Study protocol for FAXAge: A randomized, controlled clinical trial of fasting and exercise to slow aging in humans

The FAXAge study is a 52-week randomized controlled trial investigating whether time-restricted feeding, exercise, or their combination can slow biological aging in adults over 65 by measuring changes in DNA methylation clocks and other multi-omics biomarkers.

The Gist

Imagine your body is like a high-end, complex car. Over time, the engine gets a bit sluggish, the paint fades, and the parts start to wear out. This is what we call "aging." Usually, we think of aging as just a number on a birthday cake, but scientists are now looking at the "odometer" inside the car to see how much the engine has actually worn down. This internal odometer is called biological age.

The FAXAge study is a massive, year-long experiment designed to see if we can "reset" or slow down this internal odometer in older adults (people 65+) using two simple tools: Exercise and Fasting.

Here is the breakdown of the study in plain English:

1. The Big Question

Scientists know that exercise is good for you, and they know that skipping meals for a while (intermittent fasting) helps mice and monkeys live longer. But they don't know for sure if doing both together can actually slow down human aging.

Think of it like this: If you want to fix a rusty car, do you just oil the engine (exercise)? Do you just stop driving it for a while to let it rest (fasting)? Or do you do both? This study wants to find the best recipe.

2. The Experiment Setup

The researchers are recruiting 240 healthy seniors and splitting them into four different groups, like four different teams in a race:

• Team Gym (EXE): These people will do supervised strength training (lifting weights) and cardio (like walking or cycling) twice a week. They are the "active maintenance" crew.
• Team Fasting (TRF): These people will eat all their food within an 8-hour window each day and fast for the other 16 hours. They are the "rest and repair" crew.
• Team Super-Combo (FAX): These people do both the exercise and the fasting. They are the "full tune-up" crew.
• Team Chill (Control): These people continue their normal lives without changing their diet or exercise habits. They are the "baseline" crew to compare against.

3. The "Odometer" Check-ups

The most exciting part is how they measure success. Instead of just asking, "Do you feel better?", they are using high-tech tools to measure the actual "wear and tear" on the body.

• The DNA Clock: They will take a tiny drop of blood and look at your DNA. Think of DNA as the instruction manual for your body. Over time, little notes get scribbled on the pages (methylation). These notes act like a clock. The study wants to see if the interventions can stop the clock from ticking so fast.
• The "Digital Twin" Check: They will take photos of your face and record your voice. AI (computer brains) will analyze these to guess your age. If the AI thinks you look and sound younger after a year, that's a good sign!
• The Gut Garden: They will collect a stool sample. Your gut is like a garden of tiny bacteria. Fasting changes the soil, and they want to see if the garden gets healthier.
• The Physical Test: They will measure how fast you can walk, how strong your grip is, and how much oxygen your lungs can handle.

4. The Long Haul

This isn't a quick test. The main part of the study lasts one year. But the researchers are playing the long game. They will check in on these participants again in 2, 5, and even 10 years.

Why wait so long? Because real aging is slow. They want to know: If we fix the car today, will it still be running smoothly 10 years from now?

5. Why Does This Matter?

If this study proves that fasting and exercise can actually slow down the biological clock, it could change how we live.

• Health: It could mean fewer heart attacks, less diabetes, and sharper minds for older people.
• Money: If people stay healthy longer, they don't need as much medical care, saving billions of dollars.
• Life: It could mean people can stay active, work, and enjoy their families for many more years.

The Bottom Line

The FAXAge study is like a giant, scientific experiment to see if we can hit the "pause" button on aging. By combining the power of movement and the power of rest (fasting), they hope to prove that we can not only live longer but live better for longer.

Note: This is a study protocol, meaning it is the plan for the experiment. The results haven't been published yet, so we don't know the answer just yet!

Technical Summary

Based on the provided study protocol, here is a detailed technical summary of the FAXAge study.

1. Problem Statement

The global population is aging rapidly, with aging identified as the primary risk factor for chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer. While physical exercise and time-restricted feeding (TRF) have shown protective effects against age-related decline in preclinical models and isolated human studies, their combined effect on the rate of biological aging in older adults remains largely unexplored.

Furthermore, there is a lack of consensus on the most robust biomarkers for biological age and whether lifestyle interventions can actually slow or reverse the aging process in humans. Traditional clinical endpoints (e.g., disease onset) take decades to manifest, necessitating the use of validated biomarkers (such as DNA methylation clocks) to assess intervention efficacy within a feasible timeframe.

2. Methodology

Study Design:

• Type: 52-week, four-armed, randomized, controlled clinical trial (RCT).
• Registration: ClinicalTrials.gov (NCT07207044).
• Population: 240 healthy adults aged 65 and older.
• Randomization: Block randomization (block size 4) stratified by biological sex, allocating participants into four groups (60 per group):
  1. EXE: Combined cardio and strength training.
  2. TRF: Time-restricted feeding (16-hour fasting window, 8-hour eating window).
  3. FAX: Combined EXE and TRF.
  4. CON: Control group (no intervention).

Intervention Protocols:

• Exercise (EXE & FAX):
  • Resistance Training: Supervised, machine-based (Technogym) sessions twice weekly. Progressive overload model over 52 weeks (4 blocks of 13 weeks), starting with high-rep/low-load familiarization and moving to lower reps/higher load. Includes multi-joint and single-joint exercises.
  • Cardio Training: Self-chosen modality, performed twice weekly at home. Intensity >70% HRmax, monitored via fitness watches. Duration increases from 30 to 60 minutes over the first three months.
• Dietary (TRF & FAX):
  • Participants abstain from caloric intake for 16 continuous hours daily.
  • Ad libitum eating during the 8-hour window.
  • Adherence monitored via daily eating logs.
• Retention: Biweekly phone calls for all groups to support adherence and address challenges.

Assessment Timeline:

• Intensive Phase: Baseline, 3 months, 6 months, and 12 months (52 weeks).
• Long-term Follow-up: 2, 5, and 10 years post-intervention to assess sustainability and delayed effects.

Data Modalities & Outcomes:

• Primary Outcome: DNA methylation-based biological age (epigenetic clocks) measured in peripheral blood mononuclear cells (PBMCs).
• Secondary Outcomes:
  • Molecular: RNA-sequencing, metabolomics, inflammatory markers (CRP, TNF-α, IL-6, IL-8), NAD+ levels, and hematologic age.
  • Physiological: Body composition (DEXA), bone mineral density, handgrip strength, gait speed (TrackedGait system), sit-to-stand test, and VO2peak (via Seismocardiography and direct CPET).
  • Digital/Non-invasive: Portrait photo analysis and voice recording analysis using deep neural networks for age prediction.
  • Microbiome: Stool samples for 16S rRNA sequencing.
  • Cognitive/Subjective: Montreal Cognitive Assessment (MoCA), Pittsburgh Sleep Quality Index (PSQI), and health questionnaires.

Statistical Considerations:

• Sample size calculated based on a pooled effect size (Cohen's d = 1.0) for intervention groups vs. control on DNA methylation age.
• Target recruitment of 240 participants to accommodate a potential 33% dropout rate.
• Power analysis assumes a standard deviation of ~10% for epigenetic age prediction.

3. Key Contributions

• Novel Combination: This is the first known study to investigate the synergistic or additive effects of structured exercise and time-restricted feeding specifically on biological aging markers in the elderly.
• Multi-Omics Approach: The study integrates a comprehensive "deep phenotyping" strategy, combining epigenetics (DNA methylation), transcriptomics (RNA-seq), metabolomics, and microbiome analysis to create a holistic view of aging mechanisms.
• Longitudinal Scope: The inclusion of 2, 5, and 10-year follow-ups is critical for determining whether the effects of these interventions are transient or sustained, and for identifying long-term impacts on morbidity and mortality.
• Validation of Biomarkers: The study aims to validate which biomarkers (molecular vs. digital vs. physiological) are most reproducible and clinically relevant for assessing aging interventions.

4. Results

• Status: This document is a study protocol for a trial posted as a preprint (March 2, 2026).
• Outcome: No results are reported yet. The study is designed to generate data over a 12-week intervention period with follow-ups extending to 10 years. The paper outlines the hypotheses (that interventions will slow/reverse biological age and improve physiological/cognitive markers) but does not contain empirical findings.

5. Significance

• Scientific Impact: If successful, the study will provide definitive evidence on whether lifestyle interventions can alter the fundamental rate of human biological aging, moving beyond symptom management to disease prevention.
• Clinical & Public Health: It could establish affordable, scalable, and safe guidelines for healthy aging, potentially reducing the global burden of age-related chronic diseases (cardiovascular, metabolic, cognitive).
• Economic Implications: By potentially extending healthspan and delaying frailty, the interventions could significantly reduce healthcare costs and extend the productive workforce of older adults, with estimated economic returns in the trillions of dollars.
• Policy: Findings could directly influence governmental health policies and lifestyle recommendations for the aging population.

Note: As this is a preprint protocol, the findings are subject to peer review, and the actual efficacy of the interventions remains to be determined upon the completion of the trial.