Vascular Aging
Conditions
Keywords
Endothelial Function, Microbiome
Brief summary
Emerging data suggest the gut microbiota regulates multiple mechanisms related to vascular aging, but no intervention targeting the gut microbiota has been tested in older adults without cardiovascular risk factors or cardiovascular disease. Early human data suggest an increase in potentially pathological gut metabolites such as trimethylamine-N-oxide (TMAO) are associated with older age, increased vascular stiffness, increased oxidative stress, and reduced nitric oxide (NO) bioavailability as evidenced by impaired endothelium-dependent vasodilation. Based on this data, the investigators hypothesize that supplementation with Lp299v will reverse human vascular aging in healthy older adults free of known traditional cardiovascular risk factors.
Detailed description
Multiple lines of evidence suggest that aging results in significant changes in the composition and metabolism of the gut microbiota that accelerate mechanisms responsible for vascular aging. Recent work established cross-sectional associations between phenotypically older vasculature (with increased vascular stiffness and impaired brachial endothelium-dependent vasodilation) and age-related alterations on the composition of the gut microbiota and metabolites that are derived from microbial metabolism such as TMAO (trimethylamine-N-oxide), nicotinamide, tryptophan, and purines. Animal data also suggests short-chain fatty acids favorably impact endothelium-dependent vasodilation. SCFAs exert a direct anti-inflammatory effect on mononuclear cells and increase glucagon-like protein 1 (GLP-1) production which activates endothelial nitric oxide synthase (eNOS) and increases NO levels. Taken together, these data suggest aging-related changes in the gut microbiota could adversely affect vascular health through multiple mechanisms, even in the absence of concomitant cardiovascular risk factors. Six weeks of Lp299v supplementation in 36 otherwise healthy smokers reduced systemic inflammation, as evidenced by reductions in leptin (an adipokine that stimulates IL-6 production) and IL-6 levels, reduced monocyte adhesion to endothelial cells, and reduced circulating fibrinogen levels (elevated in the setting of inflammation). In addition, Lp299v supplementation reduced oxidative stress based on reduced urinary F2-isoprostanes and had a modest lowering effect on systolic blood pressure. The investigators will recruit 20 healthy older adults (10 men, 10 women ages 50 or older) without traditional cardiac risk factors or prevalent cardiovascular disease and randomize subjects into a 6-week, double-blind, randomized, placebo-controlled clinical trial of Lp299v supplementation. Measurements of micro-and macrovascular function, systemic inflammation, and stool microbiota composition will be made.
Interventions
OTHERLactobacillus Plantarum 299v in fermented oat drink
The intervention is a probiotic lactobacillus that is contained in food products in the US
OTHERHeat-Killed Placebo control fermented drink
The intervention is the GoodBelly StraightShort that has been treated to heat kill all Lp299v
Sponsors
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 99 Years
Healthy volunteers
Yes
Inclusion criteria
* Ages 50-99 years * For women: 12 months or more since last menstruation
Exclusion criteria
* Systolic Blood Pressure ≥ 130 mmHg or Diastolic BP ≥ 80mmHg * Currently taking pharmacological therapies for hypertension, dyslipidemia, or glucose control * Diabetes (type 1 or 2) or glycosylated hemoglobin ≥ 5/7% * LDL Cholesterol \> 160 mg/dL or Total Cholesterol \> 200 mg/dL * Cigarette use within 3 years of enrollment * Average of \> 7500 steps per day as measured during screening period * Received probiotics, prebiotics, and/or antibiotics within six weeks of enrollment * History of chronic renal insufficiency, liver dysfunction, or cancer besides non-melanoma skin carcinomas or localized prostate cancer requiring systemic treatment within 3 years of enrollment * History of inflammatory rheumatic diseases known to increase atherosclerotic cardiovascular risk (e.g. rheumatoid arthritis, systemic lupus erythematosus) * Known history of cognitive impairment or inability to follow study procedures * GI tract illnesses such as short gut syndrome, inflammatory bowel disease, or an ileostomy * Daily alcohol use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brachial Artery Flow Mediated Dilation (FMD% | 6 weeks | This is a measurement of endothelial function in the brachial artery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nitroglycerin-Mediated Vasodilation of the brachial artery (NMD) | 6 weeks | Measurement of vascular smooth muscle reactivity |
| Hyperemic Flow Velocity | 6 weeks | Measurement of microvascular endothelial function |
| Carotid-Femoral Pulse Wave Velocity (cfPWV) | 6 weeks | Measurement of vascular stiffness |
| Stool microbiota alpha diversity | 6 weeks | Diversity of bacterial species in the individual microbiome |
| Stool microbiota beta diversity | 6 weeks | Differences in bacterial composition between intervention arms |
| Brachial Artery Resting Diameter | 6 weeks | resting diameter of the brachial artery - representative of resting vascular tone |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichael E Widlansky, MD
Medical College of Wisconsin
Outcome results
None listed