Adjuvant Nitrate to Boost Exercise-induced Health Benefits in Older Adults

Aging-related declines in health and intrinsic capacity are linked to biological processes profoundly affecting all organ systems and tissues including skeletal muscle. Exercise is a multipotent countermeasure to these processes. However, there is significant inter-individual response heterogeneity (IRH) in the magnitude of exercise-induced health benefits. Boosting exercise responsiveness among older adults is thus a top priority. The investigators have found in older adults that supplementation with nitric oxide (NO) precursors nitrate and nitrite is safe, well tolerated, and improves: (i) physical performance; (ii) vascular endothelial function; (iii) mitochondrial function; (iv) oxidative stress; and (v) muscle inflammation. The investigators suspect deficits among some older adults in nitrate bioavailability and/or exercise-induced NO production may in part drive suboptimal exercise responsiveness. Given the powerful and sustaining impact of exercise-induced health benefits on morbidity and mortality, the investigator's fundamental premise is that exercise responsiveness of every older adult should be maximized. In the BOOST-X Trial the investigators will determine if increasing nitrate bioavailability via dietary supplementation is an efficacious approach to more older adults attaining these essential health benefits. Low cardiorespiratory fitness (CRF, VO2max) and low functional muscle quality (fMQ; strength/muscle mass) are multi-system manifestations of degenerative aging that include vascular endothelial and mitochondrial dysfunction, oxidative stress, and inflammation. CRF and fMQ are modifiable with endurance (ET) and resistance (RT) training. This planned trial will be the first to evaluate the efficacy of coupling a nitrate-rich nutritional supplement with a combined ET+RT prescription in line with DHHS weekly exercise guidelines. The investigators will test the central hypothesis that daily nitrate supplementation will augment exercise training-induced gains in CRF and fMQ accompanied by improvements in vascular endothelial and mitochondrial function. Aim 1: Assess the clinical impact of nitrate supplementation on the proportion of older adults attaining exercise-induced health benefits. N=226 participants stratified by sex and age group (60-69 vs ≥70 y) with random assignment to nitrate (400 mg, 2x/day) (n=113) vs. placebo (nitratedepleted) (n=113) during 12 wk of 3x/wk ET+RT. 1˚ Outcomes: MCID attainment for CRF and fMQ. Expected Results: Daily nitrate will reduce the proportion of older adults not attaining CRF and fMQ MCIDs by a full 1/3. Aim 2: Assess potential mechanisms underpinning adaptations to exercise +/- nitrate supplementation. The investigators will test/integrate in vivo, ex vivo, in vitro and molecular mapping assays considered central to exercise +/- nitrate adaptations and leverage a multidimensional learning framework to better understand the biocircuitry underpinning MCID attainment. 1˚ Outcomes: Vascular endothelial function, muscle mitochondrial function. Expected Results: MCID attainment will be closely linked to improvements in vascular endothelial function and muscle mitochondrial function. The acute molecular responses to exercise will be differentially regulated by nitrate supplementation, and the novel biocircuitry will reveal key features that influence adaptability.

Inclusion criteria

• Male or female aged 60 years or older
• Free of chronic disease or disorder that would preclude full participation or have the potential to confound results
• No structured exercise program (2 or more bouts/wk) within previous 12 months
• Cognitively capable of providing informed consent

Exclusion criteria

• BMI ≥ 30.0 kg/m2
• Neurodegenerative disease
• Neuromuscular, musculoskeletal or orthopedic disorder or condition that would limit ability to perform the exercise prescription and/or physical performance testing
• Diagnosed orthostatic hypotension, i.e., a drop in systolic blood pressure of at least 20 mmHg or a drop in diastolic blood pressure of at least 10 mmHg within three minutes of standing up from a sitting or lying position.
• Resting blood pressure <90/60 mmHg or >160/95 mmHg
• Uncontrolled hypertension
• Any current cardiovascular disease or cardiopulmonary instability
• Recent cardiovascular event or procedure within the preceding 6 months

• If valve replacement has been performed, patient may not be enrolled for 12 months after the procedure
• Any mechanical valve replacement that requires continuous warfarin anti-coagulation
• Anemia: Hgb <11.0 (♂),10.0 (♂) gm/dl
• Diabetes with HgbA1c >7.0% or fasting blood glucose ≥ 130 mg/dl
• Liver disease with ALT > 52 U/l)
• Chronic kidney disease (eGFR < 45)
• Any current infectious disease
• Any other disease or disorder that could influence exercise response, preclude full participation or have the potential to confound results (e.g., chronic lung disease, cognitive impairment, current cancer diagnosis or within 2 yr remission, cerebrovascular disease, pain)
• Life expectancy < 1 year Medications / lifestyle
• Insulin sensitizing/blood glucose lowering agents such as metformin
• Currently on or have used GLP-1 agonist or other metabolic / weight loss drug in previous 12 weeks
• Use of nitrate medications
• High dose statin (≥40 mg/d simvastatin equivalence)
• Chronic corticosteroids
• Testosterone or other anabolic/androgenic hormone therapy
• Lidocaine allergy
• Regular tobacco use and/or vaping > 1/wk
• Use of cannabis > 1/wk
• Excessive alcohol consumption (3 drinks/d or 7 drinks/wk for females; 4 drinks/d or 14 drinks/wk for males)
• Use of illicit drugs (e.g., cocaine, opioids)
• Unable to commit to ~4 months required to complete the study