Adjuvant Nitrate to Boost Exercise-induced Health Benefits in Older Adults (BOOST-X)

Aging-related functional declines are thought to be caused by hallmark biological processes that ultimately manifest in physical, mental, and metabolic impairments to compromise intrinsic capacity and healthspan. Exercise is the only multipotent treatment with promise to mitigate many of the aging hallmarks, but there is substantial variability in individual exercise responsiveness. Thus, the investigators approach to boosting exercise responsiveness in aging is to combine an exercise training prescription containing both endurance and resistance training (in alignment with DHHS guidelines) with a nitrate-enriched dietary supplement to augment the cellular, tissue, and systemic adaptations that induce myriad health benefits of exercise in older adults.

Study Overview

• Status: Not yet recruiting
• Conditions: Aging; Healthy Aging; Aging Well
• Intervention / Treatment: Dietary supplement: Nitrate enriched beetroot juice; Other: 12 week of combined exercise training; Dietary supplement: Nitrate depleted beetroot juice

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 226
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Craig Tuggle, MA; Phone Number: 850-202-4416; Email: ctuggle@ihmc.org

Study Locations

• United States
  • Florida
    • Pensacola, Florida, United States, 32502
      • Florida Institute for Human and Machine Cognition

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. BMI ≥ 30.0 kg/m2
2. Neurodegenerative disease
3. Neuromuscular, musculoskeletal or orthopedic disorder or condition that would limit ability to perform the exercise prescription and/or physical performance testing
4. 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.
5. Resting blood pressure <90/60 mmHg or >160/95 mmHg
6. Uncontrolled hypertension
7. Any current cardiovascular disease or cardiopulmonary instability

8. Recent cardiovascular event or procedure within the preceding 6 months

   1. If valve replacement has been performed, patient may not be enrolled for 12 months after the procedure
   2. Any mechanical valve replacement that requires continuous warfarin anti-coagulation
9. Anemia: Hgb <11.0 (♂),10.0 (♂) gm/dl
10. Diabetes with HgbA1c >7.0% or fasting blood glucose ≥ 130 mg/dl
11. Liver disease with ALT > 52 U/l)
12. Chronic kidney disease (eGFR < 45)
13. Any current infectious disease
14. 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)
15. Life expectancy < 1 year Medications / lifestyle
16. Insulin sensitizing/blood glucose lowering agents such as metformin
17. Currently on or have used GLP-1 agonist or other metabolic / weight loss drug in previous 12 weeks
18. Use of nitrate medications
19. High dose statin (≥40 mg/d simvastatin equivalence)
20. Chronic corticosteroids
21. Testosterone or other anabolic/androgenic hormone therapy
22. Lidocaine allergy
23. Regular tobacco use and/or vaping > 1/wk
24. Use of cannabis > 1/wk
25. Excessive alcohol consumption (3 drinks/d or 7 drinks/wk for females; 4 drinks/d or 14 drinks/wk for males)
26. Use of illicit drugs (e.g., cocaine, opioids)
27. Unable to commit to ~4 months required to complete the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nitrate Group; Participants will be randomized to an intervention in which they take 800 mg (2 x 400 mg) nitrate-enriched beetroot juice drink [Beet It Sport Nitrate 400 (70 ml per drink)]. Both nitrate and placebo will be purchased from Beet It.	Dietary supplement: Nitrate enriched beetroot juice; Participants will be randomized to an intervention in which they take 800 mg (2 x 400 mg) nitrate-enriched beetroot juice drink [Beet It Sport Nitrate 400 (70 ml per drink)]. Both nitrate and placebo will be purchased from Beet It.; Other: 12 week of combined exercise training; All participants: An exercise dose will be composed of 12 wk of 3d/wk laboratory based supervised prescribed with strategic variations in intensity, volume, and modality across the 3 weekly sessions. During Monday and Friday RT sessions, participants complete 3 sets x 8-12 reps to volitional fatigue for leg press, knee extension, leg curl, overhead press, lat pulldown or row, and chest press in superset fashion with a 60 s rest between supersets. On Wednesday, participants perform 2 sets of 13-15 reps of leg press, knee extension, chest press and lat pulldowns with specific cues for speed and fast contractions. RT is complemented by the ET component which follows a Moderate-High Moderate intensity schedule with 30 min of 70-75% HRR steady state cycling on Monday and Friday separated by a Wednesday 20 min high intensity interval session on a cycle ergometer (1 min on/off; 10 cycles) at near maximal intensity with a target of 90% HRR.
Placebo Comparator: Placebo Group; Participants will be randomized to an intervention in which they take 800 mg (2 x 400 mg) nitrate-deprived, manufacturer-matched beetroot juice drink [Beet It Sport Nitrate 400 (70 ml per drink)]. Both nitrate and placebo will be purchased from Beet It.	Other: 12 week of combined exercise training; All participants: An exercise dose will be composed of 12 wk of 3d/wk laboratory based supervised prescribed with strategic variations in intensity, volume, and modality across the 3 weekly sessions. During Monday and Friday RT sessions, participants complete 3 sets x 8-12 reps to volitional fatigue for leg press, knee extension, leg curl, overhead press, lat pulldown or row, and chest press in superset fashion with a 60 s rest between supersets. On Wednesday, participants perform 2 sets of 13-15 reps of leg press, knee extension, chest press and lat pulldowns with specific cues for speed and fast contractions. RT is complemented by the ET component which follows a Moderate-High Moderate intensity schedule with 30 min of 70-75% HRR steady state cycling on Monday and Friday separated by a Wednesday 20 min high intensity interval session on a cycle ergometer (1 min on/off; 10 cycles) at near maximal intensity with a target of 90% HRR.; Dietary supplement: Nitrate depleted beetroot juice; Manufacturer-matched placebo that is nitrate-depleted beetroot juice (70 ml per drink). Both nitrate and placebo will be purchased from Beet It.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the clinical impact of nitrate supplementation on a proportion of older adults attaining exercise-induced health benefits.	The primary outcome will be assessed using logistic regression with the proportion not attaining Cardiorespiratory Fitness and functional Muscle Quality Minimally Clinical Differences as the response variable and treatment adjusted for sex and age group across the 12 week intervention.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiorespiratory demand during submaximal cycle exercise.	Supportive analyses will include secondary (cardiorespiratory demand during submaximal steady state exercise) outcomes. The steady state exercise cycling will be 10 minutes at 60% of peak power (Watts) during the VO2 peak test.	12 weeks
Neuromuscular fatiguability during isometric holds.	The knee extensors will perform a 30 second isometric flexion on a dynamometer. The fatigue will be defined by the force decline across the 30 seconds.	12 weeks
10 meter max gait speed.	Participants will walk as quickly as possible across a 10 meter, straight course. Time is recorded for up to three attempts. A lower time indicates a faster speed.	12 weeks
modified Balance Error Scoring System (mBESS)	Stability is assessed with the Sway Medical tablet app via three stances: double-leg, single-leg, and tandem. Scoring is decided by losing balance or opening eyes during closed eyed tests.	12 weeks
NIH PROMIS Physical Function SF	The NIH PROMIS Physical Function Short Form (SF) is a standardized tool used to evaluate an individual's physical abilities and limitations in daily activities. It is part of the broader Patient-Reported Outcomes Measurement Information System (PROMIS), which focuses on measuring patient-reported outcomes across various health domains.	12 weeks
NIH PROMIS Fatigue SF	PROMIS Fatigue SF refers to the short form of the Patient-Reported Outcomes Measurement Information System designed to assess fatigue levels in patients. It provides a standardized way to measure fatigue, which can be used in various clinical settings to evaluate patient health status.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive function.	Cognitive function is assessed via Sway Medical reaction time via three assessments: visual processing speed: measures how quickly a person can interpret visual information.	12 weeks
Psychological state.	Depression and anxiety are assessed via the well-validated Patient Health Questionnaire 9 (PHQ-9) both via Sway. The PHQ-9, or Patient Health Questionnaire-9, is a tool used to screen for, diagnose, and measure the severity of depression. It consists of nine questions that assess how often a person has experienced symptoms of depression over the past two weeks.	12 weeks
Sleep quality and nocturnal stress.	Perceptions of sleep quality are measured using the short forms (SF) of PROMIS Sleep Disturbance and Sleep-Related Impairment. For direct monitoring, participants wear an Oura Gen-4 ring to quantify sleep behavior with stress monitored via Heart Rate /Heart Rate variability (HRV) across the full enrollment period, as we have done in previous studies including the ongoing NIA M3AX Trial (NCT06507189). The Oura ring is well validated against polysomnography for several sleep metrics and nocturnal HR/HRV.	12 weeks
Free-living activity via the Oura Gen 4.	Free-living activity is also monitored daily via the Oura Gen-4 ring worn throughout trial participation. Variables such as step count and heart rate will used to determine activity.	12 weeks

Collaborators and Investigators

• Sponsor: Florida Institute for Human and Machine Cognition

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2031
• Study Completion (Estimated): May 1, 2031

Study Registration Dates

• First Submitted: April 17, 2026
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: IRB-2026-0019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified phenotyping data will be made accessible through supplementary data tables and files alongside manuscript publication or via third-party repositories. This data will also be hosted on secure server space without any link to PHI and made accessible through a publicly available Shiny app. Primary cell aliquots and biobanked snap frozen muscle and/or frozen blood samples will be provided to investigators upon reasonable request along with de-identified metadata.
• IPD Sharing Time Frame: Data share will begin when as soon as first data collections begin. Sub award sites will enter participant data on the secure Data Entry Management System (DEMS). Data shares will continue until the close of study.
• IPD Sharing Access Criteria: Access to all study data is granted on the researcher regulatory training and local IRB approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No