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Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging. Therefore, we here ask whether TRF also exerts beneficial effects in the aged retina. We compared aged mice (24 months) on a TRF paradigm (access to food for six hours per day) for either 6 or 12 months against young control mice (8 months) and aged control mice on an ad libitum diet. We examined changes in the retina at the functional (electroretinography), structural (histology and fluorescein angiograms) and molecular (gene expression) level. TRF treatment showed amelioration of age-related reductions in both scotopic and photopic b-wave amplitudes suggesting benefits for retinal interneuron signaling. TRF did not affect age-related signs of retinal inflammation or microglial activation at either the molecular or histological level. Our data indicate that TRF helps preserve some aspects of retinal function that are decreased with aging, adding to our understanding of the health benefits that altered feeding patterns may confer.

Age-related endothelial dysfunction is a pivotal factor in the development of cardiovascular diseases, stemming, at least in part, from mitochondrial dysfunction and a consequential increase in oxidative stress. These alterations are central to the decline in vascular health seen with aging, underscoring the urgent need for interventions capable of restoring endothelial function for preventing cardiovascular diseases. Dietary interventions, notably time-restricted feeding (TRF), have been identified for their anti-aging effects on mitochondria, offering protection against age-associated declines in skeletal muscle and other organs. Motivated by these findings, our study aimed to investigate whether TRF could similarly exert protective effects on endothelial health in the vasculature, enhancing mitochondrial function and reducing oxidative stress. To explore this, 12-month-old C57BL/6 mice were placed on a TRF diet, with food access limited to a 6-h window daily for 12 months. For comparison, we included groups of young mice and age-matched controls with unrestricted feeding. We evaluated the impact of TRF on endothelial function by measuring acetylcholine-induced vasorelaxation of the aorta. Mitochondrial health was assessed using fluororespirometry, and vascular reactive oxygen species (ROS) production was quantified with the redox-sensitive dye dihydroethidium. We also quantified 4-hydroxynonenal (4-HNE) levels, a stable marker of lipid peroxidation, in the aorta using ELISA. Our findings demonstrated that aged mice on a standard diet exhibited significant impairments in aortic endothelial relaxation and mitochondrial function, associated with elevated vascular oxidative stress. Remarkably, the TRF regimen led to substantial improvements in these parameters, indicating enhanced endothelial vasorelaxation, better mitochondrial function, and reduced oxidative stress in the aortas of aged mice. This investigation establishes a vital foundation, paving the way for subsequent clinical research aimed at exploring the cardiovascular protective benefits of intermittent fasting.

Abstract 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.

IntroductionCerebrovascular pathologies contribute to cognitive decline during aging, leading to vascular cognitive impairment and dementia (VCID). Levels of circulating insulin-like growth factor 1 (IGF-1), a vasoprotective hormone, decrease during aging. Decreased circulating IGF-1 in animal models leads to the development of VCID-like symptoms, but the cellular mechanisms underlying IGF-1-deficiency associated pathologies in the aged cerebrovasculature remain poorly understood. Here, we test the hypothesis that vascular smooth muscle cells (VSMCs) play an integral part in mediating the vasoprotective effects of IGF-1.MethodsWe used a hypertension-based model of cerebrovascular dysfunction in mice with VSMC-specific IGF-1 receptor (Igf1r) deficiency and evaluated the development of cerebrovascular pathologies and cognitive dysfunction.ResultsVSMC-specific Igf1r deficiency led to impaired cerebral myogenic autoregulation, independent of blood pressure changes, which was also associated with impaired spatial learning and memory function as measured by radial arm water maze and impaired motor learning measured by rotarod. In contrast, VSMC-specific IGF-1 receptor knockdown did not lead to cerebral microvascular rarefaction.DiscussionThese studies suggest that VSMCs are key targets for IGF-1 in the context of cerebrovascular health, playing a role in vessel stability alongside other cells in the neurovascular unit, and that VSMC dysfunction in aging likely contributes to VCID.

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.

The authors would like to make the following correction to the publication dealing with Reference #3 [...]

Abstract A monoexponential model characterizing cerebral blood velocity dynamics at the onset of exercise may mask dynamic responses by the cerebrovasculature countering large fluctuations of middle cerebral artery blood velocity (MCAv) and cerebral perfusion pressure (CPP) oscillations. Therefore, the purpose of this study was to determine whether the use of a monoexponential model attributes initial fluctuations of MCAv at the start of exercise as a time delay (TD). Twenty‐three adults (10 women, 23.9 ± 3.3 yrs; 23.7 ± 2.4 kg/m2) completed 2 min of rest followed by 3 mins of recumbent cycling at 50 W. MCAv, CPP, and Cerebrovascular Conductance index (CVCi), calculated as CVCi = MCAv/MAP × 100 mmHg, were collected, a lowpass filter (0.2 Hz) was applied, and averaged into 3‐second bins. MCAv data were then fit to a monoexponential model [ΔMCAv(t) = Amp(1 – e−(t−TD)/τ)]. TD, tau (τ), and mean response time (MRT = TD + τ) were obtained from the model. Subjects exhibited a TD of 20.2 ± 18.1 s. TD was directly correlated with MCAv nadir (MCAvN), r = −0.560, p = 0.007, which occurred at similar times (16.5 ± 15.3 vs. 20.2 ± 18.1 s, p = 0.967). Regressions indicated CPP as the strongest predictor of MCAvN (Ra2 = 0.36). Fluctuations in MCAv were masked using a monoexponential model. To adequately understand cerebrovascular mechanisms during the transition from rest to exercise, CPP and CVCi must also be analyzed. A concurrent drop in cerebral perfusion pressure and middle cerebral artery blood velocity at the start of exercise forces the cerebrovasculature to respond to maintain cerebral blood flow. The use of a monoexponential model characterizes this initial phase as a time delay and masks this large important response.

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.

IntroductionMild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline.MethodologyA prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia.

IntroductionAdvanced 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.MethodsTo 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.ResultsPatients 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.DiscussionOur findings provide additional evidence in support of the concept that increased gait variability and asymmetry may predict cognitive impairment in older adults with CSVD.

Abstract 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.

Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer’s Disease (AD). Prior research shows that females are more impacted by MCI than males. On average females have a greater incidence rate of any dementia and current evidence suggests that they suffer greater cognitive deterioration than males in the same disease stage. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, the rate of hippocampal atrophy affects the progression of AD in females more than males. This study was designed to extend our understanding of the sex-related differences in the brain of participants with MCI. Specifically, we investigated the difference in the hippocampal connectivity to different areas of the brain. The Resting State fMRI and T2 MRI of cognitively normal individuals (n = 40, female = 20) and individuals with MCI (n = 40, female = 20) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that connectivity of hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females. These results improve our current understanding of the role of hippocampus-precuneus cortex and hippocampus-brainstem connectivity in sex differences in MCI. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex specific precision medicine to manipulate hippocampal-precuneus cortex and hippocampal-brainstem connectivity to decrease the progression of MCI to AD.

Age-related cerebrovascular defects contribute to vascular cognitive impairment and dementia (VCID) as well as other forms of dementia. There has been great interest in developing biomarkers and other tools for studying cerebrovascular disease using more easily accessible tissues outside the brain such as the retina. Decreased circulating insulin-like growth factor 1 (IGF-1) levels in aging are thought to contribute to the development of cerebrovascular impairment, a hypothesis that has been supported by the use of IGF-1 deficient animal models. Here we evaluate vascular and other retinal phenotypes in animals with circulating IGF-1 deficiency and ask whether the retina mimics common age-related vascular changes in the brain such as the development of microhemorrhages. Using a hypertension-induced model, we confirm that IGF-1 deficient mice exhibited worsened microhemorrhages than controls. The retinas of IGF-1 deficient animals do not exhibit microhemorrhages but do exhibit signs of vascular damage and retinal stress such as patterns of vascular constriction and Müller cell activation. These signs of retinal stress are not accompanied by retinal degeneration or impaired neuronal function. These data suggest that the role of IGF-1 in the retina is complex, and while IGF-1 deficiency leads to vascular defects in both the brain and the retina, not all brain pathologies are evident in the retina.

Dopaminergic treatment (DT), the standard therapy for Parkinson’s disease (PD), alters the dynamics of functional brain networks at specific time scales. Here, we explore the scale-free functional connectivity (FC) in the PD population and how it is affected by DT. We analyzed the electroencephalogram of: (i) 15 PD patients during DT (ON) and after DT washout (OFF) and (ii) 16 healthy control individuals (HC). We estimated FC using bivariate focus-based multifractal analysis, which evaluated the long-term memory (H(2)) and multifractal strength (ΔH15) of the connections. Subsequent analysis yielded network metrics (node degree, clustering coefficient and path length) based on FC estimated by H(2) or ΔH15. Cognitive performance was assessed by the Mini Mental State Examination (MMSE) and the North American Adult Reading Test (NAART). The node degrees of the ΔH15 networks were significantly higher in ON, compared to OFF and HC, while clustering coefficient and path length significantly decreased. No alterations were observed in the H(2) networks. Significant positive correlations were also found between the metrics of H(2) networks and NAART scores in the HC group. These results demonstrate that DT alters the multifractal coupled dynamics in the brain, warranting the investigation of scale-free FC in clinical and pharmacological studies.

The human brain consists of anatomically distant neuronal assemblies that are interconnected via a myriad of synapses. This anatomical network provides the neurophysiological wiring framework for functional connectivity (FC), which is essential for higher-order brain functions. While several studies have explored the scale-specific FC, the scale-free (i.e., multifractal) aspect of brain connectivity remains largely neglected. Here we examined the brain reorganization during a visual pattern recognition paradigm, using bivariate focus-based multifractal (BFMF) analysis. For this study, 58 young, healthy volunteers were recruited. Before the task, 3-3 min of resting EEG was recorded in eyes-closed (EC) and eyes-open (EO) states, respectively. The subsequent part of the measurement protocol consisted of 30 visual pattern recognition trials of 3 difficulty levels graded as Easy, Medium, and Hard. Multifractal FC was estimated with BFMF analysis of preprocessed EEG signals yielding two generalized Hurst exponent-based multifractal connectivity endpoint parameters, H(2) and ΔH15; with the former indicating the long-term cross-correlation between two brain regions, while the latter captures the degree of multifractality of their functional coupling. Accordingly, H(2) and ΔH15 networks were constructed for every participant and state, and they were characterized by their weighted local and global node degrees. Then, we investigated the between- and within-state variability of multifractal FC, as well as the relationship between global node degree and task performance captured in average success rate and reaction time. Multifractal FC increased when visual pattern recognition was administered with no differences regarding difficulty level. The observed regional heterogeneity was greater for ΔH15 networks compared to H(2) networks. These results show that reorganization of scale-free coupled dynamics takes place during visual pattern recognition independent of difficulty level. Additionally, the observed regional variability illustrates that multifractal FC is region-specific both during rest and task. Our findings indicate that investigating multifractal FC under various conditions – such as mental workload in healthy and potentially in diseased populations – is a promising direction for future research.

Abstract Sleep deprivation (SD) is known to be associated with decreased cognitive performance; however, the underlying mechanisms are poorly understood. As interactions between distinct brain regions depend on mental state, functional brain networks established by these connections typically show a reorganization during task. Hence, analysis of functional connectivity (FC) could reveal the task‐related change in the examined frontal brain networks. Our objective was to assess the impact of SD on static FC in the prefrontal and motor cortices and find whether changes in FC correlate with changes in neuropsychological scores. Healthy young male individuals (n = 10, 27.6 ± 3.7 years of age) participated in the study. A battery of tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and 48 channel functional near‐infrared spectroscopy (fNIRS) measurements were performed before and after 24 hr of SD. Network metrics were obtained by graph theoretical analysis using the fNIRS records in resting state and during finger‐tapping sessions. During task, SD resulted in a significantly smaller decrease in the number and strength of functional connections (characterizing FC) in the frontal cortex. Changes in the global connection strengths correlated with decreased performance in the paired association learning test. These results indicate a global impact of SD on functional brain networks in the frontal lobes.

Sepsis is a life-threatening condition, the incidence of which is significantly increased in elderly patients. One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function. Normal brain function is dependent on moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions. This homeostatic mechanism, termed neurovascular coupling (NVC, also known as functional hyperemia), is critically dependent on the production of vasodilator NO by microvascular endothelial cells in response to mediators released from activated astrocytes. The goal of this study was to test the hypothesis that sepsis in aging leads to impairment of NVC responses early after treatment and that this neurovascular dysfunction associates with impairments in cognitive performance and vascular endothelial dysfunction. To test this hypothesis, we used a commonly studied bacterial pathogen, Listeria monocytogenes, to induce sepsis in experimental animals (males, 24 months of age) and subjected experimental animals to a standard clinical protocol of 3 doses of ampicillin i.p. and 14 days of amoxicillin added to the drinking water. NVC responses, endothelial function and cognitive performance were measured in septic and age-matched control groups within 14 days after the final antibiotic treatment. Our data demonstrate that sepsis in aging significantly impairs NVC responses measured in somatosensory cortex during whisker stimulation, significantly impairs endothelial function in isolated and pressure cannulated aorta rings in response to acetylcholine stimulation. No significant impairment of cognitive function in post-sepsis aged animals has been observed when measured using the PhenoTyper homecage based system. Our findings suggest that sepsis-associated endothelial dysfunction and impairment of NVC responses may contribute to long-term cognitive deficits in older sepsis survivors.

Understanding how the brain allocates resources to match the demands of active neurons under physiological conditions is critically important. Increased metabolic demands of active brain regions are matched with hemodynamic responses known as neurovascular coupling (NVC). Several methods that allow noninvasive assessment of brain activity in humans detect NVC and early detection of NVC impairment may serve as an early marker of cognitive impairment. Therefore, non-invasive NVC assessments may serve as a valuable tool to detect early signs of cognitive impairment and dementia. Working memory tasks are routinely employed in the evaluation of cognitive task-evoked NVC responses. However, recent attempts that utilized functional near-infrared spectroscopy (fNIRS) or transcranial Doppler sonography (TCD) while using a similar working memory paradigm did not provide convincing evidence for the correlation of the hemodynamic variables measured by these two methods. In the current study, we aimed to compare fNIRS and TCD in their performance of differentiating NVC responses evoked by different levels of working memory workload during the same working memory task used as cognitive stimulation. Fourteen healthy young individuals were recruited for this study and performed an n-back cognitive test during TCD and fNIRS monitoring. During TCD monitoring, the middle cerebral artery (MCA) flow was bilaterally increased during the task associated with greater cognitive effort. fNIRS also detected significantly increased activation during a more challenging task in the left dorsolateral prefrontal cortex (DLPFC), and in addition, widespread activation of the medial prefrontal cortex (mPFC) was also revealed. Robust changes in prefrontal cortex hemodynamics may explain the profound change in MCA blood flow during the same cognitive task. Overall, our data support our hypothesis that both TCD and fNIRS methods can discriminate NVC evoked by higher demand tasks compared to baseline or lower demand tasks.

Abstract Although systemic sex‐specific differences in cardiovascular responses to exercise are well established, the comparison of sex‐specific cerebrovascular responses to exercise has gone under‐investigated especially, during high intensity exercise. Therefore, our purpose was to compare cerebrovascular responses in males and females throughout a graded exercise test (GXT). Twenty‐six participants (13 Females and 13 Males, 24 ± 4 yrs.) completed a GXT on a recumbent cycle ergometer consisting of 3‐min stages. Each sex completed 50W, 75W, 100W stages. Thereafter, power output increased 30W/stage for females and 40W/stage for males until participants were unable to maintain 60‐80 RPM. The final stage completed by the participant was considered maximum workload(Wmax). Respiratory gases (End‐tidal CO2, EtCO2), middle cerebral artery blood velocity (MCAv), heart rate (HR), non‐invasive mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV) were continuously recorded on a breath‐by‐breath or beat‐by‐beat basis. Cerebral perfusion pressure, CPP = MAP (0. 7,355 distance from heart‐level to doppler probe) and cerebral vascular conductance index, CVCi = MCAv/CPP 100mmHg were calculated. The change from baseline (Δ) in MCAv was similar between the sexes during the GXT (p = .091, ωp2 = 0.05). However, ΔCPP (p

Late life depression is an important public health problem, which associates with increased risk of morbidity and mortality. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are often prescribed to treat geriatric depression. There is increasing evidence that fluoxetine and other SSRIs exert a wide range of cardiovascular side effects. Furthermore, there is evidence that aging may increase plasma level of SSRIs. In this overview, the potential role of side effects of treatment with fluoxetine and other SSRIs in the pathogenesis of age-related cardiovascular diseases, including atherogenesis, cardiac pathologies, and cerebromicrovascular impairment, is discussed.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI). Keywords: Oxidative stress, ROS, Endothelial dysfunction, Functional hyperemia, Microcirculation

Liposomes are highly biocompatible and versatile drug carriers with an increasing number of applications in the field of nuclear medicine and diagnostics. So far, only negatively charged liposomes with intercalated radiometals, e.g., 64Cu, 99mTc, have been reported. However, the process of cellular uptake of liposomes by endocytosis is rather slow. Cellular uptake can be accelerated by recently developed cationic liposomes, which exhibit extraordinarily high membrane fusion ability. The aim of the present study was the development of the formulation and the characterization of such cationic fusogenic liposomes with intercalated radioactive [131I]I− for potential use in therapeutic applications. The epithelial human breast cancer cell line MDA-MB-231 was used as a model for invasive cancer cells and cellular uptake of [131I]I− was monitored in vitro. Delivery efficiencies of cationic and neutral liposomes were compared with uptake of free iodide. The best cargo delivery efficiency (~10%) was achieved using cationic fusogenic liposomes due to their special delivery pathway of membrane fusion. Additionally, human blood cells were also incubated with cationic control liposomes and free [131I]I−. In these cases, iodide delivery efficiencies remained below 3%.

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.