Nitrite therapy to improve mitochondrial energetics and physical activity in older adults
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Contemporary demographic patterns include the prominent growth of the older adult population. Old age is associated with declining skeletal muscle mitochondrial bioenergetics, and ramifications include decreased physical function, increased fatigability, and greater vulnerability to frailty and disability. Therefore, augmenting mitochondrial respiration may help to fundamentally improve the health and wellbeing of older adults. Our preliminary data show that inorganic sodium nitrite treatment augments skeletal muscle mitochondrial bioenergetics in older sedentary adults and that it also enhances the metabolic efficiency of walking (i.e., reduced oxygen utilization for the same submaximal walking activity). This provides strong rationale for a 3- year trial to more definitively analyze the utility of sodium nitrite treatment to enhance skeletal muscle mitochondrial respiration in older sedentary adults. Nitrites will be administered as convenient capsules, a novel preparation that we have demonstrated is well-tolerated and associated with high serum nitrite levels. Aim 1 will emphasize mitochondrial bioenergetic assessments, and include ex vivo (Oroboros) as well as in vivo (phosphorus magnetic resonance spectroscopy) mitochondrial respirometry measures to fully elucidate pertinent physiology. Furthermore, skeletal muscle RNA transcription (RNA-seq), Western blots, and transmission electron microscopy will additional enrich insights regarding nitrite effects on mitochondrial performance. In Aim 2, complementary vascular analyses will be included, with measures of vascular flow (flow-mediated dilation) and perfusion (near infrared spectroscopy) to fully delineate nitrite’s endothelial effects. Aim 3 is exploratory, and focuses on nitrite therapy’s impact on physical function, daily activity, and fatigability. Physical function is assessed both in terms of physiological measures (i.e., peak oxygen update (VO2) and VO2 at a submaximal workload) and clinical measures (i.e., endurance [tolerance of submaximal work at 70% peak VO2 until exhaustion], 6 minute walk distance, the Short Physical Performance Battery, and handgrip strength). Daily activity is measured using accelerometry. Fatigability is measured in respect to perceived and performance indices. Overall, this proposal provides a critical mechanistically-oriented perspective regarding the efficacy of nitrite; if mitochondrial bioenergetics are improved in this analysis, future studies can explore nitrite’s utility as a therapy to help surmount sedentariness in old age.
