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INTRODUCTION: Age-related blood-brain barrier (BBB) disruption, cerebromicrovascular senescence, and microvascular rarefaction substantially contribute to the pathogenesis of vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Previous studies established a causal link between age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), cerebromicrovascular dysfunction, and cognitive decline. The aim of our study was to determine the effect of IGF-1 signaling on senescence, BBB permeability, and vascular density in middle-age and old brains. METHODS: Accelerated endothelial senescence was assessed in senescence reporter mice (VE-Cadherin-CreERT2 /Igf1rfl/fl × p16-3MR) using flow cytometry. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, BBB integrity and capillary density were studied in mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2 /Igf1rfl/fl ) using intravital two-photon microscopy. RESULTS: In VE-Cadherin-CreERT2 /Igf1rfl/fl mice: (1) there was an increased presence of senescent endothelial cells; (2) cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3-40 kDa) is significantly increased, as compared to that of control mice, whereas decline in cortical capillary density does not reach statistical significance. CONCLUSIONS: These findings support the notion that IGF-1 signaling plays a crucial role in preserving a youthful cerebromicrovascular endothelial phenotype and maintaining the integrity of the BBB.
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Barreira Hematoencefálica , Fator de Crescimento Insulin-Like I , Animais , Camundongos , Barreira Hematoencefálica/patologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Peptídeos Semelhantes à Insulina , Células Endoteliais/metabolismo , Envelhecimento/patologia , Encéfalo/irrigação sanguínea , Fenótipo , Endotélio , Senescência CelularRESUMO
INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.
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Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a-i. The neuroprotective properties of nitrones, 9a-i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, 9a-i, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN) and are similar to N-acetyl-L-cysteine (NAC), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones 9f, g, B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones 9a, c). All of these possess EC50 values in the range of 1-6 µM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone 9b, B = thymine) or hard halogen substituents such as Br and Cl (nitrones 9d, e, B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (9a). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (EC50's ≈ 2-4 µM) and antioxidant (EC50's ≈ 0.4-3.5 µM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, 9c, f, g, presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at 9a and 9d (bis-nitronas 9g, i) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (9f, g) and pyrimidine (9a, c) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.
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Neuroblastoma , Fármacos Neuroprotetores , Antioxidantes/farmacologia , Humanos , Isquemia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxidos de Nitrogênio/farmacologia , Óxidos de Nitrogênio/uso terapêutico , Reperfusão , Superóxidos , UracilaRESUMO
Glioblastoma is an aggressive brain tumour found in adults, and the therapeutic approaches available have not significantly increased patient survival. Recently, we discovered that ELTD1, an angiogenic biomarker, is highly expressed in human gliomas. Polyclonal anti-ELTD1 treatments were effective in glioma pre-clinical models, however, pAb binding is potentially promiscuous. Therefore, the aim of this study was to determine the effects of an optimized monoclonal anti-ELTD1 treatment in G55 xenograft glioma models. MRI was used to assess the effects of the treatments on animal survival, tumour volumes, perfusion rates and binding specificity. Immunohistochemistry and histology were conducted to confirm and characterize microvessel density and Notch1 levels, and to locate the molecular probes. RNA-sequencing was used to analyse the effects of the mAb treatment. Our monoclonal anti-ELTD1 treatment significantly increased animal survival, reduced tumour volumes, normalized the vasculature and showed higher binding specificity within the tumour compared with both control- and polyclonal-treated mice. Notch1 positivity staining and RNA-seq results suggested that ELTD1 has the ability to interact with and interrupt Notch1 signalling. Although little is known about ELTD1, particularly about its ligand and pathways, our data suggest that our monoclonal anti-ELTD1 antibody is a promising anti-angiogenic therapeutic in glioblastomas.
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Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Receptores Acoplados a Proteínas G/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Galinhas , Glioblastoma/patologia , Humanos , Camundongos , Microvasos/efeitos dos fármacos , Microvasos/patologia , Receptores Notch/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem cancer in childhood. This rapidly progressing brainstem glioma holds a very dismal prognosis with median survival of less than 1 year. Despite extensive research, no significant therapeutic advancements have been made to improve overall survival in DIPG patients. METHODS: Here, we used an orthotopic xenograft pediatric DIPG (HSJD-DIPG-007) mouse model to monitor the effects of anti-cancer agent, OKlahoma Nitrone-007 (OKN-007), as an inhibitor of tumor growth after 28 days of treatment. Using magnetic resonance imaging (MRI), we confirmed the previously described efficacy of LDN-193189, a known activin A receptor, type I (ACVR1) inhibitor, in decreasing tumor burden and found that OKN-007 was equally efficacious. RESULTS: After 28 days of treatment, the tumor volumes were significantly decreased in OKN-007 treated mice (p < 0.01). The apparent diffusion coefficient (ADC), as a measure of tissue structural alterations, was significantly decreased in OKN-007 treated tumor-bearing mice (p < 0.0001). Histological analysis also showed a significant decrease in CD34 expression, essential for angiogenesis, of OKN-007 treated mice (p < 0.05) compared to LDN-193189 treated mice. OKN-007-treated mice also significantly decreased protein expression of the human nuclear antigen (HNA) (p < 0.001), ACVR1 (p < 0.0001), and c-MET (p < 0.05), as well as significantly increased expression of cleaved caspase 3 (p < 0.001) and histone H3 K27-trimethylation (p < 0.01), compared to untreated mouse tumors. CONCLUSIONS: With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies, and OKN-007 merits further exploration as a therapeutic agent.
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Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Animais , Neoplasias do Tronco Encefálico/tratamento farmacológico , Criança , Glioma/tratamento farmacológico , Humanos , Camundongos , Óxidos de Nitrogênio , OklahomaRESUMO
A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC50 (50% effective concentration) = 27.6-91.5 µM]. Compound 16b exhibited the highest activity against a thymidine kinase-deficient (TK-) VZV strain (EC50 = 27.59 µM), while 16d was the most potent towards TK⺠VZV (EC50 = 29.91 µM). Cytostatic properties of the compounds 14a-i-17a-i were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC50 (50% inhibitory concentration) = 29-130 µM] and L1210 cells [IC50 (50% inhibitory concentration) = 14-142 µM].
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Herpesvirus Humano 3/efeitos dos fármacos , Naftalimidas/química , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Adenina , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citostáticos/síntese química , Citostáticos/química , Citostáticos/farmacologia , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Organofosfonatos/químicaRESUMO
High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.
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Diabetes Mellitus Tipo 2 , Resiliência Psicológica , Animais , Camundongos , Fator 2 Relacionado a NF-E2/genética , Dieta Hiperlipídica/efeitos adversos , Diabetes Mellitus Tipo 2/etiologia , Senescência Celular , Envelhecimento , Obesidade/etiologia , BiomarcadoresRESUMO
Whole brain irradiation (WBI), also known as whole brain radiation therapy (WBRT), is a well-established treatment for multiple brain metastases and as a preventive measure to reduce the risk of recurrence after surgical removal of a cerebral metastasis. However, WBI has been found to lead to a gradual decline in neurocognitive function in approximately 50% of patients who survive the treatment, significantly impacting their overall quality of life. Recent preclinical investigations have shed light on the underlying mechanisms of this adverse effect, revealing a complex cerebrovascular injury that involves the induction of cellular senescence in various components of the neurovascular unit, including endothelial cells. The emergence of cellular senescence following WBI has been implicated in the disruption of the blood-brain barrier and impairment of neurovascular coupling responses following irradiation. Building upon these findings, the present study aims to test the hypothesis that WBI-induced endothelial injury promotes endothelial dysfunction, which mimics the aging phenotype. To investigate this hypothesis, we employed a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks) on young mice. Both the WBI-treated and control mice were fitted with a cranial window, enabling the assessment of microvascular endothelial function. In order to evaluate the endothelium-dependent, NO-mediated cerebral blood flow (CBF) responses, we topically administered acetylcholine and ATP, and measured the resulting changes using laser Doppler flowmetry. We found that the increases in regional CBF induced by acetylcholine and ATP were significantly diminished in mice subjected to WBI. These findings provide additional preclinical evidence supporting the notion that WBI induces dysfunction in cerebrovascular endothelial cells, which in turn likely contributes to the detrimental long-term effects of the treatment. This endothelial dysfunction resembles an accelerated aging phenotype in the cerebrovascular system and is likely causally linked to the development of cognitive impairment. By integrating these findings with our previous results, we have deepened our understanding of the lasting consequences of WBI. Moreover, our study underscores the critical role of cerebromicrovascular health in safeguarding cognitive function over the long term. This enhanced understanding highlights the importance of prioritizing cerebromicrovascular health in the context of preserving cognitive abilities.
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Acetilcolina , Células Endoteliais , Humanos , Animais , Camundongos , Qualidade de Vida , Encéfalo , Trifosfato de AdenosinaRESUMO
Hair graying, also known as canities or achromotrichia, is a natural phenomenon associated with aging and is influenced by external factors such as stress, environmental toxicants, and radiation exposure. Understanding the mechanisms underlying hair graying is an ideal approach for developing interventions to prevent or reverse age-related changes in regenerative tissues. Hair graying induced by ionizing radiation (γ-rays or X-rays) has emerged as a valuable experimental model to investigate the molecular pathways involved in this process. In this review, we examine the existing evidence on radiation-induced hair graying, with a particular focus on the potential role of radiation-induced cellular senescence. We explore the current understanding of hair graying in aging, delve into the underlying mechanisms, and highlight the unique advantages of using ionizing-irradiation-induced hair graying as a research model. By elucidating the molecular pathways involved, we aim to deepen our understanding of hair graying and potentially identify novel therapeutic targets to address this age-related phenotypic change.
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Senescência Celular , Cor de Cabelo , Camundongos , Animais , Estresse Oxidativo , Cabelo , Modelos Teóricos , Dano ao DNARESUMO
Emerging evidence from both clinical and preclinical studies underscores the role of aging in potentiating the detrimental effects of hypertension on cerebral microhemorrhages (CMHs, or cerebral microbleeds). CMHs progressively impair neuronal function and contribute to the development of vascular cognitive impairment and dementia. There is growing evidence showing accumulation of senescent cells within the cerebral microvasculature during aging, which detrimentally affects cerebromicrovascular function and overall brain health. We postulated that this build-up of senescent cells renders the aged cerebral microvasculature more vulnerable, and consequently, more susceptible to CMHs. To investigate the role of cellular senescence in CMHs' pathogenesis, we subjected aged mice, both with and without pre-treatment with the senolytic agent ABT263/Navitoclax, and young control mice to hypertension via angiotensin-II and L-NAME administration. The aged cohort exhibited a markedly earlier onset, heightened incidence, and exacerbated neurological consequences of CMHs compared to their younger counterparts. This was evidenced through neurological examinations, gait analysis, and histological assessments of CMHs in brain sections. Notably, the senolytic pre-treatment wielded considerable cerebromicrovascular protection, effectively delaying the onset, mitigating the incidence, and diminishing the severity of CMHs. These findings hint at the potential of senolytic interventions as a viable therapeutic avenue to preempt or alleviate the consequences of CMHs linked to aging, by counteracting the deleterious effects of senescence on brain microvasculature.
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Compostos de Anilina , Hipertensão , Senoterapia , Sulfonamidas , Humanos , Camundongos , Animais , Idoso , Envelhecimento/patologia , Senescência CelularRESUMO
Cerebral microhemorrhages (CMHs) are of paramount importance as they not only signify underlying vascular pathology but also have profound implications for cognitive function and neurological health, serving as a critical indicator for the early detection and management of vascular cognitive impairment (VCI). This study aimed to investigate the effects of hypertension-induced CMHs on gait dynamics in a mouse model, focusing on the utility of advanced gait metrics as sensitive indicators of subclinical neurological alterations associated with CMHs. To induce CMHs, we employed a hypertensive mouse model, using a combination of Angiotensin II and L-NAME to elevate blood pressure, further supplemented with phenylephrine to mimic transient blood pressure fluctuations. Gait dynamics were analyzed using the CatWalk system, with emphasis on symmetry indices for Stride Length (SL), Stride Time (ST), and paw print area, as well as measures of gait entropy and regularity. The study spanned a 30-day experimental period, capturing day-to-day variations in gait parameters to assess the impact of CMHs. Temporary surges in gait asymmetry, detected as deviations from median gait metrics, suggested the occurrence of subclinical neurological signs associated with approximately 50% of all histologically verified CMHs. Our findings also demonstrated that increases in gait entropy correlated with periods of increased gait asymmetry, providing insights into the complexity of gait dynamics in response to CMHs. Significant correlations were found between SL and ST symmetry indices and between these indices and the paw print area symmetry index post-hypertension induction, indicating the interdependence of spatial and temporal aspects of gait affected by CMHs. Collectively, advanced gait metrics revealed sensitive, dynamic alterations in gait regulation associated with CMHs, resembling the temporal characteristics of transient ischemic attacks (TIAs). This underscores their potential as non-invasive indicators of subclinical neurological impacts. This study supports the use of detailed gait analysis as a valuable tool for detecting subtle neurological changes, with implications for the early diagnosis and monitoring of cerebral small vessel disease (CSVD) in clinical settings.
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Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.
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Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.
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Age-related impairment of neurovascular coupling (NVC; "functional hyperemia") is a critical factor in the development of vascular cognitive impairment (VCI). Recent geroscience research indicates that cell-autonomous mechanisms alone cannot explain all aspects of neurovascular aging. Circulating factors derived from other organs, including pro-geronic factors (increased with age and detrimental to vascular homeostasis) and anti-geronic factors (preventing cellular aging phenotypes and declining with age), are thought to orchestrate cellular aging processes. This study aimed to investigate the influence of age-related changes in circulating factors on neurovascular aging. Heterochronic parabiosis was utilized to assess how exposure to young or old systemic environments could modulate neurovascular aging. Results demonstrated a significant decline in NVC responses in aged mice subjected to isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis) when compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, exposure to young blood from parabionts significantly improved NVC in aged heterochronic parabionts [A-(Y)]. Conversely, young mice exposed to old blood from aged parabionts exhibited impaired NVC responses [Y-(A)]. In conclusion, even a brief exposure to a youthful humoral environment can mitigate neurovascular aging phenotypes, rejuvenating NVC responses. Conversely, short-term exposure to an aged humoral milieu in young mice accelerates the acquisition of neurovascular aging traits. These findings highlight the plasticity of neurovascular aging and suggest the presence of circulating anti-geronic factors capable of rejuvenating the aging cerebral microcirculation. Further research is needed to explore whether young blood factors can extend their rejuvenating effects to address other age-related cerebromicrovascular pathologies, such as blood-brain barrier integrity.
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Acoplamento Neurovascular , Camundongos , Animais , Acoplamento Neurovascular/fisiologia , Rejuvenescimento , Camundongos Endogâmicos C57BL , Envelhecimento/fisiologia , ParabioseRESUMO
Intra-vital visualization of deep cerebrovascular structures and blood flow in the aging brain has been a difficult challenge in the field of neurovascular research, especially when considering the key role played by the cerebrovasculature in the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Traditional imaging methods face difficulties with the thicker skull of older brains, making high-resolution imaging and cerebral blood flow (CBF) assessment challenging. However, functional ultrasound (fUS) imaging, an emerging non-invasive technique, provides real-time CBF insights with notable spatial-temporal resolution. This study introduces an enhanced longitudinal fUS method for aging brains. Using elderly (24-month C57BL/6) mice, we detail replacing the skull with a polymethylpentene window for consistent fUS imaging over extended periods. Ultrasound localization mapping (ULM), involving the injection of a microbubble (<<10 µm) suspension allows for recording of high-resolution microvascular vessels and flows. ULM relies on the localization and tracking of single circulating microbubbles in the blood flow. A FIJI-based analysis interprets these high-quality ULM visuals. Testing on older mouse brains, our method successfully unveils intricate vascular specifics even in-depth, showcasing its utility for longitudinal studies that require ongoing evaluations of CBF and vascular aspects in aging-focused research.
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Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood-brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID.
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Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer's disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.
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Disfunção Cognitiva , Demência Vascular , Humanos , Idoso , Fator de Crescimento Insulin-Like I/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Circulação Cerebrovascular/fisiologiaRESUMO
As aging societies in the western world face a growing prevalence of vascular cognitive impairment and Alzheimer's disease (AD), understanding their underlying causes and associated risk factors becomes increasingly critical. A salient concern in the western dietary context is the high consumption of methionine-rich foods such as red meat. The present review delves into the impact of this methionine-heavy diet and the resultant hyperhomocysteinemia on accelerated cerebrovascular and brain aging, emphasizing their potential roles in cognitive impairment. Through a comprehensive exploration of existing evidence, a link between high methionine intake and hyperhomocysteinemia and oxidative stress, mitochondrial dysfunction, inflammation, and accelerated epigenetic aging is drawn. Moreover, the microvascular determinants of cognitive deterioration, including endothelial dysfunction, reduced cerebral blood flow, microvascular rarefaction, impaired neurovascular coupling, and blood-brain barrier (BBB) disruption, are explored. The mechanisms by which excessive methionine consumption and hyperhomocysteinemia might drive cerebromicrovascular and brain aging processes are elucidated. By presenting an intricate understanding of the relationships among methionine-rich diets, hyperhomocysteinemia, cerebrovascular and brain aging, and cognitive impairment, avenues for future research and potential therapeutic interventions are suggested.
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Doença de Alzheimer , Disfunção Cognitiva , Hiper-Homocisteinemia , Humanos , Metionina , Hiper-Homocisteinemia/complicações , Encéfalo , Circulação Cerebrovascular , Dieta/efeitos adversos , Doença de Alzheimer/etiologiaRESUMO
Cerebral microhemorrhages (CMHs, microbleeds), a manifestation of age-related cerebral small vessel disease, contribute to the pathogenesis of cognitive decline and dementia in older adults. Histological studies have revealed that CMHs exhibit distinct morphologies, which may be attributed to differences in intravascular pressure and the size of the vessels of origin. Our study aimed to establish a direct relationship between the size/morphology of CMHs and the size/anatomy of the microvessel of origin. To achieve this goal, we adapted and optimized intravital two-photon microscopy-based imaging methods to monitor the development of CMHs in mice equipped with a chronic cranial window upon high-energy laser light-induced photodisruption of a targeted cortical arteriole, capillary, or venule. We assessed the time course of extravasation of fluorescently labeled blood and determined the morphology and size/volume of the induced CMHs. Our findings reveal striking similarities between the bleed morphologies observed in hypertension-induced CMHs in models of aging and those originating from different targeted vessels via multiphoton laser ablation. Arteriolar bleeds, which are larger (> 100 µm) and more widely dispersed, are distinguished from venular bleeds, which are smaller and exhibit a distinct diffuse morphology. Capillary bleeds are circular and smaller (< 10 µm) in size. Our study supports the concept that CMHs can occur at any location in the vascular tree, and that each type of vessel produces microbleeds with a distinct morphology. Development of CMHs resulted in immediate constriction of capillaries, likely due to pericyte activation and constriction of precapillary arterioles. Additionally, tissue displacement observed in association with arteriolar CMHs suggests that they can affect an area with a radius of ~ 50 µm to ~ 100 µm, creating an area at risk for ischemia. Longitudinal imaging of CMHs allowed us to visualize reactive astrocytosis and bleed resolution during a 30-day period. Our study provides new insights into the development and morphology of CMHs, highlighting the potential clinical implications of differentiating between the types of vessels involved in the pathogenesis of CMHs. This information may help in the development of targeted interventions aimed at reducing the risk of cerebral small vessel disease-related cognitive decline and dementia in older adults.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Demência , Camundongos , Animais , Arteríolas/diagnóstico por imagem , Vênulas , Capilares/diagnóstico por imagem , Microscopia , Hemorragia Cerebral/etiologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/complicações , Demência/complicaçõesRESUMO
The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age-related diseases affecting the cardiovascular system and central nervous system is discussed, with a specific focus on Alzheimer's disease, Parkinson's disease, stroke, small vessel disease, and vascular cognitive impairment (VCI). Aging is a major risk factor for these diseases. Their pathogenesis involves cellular and molecular mechanisms of aging such as increased oxidative stress, impaired mitochondrial function, DNA damage, and inflammation and is influenced by environmental factors. Environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, have been identified as significant contributors to cardiovascular and brain aging disorders. These toxicants can inflict both macro- and microvascular damage and many of them can also cross the blood-brain barrier, inducing neurotoxic effects, neuroinflammation, and neuronal dysfunction. In conclusion, environmental factors play a critical role in modulating cardiovascular and brain aging. A deeper understanding of how environmental toxicants exacerbate aging processes and contribute to the pathogenesis of neurodegenerative diseases, VCI, and dementia is crucial for the development of preventive strategies and interventions to promote cardiovascular, cerebrovascular, and brain health. By mitigating exposure to harmful environmental factors and promoting healthy aging, we can strive to reduce the burden of age-related cardiovascular and brain pathologies in the aging population.