Benefits of oral nitrite supplementation on mitochondrial respiration and physical function in older adults.

Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration in older adults.

• The primary outcome was change in muscle mitochondrial respiration measured as complex I and II supported maximal oxidative phosphorylation (CI&II MaxOXPHOS).
• 64 adults (75.7 ± 5.7 years) completed the randomized, placebo-controlled, double-blind, two-arm parallel group trial.
• Participants received 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo.
• No statistically significant improvement in skeletal muscle mitochondrial respiration was observed with nitrite supplementation compared to placebo.

Nitrite supplementation was not associated with improvements in exercise capacity or physical function in older adults.

• Cardiorespiratory fitness and other physical function measures were assessed as secondary outcomes.
• Participants were sedentary older adults aged ≥70 years.
• Neither exercise capacity nor broader physical function measures showed significant improvement with 12 weeks of sodium nitrite supplementation.

Platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite.

• Platelet bioenergetics were assessed as a secondary outcome alongside skeletal muscle mitochondrial respiration.
• The response of platelet mitochondrial respiration to nitrite supplementation diverged from the non-significant response observed in skeletal muscle.
• This divergent response suggests tissue-specific pharmacokinetics and pharmacodynamics that likely impact the efficacy of nitrite supplementation.

Plasma nitrite levels increased 16- to 30-fold following an acute dose of oral nitrite, while skeletal muscle nitrite levels increased only 1.6-fold.

• Nitrite levels in plasma increased 16- to 30-fold following an acute oral nitrite dose.
• In contrast, nitrite levels in skeletal muscle increased only 1.6-fold after an acute dose.
• This large disparity between plasma and skeletal muscle nitrite accumulation suggests tissue-specific pharmacokinetic differences.
• The limited increase in skeletal muscle nitrite may explain the lack of effect on skeletal muscle mitochondrial respiration.

The study authors suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness that differ from effects of nitrite/nitrate previously demonstrated in younger adults.

• Prior studies have demonstrated improvements in mitochondrial energetics and physical function with oral nitrite and nitrate supplementation in younger adults.
• Effects in older adults (age ≥70 years) were previously unclear prior to this trial.
• The authors propose that age-related changes in drug delivery, metabolism, and mitochondrial responsiveness may account for the divergent findings in this older population compared to younger adult studies.

The trial enrolled sedentary older adults with a mean age of 75.7 years in a randomized, placebo-controlled, double-blind design.

• 64 adults completed the trial with mean age 75.7 ± 5.7 years.
• Eligibility required age ≥70 years and sedentary status.
• The design was a two-arm parallel group randomized controlled trial registered at ClinicalTrials.gov (NCT04405180).
• The intervention was 20 mg sodium nitrite three times daily for 12 weeks versus placebo.