Modifiable cardiometabolic risk factors induce the release of pro-inflammatory cytokines and reactive oxygen species from circulating peripheral blood mononuclear cells (PBMCs) resulting in increased cardiovascular disease risk and compromised immune health. These changes may be driven by metabolic reprogramming of PBMCs resulting in impaired mitochondrial respiration; however, this has not been fully tested. We aimed to determine the independent associations between cardiometabolic risk factors, such as blood pressure, BMI, and plasma lipids with impaired mitochondrial respiration in PBMCs isolated from generally healthy individuals (n=21) across the adult lifespan (12 M/ 9 F; age: 56 ± 21 years; age-range: 22-78 year; blood pressure: 123 ± 16 / 72 ± 10 mmHg; low-density lipoprotein cholesterol, LDL-C: 111 ± 22 mg/dL; and high-density lipoprotein cholesterol, HDL-C: 62 ± 16 mg/dL). PBMCs were isolated from whole blood by density dependent centrifugation and used to assess mitochondrial function by respirometry. Primary outcomes included baseline and maximal oxygen consumption rate (OCR) which were subsequently used to determine spare respiratory capacity and OCR metabolic potential. After correcting for HDL-C, SBP, and age, LDL-C was negatively associated with maximal respiration (r=-0.61, P=0.0073), spare respiratory capacity (r=-0.65, P=0.0038) and OCR metabolic potential (r=-0.59, P=0.010), respectively. In addition, there was a strong, but non-significant positive association between HDL-C and maximal respiration (r=0.46, P=0.057) and spare respiratory capacity (r=0.43, P=0.075), after correcting for other covariates. These data suggest a link between blood cholesterol and mitochondrial health that may provide insight into how cardiometabolic risk factors contribute to impaired immune cell function.

Age-related memory loss shares similar risk factors as cardiometabolic diseases including elevated serum triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C). The mechanisms linking these aberrant blood lipids to memory loss are not completely understood but may be partially mediated by reduced integrity of the hippocampus (HC), the primary brain structure for encoding and recalling memories. In this study, we tested the hypothesis that blood lipid markers are independently associated with memory performance and HC viscoelasticity—a noninvasive measure of brain tissue microstructural integrity assessed by high-resolution magnetic resonance elastography (MRE). Twenty-six individuals across the adult lifespan were recruited (14 M/12 F; mean age: 42 ± 15 y; age range: 22–78 y) and serum lipid profiles were related to episodic memory and HC viscoelasticity. All subjects were generally healthy without clinically abnormal blood lipids or memory loss. Episodic memory was negatively associated with the TG/HDL-C ratio. HC viscoelasticity was negatively associated with serum TGs and the TG/HDL-C ratio, independent of age and in the absence of associations with HC volume. These data, although cross-sectional, suggest that subtle differences in blood lipid profiles in healthy adults may contribute to a reduction in memory function and HC tissue integrity.

Stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) occurs with aging and may play a key role in memory impairment via a diminished pressure‐dampening effect, ultimately leading to loss of neuronal tissue integrity. In this regard, changes in brain tissue viscoelastic mechanical properties, an indirect measure of neuronal tissue integrity, may reflect the impact of elastic artery stiffening on brain health. Therefore, the purpose of this pilot study was to determine whether large elastic artery stiffness is associated with total brain viscoelasticity in healthy adults across the lifespan. All measures were performed in 13 healthy participants (6 females, mean age: 38 ± 15 y; age range: 22–69 y; mean BMI: 26 ± 5 kg/m2; mean BP: 111 ± 9/68 ± 10 mmHg). Carotid artery stiffness, beta‐stiffness index and compliance were assessed using B‐mode ultrasound (Logiq e, GE) coupled with applanation tonometry (SphygmoCor, AtCor Medical Inc.) and analyzed using commercial wall‐tracking software (Cardiovascular Suite, Quipu). Aortic stiffness was assessed as carotid‐to‐femoral pulse wave velocity (PWV) using applanation tonometry. Brain tissue viscoelastic mechanical properties (shear stiffness and damping ratio) were measured using magnetic resonance elastography (MRE). MRE data were acquired using 3T magnetic resonance imaging (Magnetom Prisma, Siemens, Inc.) while the brain viscoelastic property maps were generated using a nonlinear inversion algorithm. Associations between measures of age, large elastic artery stiffness and brain viscoelastic properties were determined using linear regression. PWV significantly increased with age (F = 25.6, p < 0.05, r2 = 0.7) while total brain stiffness significantly decreased with age (F = 6.1, p < 0.05, r2 = 0.36). Carotid artery stiffness (F = 4.3, p = 0.06, r2 = 0.28) and beta‐stiffness index (F = 2.9, p = 0.11, r2 = 0.21) tended to be inversely associated with total brain stiffness, whereas carotid artery compliance tended to be positively associated with total brain stiffness (F = 2.5, p = 0.14, r2 = 0.18). No relation was observed between PWV and total brain stiffness (F = 0.9, p = 0.37, r2 = 0.08). There were no associations between any measures of arterial stiffness and damping ratio. These preliminary data confirm that aging is associated with increase in arterial stiffness and loss of brain tissue integrity. They also indicate a possible association between large artery stiffening with brain tissue integrity and suggest that preserving elasticity of the carotid artery in particular may be important for protecting brain health with aging. Future work should assess the relation between carotid artery stiffness and brain mechanical properties in a larger group of individuals.Support or Funding InformationSupported by Center for Biomedical and Brain Imaging (CBBI) Pilot Grant P20GM103653 and Center of Biomedical Research Excellence (COBRE) Pilot Grant P20GM113125.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Increases in neuronal metabolic demand are typically matched by a proportional increase in brain blood flow. This neurovascular coupling (NVC) response is impaired with healthy aging and in Alzheimer's disease and has been attributed to an imbalance of reactive oxygen species (ROS) relative to endogenous antioxidant defenses (oxidative stress) in animal models; however, the role of ROS on NVC in healthy humans is not completely understood. High levels of ROS in the vasculature impairs endothelium‐dependent vasodilatation whereas smaller amounts of ROS in neurons may be necessary for NVC. Therefore, we aimed to investigate the effect of an acute antioxidant infusion (vitamin C; VTC) on NVC and shear‐mediated dilation of the internal carotid artery (ICA) in healthy adults. We hypothesized that, compared with control (saline), acute infusion of the antioxidant VTC would augment NVC in healthy adults. Seven healthy adults (2 males/5 females, age: 38 ± 24 years; BMI: 24.0 ± 3.5 kg/m2; blood pressure (BP): 104 ± 8/62 ± 5 mmHg) participated in this randomized, double‐blind placebo‐controlled intervention. Participants received a 20‐minute priming bolus infusion of either saline or 0.06 g ascorbic acid per kg fat‐free mass (FFM), followed by a drip‐infusion of either saline or 0.02 g ascorbic acid per kg FFM. Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler (TCD) ultrasound (Spencer Technologies, Redmond, WA) at an average insonation depth of 48.0 ± 6.0 mm. Cerebrovascular conductance (CVC) was calculated as mean MCAV divided by beat‐beat mean arterial pressure (FINAPRES NOVA, Enschede, Netherlands). NVC was assessed as the percent change (from baseline) in CVC (CVC%Δ) during an incrementally difficult cognitive challenge (N‐back task) after acute infusion of VTC vs. saline. Shear‐mediated vasodilation of the ICA to a transient (30 second) hypercapnia stimulus was also assessed at each time point as a measure of vascular function independent of neuronal demand. To quantify the NVC response, post infusion CVC and performance at each stage of the N‐back test were analyzed using a 2×2 repeated measures ANOVA with treatment (saline vs. VTC) and stage of the N‐back test as factors. Post‐infusion vasodilation of the ICA to transient hypercapnia was analyzed between treatment conditions using a paired t‐test. Data are presented as mean ± SD. Post‐infusion CVC%Δ was blunted at all levels of the N‐Back task after the infusion of VTC vs. saline (0‐Back: −3.94 ± 7.23% vs. 0.95 ± 3.23%; 1‐Back,: −4.16 ± 8.15% vs. 2.23 ± 4.72%; 2‐Back: −4.83 ± 14.94% vs. 4.79 ± 6.13%; Treatment effect: P = 0.045; F‐statistic (1,18) = 4.66). While there were no significant differences between stages, the number of correct responses decreased as the difficulty of the test increased. No significant differences in the ICA response to transient hypercapnia were observed after infusion of VTC vs. saline (4.08 ± 1.44% vs. 4.62 ± 0.76%; P = 0.54). These data suggest that ROS may be necessary to elicit an appropriate NVC response in healthy adults.Support or Funding InformationThis work was supported by a pilot grant through the Center of Biomedical Research Excellence in Cardiovascular Health P20GM113125.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No abstract