Aging, Aging Well, Healthy Aging
Conditions
Brief summary
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.
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.
Interventions
DIETARY_SUPPLEMENTNitrate 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.
DIETARY_SUPPLEMENTNitrate 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.
OTHER12 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.
Sponsors
Florida Institute for Human and Machine Cognition
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Participants will be randomized in double-blind fashion to consume 2x/day nitrate-rich beetroot juice (Beet-it®, 400 mg inorganic nitrate per dose x 2/day) or nitrate-depleted placebo beetroot juice. To bolster trial rigor, the placebo is also produced by Beet-it®, is taste- and volume-matched, contains all other potentially bioactive ingredients sans nitrate, and active vs. placebo bottles are indistinguishable. The blind will be held by independent research staff not involved in the study. Daily consumption of each dose will be closely monitored via a phone-based logging app integrated with the electronic DEMS. The app also enables research staff to push reminders to participants as needed. Participant tolerance has not been a concern in our prior and ongoing studies. However, the investigators will monitor individual tolerance and address any issues on a case-by-case basis.
Intervention model description
Parallel randomized controlled trials typically aim to test whether intervention "A" outperforms placebo "B" in group wise analyses based on a statistical analysis of variance comparing group means, where the mathematical probability of detecting "significance" between A and B increases with the degree of homogeneity of individual responses in group A and in group B. Our analytic plan in BOOST-X is far more innovative; it leverages the heterogeneity among individuals. After over two decades of studying potential mechanisms of Individual Response Heterogeneity (IRH) and strategies to boost response rates including exercise dosing, adjuvant nutrition, and adjuvant medication, the investigators have come to expect IRH. The goal is to maximize the proportion of individuals who attain clinically important health benefits, specifically MCIDs for CRF and fMQ. And the investigators hypothesize adjuvant nitrate will substantially boost this proportion.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess the clinical impact of nitrate supplementation on a proportion of older adults attaining exercise-induced health benefits. | 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiorespiratory demand during submaximal cycle exercise. | 12 weeks | 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. |
| Neuromuscular fatiguability during isometric holds. | 12 weeks | 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. |
| 10 meter max gait speed. | 12 weeks | 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. |
| modified Balance Error Scoring System (mBESS) | 12 weeks | 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. |
| NIH PROMIS Physical Function SF | 12 weeks | 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. |
| NIH PROMIS Fatigue SF | 12 weeks | 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. |
Countries
United States
Contacts
CONTACTCraig Tuggle, MA
Outcome results
None listed