Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: a pilot trial in middle-aged and older adults

Abstract

Advancing age is associated with reductions in nitric oxide bioavailability and changes in metabolic activity, which are implicated in declines in motor and cognitive function. In preclinical models, sodium nitrite supplementation (SN) increases plasma nitrite and improves motor function, whereas other nitric oxide-boosting agents improve cognitive function. This pilot study was designed to translate these findings to middle-aged and older (MA/O) humans to provide proof-of-concept support for larger trials. SN (10 weeks, 80 or 160 mg/day capsules, TheraVasc, Inc.) acutely and chronically increased plasma nitrite and improved performance on measures of motor and cognitive outcomes (all p<0.05 or better) in healthy MA/O adults (62 ± 7 years). Untargeted metabolomics analysis revealed that SN significantly altered 33 (160 mg/day) to 45 (80 mg/day) different metabolites, 13 of which were related to changes in functional outcomes; baseline concentrations of 99 different metabolites predicted functional improvements with SN. This pilot study provides the first evidence that SN improves aspects of motor and cognitive function in healthy MA/O adults, and that these improvements are associated with, and predicted by, the plasma metabolome. Our findings provide the necessary support for larger clinical trials on this promising pharmacological strategy for preserving physiological function with aging.

Dietary nitrate-induced increases in human muscle power: high versus low responders

“…We observed a similar dietary NO 3 À -induced enhancement of maximal neuromuscular power in athletes (Rimer et al 2016), and an even greater increase (i.e., 13%) in patients with HF (Coggan et al 2015a). NO 3 À (or nitrite (NO 2 À )) -induced improvements in muscle contractility have also been observed in some (Haider and Folland 2014;Justice et al 2015;Whitfield et al 2017), albeit not all (Hoon et al 2015), recent studies of voluntary or electrically stimulated isometric exercise. Based on these previous studies (Haider and Folland 2014;Coggan et al 2015a,b;Justice et al 2015;Rimer et al 2016;Whitfield et al 2017), it therefore appears that dietary NO 3 À can enhance the inherent contractile properties of human muscle.…”

“…Based on these previous studies (Haider and Folland ; Coggan et al ,b; Justice et al ; Rimer et al ; Whitfield et al ), it therefore appears that dietary NO 3 − can enhance the inherent contractile properties of human muscle. However, as with NO 3 − ‐induced improvements in endurance performance (Christensen et al.…”

“…We observed a similar dietary NO 3 − ‐induced enhancement of maximal neuromuscular power in athletes (Rimer et al ), and an even greater increase (i.e., 13%) in patients with HF (Coggan et al 2015a). NO 3 − (or nitrite (NO 2 − )) ‐induced improvements in muscle contractility have also been observed in some (Haider and Folland ; Justice et al ; Whitfield et al ), albeit not all (Hoon et al ), recent studies of voluntary or electrically stimulated isometric exercise.…”

“…Maximal neuromuscular power is an important determinant of athletic performance and is also highly significant from a clinical perspective, as reductions in power contribute to impaired quality of life, disability, and possibly even mortality in various patient populations (e.g., the elderly (Guralnik et al 1994), heart failure (HF) patients (H€ ulsmann et al 2004)). It is therefore noteworthy that recent studies have demonstrated that acute or chronic supplementation with dietary nitrate (NO 3 À ), a source of nitric oxide (NO) via the enterosalivary pathway (Lundberg and Weitzberg 2009), can influence muscle contractile properties (Haider and Folland 2014;Coggan et al 2015a,b;Justice et al 2015;Rimer et al 2016;Whitfield et al 2017). In a previous study, for example, we found that acute ingestion of NO 3 À increased maximal knee extensor speed and power in healthy, untrained individuals by 11 and 6%, respectively, (Coggan et al 2015b).…”

Nutrition and other lifestyle influences on arterial aging

“…Moreover, recent reports show that supplementation with nitrite (DeVan et al, 2016) and nitrate (Rammos et al, 2014) improves endothelial function in middle-aged/older adults without clinical CVD. Nitrite seems particularly promising, as it also is reported to improve motor (neuromuscular) and cognitive functions (Justice et al, 2015), and larger trials to establish efficacy and broader mechanisms are underway (clinicaltrials.gov/ct2/show/NCT02393742).…”