Multidimensional Predictive Modeling to Understand Mechanisms of Exercise Response Heterogeneity in Older Adults (M3AX)

NCT ID: NCT06507189

Last Updated: 2025-08-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-27
• Study Completion Date: 2029-08-31

Brief Summary

Aging-related functional declines are thought to be caused by hallmark biological processes that ultimately manifest in physical, mental, and metabolic impairments that compromise healthspan and quality of life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in exercisƒe responsiveness. Combining endurance and resistance training in alignment with public health guidelines will be used to better understand variable exercise responsiveness in older adults with the ultimate goal of improving each older adult's capacity to attain the many health benefits of exercise.

Detailed Description

Aging-related functional declines are thought to be caused by hallmark biological processes1 that ultimately manifest in physical, mental, and metabolic impairments - compromising healthspan and quality of life (QoL). Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in individual exercise responsiveness. This inter-individual response heterogeneity (IRH) was first identified and extensively interrogated by Bouchard and colleagues in the context of endurance training (ET). Subsequently, the investigators have demonstrated resistance training (RT) IRH and have studied potential IRH mechanisms. The investigators then led multiple trials in older adults examining dose titration, adjuvant nutrition or medication in attempts to lower poor response rates. Many knowledge gaps remain as summarized in the National Institutes of Aging (NIA) workshop on IRH seeding this Requests for Applications (RFA). The investigators have assembled an interdisciplinary team to address the RFA's central goal, "to better understand factors underlying response variability to exercise training in older adults." Although Health and Human Services (HHS) guidelines specify combined ET and RT to maximize health benefits in aging adults, large-scale exercise trials studying IRH (i.e., HERITAGE, MoTrPAC) have restricted participants to a single exercise mode. For this project, the investigators propose the innovative, but logical, strategy to use combined ET and RT. Low cardiorespiratory fitness (CRF, VO2max) and low functional muscle quality (fMQ; strength/muscle mass) are multi-system manifestations of the deterioration of the cellular hallmarks of aging. Importantly, both CRF and fMQ are modifiable with ET and RT. Thus, the investigators design premise is that combined ET+RT is an excellent strategy for elucidating factors underlying IRH, as it forges a path toward understanding and mitigating IRH in aging with direct translatability to best-evidence public health recommendations.

It is yet to be determined how the hallmarks of aging interact to influence exercise responsiveness. For example, muscle mitochondrial energetics and proteostasis are inextricably linked, and poor responder status may be caused by lack of energetic resources to maintain proteostasis throughout an exercise program. Similarly, aging disrupts circadian clocks, leading to inflammation and disrupted cell signaling, which may also contribute to IRH.

While sources of IRH are a constellation of modifiable and non-modifiable factors, the investigators will test the hypothesis that factors central to aging itself - aging hallmarks such as proteostasis, mitochondrial energetics, and inflammation, as well as systemic and muscle-specific circadian clock function and output - are chief contributors to the multidimensional circuitry that determines whether an individual achieves the minimum clinically important difference (MCID) in CRF and/or fMQ with exercise training. The investigators will also test the hypothesis that altered exercise dosing coupled with lifestyle recommendations will promote attainment of MCIDs among older adults who do not initially respond. With CRF and fMQ as primary clinical outcomes, the investigators will use a 2-phase Sequential Multiple Assignment Randomized Trial (SMART) of combined ET+RT with clinical phenotyping and blood/muscle molecular and cellular analyses.

Conditions

Sarcopenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Interrogation

In Interrogation, all participants will exercise train using an exercise prescription that is in accordance with current public health recommendations19. At the end of Phase I participants will be classified into one of the four categories listed in Fig. A: (1) CRF-/fMQ-, 2) CRF-/fMQ+, 3) CRF+/fMQ- and 4) CRF+/fMQ+).

Group Type: EXPERIMENTAL

Combined endurance and resistance training

Intervention Type: OTHER

ET will consist of 3x/wk training (MWF) with MF being steady state cycling, treadmill, or elliptical at 70-75% HRR for 30 min and the W session being a 20 min high intensity interval session on a cycle ergometer (1 min on/off; 10 cycles) targeting 85-90% HRR. The treadmill and elliptical on M or F will be provided for variety but the mainstay will be cycle ergometry. On MF participants will complete 3 sets x 8-12 repetitions for leg press, knee extension, hamstring curl, chest press, seated row, overhead press, lat pulldown, triceps push-down, and biceps curl in superset fashion \[i.e., alternate between opposing muscle groups without rest (chest press followed by seated row)\] with a 60 s rest between supersets. Sets will be performed with load progression to ensure volitional fatigue in the 8-12 rep range. Core exercises (trunk flexion and extension) will also be included using bodyweight only for 3 sets.

Mitigation

Based on these categories of responsiveness, exercise training will be boosted in the three groups that are nonresponsive in one or both outcomes. CRF-/fMQ+ will receive boosted ET, CRF+/fMQ- will receive boosted RT, and CRF-/fMQ- will receive boosting in both. All three of these classifications will also receive education on wearable device data and other free-living recommendations four times during Mitigation

Group Type: EXPERIMENTAL

Combined endurance and resistance training

Intervention Type: OTHER

ET will consist of 3x/wk training (MWF) with MF being steady state cycling, treadmill, or elliptical at 70-75% HRR for 30 min and the W session being a 20 min high intensity interval session on a cycle ergometer (1 min on/off; 10 cycles) targeting 85-90% HRR. The treadmill and elliptical on M or F will be provided for variety but the mainstay will be cycle ergometry. On MF participants will complete 3 sets x 8-12 repetitions for leg press, knee extension, hamstring curl, chest press, seated row, overhead press, lat pulldown, triceps push-down, and biceps curl in superset fashion \[i.e., alternate between opposing muscle groups without rest (chest press followed by seated row)\] with a 60 s rest between supersets. Sets will be performed with load progression to ensure volitional fatigue in the 8-12 rep range. Core exercises (trunk flexion and extension) will also be included using bodyweight only for 3 sets.

Interventions

Combined endurance and resistance training

ET will consist of 3x/wk training (MWF) with MF being steady state cycling, treadmill, or elliptical at 70-75% HRR for 30 min and the W session being a 20 min high intensity interval session on a cycle ergometer (1 min on/off; 10 cycles) targeting 85-90% HRR. The treadmill and elliptical on M or F will be provided for variety but the mainstay will be cycle ergometry. On MF participants will complete 3 sets x 8-12 repetitions for leg press, knee extension, hamstring curl, chest press, seated row, overhead press, lat pulldown, triceps push-down, and biceps curl in superset fashion \[i.e., alternate between opposing muscle groups without rest (chest press followed by seated row)\] with a 60 s rest between supersets. Sets will be performed with load progression to ensure volitional fatigue in the 8-12 rep range. Core exercises (trunk flexion and extension) will also be included using bodyweight only for 3 sets.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Male or female aged 60 or above

2. Free of chronic disease

3. No structured exercise program (2 or more bouts/wk) within previous 12 months

4. Cognitively capable of providing informed consent

Exclusion Criteria

1. Neuromuscular or musculoskeletal disorder that would limit ability to perform the exercise and/or testing bouts

2. Cardiopulmonary disorders or reduced breathing capacity (FEV1 < 80% expected)

3. Metabolic diseases including markers of liver disease (ALT > 52 U/l) and type 2 diabetes (HbA1C ≥ 6.5, fasting blood glucose ≥ 126 mg/dl)

4. Any other disease or disorder that would influence exercise response (e.g., chronic kidney disease, dementia, current cancer diagnosis or within 2 yr remission, cerebrovascular disease)

5. Any current infectious disease

6. Life expectancy < 1 year

7. Insulin sensitizing/blood glucose lowering agents such as metformin

8. High dose lipophilic statin (≥40 mg/d)

9. Lidocaine allergy

10. Regular tobacco use and/or vaping

11. Excessive alcohol consumption (3 drinks/d or 7 drinks/wk for females; 4 drinks/d or 14 drinks/wk for males)

12. BMI ≥ 30.0 kg/m2

13. Unable to commit to ~6 months required to complete the study

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Florida

OTHER

Sponsor Role: collaborator

Oklahoma Medical Research Foundation

OTHER

Sponsor Role: collaborator

Florida Institute for Human and Machine Cognition

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marcas Bamman

Role: PRINCIPAL_INVESTIGATOR

Florida Institute for Human and Machine Cognition

Locations

Florida Institute for Human and Machine Cognition

Pensacola, Florida, United States

Site Status: RECRUITING

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Craig Tuggle

Role: CONTACT

ctuggle@ihmc.org

205-352-6036

Marcas Bamman, PHD

Role: CONTACT

mbamman@ihmc.org

Facility Contacts

Craig Tuggle

Role: primary

ctuggle@ihmc.org

205-352-6036

Ben Miller, PHD

Role: primary

Benjamin-Miller@omrf.org

405-271-7767

Other Identifiers

IRB-2024-0083

Identifier Type: -

Identifier Source: org_study_id