mass spectrometry and extended multiplexing (24 biological samples) with tandem mass tags (TMT) labeling to analyze proteomes of epididymal adipose tissues isolated from mice fed either low or high fat diet for a short or a long-term, and from mice that aged on low [i]versus[/i] high fat diets. The peripheral metabolic health (as measured by body weight, adiposity, plasma fasting glucose, insulin, triglycerides, total cholesterol levels, and glucose and insulin tolerance tests) deteriorated with diet and advancing age, with long-term high fat diet exposure being the worst. In response to short-term high fat diet, 43 proteins representing lipid metabolism ([i]e.g.[/i] AACS, ACOX1, ACLY) and red-ox pathways ([i]e.g.[/i] CPD2, CYP2E, SOD3) were significantly altered (FDR < 10%). Long-term high fat diet significantly altered 55 proteins associated with immune response ([i]e.g.[/i] IGTB2, IFIT3, LGALS1) and rennin angiotensin system ([i]e.g.[/i] ENPEP, CMA1, CPA3, ANPEP). Age-related changes on low fat diet significantly altered only 18 proteins representing mainly urea cycle ([i]e.g.[/i] OTC, ARG1, CPS1), and amino acid biosynthesis ([i]e.g.[/i] GMT, AKR1C6). Surprisingly, high fat diet driven age-related changes culminated with alterations in 155 proteins involving primarily the urea cycle ([i]e.g.[/i] ARG1, CPS1), immune response/complement activation ([i]e.g.[/i] C3, C4b, C8, C9, CFB, CFH, FGA), extracellular remodeling ([i]e.g.[/i] EFEMP1, FBN1, FBN2, LTBP4, FERMT2, ECM1, EMILIN2, ITIH3) and apoptosis ([i]e.g.[/i] YAP1, HIP1, NDRG1, PRKCD, MUL1) pathways. Using our adipose tissue tailored approach we have identified both age-related and high fat diet specific proteomic signatures highlighting a pronounced involvement of arginine metabolism in response to advancing age, and branched chain amino acid metabolism in early response to high fat feeding. Data are available via ProteomeXchange with identifier PXD005953.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Diet, High-Fat
- Epididymis
- Gene Regulatory Networks
- Immunoblotting
- Male
- Mass Spectrometry
- Metabolic Networks and Pathways
- Mice, Inbred C57BL
- Proteome
- Proteomics
- Reproducibility of Results
- Sample Size
There have been a few descriptive studies in aged rodents about transcriptome changes in the hippocampus, most of them in males. Here, we assessed the age changes in spatial memory performance and hippocampal morphology in female rats and compared those changes with changes in the hippocampal transcriptome. Old rats displayed significant deficits in spatial memory. In both age groups, hole exploration frequency showed a clear peak at hole 0 (escape hole), but the amplitude of the peak was significantly higher in the young than in the old animals. In the hippocampus, there was a dramatic reduction in neurogenesis, whereas reactive microglial infiltrates revealed an inflammatory hippocampal state in the senile rats. Hippocampal RNA-sequencing showed that 210 genes are differentially expressed in the senile rats, most of them being downregulated. Our RNA-Seq data showed that various genes involved in the immune response, including TYROBP, CD11b, C3, CD18, CD4, and CD74, are overexpressed in the hippocampus of aged female rats. Enrichment analysis showed that the pathways overrepresented in the senile rats matched those of an exacerbated inflammatory environment, reinforcing our morphologic findings. After correlating our results with public data of human and mouse hippocampal gene expression, we found an 11-gene signature of overexpressed genes related to inflammatory processes that was conserved across species. We conclude that age-related hippocampal deficits in female rats share commonalities between human and rodents. Interestingly, the 11-gene signature that we identified may represent a cluster of immune and regulatory genes that are deregulated in the hippocampus and possibly other brain regions during aging as well as in some neurodegenerative diseases and low-grade brain tumors. Our study further supports neuroinflammation as a promising target to treat cognitive dysfunction in old individuals and some brain tumors. © 2017 Wiley Periodicals, Inc.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Dementia
- Female
- Gene Expression
- Hippocampus
- Humans
- Male
- Maze Learning
- Microglia
- Middle Aged
- Neurogenesis
- Neurons
- Rats, Sprague-Dawley
- Spatial Memory
- Species Specificity
- Transcriptome
- Young Adult
Keywords
- Barnes maze
- aging
- hippocampal transcriptome
- immune pathways
- spatial memory
{{medline-entry |title=Normative data for parameters of sagittal spinal alignment in healthy subjects: an analysis of gender specific differences and changes with aging in 626 asymptomatic individuals. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27771788 |abstract=This study aims to establish normative data for parameters of spino-pelvic and spinal sagittal alignment, gender related differences and age-related changes in asymptomatic subjects. A total of 626 asymptomatic volunteers from Japanese population were enrolled in this study, including 50 subjects at least for each gender and each decade from 3rd to 8th. Full length, free-standing spine radiographs were obtained. Cervical lordosis (CL; C3-7), thoracic kyphosis (TK; T1-12), lumbar lordosis (LL; T12-S1), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and sagittal vertical axis (SVA) were measured. The average values (degrees) are 4.1 ± 11.7 for CL, 36.0 ± 10.1 for TK, 49.7 ± 11.2 for LL, 53.7 ± 10.9 for PI, 14.5 ± 8.4 for PT, and 39.4 ± 8.0 for SS. Mean SVA is 3.1 ± 12.6 mm. Advancing age caused an increase in CL, PT and SVA, and a decrease in LL and SS. There was a significant gender difference in CL, TK, LL, PI, PT and SVA. From 7th decade to 8th decade, remarkable decrease of LL