Abstract P058: Female Rats Artificially Selected For Low Vs. High Intrinsic Aerobic Capacity Display Divergent Mechanisms In Vascular Inflammation

Hypertension is an important clinical symptom of metabolic syndrome (MetS). Rats selectively bred for low intrinsic aerobic capacity (LCR) are animal models for MetS, and present with increased blood pressure and vascular dysfunction. In contrast, rats selected for high intrinsic aerobic capacity (HCR) display reduced vascular inflammation and no metabolic abnormalities. Two important enzymes for vascular inflammation and the resolution of inflammation are cyclooxygenase (COX) and lipoxygenase (LOX), respectively; however, it is unknown whether COX and LOX play a role in the vascular function of LCR and HCR. We hypothesized that mesenteric resistance arteries (MRA) from untrained LCR present increased COX activity, while arteries from HCR show decreased COX and increased LOX activity. Female (18-38 weeks old) LCR, HCR, and high response trained (HRT) rats, control, were used. HRT rats present higher intrinsic aerobic capacity than LCR, but lower than HCR. MRA were mounted onto a wire myograph. One-way ANOVA: p<0.05: *vs. control (HRT); # vs. HCR; & vs. absence of indomethacin (INDO), a COX inhibitor. LCR rats showed increased periovarian fat pad [HRT: 0.95±0.1 (n=7) vs. LCR: 1.80±0.1* # (n=7) vs. HCR: 1.18±0.1 (n=7) (g)]. No significant differences were observed in the KCl (120 mM), acetylcholine, and sodium-nitroprusside-induced responses. However, LCR presented a decrease in phenylephrine (PE)-induced contraction [PE: E max %: HRT: 103±3 (n=8); LCR: 74±9* # (n=11); HCR: 112±5 (n=9)]. Inhibiting COX [INDO, 10 μM] decreased contraction in HRT arteries, but had little effect on HCR arteries. Contrarily, INDO abolished contraction in MRA from LCR [PE+INDO: E max %: HRT: 31±18 & (n=7); LCR: 2±0.9 & (n=8); HCR: 77±9 (n=8)]. Lipoxin (LXA4), a LOX-derived mediator for resolution of inflammation, induced contraction in MRA from HCR, but relaxation in LCR and HRT arteries [LXA4: E max %: HRT: -69±19 (n=4); LCR: -18±9 (n=3); HCR: 11±5 (n=4)*]. Thus, HCR are unresponsive to COX inhibition, suggesting a change from a normal inflammatory state to a higher resolution state. LCR display low-grade chronic inflammation via increased COX activity. These data reveal novel, inherited mechanisms for vascular physiology in high vs. low intrinsic aerobic capacity.

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Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats

Thrombosis and Haemostasis ◽

10.1160/th13-04-0313 ◽

2014 ◽

Vol 111 (01) ◽

pp. 154-164 ◽

Cited By ~ 18

Author(s):

Su-Emmanuelle Degirmenci ◽

Fatiha Zobairi ◽

Asael Berger ◽

Grégory Meyer ◽

Mélanie Burban ◽

...

Keyword(s):

Septic Shock ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Activated Protein C ◽

Resistance Arteries ◽

Pharmacological Modulation ◽

Circulating Microparticles ◽

Haemodynamic Improvement

SummaryCirculating microparticles play a pro-inflammatory and procoagulant detrimental role in the vascular dysfunction of septic shock. It was the objective of this study to investigate mechanisms by which a pharmacological modulation of microparticles could affect vascular dysfunction in a rat model of septic shock. Septic or sham rats were treated by activated protein C (aPC) and resuscitated during 4 hours. Their microparticles were harvested and inoculated to another set of healthy recipient rats. Haemodynamic parameters were monitored, circulating total procoagulant microparticles assessed by prothrombinase assay, and their cell origin characterised. Mesenteric resistance arteries, aorta and heart were harvested for western blotting analysis. We found that a) the amount and phenotype of circulating microparticles were altered in septic rats with an enhanced endothelial, leucocyte and platelet contribution; b) aPC treatment significantly reduced the generation of leucocyte microparticles and norepinephrine requirements to reach the mean arterial pressure target in septic rats; c) Microparticles from untreated septic rats, but not from aPC-treated ones, significantly reduced the healthy recipients’ mean arterial pressure; d) Microparticle thromboxane content and aPC activity were significantly increased in aPC-treated septic rats. In inoculated naïve recipients, microparticles from aPC-treated septic rats prompted reduced NF-κB and cyclooxygenase-2 arterial activation, blunted the generation of pro-inflammatory iNOS and secondarily increased platelet and endothelial microparticles. In conclusion, in this septic shock model, increased circulating levels of procoagulant microparticles led to negative haemodynamic outcomes. Pharmacological treatment by aPC modified the cell origin and levels of circulating microparticles, thereby limiting vascular inflammation and favouring haemodynamic improvement.

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Abstract P217: Nox Compartmentalization, Protein Oxidation and ER Stress in Vascular Smooth Muscle Cells in Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.p217 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Livia L Camargo ◽

Augusto C Montezano ◽

Adam Harvey ◽

Sofia Tsiropoulou ◽

Katie Hood ◽

...

Keyword(s):

Er Stress ◽

Protein Oxidation ◽

Vascular Function ◽

Vascular Reactivity ◽

Stress Proteins ◽

Vascular Dysfunction ◽

Mesenteric Arteries ◽

Resistance Arteries ◽

Post Translational Modification ◽

Wistar Kyoto

In hypertension, activation of NADPH oxidases (Noxs) is associated with oxidative stress and vascular dysfunction. The exact role of each isoform in hypertension-associated vascular injury is still unclear. We investigated the compartmentalization of Noxs in VSMC from resistance arteries of Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Expression of Nox1 and Nox4 was increased in SHR cells (96.6±28.7% and 48.2±21.2% vs WKY, p<0.05), as well as basal ROS levels measured by chemiluminescence (110.2±26.4% vs WKY, p<0.05) and amplex red (105.2±33.2% vs WKY, p<0.05). Phosphorylation of unfolded protein response activators, PERK and IRE1α, and expression of ER chaperone BiP were elevated in SHR cells (p<0.05 vs WKY), indicating activation of ER stress response. Immunoblotting after organelle fractionation demonstrated that Noxs are expressed in an organelle-specific manner, with Nox1, 2 and 4 present in plasma membrane, ER and nucleus, but not in mitochondria. In SHR cells, NoxA1ds (Nox1 inhibitor, 10μM) and GKT136901 (Nox1/4 inhibitor, 10μM) decreased AngII-induced ROS levels (p<0.001 vs Ctl). Additionally, mito-tempol (mitochondrial-targeted antioxidant, 50nM) and 4-PBA (ER stress inhibitor, 1mM) decreased basal ROS levels in SHR cells (p<0.05 vs Ctl). Furthermore, oxidation of the antioxidant enzymes Peroxiredoxins (Prx) was increased in SHRSP compared to WKY (2.51±0.14 vs 0.56±0.07, p<0.001). One-dimensional isoelectric focusing revealed that cytosolic Prx2 and mitochondrial Prx3 were more oxidized in SHRSP than WKY cells. Using a biotin-tagged dimedone-based probe (DCP-Bio) we identified oxidation of ER stress proteins BiP and IRE1. To investigate the effect of protein oxidation in vascular function, vascular reactivity was evaluated in isolated mesenteric arteries. Inhibition of general oxidation (DTT 1mM; Emax: 111.7±33.1) and peroxiredoxin (Conoidin A 10nM; Emax: 116.0±7.3) reduces vascular contraction in response to noradrenalin in WKY rats (Emax: 166.6±30.2; p<0.05). These findings suggest an important role for Nox1/4 in redox-dependent organelle dysfunction and post-translational modification of proteins, processes that may play an important role in vascular dysfunction in hypertension.

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Vascular Dysfunction and Insulin Resistance in Aging

Current Vascular Pharmacology ◽

10.2174/1570161117666181129113611 ◽

2019 ◽

Vol 17 (5) ◽

pp. 465-475 ◽

Cited By ~ 2

Author(s):

Agnieszka Baranowska-Bik ◽

Wojciech Bik

Keyword(s):

Insulin Resistance ◽

Vascular Function ◽

Vascular Dysfunction ◽

Pathological Condition ◽

Normal Serum ◽

Metabolic Effects ◽

Low Grade ◽

Physiological Concentration ◽

Repair Capacity ◽

Increased Risk

: Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function. : Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.

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Abstract 22: Formyl Peptide Receptor-1 Activation Is Crucial For The Cause Of Spontaneous Hypertension In Dahl Salt Sensitive Rats

Hypertension ◽

10.1161/hyp.76.suppl_1.22 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Jonnelle M Edwards ◽

Sarah Galla ◽

Nicole R Bearss ◽

Blair Mell ◽

Xi Cheng ◽

...

Keyword(s):

Vascular Injury ◽

Vascular Function ◽

Vascular Dysfunction ◽

Formyl Peptide Receptor ◽

Spontaneous Hypertension ◽

Leaky Gut ◽

Cell Necrosis ◽

Resistance Arteries ◽

Peptide Receptor ◽

Formyl Peptide

Mitochondria evolved from bacteria and use N-formylated peptides (NFPs) to synthetize protein. Bacterial and mitochondrial NFPs activate formyl peptide receptor 1 (FPR-1) and lead to vascular injury. We previously observed that Dahl Salt Sensitive rats (S) fed a low-salt (LS, 0.3% NaCl) diet presented spontaneous hypertension, vascular dysfunction, and overexpression of FPR-1 in arteries when compared to Dahl Salt Resistant (R) rats. High salt (HS, 2% NaCl) diet worsened these phenotypes in S rats. Interestingly, HS diet induced leaky gut and amoxicillin (AMO) treatment decreased BP in S-HS. Due to the dual sources of NFPs (microbiota and host mitochondria), we hypothesized that cell death-derived mitochondria and/or leaky gut-derived bacterial NFPs lead to FPR-1 activation, vascular injury and elevated BP in S rats independent of HS diet. For this, we used flow cytometry to measure cell necrosis and early and late apoptosis in kidney, bone marrow-derived macrophages and mesenteric resistance arteries (MRA) from male S and R rats (8-week old) on a LS diet. Zonulin, a biomarker for leaky gut, was measured in plasma. In another group, rats were treated with FPR-1 antagonist [Cyclosporin H (CsH), 0.3 mg/kg/day, osmotic mini-pump, 14 days], vehicle (VEH) or received water with AMO (5 mg/kg/day) for 21 days to deplete bacteria. BP was measured by telemetry and vascular function and structure were assessed in MRA. S rats presented increased kidney cell necrosis (R: 3.8±0.3 vs. S: 5.3±0.5* %). CsH decreased spontaneous elevation of BP [Diastolic: R+VEH: 77±2.7 vs. R+CsH: 81±1.2 vs. S+VEH: 126±3.0* vs. S+CsH:115±2.7 # ] and vascular hypercontractility [KCl (120mM): R+VEH: 9.4±1 vs. R+CsH: 10.2±0.4; S+VEH: 15.5±0.9* vs. S+CsH:11.7±0.8 # mN; Phenylephrine (10μM): R+VEH: 9.3±1 vs. R+CsH: 9.7±1; S+VEH: 14.5±1*vs. S+CsH: 11.4±0.6 # mN) in S-LS rats. AMO did not change vascular contraction or BP. Leaky gut was not observed in Dahl S-LS diet. In conclusion, FPR-1 can serve as a causative agent for the spontaneous elevation of BP and kidney-derived mitochondria, but not gut-derived microbiota, are the main source for NFPs.

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30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

Journal of Endocrinology ◽

10.1530/joe-17-0009 ◽

2017 ◽

Vol 234 (1) ◽

pp. T67-T82 ◽

Cited By ~ 42

Author(s):

Jennifer J DuPont ◽

Iris Z Jaffe

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Mineralocorticoid Receptor ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Kidney Injury ◽

Vascular Pathology ◽

The Impact

Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality.

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Role of Exercise in Vascular Function and Inflammatory Profile in Age-Related Obesity

Journal of Immunology Research ◽

10.1155/2018/7134235 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Anna Pedrinolla ◽

Massimo Venturelli ◽

Emine Kirmizi ◽

Federica Moschetta ◽

Monica Zardini ◽

...

Keyword(s):

Vascular Function ◽

Vascular Dysfunction ◽

Exercise Program ◽

Normal Weight ◽

Low Grade ◽

Supervised Exercise ◽

Age Related ◽

Long Term Effect ◽

Negative Effect ◽

Inflammatory Profile

In western countries, aging is often accompanied by obesity and age-related obesity is characterized by vascular dysfunction and a low-grade inflammatory profile. Exercise is a nonpharmacological strategy able to decrease the development and incidence of risk factors for several health-threatening diseases. Nonetheless, its long-term effect on vascular function and inflammation in age-related obesity is still unclear. The aim of this study was to investigate the effect of regular, supervised exercise on inflammatory profile and vascular function in age-related obesity. We also hypothesized that vascular function and inflammatory profile would have been correlated in overweight and obese individuals. Thirty normal weight (NW; 70 ± 5 years, 23.9 ± 2.6 BMI) and forty overweight and obese elderly (OW&OB; 69 ± 5 years, 30.1 ± 2.3 BMI) regularly taking part in a structured, supervised exercise program were enrolled in the study and evaluated for vascular function (flow-mediated dilation; FMD) and inflammatory profile (plasma CRP, IL-1β, IL-1ra, IL-6, IL-8, IL-10, TNF-α, and MCP-1). Although no differences between groups were found concerning performance and the weekly amount of physical activity, the OW&OB group compared with the NW group demonstrated higher systolic and diastolic blood pressure (+10%, p=0.001; +9%, p=0.005, respectively); lower FMD% (−36%, p<0.001) and FMD/shear rate (−40%, p=0.001); and higher levels of CRP (+33%, p=0.005), IL-6 (+36%, p=0.048), MCP-1 (+17%, p=0.004), and TNF-α (+16%, p=0.031). No correlations between vascular function and inflammation were found in OW&OB or NW. Although exercising regularly, overweight and obese elderly exhibited poorer vascular function and higher proinflammatory markers compared with the leaner group. These results support the idea that exercise alone cannot counteract the negative effect of adiposity on vascular function and inflammatory profile in elderly individuals and these two processes are not necessarily related.

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Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052366 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2366

Author(s):

Joshua Bond ◽

Tessa Nielsen ◽

Lynette Hodges

Keyword(s):

Chronic Fatigue Syndrome ◽

Vascular Function ◽

Augmentation Index ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Control Group ◽

Fatigue Syndrome ◽

The Impact

Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery. Methods: ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation). Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively). Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).

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Ιmmunity, Vascular Aging, and Stroke

Current Medicinal Chemistry ◽

10.2174/0929867329666220103101700 ◽

2022 ◽

Vol 29 ◽

Author(s):

Anna-Maria Louka ◽

Dimitrios Sagris ◽

George Ntaios

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Brain Barrier ◽

Low Grade ◽

Vascular Aging ◽

Barrier Dysfunction ◽

Blood Brain

Abstract: Stroke is one of the most devastating manifestations of cardiovascular disease. Growing age, arterial hypertension, and atherosclerosis are identified as independent risk factors for stroke, primarily due to structural and functional alterations in the cerebrovascular tree. Recent data from in vitro and clinical studies have suggested that the immune system influences atherosclerosis, promoting vascular stiffness and vascular aging and contributing to ischemic stroke, intracranial haemorrhage and microbleeds, white matter disease, and cognitive decline. Furthermore, aging is related to a chronic low-grade inflammatory state, in which macrophage, neutrophils, natural killer (NK cells), and B and T lymphocytes act as major effectors of the immune-mediated cell responses. Moreover, oxidative stress and vascular inflammation are correlated with endothelial dysfunction, vascular aging, blood-brain barrier disruption, lacunar lesions, and neurodegenerative disorders. This review discusses the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including the complex interplay between them and innate immunity, as well as vascular dysfunction, arterial stiffness, atherosclerosis, atherothrombosis, systemic inflammation, and blood-brain barrier dysfunction.

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Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

Biomedicines ◽

10.3390/biomedicines8010004 ◽

2020 ◽

Vol 8 (1) ◽

pp. 4 ◽

Cited By ~ 2

Author(s):

Ginevra Nannelli ◽

Marina Ziche ◽

Sandra Donnini ◽

Lucia Morbidelli

Keyword(s):

Aldehyde Dehydrogenase ◽

Vascular Function ◽

Vascular Dysfunction ◽

Low Grade ◽

Loss Of Function ◽

Aldehyde Dehydrogenase 2 ◽

Main Determinants ◽

And Function ◽

Low Grade Inflammation

Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, thus igniting a vicious cycle. We have furthermore to consider the physiological manifestation of vascular dysfunction and chronic low-grade inflammation during ageing, also known as inflammageing. Based on these considerations, knowledge of the molecular mechanism(s) responsible for endothelial loss-of-function can be pivotal to identify novel targets of intervention with the aim of maintaining endothelial wellness and vessel trophism and function. In this review we have examined the role of the detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) in the maintenance of endothelial function. Its impairment indeed is associated with oxidative stress and ageing, and in the development of atherosclerosis and neurodegenerative diseases. Strategies to improve its expression and activity may be beneficial in these largely diffused disorders.

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Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00786.2014 ◽

2015 ◽

Vol 309 (2) ◽

pp. H285-H296 ◽

Cited By ~ 26

Author(s):

Hooi H. Ng ◽

Maria Jelinic ◽

Laura J. Parry ◽

Chen-Huei Leo

Keyword(s):

Nitric Oxide ◽

Vascular Function ◽

Vascular Dysfunction ◽

Superoxide Production ◽

Resistance Arteries ◽

Vascular Effects ◽

Small Resistance ◽

Ros Scavenger ◽

Relaxation Responses ◽

Endothelial Nitric Oxide

The vascular effects of exogenous relaxin (Rln) treatment are well established and include decreased myogenic reactivity and enhanced relaxation responses to vasodilators in small resistance arteries. These vascular responses are reduced in older animals, suggesting that Rln is less effective in mediating arterial function with aging. The present study investigated the role of endogenous Rln in the aorta and the possibility that vascular dysfunction occurs more rapidly with aging in Rln-deficient ( Rln−/−) mice. We compared vascular function and underlying vasodilatory pathways in the aorta of male wild-type ( Rln+/+) and Rln−/− mice at 4 and 16 mo of age using wire myography. Superoxide production, but not nitrotyrosine or NADPH oxidase expression, was significantly increased in the aorta of young Rln−/− mice, whereas endothelial nitric oxide (NO) synthase and basal NO availability were both significantly decreased compared with Rln+/+ mice. In the presence of the cyclooxygenase inhibitor indomethacin, sensitivity to ACh was significantly decreased in young Rln−/− mice, demonstrating altered NO-mediated relaxation that was normalized in the presence of a membrane-permeable SOD or ROS scavenger. These vascular phenotypes were not exacerbated in old Rln−/− mice and, in most cases, did not differ significantly from old Rln+/+ mice. Despite the vascular phenotypes in Rln−/− mice, endothelium-dependent and -independent vasodilation were not adversely affected. Our data show a role for endogenous Rln in reducing superoxide production and maintaining NO availability in the aorta but also demonstrate that Rln deficiency does not compromise vascular function in this artery or exacerbate endothelial dysfunction associated with aging.

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