CCL11
Eotaxin precursor (C-C motif chemokine 11) (Eosinophil chemotactic protein) (Small-inducible cytokine A11) [SCYA11]
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CCL-11 (eotaxin) is a chemokine with an important role in allergic conditions. Recent evidence indicates that CCL-11 plays a role in brain disorders as well. This paper reviews the associations between CCL-11 and aging, neurodegenerative, neuroinflammatory and neuropsychiatric disorders. Electronic databases were searched for original articles examining CCL-11 in neuropsychiatric disorders. CCL-11 is rapidly transported from the blood to the brain through the blood-brain barrier. Age-related increases in CCL-11 are associated with cognitive impairments in executive functions and episodic and semantic memory, and therefore, this chemokine has been described as an "Endogenous Cognition Deteriorating Chemokine" (ECDC) or "Accelerated Brain-Aging Chemokine" (ABAC). In schizophrenia, increased CCL-11 is not only associated with impairments in cognitive functions, but also with key symptoms including formal thought disorders. Some patients with mood disorders and premenstrual syndrome show increased plasma CCL-11 levels. In diseases of old age, CCL-11 is associated with lowered neurogenesis and neurodegenerative processes, and as a consequence, increased CCL-11 increases risk towards Alzheimer's disease. Polymorphisms in the CCL-11 gene are associated with stroke. Increased CCL-11 also plays a role in neuroinflammatory disease including multiple sclerosis. In animal models, neutralization of CCL-11 may protect against nigrostriatal neurodegeneration. Increased production of CCL-11 may be attenuated by glucocorticoids, minocycline, resveratrol and anti-CCL11 antibodies. Increased CCL-11 production during inflammatory conditions may play a role in human disease including age-related cognitive decline, schizophrenia, mood disorders and neurodegenerative disorders. Increased CCL-11 production is a new drug target in the treatment and prevention of those disorders.
Keywords
- Alzheimer’s disease
- CCL-11
- aging
- behaviour
- biomarkers
- brain
- cytokines
- eotaxin
- prevention
- schizophrenia
- stroke
Recent animal studies on heterochronic parabiosis (a technique combining the blood circulation of two animals) have revealed that young blood has a powerful rejuvenating effect on brain aging. Circulating factors, especially growth differentiation factor 11 (GDF11) and C-C motif chemokine 11 (CCL11), may play a key role in this effect, which inspires hope for novel approaches to treating age-related cerebral diseases in humans, such as neurodegenerative and neurovascular diseases. Recently, attempts have begun to translate these astonishing and exciting findings from mice to humans and from bench to bedside. However, increasing reports have shown contradictory data, questioning the capacity of these circulating factors to reverse age-related brain dysfunction. In this review, we summarize the current research on the role of young blood, as well as the circulating factors GDF11 and CCL11, in the aging brain and age-related cerebral diseases. We highlight recent controversies, discuss related challenges and provide a future outlook.
MeSH Terms
- Age Factors
- Aging
- Animals
- Blood
- Bone Morphogenetic Proteins
- Chemokine CCL11
- Enzyme Therapy
- Enzymes
- Growth Differentiation Factors
- Mice
- Neurodegenerative Diseases
- Parabiosis
- Vascular Diseases
Keywords
- C-C motif chemokine 11
- Circulating factor
- Growth differentiation factor 11
- Neurodegenerative diseases
- Neurovascular diseases
- Young blood
Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C-C motif chemokine ligand 11 (CCL11) and β2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing β2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease.
MeSH Terms
- Age Factors
- Aging
- Animals
- Bone Marrow Transplantation
- Chemokine CCL11
- Cognition
- Hippocampus
- Learning
- Male
- Memory
- Mice, Congenic
- Mice, Inbred C57BL
- Mice, Transgenic
- Neurogenesis
- Rejuvenation
- beta 2-Microglobulin
Essential hypertension (EG) is an age-associated disease. Often EG of elderly patients haven't good way of treatment. Thus, the search of new target molecules for EG therapy is an actual goal of gerontology and molecular medicine. It was shown, that during EG concentrations of GDF11 «youth protein» decreased in 3,3 times and GDF15, JAM-A/1, CCL11 «aging proteins» increased in 1,4-2,4 times. EG patients have abnormal microcirculation processes. It was shown as decreasing in 1,3 and 1,7 times of hemodynamic HI1 and H1-H3 indexes. EG patients have negative correlation of GDF15 concentration with arterial pressure. EG patients have no correlation of JAM-A/1 concentration with arterial pressure. Normal is positive correlation with GDF15, JAM-A/1 concentration with arterial pressure. GDF15 blood level during EG have positive correlation with HI1-HI3 and negative correlation with NEUR_HI2 and MAYER_HI3 indexes. It can show on pathogenesis mechanisms of endothelial and smooth muscles function of vessels tissues. We suppose, that the regulation of GDF11, GDF15, JAM-A/1, CCL11 «youth and aging proteins» can be target object of EG therapy.
MeSH Terms
- Aged
- Aging
- Arterial Pressure
- Essential Hypertension
- Growth Differentiation Factor 15
- Hemodynamics
- Humans
- Proteins
Keywords
- CCL11
- GDF11
- GDF15
- JAM-A/1
- aging
- essential hypertension
The chemokine CCL11 has been implicated in age-related cognitive deterioration in mice, yet evidence on the relationship between CCL11 and cognitive function in humans is limited. This study explored associations between CCL11 and cognition in rural and urban community-dwelling older adults. Participants were 515 urban dwellers from the 3C-Bordeaux cohort and 318 rural dwellers from the AMI cohort. Plasma CCL11 was measured using an enzyme-linked immunoassay. Mini Mental State Examination (MMSE) test scores were used as the main measure of cognitive performance. Multivariate regression analysis was used to evaluate the cross-sectional association between CCL11 and cognitive performance. CCL11 was significantly higher in rural dwellers compared to city dwellers (median [IQR]: 145 [115-201] pg/mL vs. 103 [85-129] pg/mL; p < 0.001). After adjustment for confounders, CCL11 was found to be negatively associated with cognitive performance in rural dwellers but not in city dwellers. These results suggest that CCL11 may be an independent determinant of cognitive function in older rural dwellers and that the residential environment modifies this association.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Chemokine CCL11
- Cognition
- Cognitive Dysfunction
- Cross-Sectional Studies
- Female
- France
- Geriatric Assessment
- Humans
- Independent Living
- Logistic Models
- Male
- Mental Status and Dementia Tests
- Multivariate Analysis
- Rural Population
- Urban Population
Keywords
- Ageing
- CCL11
- Cognitive impairment
- Cohort
- Dwelling environment
The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti-inflammatory therapies aiming to improve nerve regeneration in old age.
MeSH Terms
- Aging
- Animals
- Anti-Inflammatory Agents
- Aspirin
- Chemokine CCL11
- Ganglia, Spinal
- Inflammation
- Mice, Inbred C57BL
- Myelin Sheath
- Nerve Crush
- Nerve Regeneration
- Peripheral Nerve Injuries
- Peripheral Nerves
- Schwann Cells
- Sciatic Nerve
Keywords
- aging
- inflammaging
- macrophages
- neural regeneration
- peripheral nervous system
- schwann cell
Pulp regeneration by stem cell transplantation declines due to age-related reduction. We hypothesized that administration of a cytokine together with the cell transplantation may improve the stem cell niche microenvironment and promote regeneration. CCL11 is implicated as a factor in aging. This investigation was performed to investigate the changes in the quality of the regenerated pulp by administration of CCL11 antibody in the aged mice and elucidate the underlying mechanisms. Mobilized dental pulp stem cell (MDPSC) transplants were characterized in an ectopic tooth root transplantation model in both the aged and young mice. The amount of regenerated pulp tissue was analyzed in the transplants with continuous administration of CCL11 antibody compared with those without the antibody administration. Blood CCL11 levels were assessed at the onset of the experiment. Furthermore, immunostaining of CD68 together with CD11c or CD206 for M1 and M2 macrophage, respectively, were performed. Each double-positive cell count of M1 and M2 macrophages and M1/M2 ratio in the transplants with administration were compared with those without administration both in the aged and young mice. The administration of CCL11 antibody enhanced pulp regeneration and significantly reduced the blood CCL11 level in the aged mice. As the number of M1 macrophages decreased, the M1/M2 ratio in the treated aged mouse was less than that in the untreated aged mouse. There was, however, significant difference between the treated aged mouse and the untreated young mouse. CCL11 antibody has the potential to enhance and stimulate pulp regeneration in the aged mice.
MeSH Terms
- Aging
- Animals
- Antibodies, Neutralizing
- Cell Differentiation
- Chemokine CCL11
- Dental Pulp
- Mice
- Mice, SCID
- Regeneration
- Stem Cell Transplantation
- Stem Cells
- Swine
- Tooth Replantation
Keywords
- growth factor
- regeneration
- rejuvenation
- stem cells
Degeneration of central neurons and fibers has been observed in postmortem brains of heroin dependent patients. However, there are no biomarkers to predict the severity of neurodegeneration related to heroin dependence. A correlation has been reported between inflammatory C-C motif chemokine ligand 11 (CCL11, or eotaxin-1) and neurodegeneration in Alzheimer's disease. Three-hundred-forty-four heroin dependent, Taiwanese patients under methadone maintenance treatment (MMT) were included with clinical assessment and genomics information. Eighty-seven normal control subjects were also recruited for comparison. Using receiver operating characteristics curve analyses, CCL11 showed the strongest sensitivity and specificity in correlation with age by a cut-off at 45 years (AUC = 0.69, P < 0.0001) in MMT patients, but not normal controls. Patients 45 years of age or older had significantly higher plasma levels of CCL11, fibroblast growth factor 2 (FGF-2), nicotine metabolite cotinine, and a longer duration of addiction. Plasma level of CCL11 was correlated with that of FGF-2 (partial r = 0.24, P < 0.0001). Carriers with the mutant allele of rs1129844, a functional single nucleotide polymorphism (Ala23Thr) in the CCL11 gene, showed a higher plasma level of Aß42, ratio of Aß42/Aß40, and insomnia side effect symptom score than the GG genotype carriers among MMT responders with morphine-negative urine results. The results suggest possible novel mechanisms mediated through CCL11 involving neurotoxicity in heroin dependent patients.
MeSH Terms
- Adult
- Aging
- Amyloid beta-Peptides
- Brain
- Case-Control Studies
- Chemokine CCL11
- Cotinine
- Female
- Fibroblast Growth Factor 2
- Genotype
- Heroin Dependence
- Humans
- Male
- Methadone
- Middle Aged
- Opiate Substitution Treatment
- Peptide Fragments
- Polymorphism, Single Nucleotide
- Sleep Initiation and Maintenance Disorders
Keywords
- Amyloid beta
- CCL11
- FGF-2
- Insomnia
- Methadone
The paper presents the latest literature data on the structure and functions of «protein of juvenility» - CCL11 and «protein of senility» - GDF11. Chemokine CCL11 injected to young animals has been shown to lead to degenerative changes in the central nervous system (CNS), disturb cognitive functions and impede tissue regeneration. CCL11 concentration increases dramatically in schizophrenia, Alzheimer's disease, neuro-inflammatory disorders, cerebral malaria, drug addiction, as well as in atherosclerosis, periodontal disease, macular degeneration, cancer and other pathologies. In contrast to CCL11, differentiation growth factor 11 (GDF11), being administered to old mice, eliminates age-associated hypertrophy of the heart, improves muscle tone and prevents degenerative changes in the CNS, improves cognitive functions and enhances tissue regeneration. Its concentration decreases in cardiovascular disease, osteoporosis, and other «diseases of old age». At the same time, the higher the GDF11 level in the blood, the milder myocardial infarction, stroke and other age-related diseases of the cardiovascular system.
MeSH Terms
- Aging
- Animals
- Bone Morphogenetic Proteins
- Chemokine CCL11
- Growth Differentiation Factors
- Humans
- Late Onset Disorders
Keywords
- age-associated diseases
- cognitive functions
- heterogeneous parabiosis
- «proteins of juvenility and senility» CCL11 and GDF11
Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ.
MeSH Terms
- Adult
- Aging, Premature
- Biomarkers
- Chemokine CCL11
- Cognitive Dysfunction
- Female
- Gray Matter
- Humans
- Magnetic Resonance Imaging
- Male
- Memory, Episodic
- Middle Aged
- Schizophrenia
- Telomere Shortening
Keywords
- biomarkers
- episodic memory
- gray matter volume
- pathological accelerated aging
- schizophrenia
Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases.
MeSH Terms
- Aging
- Animals
- Chemokine CCL11
- Chemokine CCL24
- Chemokine CCL26
- Humans
- Immunity, Innate
- Neurodegenerative Diseases
- Receptors, CCR3
Keywords
- Aging
- CCL11
- Eotaxin
- Multiple sclerosis
- Neurodegeneration
- Neurogenesis
In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.
MeSH Terms
- Aging
- Animals
- Brain
- Cognition
- Humans
- Memory
- Neurons
- Rejuvenation
Cytokines CCL11 (eotaxin) and HMGB1 (alarmin1) are molecular markers of ageing and neurological, cardiovascular and immune diseases. Created in St. Petersburg Institute of Bioregulation and Gerontology short peptides are known to regulate gene expression and protein synthesis. They promote the mortality decrease and slowdown the development of pathology in the elderly. The article presents the proposed role of dipeptide vilon (Lys-Glu) and tetrapeptide epitalon (Ala-Glu-Asp-Gly) in CCL11 and HMGB1 genes regulation as activators of their expression. Geroprotective action of vilon and epitalon probably realizes in suppression of these genes.
MeSH Terms
- Aging
- Animals
- Atherosclerosis
- Base Sequence
- Binding Sites
- Biomarkers
- Chemokine CCL11
- Dipeptides
- Gene Expression Regulation
- HMGB1 Protein
- Humans
- Molecular Sequence Data
- Neurodegenerative Diseases
- Oligopeptides
It has been known for some time that blood from young mice can positively impact aged animals, while blood from old mice has the opposite effect. Recent studies report that rejuvenating effects of young blood extend to multiple tissues and have identified GDF11 and CCL11 as factors mediating these effects.
MeSH Terms
- Aging
- Animals
- Bone Morphogenetic Proteins
- Chemokine CCL11
- Growth Differentiation Factors
- Mice
- Parabiosis
In aged mice, we assessed how intensive exercise affects brain bioenergetics, inflammation, and neurogenesis-relevant parameters. After 8 weeks of a supra-lactate threshold treadmill exercise intervention, 21-month-old C57BL/6 mice showed increased brain peroxisome proliferator-activated receptor gamma coactivator-1α protein, mammalian target of rapamycin and phospho-mammalian target of rapamycin protein, citrate synthase messenger RNA, and mitochondrial DNA copy number. Hippocampal vascular endothelial growth factor A (VEGF-A) gene expression trended higher, and a positive correlation between VEGF-A and PRC messenger RNA levels was observed. Brain doublecortin, brain-derived neurotrophic factor, tumor necrosis factor-α, and CCL11 gene expression, as well as plasma CCL11 protein levels, were unchanged. Despite these apparent negative findings, a negative correlation between plasma CCL11 protein levels and hippocampal doublecortin gene expression was observed; further analysis indicated exercise may mitigate this relationship. Overall, our data suggest supra-lactate threshold exercise activates a partial mitochondrial biogenesis in aged mice, and a gene (VEGF-A) known to support neurogenesis. Our data are consistent with another study that found systemic inflammation in general, and CCL11 protein specifically, suppresses hippocampal neurogenesis. Our study supports the view that intense exercise above the lactate threshold may benefit the aging brain; future studies to address the extent to which exercise-generated lactate mediates the observed effects are warranted.
MeSH Terms
- Aging
- Animals
- Brain
- Chemokine CCL11
- Citrate (si)-Synthase
- DNA, Mitochondrial
- Gene Dosage
- Hippocampus
- Humans
- Inflammation
- Lactates
- Male
- Mice, Inbred C57BL
- Microtubule-Associated Proteins
- Mitochondria
- Neurogenesis
- Neuropeptides
- Organelle Biogenesis
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Physical Conditioning, Animal
- RNA, Messenger
- TOR Serine-Threonine Kinases
- Transcription Factors
- Vascular Endothelial Growth Factor A
Keywords
- Aging brain
- Exercise
- Inflammation
- Mitochondrial biogenesis
- Neurogenesis
Cannabis is a widely used recreational drug. Its effect on human health and psychosis remains controversial. In this study, we aimed to explore the possibility that cannabis use influenced CCL11 plasma levels. Increased CCL11 chemokine has been reported in schizophrenia and cannabis is a known trigger of schizophrenia. Additionally, plasma levels of the chemokine CCL11 have recently been shown to increase with age and with cognitive deficits and hippocampal neurogenesis. For this study, a total of 87 healthy volunteers (68% men, age range 18-35 years) completed the Cannabis Experience Questionnaire that included information on sociodemographic and morphometric data and provided a blood sample for CCL11 measurement. 'Current users' of cannabis (n=18) had significantly higher CCL11 plasma levels compared to 'past users' (n=33) and 'never users' (n=36) [F(3,84)=3.649; p=0.030]. The latter two groups had similar CCL11 levels. Higher CCL11 plasma levels could not be attributed to gender, age, body mass index, physical activity or use of other legal/illegal drugs. These results suggest that cannabis use increases CCL11 plasma levels and the effects are reversible when cannabis use ceases.
MeSH Terms
- Adolescent
- Adult
- Biomarkers
- Chemokine CCL11
- Female
- Healthy Volunteers
- Humans
- Male
- Marijuana Smoking
- Single-Blind Method
- Surveys and Questionnaires
- Young Adult
Keywords
- Aging
- BMI
- Body mass index
- CCL11
- CEQ
- Cannabis
- Cannabis Experience Questionnaire
- Chemokine
- PAI
- Physical Activity Index
- Psychosis
- SD
- Schizophrenia
- Standard deviation
The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4( ) effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response; the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-γ, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-γ ratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline.
MeSH Terms
- Adaptive Immunity
- Aging
- Animals
- Blood-Brain Barrier
- Brain
- Cell Proliferation
- Choroid Plexus
- Epithelium
- Hippocampus
- Immunologic Memory
- Lymphopenia
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neuroimmunomodulation
- Receptors, Interferon
- Th2 Cells
As mammals age, the rate of neurogenesis in the brain declines with a concomitant reduction in cognitive ability. Recent data suggest that plasma-borne factors are responsible for inhibition of neurogenesis. When the circulatory systems of old and young mice are connected, the old mice experience increased neurogenesis and the young mice exhibit less neurogenesis, suggesting the importance of systemic circulating factors. Chemokine CCL11/eotaxin has been identified as a factor that increases with aging. Injections of CCL11 inhibit neurogenesis in young mice, an effect likely mediated by CCR3 receptors on neural stem cells. Identification of a specific factor that plays a causative role in stem cell dysfunction in aging is consistent with data showing that transforming growth factor-β (TGF-β) inhibits satellite cell-mediated repair. Together, these data suggest that the systemic milieu plays a critical role in the aging of adult stem cells. Because adult stem cells help maintain homeostasis by providing the possibility of replacing metabolically damaged differentiated cells, aging of the systemic milieu and stem cell niches may drive functional decline during aging. The identification of a specific systemic change suggests that aging is more amenable to therapeutic modulation than work on global metabolism-derived damage and cellular senescence implies.
MeSH Terms
- Aging
- Animals
- Brain
- Cellular Senescence
- Chemokine CCL11
- Cognition
- Immune System
- Memory
- Mice
- Neural Stem Cells
- Neurogenesis
- Receptors, CCR3
- Stem Cells
- Transforming Growth Factor beta
To explore the molecular mechanisms by which the C-C chemokine receptor type 3 (CCR3) and chemokine (C-C motif) ligand 11 (CCL11) regulate choroidal endothelial cell (CEC) migration and the interactions with the vascular endothelial growth factor (VEGF) signaling pathway. Human retinal sections from young and aged donor normal eyes were immunolabeled. By real-time PCR, CCR3 mRNA was measured in retinal pigmented epithelium (RPE)/choroids obtained from young and aged human donor eyes and in cultured CECs exposed to hydrogen peroxide. CCR3 ligand and CCL11- or VEGF-stimulated CEC migration was also measured in the presence of the CCR3 inhibitor or control using fluorescence microscopy. Activation of Rac1, phosphorylated Akt as a readout for phosphoinositol 3-kinase signaling, and VEGFR2 activation were measured in CECs incubated with CCL11, VEGF, or combined CCL11/VEGF. CCR3 was expressed to a greater level in older compared with that in younger human retinas or RPE/choroids. Ligand-activated CCR3 increased CEC migration, which was inhibited by the CCR3 inhibitor. Rac1 activity, p-Akt, and p-VEGFR2 were significantly increased in CECs incubated with CCL11. The CCR3 inhibitor prevented VEGF-induced CEC migration and Rac1 activation in CECs. Rac1 activity was additively increased in CECs treated with CCL11 and VEGF compared with that in cells with CCL11 or VEGF treatment alone. Ligand-activated CCR3 caused VEGFR2 phosphorylation and coimmunoprecipitation of VEGFR2 and CCR3. Activated CCR3 promotes CEC migration and Rac1 activation and causes an association with and activation of VEGFR2. Cross-talk between CCR3 and VEGF signaling exists and may be important in choroidal neovascularization in human age-related macular degeneration.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cell Movement
- Cells, Cultured
- Chemokine CCL11
- Choroid
- Choroid Neoplasms
- Endothelial Cells
- Humans
- Macular Degeneration
- Receptor Cross-Talk
- Receptors, CCR3
- Retinal Pigment Epithelium
- Signal Transduction
- Stress, Physiological
- Up-Regulation
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factor Receptor-2
- Young Adult
- rac1 GTP-Binding Protein
In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.
MeSH Terms
- Aging
- Animals
- Chemokine CCL11
- Chemokines
- Female
- Learning
- Learning Disabilities
- Male
- Memory Disorders
- Mice
- Mice, Inbred C57BL
- Neurogenesis
- Parabiosis
- Plasma
- Time Factors