Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.

INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

Exploring the Influence of Gut-Brain Axis Modulation on Cognitive Health: A Comprehensive Review of Prebiotics, Probiotics, and Symbiotics.

Recent research exploring the relationship between the gut and the brain suggests that the condition of the gut microbiota can influence cognitive health. A well-balanced gut microbiota may help reduce inflammation, which is linked to neurodegenerative conditions. Prebiotics, probiotics, and symbiotics are nutritional supplements and functional food components associated with gastrointestinal well-being. The bidirectional communication of the gut-brain axis is essential for maintaining homeostasis, with pre-, pro-, and symbiotics potentially affecting various cognitive functions such as attention, perception, and memory. Numerous studies have consistently shown that incorporating pre-, pro-, and symbiotics into a healthy diet can lead to improvements in cognitive functions and mood. Maintaining a healthy gut microbiota can support optimal cognitive function, which is crucial for disease prevention in our fast-paced, Westernized society. Our results indicate cognitive benefits in healthy older individuals with probiotic supplementation but not in healthy older individuals who have good and adequate levels of physical activity. Additionally, it appears that there are cognitive benefits in patients with mild cognitive impairment and Alzheimer's disease, while mixed results seem to arise in younger and healthier individuals. However, it is important to acknowledge that individual responses may vary, and the use of these dietary supplements should be tailored to each individual's unique health circumstances and needs.

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging.

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

Impaired Neurovascular Coupling and Increased Functional Connectivity in the Frontal Cortex Predict Age-Related Cognitive Dysfunction.

Impaired cerebrovascular function contributes to the genesis of age-related cognitive decline. In this study, the hypothesis is tested that impairments in neurovascular coupling (NVC) responses and brain network function predict cognitive dysfunction in older adults. Cerebromicrovascular and working memory function of healthy young (n = 21, 33.2±7.0 years) and aged (n = 30, 75.9±6.9 years) participants are assessed. To determine NVC responses and functional connectivity (FC) during a working memory (n-back) paradigm, oxy- and deoxyhemoglobin concentration changes from the frontal cortex using functional near-infrared spectroscopy are recorded. NVC responses are significantly impaired during the 2-back task in aged participants, while the frontal networks are characterized by higher local and global connection strength, and dynamic FC (p < 0.05). Both impaired NVC and increased FC correlate with age-related decline in accuracy during the 2-back task. These findings suggest that task-related brain states in older adults require stronger functional connections to compensate for the attenuated NVC responses associated with working memory load.

Improving Cognitive Function with Nutritional Supplements in Aging: A Comprehensive Narrative Review of Clinical Studies Investigating the Effects of Vitamins, Minerals, Antioxidants, and Other Dietary Supplements.

Cognitive impairment and dementia are burgeoning public health concerns, especially given the increasing longevity of the global population. These conditions not only affect the quality of life of individuals and their families, but also pose significant economic burdens on healthcare systems. In this context, our comprehensive narrative review critically examines the role of nutritional supplements in mitigating cognitive decline. Amidst growing interest in non-pharmacological interventions for cognitive enhancement, this review delves into the efficacy of vitamins, minerals, antioxidants, and other dietary supplements. Through a systematic evaluation of randomized controlled trials, observational studies, and meta-analysis, this review focuses on outcomes such as memory enhancement, attention improvement, executive function support, and neuroprotection. The findings suggest a complex interplay between nutritional supplementation and cognitive health, with some supplements showing promising results and others displaying limited or context-dependent effectiveness. The review highlights the importance of dosage, bioavailability, and individual differences in response to supplementation. Additionally, it addresses safety concerns and potential interactions with conventional treatments. By providing a clear overview of current scientific knowledge, this review aims to guide healthcare professionals and researchers in making informed decisions about the use of nutritional supplements for cognitive health.

The Possible Role of Food and Diet in the Quality of Life in Patients with COPD-A State-of-the-Art Review.

Diet has been described as a modifiable risk factor for the development and progression of chronic diseases, and emerging evidence increasingly points to its preventive and therapeutic role in chronic obstructive pulmonary disease (COPD). While the relationship between the underlying disease and diet is natural in conditions such as metabolic disorders, obesity, diabetes, etc., the direct effect is not so evident in chronic obstructive pulmonary disease. Poor diet quality and the development of nutrient deficiencies in respiratory diseases, including COPD, can be associated with disease-specific factors such as the exacerbation of respiratory symptoms. These symptoms can be improved by dietary interventions, leading to positive changes in the pathogenesis of the disease and the quality of life of patients. Therefore, our aim was to review the latest randomized controlled trials (RCTs) of dietary interventions in chronic respiratory patients and describe their effects on respiratory function, physical activity, systemic inflammatory parameters, and quality of life. We conducted a literature search on dietary interventions for COPD patients in the PubMed, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, focusing on publications from 1 July 2018 to 1 July 2023. We used specific keywords and MESH terms, focusing on RCTs. A total of 26 articles and 1811 COPD patients were included in this review. On the basis of our findings, dietary interventions, in particular components of the Mediterranean diet such as protein, omega-3 polyunsaturated fatty acids, and vegetables, appear to have beneficial effects in patients with chronic respiratory diseases, and their application is beneficial. However, long-term follow-up studies are still needed to examine the effects of dietary interventions in this patient population.

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression.

Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

The Effectiveness of Supplementation with Key Vitamins, Minerals, Antioxidants and Specific Nutritional Supplements in COPD-A Review.

Currently, an increasing amount of evidence supports the notion that vitamins C, D and E, carotenoids, and omega-3 fatty acids may protect against the progression of chronic respiratory diseases. Although chronic obstructive pulmonary disease (COPD) primarily affects the lung, it is often accompanied by extrapulmonary manifestations such as weight loss and malnutrition, skeletal muscle dysfunction, and an excess of harmful oxidants, which can lead to a decline in quality of life and possible death. Recently, the role of various vitamins, minerals, and antioxidants in mitigating the effects of environmental pollution and smoking has received significant attention. Therefore, this review evaluates the most relevant and up-to-date evidence on this topic. We conducted a literature review between 15 May 2018 and 15 May 2023, using the electronic database PubMed. Our search keywords included COPD, chronic obstructive pulmonary disease, FEV1, supplementation: vitamin A, vitamin D, vitamin E, vitamin C, vitamin B, omega-3, minerals, antioxidants, specific nutrient supplementations, clinical trials, and randomized controlled trials (RCTs). We focused on studies that measured the serum levels of vitamins, as these are a more objective measure than patient self-reports. Our findings suggest that the role of appropriate dietary supplements needs to be reconsidered for individuals who are predisposed to or at risk of these conditions.

Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain.

Chemotherapy-induced cognitive impairment ("chemobrain") is a frequent side-effect in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for PTX-induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that PTX induces endothelial senescence, which impairs microvascular function and contributes to the genesis of cognitive decline. We treated transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle). PTX-treated and control mice were tested for spatial memory performance, neurovascular coupling (NVC) responses (whisker-stimulation-induced increases in cerebral blood flow), microvascular density, blood-brain barrier (BBB) permeability and the presence of senescent endothelial cells (by flow cytometry and single-cell transcriptomics) at 6 months post-treatment. PTX induced senescence in endothelial cells, which associated with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation, and impaired performance on cognitive tasks. To establish a causal relationship between PTX-induced senescence and impaired microvascular functions, senescent cells were depleted from PTX-treated animals (at 3 months post-treatment) by genetic (ganciclovir) or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In PTX treated mice, both treatments effectively eliminated senescent endothelial cells, rescued endothelium-mediated NVC responses and BBB integrity, increased capillarization and improved cognitive performance. Our findings suggest that senolytic treatments can be a promising strategy for preventing chemotherapy-induced cognitive impairment.

Accelerated ageing and coronary microvascular dysfunction in chronic heart failure in Tgαq*44 mice.

Age represents a major risk factor in heart failure (HF). However, the mechanisms linking ageing and HF are not clear. We aimed to identify the functional, morphological and transcriptomic changes that could be attributed to cardiac ageing in a model of slowly progressing HF in Tgαq*44 mice in reference to the cardiac ageing process in FVB mice. In FVB mice, ageing resulted in the impairment of diastolic cardiac function and in basal coronary flow (CF), perivascular and interstitial fibrosis without changes in the cardiac activity of angiotensin-converting enzyme (ACE) or aldosterone plasma concentration. In Tgαq*44 mice, HF progression was featured by the impairment of systolic and diastolic cardiac function and in basal CF that was associated with a distinct rearrangement of the capillary architecture, pronounced perivascular and interstitial fibrosis, progressive activation of cardiac ACE and systemic angiotensin-aldosterone-dependent pathways. Interestingly, cardiac ageing genes and processes were represented in Tgαq*44 mice not only in late but also in early phases of HF, as evidenced by cardiac transcriptome analysis. Thirty-four genes and 8 biological processes, identified as being ageing related, occurred early and persisted along HF progression in Tgαq*44 mice and were mostly associated with extracellular matrix remodelling and fibrosis compatible with perivascular fibrosis resulting in coronary microvascular dysfunction (CMD) in Tgαq*44 mice. In conclusion, accelerated and persistent cardiac ageing contributes to the pathophysiology of chronic HF in Tgαq*44 mice. In particular, prominent perivascular fibrosis of microcirculation resulting in CMD represents an accelerated cardiac ageing phenotype that requires targeted treatment in chronic HF.

Gait variability predicts cognitive impairment in older adults with subclinical cerebral small vessel disease.

Introduction: Advanced methods of gait research, including approaches to quantify variability, and orderliness/regularity/predictability, are increasingly used to identify patients at risk for the development of cognitive impairment. Cerebral small vessel disease (CSVD) is highly prevalent in older adults and is known to contribute to the development of vascular cognitive impairment and dementia (VCID). Studies in preclinical models demonstrate that subclinical alterations precede CSVD-related cognitive impairment in gait coordination. In humans, CSVD also associates with gait abnormalities. The present study was designed to test the hypothesis that increased gait variability and gait asymmetry predict a decline in cognitive performance in older adults with CSVD. Methods: To test this hypothesis, we compared cognitive performance and gait function in patients with CSVD (age: 69.8 ± 5.3 years; n = 11) and age- and sex-matched control participants (age: 70.7 ± 5.8 years; n = 11). Based on imaging findings, patients with CSVD were identified [presence of white matter hyperintensities plus silent brain infarcts and/or microhemorrhages on magnetic resonance imaging (MRI) assessment]. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Gait parameters were measured during the single and dual tasks, during which participants, in addition to the motor task, completed a series of mental arithmetic calculations. Spatial and temporal parameters of gait variability, symmetry, and permutation entropy were determined using a pressure-sensitive gait mat during single and dual cognitive task conditions. Results: Patients with CSVD exhibited lower performance in a visual learning test (p = 0.030) and in a sustained attention test (p = 0.007). CSVD also affected step time variability (p = 0.009) and step length variability (p = 0.017). Step lengths of CSVD participants were more asymmetric (p = 0.043) than that of controls, while the two groups were statistically similar regarding step time symmetry and entropy of step time and length. Gait variability was inversely associated with sustained attention, especially among CSVD patients, and this relationship was significantly different between the two groups. The association of sustained attention with gait symmetry was also significantly different between the two groups. Discussion: Our findings provide additional evidence in support of the concept that increased gait variability and asymmetry may predict cognitive impairment in older adults with CSVD.

Urinary Biomarkers of Oxidative Stress in Aging: Implications for Prediction of Accelerated Biological Age in Prospective Cohort Studies.

Background: Aging is a major risk factor for a range of chronic diseases. Oxidative stress theory of aging has been previously proposed as one of the mechanisms responsible for the age-related decline in organ/tissue function and the development of age-related diseases. Urine contains rich biological information on the health status of every major organ system and can be an important noninvasive source for biomarkers of systemic oxidative stress in aging. Aims: The objective of this cross-sectional study was to validate a novel panel of urinary oxidative stress biomarkers. Methods: Nucleic acid oxidation adducts and oxidative damage markers of lipids and proteins were assessed in urine samples from nondiabetic and currently nonsmoking subjects (n = 198) across different ages (20 to 89 years old). Urinary parameters and chronological age were correlated then the biological age of enrolled individuals was determined from the urinary oxidative stress markers using the algorithm of Klemera and Doubal. Results: Our findings showed that 8-oxo-7,8-deoxyguanosine (8-oxoG), 8-oxo-7,8-dihydroguanosine (8-OHdG), and dityrosine (DTyr) positively correlated with chronological age, while the level of an F2-isoprostane (iPF2 α-VI) correlated negatively with age. We found that 8-oxoG, DTyr, and iPF2 α-VI were significantly higher among accelerated agers compared to nonaccelerated agers and that a decision tree model could successfully identify accelerated agers with an accuracy of >92%. Discussion. Our results indicate that 8-oxoG and iPF2 α-VI levels in the urine reveal biological aging. Conclusion: Assessing urinary biomarkers of oxidative stress may be an important approach for the evaluation of biological age by identifying individuals at accelerated risk for the development of age-related diseases.

Comorbidities and increased mortality of COVID-19 among the elderly: A systematic review.

Purpose: The purpose of current review is to conduct a systematic overview of articles published between 2019 and 2021 on the relationship of comorbidities and mortality due to Coronavirus Disease 2019 (COVID-19) among the elderly population. Methods: We conducted a systematic search on PubMed for articles published between 2019 and 2021 to identify any cohort and case-control studies that investigated the relationship of comorbidities and COVID-19 mortality among the elderly, defined as 60 years of age and above. Databases were searched independently by two authors. Disagreements were resolved by the inclusion of a third investigator. Reviews, systematic reviews, and meta-analyses were excluded from our systematic review. Results: A total of 15 studies were selected for our systematic review. Of the included studies, 3 were case-control, 3 were prospective cohort studies and 9 were retrospective cohort studies. As for size, 10 studies were conducted on populations of <1000 participants, 3 ranging from 1001 to 10,000, and 2 on populations of >10,000 individuals. The included studies found that the presence of certain conditions, such as cardiovascular, respiratory, renal diseases, malignancies, diseases of the nervous system and diabetes are associated to increased mortality in populations that consisted of elderly patients. Conclusion: Results of our systematic review suggest that comorbidities contribute to increased COVID-19 mortality among the elderly. The detrimental effect of comorbidities and advanced age on the immune response could lead to a more frequent occurrence of symptomatic and severe infections with COVID-19.

Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease, increasing the risk of cognitive decline in older adults.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

Old blood from heterochronic parabionts accelerates vascular aging in young mice: transcriptomic signature of pathologic smooth muscle remodeling.

Vascular aging has a central role in the pathogenesis of cardiovascular diseases contributing to increased mortality of older adults. There is increasing evidence that, in addition to the documented role of cell-autonomous mechanisms of aging, cell-nonautonomous mechanisms also play a critical role in the regulation of vascular aging processes. Our recent transcriptomic studies (Kiss T. et al. Geroscience. 2020;42(2):727-748) demonstrated that circulating anti-geronic factors from young blood promote vascular rejuvenation in aged mice. The present study was designed to expand upon the results of this study by testing the hypothesis that circulating pro-geronic factors also contribute to the genesis of vascular aging phenotypes. To test this hypothesis, through heterochronic parabiosis, we determined the extent to which shifts in the vascular transcriptome (RNA-seq) are modulated by the old systemic environment. We reanalyzed existing RNA-seq data, comparing the transcriptome in the aorta arch samples isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] and young isochronic parabiont (6-month-old) mice [Y-(Y)] and also assessing transcriptomic changes in the aortic arch in young (6-month-old) parabiont mice [Y-(A); heterochronic parabiosis for 8 weeks] induced by the presence of old blood derived from aged (20-month-old) parabionts. We identified 528 concordant genes whose expression levels differed in the aged phenotype and were shifted towards the aged phenotype by the presence of old blood in young Y-(A) animals. Among them, the expression of 221 concordant genes was unaffected by the presence of young blood in A-(Y) mice. GO enrichment analysis suggests that old blood-regulated genes may contribute to pathologic vascular remodeling. IPA Upstream Regulator analysis (performed to identify upstream transcriptional regulators that may contribute to the observed transcriptomic changes) suggests that the mechanism of action of pro-geronic factors present in old blood may include inhibition of pathways mediated by SRF (serum response factor), insulin-like growth factor-1 (IGF-1) and VEGF-A. In conclusion, relatively short-term exposure to old blood can accelerate vascular aging processes. Our findings provide additional evidence supporting the significant plasticity of vascular aging and the existence of circulating pro-geronic factors mediating pathological remodeling of the vascular smooth muscle cells and the extracellular matrix.

A Central Role for TRPM4 in Ca2+-Signal Amplification and Vasoconstriction.

Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca2+ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca2+ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca2+ concentration, suggesting an inhibition of Ca2+ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca2+ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca2+-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca2+ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.

Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases.

BACKGROUND: An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development of the most important age-related diseases. OBJECTIVE: The aim of this review is to provide an overview of the relationship between nutrition and critical age-associated diseases. METHODS: A literature review was conducted to survey recent pre-clinical and clinical findings related to the role of nutritional factors in modulation of fundamental cellular and molecular mechanisms of aging and their role in prevention of the genesis of the diseases of aging. RESULTS: Studies show that the development of cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cognitive impairment and dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects of diets, at least in part, may be mediated by their beneficial macro- (protein, fat, carbohydrate) and micronutrient (vitamins, minerals) composition. CONCLUSIONS: Certain diets, such as the Mediterranean diet, may play a significant role in healthy aging by preventing the onset of certain diseases and by improving the aging process itself. This latter can be strengthened by incorporating fasting elements into the diet. As dietary recommendations change with age, this should be taken into consideration as well, when developing a diet tailored to the needs of elderly individuals. Future and ongoing clinical studies on complex anti-aging dietary interventions translating the results of preclinical investigations are expected to lead to novel nutritional guidelines for older adults in the near future.

Sleep deprivation impairs cognitive performance, alters task-associated cerebral blood flow and decreases cortical neurovascular coupling-related hemodynamic responses.

Sleep deprivation (SD) is a common condition and an important health concern. In addition to metabolic and cardiovascular risks, SD associates with decreases in cognitive performance. Neurovascular coupling (NVC, "functional hyperemia") is a critical homeostatic mechanism, which maintains adequate blood supply to the brain during periods of intensive neuronal activity. To determine whether SD alters NVC responses and cognitive performance, cognitive and hemodynamic NVC assessments were conducted prior to and 24 h post-SD in healthy young male individuals (n = 10, 27 ± 3 years old). Cognition was evaluated with a battery of tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Hemodynamic components of NVC were measured by transcranial Doppler sonography (TCD) during cognitive stimulation, dynamic retinal vessel analysis (DVA) during flicker light stimulation, and functional near infrared spectroscopy (fNIRS) during finger tapping motor task. Cognitive assessments revealed impairments in reaction time and sustained attention after 24 h of SD. Functional NIRS analysis revealed that SD significantly altered hemodynamic responses in the prefrontal cortex and somatosensory cortex during a motor task. NVC-related vascular responses measured by DVA and TCD did not change significantly. Interestingly, TCD detected decreased task-associated cerebral blood flow (CBF) in the right middle cerebral artery in sleep deprived participants. Our results demonstrate that 24 h of SD lead to impairments in cognitive performance together with altered CBF and hemodynamic components of cortical NVC responses.

Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice.

Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype.

Age-related impairment of neurovascular coupling (NVC; or "functional hyperemia") compromises moment-to-moment adjustment of regional cerebral blood flow to increased neuronal activity and thereby contributes to the pathogenesis of vascular cognitive impairment (VCI). Previous studies established a causal link among age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), neurovascular dysfunction and cognitive impairment. Endothelium-mediated microvascular dilation plays a central role in NVC responses. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, endothelium-mediated NVC responses were studied in a novel mouse model of accelerated neurovascular aging: mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2/Igf1rf/f). Increases in cerebral blood flow in the somatosensory whisker barrel cortex (assessed using laser speckle contrast imaging through a cranial window) in response to contralateral whisker stimulation were significantly attenuated in VE-Cadherin-CreERT2/Igf1rf/f mice as compared to control mice. In VE-Cadherin-CreERT2/Igf1rf/f mice, the effects of the NO synthase inhibitor L-NAME were significantly decreased, suggesting that endothelium-specific disruption of IGF1R signaling impairs the endothelial NO-dependent component of NVC responses. Collectively, these findings provide additional evidence that IGF-1 is critical for cerebromicrovascular endothelial health and maintenance of normal NVC responses.