NCT04405180

Nitrites, Skeletal Muscle Mitochondrial Bioenergetics, and Physical Activity in Old Age

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 64 (actual)
• Sponsor: Gladwin, Mark, MD · Individual
• Sex: All
• Age: 70 Years
• Healthy volunteers: Not accepted

Summary

This 2-site randomized double blinded controlled trial is to confirm and more definitively clarify the impact of a 12-week course of nitrite versus placebo on mitochondrial bioenergetics in older sedentary adults. This investigator will take an integrative physiology approach to determine the effect of nitrite therapy on a comprehensive assessment of mitochondrial energetics, skeletal muscle vascular function, and whole body physical function (cardiorespiratory function, exercise endurance, strength, balance, and physical activity) and fatigability.

Detailed description

Old age is associated with declining skeletal muscle mitochondrial bioenergetics with related decrements in cardiorespiratory fitness (CRF) and physical function that predispose to frailty, disability, and diminished quality of life. While exercise training may moderate and possibly even reverse declines in mitochondrial bioenergetics, potential for such benefit is typically confounded by exercise intolerance with early fatigability that results from the same age-related mitochondrial declines. Consequently, sedentariness is endemic and insidious among the growing population of older adults. This trial is to study the utility of inorganic nitrite salts as a novel means to modify this detrimental pattern. Classic studies demonstrate that nitrite facilitates hypoxic vasodilation in muscle. This investigator's preliminary data suggests that nitrite treatment also augments skeletal muscle mitochondrial bioenergetics in older adults. This investigator proposes improving mitochondrial function will also be reflected in clinical parameters, including CRF as well as broader functional attributes (endurance, strength, and balance) that enable physical activity (PA) and opportunity to mitigate frailty and disability. As such, this application is in line with the National Institute on Aging's mission to develop targeted interventions to prevent and treat age-associated conditions. This multi-disciplinary team has published seminal work indicating that mitochondrial bioenergetics and CRF are significant determinants of physical function in older adults. In parallel efforts, this investigative team showed efficacy of chronic nitrite therapy to improve mitochondrial bioenergetics in older sedentary adults. Only one month of nitrite therapy significantly improved ex vivo assessments of mitochondrial energetics in skeletal muscle biopsies, concomitant with increased skeletal muscle sirtuin-3 expression, a nicotinamide adenine dinucleotide (NAD) dependent lysine deacetylase and key regulator of mitochondrial metabolism. These key data reinforce the premise that nitrite enhances vital mitochondrial metabolism in older adults. Moreover, improvement in muscle energetics in nitrite-treated older adults was linked with increased exercise efficiency as evidenced by reduced oxygen consumption (VO2) during submaximal steady-state walking. This data supports the hypothesis that nitrite will make physical function easier such that physical activity will increase.

Conditions

• Aging
• Sedentary Lifestyle
• Frailty

Interventions

Type	Name	Description
DRUG	Placebos	Oral placebo capsule at a dose of 20 mg administered three times per day, during the day.
DRUG	20mg sodium nitrite tid	Oral, inorganic sodium nitrite capsule at a dose of 20 mg administered three times per day, during the day.

Timeline

• Start date: 2021-04-23
• Primary completion: 2023-07-14
• Completion: 2023-07-14
• First posted: 2020-05-28
• Last updated: 2024-10-10
• Results posted: 2024-10-10

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study