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NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging.

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Waste from the agri-food chain represents a valuable reservoir of organic compounds with health-promoting properties. Momast Plus 30 Bio (MP30B) is a derivative obtained from olive-oil wastewater. Its enrichment in hydroxytyrosol (HT) via a patented technique has paved the way for its potential application as a dietary supplement in preventing cardiovascular diseases. MP30B demonstrates no significant alteration in cardiac and vascular parameters in "ex vivo" studies. However, it exhibits a strong ability to remove reactive oxygen species and exerts anti-inflammatory effects, notably reducing the concentration of iNOS and mitigating heart infections in "in vitro" experiments. Furthermore, MP30B slightly decreases the stiffness of the "ex vivo" thoracic aorta, potentially resulting in lowered arterial pressure and enhanced energy transfer to a normal ventricle. Based on these findings, we posit MP30B as a promising extract for cardiovascular disease prevention, and its specific antibacterial properties suggest its utility in preventing cardiac infections.

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Background: Previous studies on the direction of the association between arterial stiffness (AS) and chronic kidney disease (CKD) were inconsistent, leaving a knowledge gap in understanding the temporal sequence of the association. Objectives: This study sought to assess the temporal and longitudinal relationship between AS and CKD. Methods: The temporal relationship between AS measured by brachial ankle pulse wave velocity and CKD measured by estimated glomerular filtration rate (eGFR) was analyzed among 7,753 participants with repeated examinations in the Kailuan study using cross-lagged panel analysis. The longitudinal associations of AS status and vascular aging (VA) phenotype with incident CKD were analyzed among 10,535 participants. Results: The adjusted cross-lagged path coefficient (ß 1 = -0.03; 95% CI: -0.06 to -0.01; P < 0.0001) from baseline brachial ankle pulse wave velocity to follow-up eGFR was significantly greater than the path coefficient (ß 2 = -0.01; 95% CI: -0.02 to 0.01; P = 0.6202) from baseline eGFR to follow-up brachial ankle pulse wave velocity (P < 0.0001 for the difference). During a median follow-up of 8.48 years, 953 cases of incident CKD (9.05%) occurred. After adjustment for confounders, borderline (HR: 1.17; 95% CI: 1.08-1.38) and elevated AS (HR: 1.39; 95% CI: 1.12-1.72) was associated a higher risk of CKD, compared with normal AS. Consistently, supernormal VA (HR: 0.76; 95% CI: 0.66-0.86) was associated with a decreased and early VA (HR: 1.36; 95% CI: 1.29-1.43) was associated with an increased risk of CKD, compared with normal VA. Conclusions: AS appeared to precede the decrease in eGFR. Additionally, increased AS and early VA were associated with an increased risk of incident CKD.

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BACKGROUND: No research report has been conducted to investigate the impact of oxidation balance score (OBS) on the estimated pulse wave velocity(ePWV).We aimed to examine the association between OBS and ePWV. METHOD: We evaluated data for 13,073 patients from the National Health and Nutrition Examination Survey (NHANES). The exposure variable was OBS. The outcome variables was combination of ePWV and arterial stiffness. RESULTS: We observed a significant negative correlation between OBS (Per 1SD increase) and ePWV in the gradually adjusted models. Based on the aforementioned results, a two-piecewise logistic regression adjusted model was subsequently employed to establish the association between OBS and elevated ePWV, and the inflection point was determined as 5. The increased risk of elevated ePWV (OR:0.70; 95%CI:0.51-0.94) gradually decreases with the increase of OBS on the left side of the inflection point; however, when OBS exceeds 5, this decrease in risk of elevated ePWV(OR:1.00; 95%CI:0.96-1.04) is no longer observed (P for log likelihood ratio test = 0.028). CONCLUSIONS: There exists a significant association between OBS and ePWV in the context of American adults. Specifically, OBS exhibits a negative correlation with ePWV; however, when considering an elevated ePWV, a saturation effect is observed in relation to OBS.

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Vascular aging, a common pathogenesis of senile chronic diseases, significantly increases morbidity and mortality in older adults; its intricate cellular and molecular mechanisms necessitate further investigation. Lumican (LUM) and integrin α2ß1(ITGα2ß1) are profibrotic extracellular matrix proteins and vital cell regulatory receptors, respectively. However, their roles in vascular aging remain unclear. This study sought to elucidate the connection between LUM and vascular aging as well as the biological mechanism of LUM/ITGα2ß1 in this process. Using an enzyme-linked immunosorbent assay, we discovered that plasma LUM was elevated in vascular aging individuals and was positively correlated with brachial-ankle pulse wave velocity. Additionally, immunohistochemical and western blot analyses confirmed LUM upregulation in arteries of older adults and aged mice, as well as in senescent vascular smooth cells (VSMCs). Wild-type and LUM semiknockout (Lum-/+) mice, along with primary VSMCs extracted from these mice, were exposed to angiotensin II (Ang II) to induce stress-induced senescence model. LUM semiknockout mitigated Ang Ⅱ-induced arteriosclerosis, hypertension, vascular aging and remodeling in mice. Both in vitro and in vivo studies revealed that LUM deficiency suppressed p53, p21, collagen 1 and collagen 3 upregulation and synthetic phenotype formation in VSMCs stimulated by Ang Ⅱ. Treating VSMCs with a ITGα2ß1 antagonist reversed the aforementioned changes triggered by LUM proteins. Briefly, LUM functions as a potential marker and risk factor for vascular aging and promotes pathological changes by affecting ITGα2ß1 in VSMCs. This study introduces a novel molecular target for the early diagnosis and treatment of vascular aging and age-related vascular diseases.

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Aging is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Two major age-associated arterial phenotypes, endothelial dysfunction and large elastic arterial stiffness, are autonomous predictors of future CVD diagnosis and contribute to the progression of CVD in older adults. Senescent cells lose the capacity to proliferate but remain metabolically active and secrete inflammatory factors termed senescence-associated secretory phenotype (SASP), leading to an increase in inflammation and oxidative stress. Accumulation of senescent cells is linked with the progression of age-related diseases and has been known to play a role in cardiovascular disease. In this brief review, we describe the characteristics and mechanisms of senescent cell accumulation and how senescent cells promote endothelial dysfunction and arterial stiffness. We focus on a range of novel therapeutic strategies aimed at reducing the burden of endothelial dysfunction leading to atherosclerosis through targeting senescent cells. Studies have begun to investigate a specific class of drugs that are able to selectively eliminate senescent cells, termed senolytics, which have shown great promise in reversing the aging phenotype and ameliorating pathologies in age-related disorders, creating a new opportunity for aging research. Generating therapies targeting the elimination of senescent cells would improve health span and increase longevity, making senolytics a promising therapy for cardiovascular diseases.

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The aim of this study was to analyze the relationship between healthy vascular aging (HVA) and the Mediterranean diet alongside other lifestyles in a Spanish population aged 35 to 75 years without previous cardiovascular diseases. METHODS: In this cross-sectional descriptive study, 501 individuals aged 35 to 75 years were recruited from five health centers by random sampling stratified by age and sex (55.90 ± 14.24 years, 49.70% men). HVA was determined in two steps. Step 1: Subjects with vascular damage to the carotid arteries or peripheral arterial disease were classified as non-HVA. Step 2: The study population was classified by age and sex using the percentiles of the vascular aging index (VAI), with VAI ≤p25 considered HVA and >p25 considered non-HVA. The VAI was estimated using the following formula (VAI = (log (1.09) × 10 cIMT + log (1.14) cfPWV) × 39.1 + 4.76. Carotid-femoral pulse wave velocity (cfPWV) was measured with the SphygmoCor® device, and carotid intima-media thickness using Sonosite Micromax® ultrasound. Mediterranean diet (MD) adherence, alcohol and tobacco use were recorded through validated questionnaires. Physical activity was assessed with the ActiGraph-GT3X® accelerometer. RESULTS: The mean VAI value was 61.23 ± 12.86 (men-63.47 ± 13.75 and women-59.04 ± 11.54; p < 0.001). HVA was found in 18.9% (men-19.9% and women-17.8%). In the multiple regression analysis after adjusting for possible confounding factors, the mean VAI value showed a positive association with alcohol use (ß = 0.020) and sedentary hours per week (ß = 0.109) and a negative association with hours of activity per week (ß = -0.102) and with the number of healthy lifestyles (ß = -0.640). In the logistic regression analysis, after adjusting for possible confounding factors and compared to those classified as non-HVA, subjects classified as HVA were more likely to show MD adherence (OR = 0.571), do more than 26 h per week of physical activity (OR = 1.735), spend under 142 h per week being sedentary (OR = 1.696), and have more than two healthy lifestyles (OR = 1.877). CONCLUSION: The results of this study suggest that the more time spent doing physical activity and the less time spent in a sedentary state, the lower the vascular aging index and the greater the likelihood of being classified in the group of subjects with HVA.

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BACKGROUND: Vascular oxidative stress and low-grade inflammation are important in the pathology of cardiovascular disorders, including hypertension. Cell culture and animal studies suggest that inorganic dietary nitrate may attenuate oxidative stress and inflammation through nitric oxide (NO), and there is a need to investigate whether this translates to humans. AIM: In this randomised, placebo-controlled crossover study, by measuring a combination of multiple blood biomarkers, we evaluated whether previously reported benefits of dietary nitrate translate to a reduced oxidative stress and an improved inflammation status in 15 men and women (age range: 56-71 years) with treated hypertension. METHODS: We investigated the effects of a single ∼400 mg-dose of nitrate at 3 h post-ingestion (3H POST) and the daily consumption of 2 × âˆ¼400 mg of nitrate over 4 weeks (4WK POST), through nitrate-rich versus nitrate-depleted (placebo) beetroot juice. Measurements included plasma nitrate and nitrite (NOx), oxidised low-density lipoprotein (oxLDL), F2-isoprostanes, protein carbonyls, oxidised (GSSG) and reduced glutathione (GSH); and serum high-sensitive C-reactive protein (hsCRP), chemokines, cytokines, and adhesion molecules. Flow cytometry was used to assess the relative proportion of blood monocyte subsets. RESULTS: At 4WK POST nitrate intervention, the oxLDL/NOx ratio decreased (mainly due to increases in plasma nitrate and nitrite) and the GSH/GSSG ratio (a sensitive biomarker for alterations in the redox status) increased, compared with placebo (for both ratios P < 0.01). The relative proportion of classical (CD14+CD16-) monocytes decreased at 4WK POST for placebo compared to nitrate intervention (P < 0.05). Other oxidative stress and inflammatory markers were not altered by increased nitrate intake relative to placebo. CONCLUSIONS: The data from this study point toward a subtle alteration in the redox balance toward a less pro-oxidative profile by a regular intake of inorganic nitrate from plant foods. CLINICAL TRIAL REGISTRY NUMBER: NCT04584372 (ClinicialTrials.gov).

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Plant Extracts (PE) are natural substances extracted from plants, rich in various bioactive components. Exploring the molecular mechanisms and interactions involved in the vascular protective effects of PE is beneficial for the development of further strategies to protect aging blood vessels. For this review, the content was obtained from scientific databases such as PubMed, China National Knowledge Infrastructure (CNKI), and Google Scholar up to July 2024, using the search terms "Plant extracts", "oxidative stress", "vascular aging", "endothelial dysfunction", "ROS", and "inflammation". This review highlighted the effects of PE in protecting aging blood vessels. Through pathways such as scavenging reactive oxygen species, activating antioxidant signaling pathways, enhancing respiratory chain complex activity, inhibiting mitochondrial-reactive oxygen species generation, improving nitric oxide bioavailability, downregulating the secretion of inflammatory factors, and activating sirtuins 1 and Nrf2 signaling pathways, it can improve vascular structural and functional changes caused by age-related oxidative stress, mitochondrial dysfunction, and inflammation due to aging, thereby reducing the incidence of age-related cardiovascular diseases.

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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.

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BACKGROUND: In this paper, we use the Health and Retirement Study (HRS) to examine the relationship between an estimated measure of pulse wave velocity (ePWV) and cognitive impairment with no dementia and dementia, respectively. METHODS: We modeled the relationship between ePWV and cognitive status in 2006/2008 using data from 8,492 men and women (mean age 68.6 years) controlling for age, blood pressure, sociodemographic and socioeconomic characteristics (sex, race and ethnicity, education, income, wealth), health behaviors (smoking and physical activity), body mass index (BMI), health status and related medication use (history of cardiovascular disease, diabetes, and stroke), and cerebrovascular disease (CVD)-related biomarkers (C-reactive protein, cystatin-C, hemoglobin A1c, total cholesterol, high-density lipoprotein [HDL] cholesterol). We assess cognitive function with the 27-item Langa-Weir Telephone Interview for Cognitive Status (TICS) scale. ePWV is derived from an equation based on participant age and resting blood pressure. RESULTS: In a model that controlled for the constituent components of ePWV (age, age squared, systolic and diastolic blood pressure), ePWV is associated with increased odds of having cognitive impairment with no dementia (OR=2.761) and dementia (OR=6.344) relative to a group with no cognitive impairment or dementia. After controlling for the constituent components of ePWV, sociodemographic and socioeconomic characteristics, health status and medication use, health behaviors, BMI, and CVD-related biomarkers, ePWV remains significantly associated with dementia (OR=3.969) but not cognitive impairment with no dementia (OR=1.782). CONCLUSIONS: These findings suggest that ePWV may be a novel research tool and biomarker of vascular aging that can be used in large, population-representative studies to examine cognitive aging and dementia risk.

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Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age-related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age-related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age-related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low-grade chronic inflammation, in conjunction with the senescence-associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age-related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity-associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes-related metabolic disturbances further impair cardiac function. CKD-related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin-angiotensin-aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age-related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant-based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age-related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti-inflammatory drugs like interleukin (IL)-1ß inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age-related HF burden.

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BACKGROUND: Myostatin is a protein compound, structurally related to the transforming growth factor-beta protein, which plays a pivotal role in regulating muscle growth and extracellular matrix production. It exerts both profibrotic and antihypertrophic effects on vascular smooth muscle cells. Aim of the study was to explore the potential association between serum myostatin levels (sMSTN) and carotid-femoral pulse wave velocity (cf-PWV), carotid-radial pulse wave velocity (cr-PWV), and their ratio (PWVr), in a cohort of healthy adolescents. METHODS: A cohort of 128 healthy subjects (mean age 17 ±â€…2 years, 59% male) was randomly selected from participants to the MACISTE (Metabolic And Cardiovascular Investigation at School, TErni) study. sMSTN was assessed utilizing an enzyme-linked immunosorbent assay. PWVs were measured in the supine position using high-fidelity applanation tonometry. RESULTS: The mean cf-PWV was 5.1 ±â€…0.9 m/s, cr-PWV was 6.9 ±â€…0.9 m/s, and PWVr was 0.75 ±â€…0.12. PWVr exhibited a linear increase across increasing quartiles of sMSTN (0.71 ±â€…0.1, 0.74 ±â€…0.1, 0.7 ±â€…0.1, 0.77 ±â€…0.1, P for trend = 0.03), whereas the association between sMSTN and each single component of PWVr (cf-PWV, cr-PWV) did not attain statistical significance. Quartiles of sMSTN displayed a positive trend with serum HDL-cholesterol (P = 0.01) and a negative one with LDL-cholesterol (P = 0.01). In a multivariate linear model, the association between PWVr and sMSTN was independent of SBP values, age, sex, heart rate, BMI, HDL-cholesterol, and HOMA Index. CONCLUSIONS: In healthy adolescents, sMSTN showed independent associations with PWVr, a measure of central-to-peripheral arterial stiffness gradient. sMSTN may exert differential effects on the structural and functional properties of the arterial wall.

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Cellular senescence, a permanent halt in cell division due to stress, spurs functional and structural changes, contributing to vascular aging characterized by endothelial dysfunction and vascular remodeling. This process raises the risk of ischemic stroke (IS) in older individuals, with its mechanisms still not completely understood despite ongoing research efforts. In this review, we have analyzed the impact of vascular aging on increasing susceptibility and exacerbating the pathology of IS. We have emphasized the detrimental effects of endothelial dysfunction and vascular remodeling influenced by oxidative stress and inflammatory response on vascular aging and IS. Our goal is to aid the understanding of vascular aging and IS pathogenesis, particularly benefiting older adults with high risk of IS.

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Life expectancy has increased worldwide alongside a rise in disability prevalence during old age. The impact and interrelationship among the precursors of disability in midlife remain to be better understood. Furthermore, investigating whether lifestyle factors may potentially influence health outcomes and the prognosis of vascular disease could be especially relevant among the middle-aged population, which is a priority subpopulation when prevention is the goal. This is an observational, cross-sectional and population-based study. Participants, between 50 and 55 years old, are randomly selected from the municipality of Toledo (Spain). There are six non-consecutive days for the assessments, providing enough rest between evaluations. Participants perform the interview of the Toledo Study for Healthy Aging. Blood pressure monitoring and a resting electrocardiogram are also recorded. Then, resting peripheral and cerebral vascular measurements along with muscle size and architecture are assessed. Blood and urine samples, and body composition data are collected after an overnight fasting. On a different visit, physical performance and muscle function tests are performed. Additionally, brain magnetic resonance imaging is conducted. And finally, an accelerometer is given to the participants for a week. Frailty is evaluated by Frailty Trait Scale and Fried Frailty Phenotype. This project will shed light on the associations between frailty, early cognitive impairment, and vascular aging during midlife, and on the role that lifestyles play in their development. Lastly, this project will provide meaningful implications for public health strategies aimed at promoting healthy aging in later life.

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BACKGROUND: Pulse Wave Velocity (PWV) remains the gold-standard method to assess Early Vascular Aging (EVA) defined by arterial stiffness. However, its high cost, time-consuming process, and need for qualified medical staff shows the importance of identifying alternative methods for the EVA evaluation. OBJECTIVE: In order to simplify the process of assessing patients' EVA, we recently developed the Early Vascular Aging Ambulatory score (EVAAs), a simple tool to predict the risk of EVA. The aim of the present study was the external validation of EVAAs in an independent population. METHODS: Eight hundred seventy-nine (46.3% men) patients who were referred to our Hypertension ESH Excellence Center were included in this study. The mean age was 46.43 ± 22.87 years. EVA was evaluated in two different ways. The first assessment included c-f PWV values, whereas the second one included EVAAs without the direct measurement of carotid-femoral PWV. RESULTS: The null hypothesis was that the prediction of EVA based on EVAAs does not present any statistically significant difference compared to the prediction based on the calculation from c-f PWV. Mean squared error (MSE) was used for the assessment of the null hypothesis, which was found to be 0.40. The results revealed that the EVAAs show the probability of EVA with 0.98 sensitivity and 0.75 specificity. The EVAAs present 95% positive predictive value and 92% negative predictive value. CONCLUSION: Our study revealed that EVAAs could be as reliable as the carotid-femoral PWV to identify patients with EVA. Hence, we hope that EVAAs will be a useful tool in clinical practice.

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OBJECTIVES: The obesity rate among middle-aged and young adults in China is increasing annually, and the incidence of cardiovascular diseases is becoming more prevalent in younger populations. However, it has not yet been reported whether obesity is associated with early vascular aging (EVA). This study aims to explore the correlation between obesity and EVA in middle-aged and young adult health check-up populations, providing a reference for the prevention of cardiovascular diseases. METHODS: A total of 15 464 middle-aged and young adults aged 18-59 who completed brachial-ankle pulse wave velocity (baPWV) test in the Third Xiangya Hospital of Central South University from January to December 2020 were included. Among them, 1 965 individuals with normal blood pressure and no cardiovascular risk factors were selected as the healthy population. The baPWV thresholds for determining EVA in each age group for males and females were calculated based on the baPWV values of the healthy population. The number and percentage of individuals meeting the EVA criteria in the middle-aged and young adult health check-up populations were statistically analyzed by age and gender. The differences in obesity indicators [visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC)] between the EVA and non-EVA groups for males and females were compared. Using EVA as the dependent variable, VAI, BMI, and WC were included as independent variables in a Logistic model to analyze the correlation between each obesity indicator and EVA before and after adjusting for other influencing factors. Furthermore, the correlation between each obesity indicator and EVA in each age group was analyzed. RESULTS: In the health check-up populations, the detection rate of EVA in different age groups was 1.65%-10.92% for males, and 1.16%-10.50% for females, the detection rate of EVA increased with age in both males and females. Except for the 40-<50 age group, the EVA detection rate was higher in males than in females in all other age groups. Regardless of gender, obesity indicators VAI, BMI, and WC were significantly higher in the EVA group than in the non-EVA group (all P<0.01). Before and after adjusting for other influencing factors, VAI and WC were both correlated with EVA (both P<0.05). BMI was a risk factor for EVA before adjusting for other influencing factors (P<0.01), but after adjustment, the correlation between BMI and EVA was not statistically significant (P=0.05). After adjusting for other influencing factors, the correlation between VAI and EVA was statistically significant in the 18-<40 and 50-<60 age groups (both P<0.05), while the correlation between BMI and WC with EVA was not statistically significant (both P>0.05). In the 40-<50 age group, the correlation between VAI and BMI with EVA was not statistically significant (both P>0.05), but the correlation between WC and EVA was statistically significant (P<0.01). CONCLUSIONS: VAI is closely related to the occurrence of EVA in middle-aged and young adults aged 18-<40 and 50-<60 years, while WC is closely related to the occurrence of EVA in those aged 40-<50 years.

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Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.

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Prior work has yet to determine whether the reduction of dietary nitrate (NO3-) to NO, via the enterosalivary pathway, may modify cutaneous vascular conductance (CVC) responses to local heating in older women. Changes occurring with the transition to menopause related to hormonal flux, increased adiposity, and/or decreased physical activity may further compound the negative influence of aging on nitric oxide (NO)-dependent CVC. Herein, we characterized changes in NO-dependent CVC following acute ingestion of 140 mL of NO3--rich beetroot juice in 24 older women (age: 65 ± 5 y, BMI: 31.2 ± 3.7 kg/m2). Red blood cell (RBC) flux was measured continuously via laser-Doppler flowmetry on the dorsal aspect of the forearm during local skin heating to 39 °C/44 °C before and 3 h after NO3- ingestion. NO-dependent changes in CVC were calculated as RBC flux/mean arterial blood pressure at 39 °C and normalized as a proportion of maximal CVC at 44 °C (%CVCmax). Changes (Δ) in fractional exhaled NO (FeNO) following NO3- ingestion were used an index of NO bioavailability. Despite increased FeNO (+81 ± 70 %, P < 0.001), %CVCmax at 39 °C was reduced (-16 ± 10 %, P < 0.001) following NO3- ingestion. A greater reduction in %CVCmax was weakly to moderately associated with higher body fat% (r = 0.45 [0.05-0.72], P = 0.029), central adiposity% (r = 0.50 [0.13-0.75], P = 0.012), neutrophil% (r = 0.42 [0.02-0.70], P = 0.041), and higher neutrophil to lymphocyte ratio (r = 0.49 [0.11-0.75], P = 0.016). These findings demonstrate a single dose of dietary NO3- does not promote CVC responses to local heating in sedentary older women with overweight and obesity. Correlation with multiple biomarkers suggest systemic inflammation may be involved.

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