Multidimensional Modeling to Maximize Adaptations to eXercise: the M³AX trial rationale and study design

Area of Science:

• Gerontology
• Exercise Physiology
• Personalized Medicine

Background:

• Age-related functional declines are linked to biological aging processes, affecting intrinsic capacity and quality of life.
• Exercise is a promising intervention for aging, but individual responses vary significantly (interindividual response heterogeneity - IRH).
• Understanding the mechanisms behind IRH is crucial for optimizing exercise efficacy in older adults.

Purpose of the Study:

• To investigate interindividual response heterogeneity (IRH) to combined endurance and resistance training in older adults.
• To identify mechanistic underpinnings of IRH through deep phenotyping.
• To develop strategies for boosting exercise response rates and creating personalized exercise prescriptions.

Main Methods:

• A two-phase Sequential Multiple Assignment Randomized Trial (SMART) design (M3AX Trial) enrolling 250 older adults.
• Phase I (12 weeks) focuses on classifying individual responsiveness and interrogating mechanistic factors.
• Phase II (10 weeks) aims to boost responsiveness, utilizing deep in vivo, ex vivo, and molecular phenotyping across multiple domains.

Main Results:

• The M3AX trial is the first to specifically address IRH in older adults undergoing combined training.
• Deep phenotyping will cover physiological, metabolic, cognitive, behavioral, cellular, and molecular aspects.
• Multidimensional biocircuitry of responsiveness will be established to build predictive models.

Conclusions:

• This study will provide novel insights into the biological basis of exercise response variability in aging.
• Findings are expected to facilitate the development of personalized exercise interventions to maximize healthspan and quality of life.
• The M3AX trial design enables both interrogation and mitigation of IRH, advancing exercise science for older populations.