Nitrite Supplementation for Improving Physiological Function in Older Adults (NITRITE)

Efficacy of Oral Sodium Nitrite for Improving Physiological Functions in Older Adults

Nitric oxide (NO) is an essential molecule in the body that decreases with aging and causes reductions in vascular, movement ("motor") and cognitive functions. This study will determine if daily oral supplementation (3 months) with a compound that increases NO in the body, i.e., sodium nitrite, improves vascular, motor and cognitive function in older adults. The project also seeks to provide insight into the biological reasons (mechanisms) by which supplementation with sodium nitrite improves physiological function in older adults. Overall, this research will provide scientific evidence supporting the use of sodium nitrite for preserving physiological function and preventing clinical disease and disability with aging.

Study Overview

• Status: Completed
• Conditions: Ageing
• Intervention / Treatment: Drug: Placebo; Drug: Sodium nitrite

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Boulder, Colorado, United States, 80309
      • Clinical Translational Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• • Age 60-79 years. Women will be confirmed as postmenopausal (either natural or surgical) based on cessation of menses for >1 year.

  • Ability to provide informed consent
  • Score >22 on the mini mental state exam (MMSE) to allow a broad range of normal and mildly-impaired cognitive abilities, but function adequate to understand and complete trials (214)
  • Baseline brachial flow-mediated dilation (FMD) < 7%Δ (rationale: non-invasive screening to ensure exclusion of subjects with exceptionally high baseline endothelial function(215))
  • Blood pressure (BP) >100/60 mmHg for past 3 mo (rationale: blood pressure below 100/60 mmHg may elevate the normally small risk of hypotension with sodium nitrite treatment)
  • Ability to perform motor and cognitive tests (e.g., can rise from a chair, walk for 2 min, climb 10 stairs)
  • Willing to accept random assignment to condition (older adults)

Exclusion Criteria:

• • High dietary nitrate intake or current nitrite supplementation; hypersensitivity to nitrates or nitrites

  • Glucose-6-phosphate dehydrogenase deficiency or blood methemoglobin >2%
  • Current smoking
  • Having past or present alcohol dependence or abuse, as defined by the American Psychiatry Association, Diagnostic and Statistical Manual of Mental Disorders
  • Body mass index (BMI) >40 kg/m2 (FMD measurements can be inaccurate in severely obese patients)
  • Chronic clinical diseases (e.g., coronary artery/peripheral artery/cerebrovascular diseases, diabetes, chronic kidney disease requiring dialysis, neurological disorders or diseases that may affect motor/cognitive functions [multiple sclerosis, Parkinson's disease, polio, Alzheimer's disease, dementia or other brain diseases of aging]), except hypertension and hyperlipidemia.
  • Regular vigorous aerobic/endurance exercise (>3 vigorous bouts/week)
  • Not weight stable in the prior 3 months (>2 kg weight change) or unwilling to remain weight stable throughout study (rationale: recent weight change or weight loss can influence vascular function and small metabolite signature(216))
  • Current treatment or recent cessation (< 3 mo) of hormone replacement therapy.
  • Moderate or severe peripheral artery disease (ankle-brachial index <0.7)(183)
  • A graded exercise test will be performed by all subjects, if there is physician concern or an adverse event, the subject will not participate in a maximal oxygen consumption test (this will be determined in accordance with stated contraindications for exercise testing provided by the American Heart Association)(217)
  • Claustrophobia, metal implants, etc., affecting feasibility and/or safety of the fMRI scanning.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Nitrite Supplementation; 80 mg/day (40 mg 2x/day) slow release sodium nitrite (TheraVasc, Inc) for 3 months	Drug: Sodium nitrite
Placebo Comparator: Placebo; placebo 2x/day for 3 months	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular Function	flow mediated dilation	3 months
Motor Function	rate of torque development	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic oxidative stress and inflammation	circulating markers of oxidative stress and inflammation	3 months
Number of participants with additional measures of motor ability	tests of balance, endurance, strength, and dexterity	3 months
endothelial cell oxidative stress and inflammation	inflammatory and oxidative stress markers in biopsied endothelial cells	3 months
plasma metabolites		3 months
NIH Toolbox cognition test battery	Cognitive Function	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
neural activation	brain activity measured during n-back task in functional magnetic resonance imaging (fMRI)	3 months

Collaborators and Investigators

• Sponsor: University of Colorado, Boulder
• Investigators: Study Director: Matthew J Rossman, PhD, University of Colorado, Boulder

Publications and helpful links

General Publications

• Jones AM, Vanhatalo A, Seals DR, Rossman MJ, Piknova B, Jonvik KL. Dietary Nitrate and Nitric Oxide Metabolism: Mouth, Circulation, Skeletal Muscle, and Exercise Performance. Med Sci Sports Exerc. 2021 Feb 1;53(2):280-294. doi: 10.1249/MSS.0000000000002470.
• Rossman MJ, Gioscia-Ryan RA, Santos-Parker JR, Ziemba BP, Lubieniecki KL, Johnson LC, Poliektov NE, Bispham NZ, Woodward KA, Nagy EE, Bryan NS, Reisz JA, D'Alessandro A, Chonchol M, Sindler AL, Seals DR. Inorganic Nitrite Supplementation Improves Endothelial Function With Aging: Translational Evidence for Suppression of Mitochondria-Derived Oxidative Stress. Hypertension. 2021 Apr;77(4):1212-1222. doi: 10.1161/HYPERTENSIONAHA.120.16175. Epub 2021 Mar 1.

Helpful Links

• description of our laboratory

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: March 13, 2015
• First Submitted That Met QC Criteria: March 18, 2015
• First Posted (Estimate): March 19, 2015

Study Record Updates

• Last Update Posted (Actual): December 5, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Other Study ID Numbers: R01AG013038-19 (U.S. NIH Grant/Contract)