No abstract

Aging is associated with stiffening of the large elastic arteries and consequent increases in systolic blood pressure (SBP), which together increase cardiovascular disease risk; however, the upstream mechanisms are incompletely understood. Using complementary translational approaches in mice and humans, we investigated the role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in age-related aortic stiffening and increased SBP. Aortic stiffness was measured using carotid-femoral or aortic pulse wave velocity (PWV) in humans and mice, respectively. Study 1: Plasma TMAO concentrations were elevated ( P <0.001) in healthy middle-aged to older (6.3±5.8 µmol/L) versus young (1.8±1.4 µmol/L) humans and positively related to carotid-femoral PWV ( r 2 =0.15, P <0.0001) and SBP ( r 2 =0.09, P <0.001), independent of traditional cardiovascular risk factors. Study 2: Dietary supplementation with TMAO increased aPWV in young mice and exacerbated the already elevated aPWV of old mice, accompanied by increases in SBP of ≈10 mm Hg in both groups. TMAO-supplemented versus control-fed mice also had higher intrinsic mechanical stiffness of the aorta (stress-strain testing) associated with higher aortic abundance of advanced glycation end-products, which form crosslinks between structural proteins to promote aortic stiffening. Study 3: Ex vivo incubation of aortic rings with TMAO increased intrinsic stiffness, which was attenuated by the advanced glycation end-products crosslink breaker alagebrium and prevented by inhibition of superoxide signaling. TMAO induces aortic stiffening and increases SBP via formation of advanced glycation end-products and superoxide-stimulated oxidative stress, which together increase intrinsic wall stiffness. Increases in circulating TMAO with aging represent a novel therapeutic target for reducing risk of aortic stiffening-related clinical disorders.

Aging is associated with elevated systolic blood pressure (SBP) and impaired vascular function, characterized by endothelial dysfunction and stiffening of the large elastic arteries, which all increase risk for cardiovascular diseases (CVD). Passive repeated heat exposure (“heat therapy”) is associated with lower CVD risk at the population level and improves CV function in animals, healthy young adults, and selective groups of patients with clinical disease. It is unknown, however, if heat therapy lowers SBP and/or improves vascular function in late middle‐aged to older (MA/O) adults free of clinical diseases/disorders.PurposeTo determine if heat therapy via hot water immersion in healthy MA/O adults lowers SBP and/or improves markers of vascular health that are independent risk factors for CVD.MethodsTen healthy MA/O men and post‐menopausal women (57–76 years) were randomly assigned to participate in thirty 60‐min sessions of either hot (40.5°C; N=6, 3M/3F, 67±3 years) or thermoneutral (36°C, “sham”; N=4, 1M/3F, 69±2 years) water immersion. Resting (casual) BP and ultrasound‐ and tonometry‐based measures of vascular function and structure were measured at baseline and 24–72 h after the last water immersion session. Data are mean±S.E. Changes in outcome variables were compared within groups by paired t‐test.ResultsHot water immersion increased rectal temperature (Tre) from 36.9±0.2 to 38.7±0.1°C (p<0.001; data from first session), whereas no changes in Tre were observed in sham subjects (resting: 37.2±0.1 vs. peak: 37.3±0.1°C, p=0.23). Adherence was good, with subjects completing all sessions in 9.8±0.4 weeks (3.1±0.1 sessions/week). Heat therapy was well‐tolerated, with only 3% of sessions ending early due to occurrence of mild heat‐related symptoms (e.g., lightheadedness). Heat therapy decreased SBP by 10 mmHg on average (130±4 vs. 120±5 mmHg, p=0.04), increased endothelial function by ~50% (brachial artery flow‐mediated dilation, FMDBA: 4.4±0.7 vs. 6.5±0.9%, p<0.01), and decreased carotid intima media thickness (cIMT) by ~10% (0.70±0.02 vs. 0.64±0.03 mm, p=0.02), but did not significantly alter arterial stiffness (carotid‐femoral pulse wave velocity, PWV: 8.6±0.4 vs. 8.2±0.7 m/s, p=0.48), or diastolic BP (DBP: 81±4 vs. 78±5 mmHg, p=0.36). No effects were observed in sham subjects (SBP: 133±11 vs. 131±12 mmHg, p=0.31; FMDBA: 4.9±0.9 vs. 4.8±0.7%, p=0.92; cIMT: 0.69±0.02 vs. 0.68±0.03 mm, p=0.77; PWV: 9.6±1.6 vs. 9.3±1.6 m/s, p=0.35; DBP: 79±3 vs. 74±2 mmHg, p=0.17).ConclusionOur preliminary results suggest that in healthy MA/O adults, heat therapy is safe, is associated with excellent adherence, and induces clinically‐significant reductions in casual SBP and improvements in endothelial function comparable to or greater than those typically observed with aerobic exercise training. Heat therapy also induces a unique reduction in cIMT typically found only with longer‐term pharmacological therapies. Heat therapy may be a promising lifestyle‐based strategy for reducing SBP, endothelial dysfunction and, possibly, CVD risk with aging.Support or Funding InformationNCT03264508This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Age-related increases in aortic stiffness, assessed by pulse wave velocity (PWV), predict cardiovascular (CV)-related mortality, but the upstream drivers are incompletely understood. Purpose To determine if higher circulating levels of the gut microbiome-derived metabolite trimethylamine-N-oxide (TMAO) contribute to age-related aortic stiffening. Methods and Results Plasma TMAO concentrations were higher in healthy middle-aged-to-older (45–79 y; N = 83) vs. young (18–27 y; N = 14) humans (6.3 ± 0.6 vs. 1.8 ± 0.3 μM; p < 0.01) and positively related to carotid-femoral (c-f) PWV (r2 = 0.15, p < 0.0001). To determine the role of TMAO in established age-related aortic stiffness, we supplemented old mice (27 mo; N = 12–16/group) with 1% 3,3-dimethyl-1-butanol (DMB; suppresses microbiota-dependent TMAO production) in drinking water for 8–10 weeks vs. normal drinking water (control). Relative to young mice (3 mo; N = 23), old mice had higher aortic (a) PWV (412 ± 17 vs. 349 ± 11 cm/s; p < 0.01), but DMB had no effect on aPWV (p = 0.58 vs. control) despite suppressing plasma TMAO (control: 8.7 ± 6.3 vs. DMB: 4.3 ± 1.2 µM, p = 0.07) to young levels (3.8 ± 2.6 µM). Next, to determine if TMAO contributes to the development of aortic stiffening, we initiated DMB at mid-life (18 mo; i.e., before the onset of stiffening; N = 8–21/age/treatment). aPWV was similar between young and 18 month-old mice (363 ± 5 cm/s; p = 0.58), but increased progressively with age in control mice (24 mo: 401 ± 13 cm/s, p = 0.03 vs. young; 27 mo: 442 ± 10 cm/s, p < 0.001 vs. young), whereas age-related increases in PWV were considerably attenuated by DMB (24 mo: 359 ± 9 cm/s; 27 mo: 388 ± 10 cm/s, both p < 0.01 vs. control). Conclusions Age-related increases in TMAO contribute to the development of aortic stiffness. TMAO-targeted interventions initiated in mid-life may prevent/delay age-related aortic stiffening and reduce CV risk. Funding HL134887-02S1, AG060884, HL140875, AG000279.

Fluid cognitive function (the domain of cognition most impaired in Alzheimer’s Disease) declines with aging, predisposing older adults to Alzheimer’s Disease and related dementias. Age-related cerebrovascular dysfunction contributes to cognitive decline by impairing brain blood flow such that there is chronic cerebral hypoperfusion, which has been linked to cognitive impairment. Increased oxidative stress and the resultant loss of nitric oxide (NO) bioavailability likely play mechanistic roles in age-related cerebrovascular dysfunction. Passive heat therapy (i.e., regular heat exposure) improves peripheral vascular outcomes and reduces oxidative stress and, therefore, may also improve cognitive and cerebrovascular function. Purpose: To test the hypotheses that heat therapy would 1) improve fluid cognitive function, 2) increase total cerebral blood flow (tCBF), and 3) reduce cerebrovascular reactive oxygen species (ROS) production and increase NO bioavailability. Methods and results: Midlife and older (ML/O) adults (50+ years) were randomized to 8-10 weeks of passive heat therapy (via hot [40 °C] water immersion; 30 x 60-min sessions) or sham control (via thermoneutral [36 °C] water immersion; NCT03264508). The following preliminary results were collected at baseline (pre) and at the end (post) of the heat therapy or sham intervention (n=6-10/group). Fluid Cognition Composite scores, assessed using the NIH Toolbox Cognition Battery, increased from 97± 3 (mean ± SEM) at baseline to 100± 3 at end-intervention (p=0.03) in subjects who underwent heat therapy, an improvement from the 42nd to 50th percentile of all U.S. adults, but there was no consistent change in sham subjects (p=0.16). tCBF, assessed via duplex ultrasonography of the vertebral and internal carotid arteries, increased from 766± 99 mL/min at baseline to 841± 123 mL/min after heat therapy (p=0.03), whereas there was no change following sham (pre: 723± 20 vs. post: 729± 26 mL/min; p=0.89). Cerebrovascular ROS production and NO bioavailability were assessed with fluorescent probes in vitro using human brain endothelial cells (HBECs; technical replicates n=24-29) cultured in hot (39 °C; to match in vivo body core temperature during heat therapy sessions) and standard (37 °C) conditions. HBECs cultured in hot conditions had lower basal ROS production (hot: 860± 7 AU vs. standard: 907± 5 AU; p<0.01) and higher acetylcholine-stimulated NO production (hot: 1.5± 0.06 vs. standard: 1.3± 0.04 fold change in NO production; p=0.03). Conclusions: These results suggest that heat therapy can improve fluid cognition and brain blood flow in ML/O adults, possibly by reducing brain endothelial cell ROS production and increasing NO bioavailability. Heat therapy shows potential to protect cognitive performance in the domain most affected by Alzheimer’s Disease and improve cerebrovascular function in ML/O adults. NIH/NCATS UL1 TR002535; T32 AG000279; R01 AG073117 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.