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Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial firing stability. These genes were enriched among interneurons and related to synaptic transmission. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.
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During aging, microglia - the resident macrophages of the brain - exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFß1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an inflammatory state. Furthermore, we utilized single-cell RNA-Seq in conjunction with an in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse model, to demonstrate that microglia advancement through intermediate aging states drives inflammatory activation and associated hippocampal-dependent cognitive decline.
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Most reports agree that aging negatively impacts pain processing and that the prevalence of chronic pain increases significantly with age. To improve current therapies, it is critical that aged animals be included in preclinical studies. Here we compared sensitivities to pain and itch-provoking stimuli in naïve and injured young and aged mice. Surprisingly, we found that in the absence of injury, aged male and female mice are significantly less responsive to mechanical stimuli and, in females, also to noxious thermal (heat) stimuli. In both older male and female mice, compared to younger (6-month-old mice), we also recorded reduced pruritogen-evoked scratching. On the other hand, after nerve injury, aged mice nevertheless developed significant mechanical hypersensitivity. Interestingly, however, and in contrast to young mice, aged mice developed both ipsilateral and contralateral postinjury mechanical allodynia. In a parallel immunohistochemical analysis of microglial and astrocyte markers, we found that the ipsilateral to the contralateral ratio of nerve injury-induced expression decreased with age. That observation is consistent with our finding of contralateral hypersensitivity after nerve injury in the aged but not the young mice. We conclude that aging has opposite effects on baseline versus postinjury pain and itch processing. PERSPECTIVE: Aged male and female mice (22-24 months) are less sensitive to mechanical, thermal (heat), and itch-provoking stimuli than are younger mice (6 months).
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Dor , Prurido , Masculino , Feminino , Camundongos , Animais , Hiperalgesia/etiologiaRESUMO
Loss of cognitive function with age is devastating. EGL-30/GNAQ and Gαq signaling pathways are highly conserved between C. elegans and mammals, and murine Gnaq is enriched in hippocampal neurons and declines with age. We found that activation of EGL-30 in aged worms triples memory span, and GNAQ gain of function significantly improved memory in aged mice: GNAQ(gf) in hippocampal neurons of 24-month-old mice (equivalent to 70- to 80-year-old humans) rescued age-related impairments in well-being and memory. Single-nucleus RNA sequencing revealed increased expression of genes regulating synaptic function, axon guidance, and memory in GNAQ-treated mice, and worm orthologs of these genes were required for long-term memory extension in worms. These experiments demonstrate that C. elegans is a powerful model to identify mammalian regulators of memory, leading to the identification of a pathway that improves memory in extremely old mice. To our knowledge, this is the oldest age at which an intervention has improved age-related cognitive decline.
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Caenorhabditis elegans , Cognição , Humanos , Animais , Camundongos , Idoso , Pré-Escolar , Idoso de 80 Anos ou mais , Caenorhabditis elegans/metabolismo , Cognição/fisiologia , Transdução de Sinais/fisiologia , Neurônios/metabolismo , Memória/fisiologia , Proteínas de Ligação ao GTP/metabolismo , Hipocampo/metabolismo , Envelhecimento/metabolismo , Mamíferos/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismoRESUMO
Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.
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Envelhecimento , Cognição , Disfunção Cognitiva , Doenças Neuroinflamatórias , Nootrópicos , Fator Plaquetário 4 , Animais , Masculino , Camundongos , Envelhecimento/sangue , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/complicações , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/prevenção & controle , Fator Plaquetário 4/sangue , Fator Plaquetário 4/metabolismo , Fator Plaquetário 4/farmacologia , Fator Plaquetário 4/uso terapêutico , Nootrópicos/sangue , Nootrópicos/metabolismo , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Plasma/química , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Transcrição Gênica/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.
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Envelhecimento , Disfunção Cognitiva , Neurogênese , Fator Plaquetário 4 , Animais , Camundongos , Plaquetas , Cognição , Hipocampo , Fatores ImunológicosRESUMO
Platelet factors regulate wound healing and can signal from the blood to the brain1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.
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Envelhecimento , Longevidade , Animais , Camundongos , Fatores de Coagulação Sanguínea , Cognição , Fator Plaquetário 4RESUMO
Introduction: Alzheimer's disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood. Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls. Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation. Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.
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Aging induces molecular, cellular and functional changes in the adult brain that drive cognitive decline and increase vulnerability to dementia-related neurodegenerative diseases. Leveraging systemic and lifestyle interventions, such as heterochronic parabiosis, administration of 'young blood', exercise and caloric restriction, has challenged prevalent views of brain aging as a rigid process and has demonstrated that aging-associated cognitive and cellular impairments can be restored to more youthful levels. Technological advances in proteomic and transcriptomic analyses have further facilitated investigations into the functional impact of intertissue communication on brain aging and have led to the identification of a growing number of pro-aging and pro-youthful factors in blood. In this review, we discuss blood-to-brain communication from a systems physiology perspective with an emphasis on blood-derived signals as potent drivers of both age-related brain dysfunction and brain rejuvenation.
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Proteômica , Rejuvenescimento , Rejuvenescimento/fisiologia , Encéfalo , CabeçaRESUMO
DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.
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Dioxigenases , Proteínas Proto-Oncogênicas , Animais , Camundongos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a DNA/metabolismo , 5-Metilcitosina/metabolismo , Dioxigenases/genética , Metilação de DNA/genética , Cognição , Neurônios/metabolismo , Hipocampo/metabolismoRESUMO
Parvalbumin-positive (PV+) interneurons play a critical role in maintaining circuit rhythm in the brain, and their reduction is implicated in autism spectrum disorders. Animal studies demonstrate that maternal immune activation (MIA) leads to reduced PV+ interneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown. Here, we show that MIA down-regulates microglial Gpr56 expression in fetal brains in an interleukin-17a-dependent manner and that conditional deletion of microglial Gpr56 [Gpr56 conditional knockout (cKO)] mimics MIA-induced PV+ interneuron defects and autism-like behaviors in offspring. We further demonstrate that elevated microglial tumor necrosis factor-α expression is the underlying mechanism by which MIA and Gpr56 cKO impair interneuron generation. Genetically restoring Gpr56 expression in microglia ameliorates PV+ interneuron deficits and autism-like behaviors in MIA offspring. Together, our study demonstrates that microglial GPR56 plays an important role in PV+ interneuron development and serves as a salient target of MIA-induced neurodevelopmental disorders.
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Transtorno do Espectro Autista , Transtorno Autístico , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Modelos Animais de Doenças , Interneurônios/metabolismo , Microglia/metabolismo , Parvalbuminas/metabolismoRESUMO
Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.
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Antígenos de Histocompatibilidade Classe I/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Envelhecimento/metabolismo , Animais , Ciclo Celular , Proliferação de Células , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , NeurogêneseRESUMO
While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.
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Envelhecimento/fisiologia , Células-Tronco Hematopoéticas/citologia , Rejuvenescimento/fisiologia , Animais , Medula Óssea/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/genéticaRESUMO
The aged systemic milieu promotes cellular and cognitive impairments in the hippocampus. Here, we report that aging of the hematopoietic system directly contributes to the pro-aging effects of old blood on cognition. Using a heterochronic hematopoietic stem cell (HSC) transplantation model (in which the blood of young mice is reconstituted with old HSCs), we find that exposure to an old hematopoietic system inhibits hippocampal neurogenesis, decreases synaptic marker expression, and impairs cognition. We identify a number of factors elevated in the blood of young mice reconstituted with old HSCs, of which cyclophilin A (CyPA) acts as a pro-aging factor. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Together, these data identify age-related changes in the hematopoietic system as drivers of hippocampal aging.
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Envelhecimento , Disfunção Cognitiva , Células-Tronco Hematopoéticas , Hipocampo , Animais , Masculino , Camundongos , Envelhecimento/patologia , Disfunção Cognitiva/fisiopatologia , Células-Tronco Hematopoéticas/patologia , Hipocampo/fisiopatologiaRESUMO
Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked ß-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.
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Envelhecimento/fisiologia , Diferenciação Celular/fisiologia , Glucosamina/análogos & derivados , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Fator de Transcrição STAT3/metabolismo , Animais , Proliferação de Células , Biologia Computacional , Regulação da Expressão Gênica , Glucosamina/metabolismo , Hipocampo/citologia , Camundongos , Neurogênese , Fator de Transcrição STAT3/genética , Análise de Sequência de RNARESUMO
Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation. Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.
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Tecido Adiposo/fisiologia , Eosinófilos/fisiologia , Imunidade , Inflamação/patologia , Aptidão Física/fisiologia , Tecido Adiposo/patologia , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiologia , Adulto , Idoso , Envelhecimento , Animais , Eosinófilos/imunologia , Eosinófilos/patologia , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Homeostase , Humanos , Interleucina-4/imunologia , Interleucina-4/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Força Muscular , Células Satélites de Músculo Esquelético/metabolismo , Adulto JovemRESUMO
Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.
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Envelhecimento/sangue , Encéfalo/fisiologia , Cognição/fisiologia , Fígado/enzimologia , Neurogênese , Fosfolipase D/sangue , Condicionamento Físico Animal , Animais , Circulação Sanguínea , Encéfalo/irrigação sanguínea , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Glicosilfosfatidilinositóis/metabolismo , Camundongos , Fosfolipase D/metabolismo , Regeneração , Transdução de SinaisRESUMO
Remyelination declines in the aging central nervous system due to oligodendrocyte precursor cell (OPC) dysfunction. In the latest issue of Cell Stem Cell, Neumann et al. (2019) demonstrate that aged OPCs are amenable to functional rejuvenation by systemic interventions involving alternate-day fasting or treatment with the fasting mimetic metformin.