Exercise for an Aging Liver (EXALIVER) (EXALIVER)

Evaluation of the Impact of Physical Exercise on Metabolic Dysfunction-associated Steatotic Liver Disease in the Elderly

The goal of this clinical trial is to learn how physical exercise affects liver health in adults with metabolic dysfunction-associated steatotic liver disease (MASLD) or at-risk metabolic dysfunction-associated steatohepatitis (MASH); comparing responses between middle-aged adults (40-60 years old) and older adults (70 years and older) of any sex, as well as between participants with low-risk MASLD and high-risk MASH. The main question it aims to answer is:

Could an exercise program reduce liver fat, inflammation and fibrosis, regardless of age and disease severity?

Researchers will compare 4 different groups:

A) older adults with at risk MASH who will exercise B) middle-aged people with at risk MASH who will exercise C) middle-aged people with low-risk MASLD who will exercise D) middle-aged people with low-risk MASLD who will not exercise, receiving usual care.

Participants in the exercise groups will take part in a supervised 12-week exercise program that includes both strength and aerobic training, completed twice a week.

All participants, including those receiving usual care, will have health asssessments before and after the 12-week period to measure changes in liver health.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Fibrosis/NASH; MASH - Metabolic Dysfunction-Associated Steatohepatitis; MASLD - Metabolic Dysfunction-Associated Steatotic Liver Disease
• Intervention / Treatment: Behavioral: Exercise; Behavioral: Usual Care

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jose Serra-Rexach, PhD; Phone Number: +34915868835; Email: joseantonio.serra@salud.madrid.es

Study Locations

• Spain
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
    • Contact: Carlos Rodriguez Lopez, PhD; Phone Number: +34915868835; Email: crlopez@salud.madrid.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Middle-aged adults (40 to 60 years old) and older adults (aged 70 years or older)
• People diagnosed with Metabolic Disfunction-Associated Steatotic Liver Disease (MASLD); defined as the presence of hepatic steatosis (≥5% fat content) in conjunction with at least one cardiometabolic risk factor (overweight or obesity, dysglycaemia or Type II diabetes, elevated plasma triglycerides, reduced HDL-cholesterol or high blood preassure) with no other discernable cause.
• People diagnosed with at-risk Metabolic Disfunction-Associated SteatoHepatitis (MASH) according to the following criteria: I) a positive liver biopsy (NAS score ≥ 4 points (with at least one point in each of the components of the score: steatosis, lobular inflammation and ballooning, AND significant (F2) or advanced (F3) fibrosis), or II) a FAST score >0.65.

Exclusion Criteria:

• Descompensated cirrhosis or end-stage liver disease.
• Other causes of liver disease, such as alcohol abuse or drug-induced, virus-related, or hereditary disease.
• History of a major adverse cardiovascular event, clinically significant kidney, endocrine, or neurological disease, bariatric surgery, HIV/AIDS, known inflammatory and/or rheumatologic disease, cancer, or other medical condition in which exercise is absolute contraindicated.
• Recent or planned major surgery, as well as anticancer therapies.
• Participating in a weight loss, a weight-management program or a supervised exercise program (more than 30 minutes three times per week, or 45 minutes twice a week, moderate/vigorous intensity).
• Body weight instability. Participants must have maintained the body weight registered at screening visit (tolerance: 5%) for more than 3 months.
• Regular use of medication or compounds that may affect study outcomes based on research staff criteria.
• Pregnancy and lactation or planned pregnancy (within the study period).
• Frequent travel over time zones during the study period.
• Fear of needles and claustrophobia to magnetic resonance imaging (MRI).
• Low physical function (ie, ambulation dependency)
• Being unable to understand and to accept the instructions or the study objectives and protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Older adults with at risk MASH who exercise; Older adults with Metabolic Dysfunction-Associated SteatoHepatitis aged 70 years or older who will complete the supervised 12-week exercise program.	Behavioral: Exercise; The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program to achieve a minimum of 135 minutes per week.
Experimental: Middle-age adults with at risk MASH who exercise; Middle-aged adults (40 to 60 years old) with at-risk metabolic dysfunction-associated SteatoHepatitis (MASH) who will complete a supervised 12-week exercise program	Behavioral: Exercise; The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program to achieve a minimum of 135 minutes per week.
Experimental: Middle-age adults with MASLD who exercise; Middle-aged adults (40 to 60 years old) with metabolic dysfunction-associated steatotic liver disease (MASLD) who will complete a supervised 12-week exercise program. This study arm will not recruit new participants. Instead, participants will be selected from a concluded clinical trial (NCT05897073; Study Arm: Experimental - Supervised Exercise Intervention), in which they completed the same exercise program and the same study outcome assessments of the present trial. These participants will be matched by sex, age and potential confounders to the individuals enrolled in the "Middle-aged adults with at-risk MASH who exercise" arm of the present study.	Behavioral: Exercise; The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program to achieve a minimum of 135 minutes per week.
Active Comparator: Middle-age adults with MASLD receiving usual care; Middle-aged adults (40 to 60 years old) with metabolic dysfunction-associated steatotic liver disease (MASLD) who receive usual care. This study arm will not recruit new participants. Instead, participants will be selected from a concluded clinical trial (NCT05897073, Study Arm: No Intervention: Usual-care control group), in which they received usual care and the same study outcome assessments of the present trial. These participants will be matched by sex, age and potential confounders to the individuals enrolled in the "Middle-aged adults with at-risk MASH who exercise" arm of the present study.	Behavioral: Usual Care; Participants will receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hepatic fat content	Hepatic fat content will be determined by Proton Density Fat Fraction (PDFF) assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in liver inflammation and fibrosis	Iron-corrected T1 (cT1) will be determined though MRI to reflect liver tissue water content, correlating with histological features of fibroinflammation (ballooning, fibrosis, and NAS)	Change from baseline to 12 weeks
Change in liver stiffness	Determined by vibration-controlled Transient Elastography (Fibroscan ®, VCTE). This is an ultrasound-based technique widely used in clinical practice to diagnose and monitor fibrosis progression. Liver stifness measurement increases with liver fibrosis.	Change from baseline to 12 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in visceral adipose tissue	Visceral adipose tissue will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in pancreatic fat content	Pancreatic fat content will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in values of fasting glucose	Fasting blood samples will be used to assess glucose	Change from baseline to 12 weeks
Change in values of fasting insulin	Fasting blood samples will be used to assess insulin	Change from baseline to 12 weeks
Change in Cardiorespiratory Fitness	Cardiorespiratory fitness measured by maximum treadmill test	Change from baseline to 12 weeks
Change in Upper muscular strength	Upper body muscular strength measured by hand grip strength test.	Change from baseline to 12 weeks
Change in abdominal subcutaneous adipose tissue	Abdominal subcutaneous adipose tissue will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in abdominal intermuscular fat content	Abdominal intermuscular fat content will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in abdominal skeletal muscle tissue	Abdominal skeletal muscle tissue will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in Enhanced Liver Fibrosis (ELF) Score	Fasting blood samples will be used to assess the Enhanced Liver Fibrosis (ELF) serum biomarker. The ELF score reflects the risk of advanced liver fibrosis, with higher values indicating higher risk.	Change from baseline to 12 weeks
Change in Pro-C3 serum levels	Fasting blood samples will be used to asses Pro-C3 serum levels, a biomarker of liver fibrosis. Higher PRO-C3 levels indicate ongoing fibrotic activity	Change from baseline to 12 weeks
Change in NIS4 serum biomarker of liver fibrosis	Fasting blood samples will be used to asses NIS4, a blood-based diagnostic tool designed to identify patients with at-risk MASH. It generates a composite score stratifying patients by risk.	Change from baseline to 12 weeks
Change in Metabolomics Advanced Steatohepatitis Fibrosis Score (MASEF)	Fasting blood samples will be used to asses Metabolomics Advanced Steatohepatitis Fibrosis Score (MASEF) in serum samples. Is a proprietary algorithm that generates a numeric score that reflects the likelihood of a patient having at-risk MASH.	Change from baseline to 12 weeks
Change in abdominal intramuscular fat content	Abdominal intramuscular fat content will be assessed by Magnetic Resonance Imaging (MRI)	Change from baseline to 12 weeks
Change in values of HbA1c	Fasting blood samples will be used to assess HbA1c. Higher fasting HbA1C values indicates poorer glucemic control.	Change from baseline to 12 weeks
Change in levels of mean glucose (Continuous Glucose Monitoring)	24-hour, diurnal and nocturnal mean glucose over 14 days will be assessed by Continuous Glucose Monitoring during 2 weeks	Change from baseline to 12 weeks.
Change in fasting lipid profile	Fasting blood samples will be used to assess levels of triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol an total cholesterol.	Change from baseline to 12 weeks
Change in alkaline phosphatase	Fasting blood samples will be used to assess serum alkaline phosphatase using standard clinical chemistry methods.	Baseline to 12 weeks
Change in alanine aminotransferase (ALT)	Fasting blood samples will be used to assess serum alanine aminotransferase (ALT) using standard clinical chemistry methods.	Baseline to 12 weeks
Change in gamma-glutamyl transferase (GGT)	Fasting blood samples will be used to assess serum gamma-glutamyl transferase (GGT) using standard clinical chemistry methods.	Baseline to 12 weeks
Change in total bilirubin	Fasting blood samples will be used to assess total serum bilirubin using standard clinical chemistry methods.	Baseline to 12 weeks
Change in creatinine	Fasting blood samples will be used to assess serum creatinine using standard clinical chemistry methods.	Baseline to 12 weeks
Change in estimated glomerular filtration rate (eGFR)	eGFR will be calculated from serum creatinine using a standard equation (e.g., CKD-EPI 2021), as implemented by the study laboratory.	Baseline to 12 weeks
Change in values of C-reactive protein	Fasting blood samples will be used to assess levels of C-reactive protein. Higher values indicate inflammation in the body.	Change from baseline to 12 weeks
Change in values of interleukin 6	Fasting blood samples will be used to assess levels of interleukin 6. Higher basal levels often indicating greater inflammation or metabolic stress.	Change from baseline to 12 weeks]
Change in blood pressure	Systolic and Diastolic blood pressure will be assessed by blood pressure monitor	Change from baseline to 12 weeks
Change in waist, hip and neck circumference	Circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry	Change from baseline to 12 weeks.
Change in body weight	Body weight will be measured by a digital scale	Change from baseline to 12 weeks
Change in moderate-to-vigorous physical activity (MVPA)	Moderate-to-vigorous physical activity (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period.	Baseline to 12 weeks
Change in light physical activity	Light physical activity (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period.	Baseline to 12 weeks
Change in sedentary time	Sedentary time (minutes per day) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period.	Baseline to 12 weeks
Change in total activity counts	Total activity counts per day will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period.	Baseline to 12 weeks
Change in Subjective sleep quality	Subjective sleep quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI). Minimum value is 0 (never) and maximum value is 3 (3 or more times per week). Higher values mean a worse outcome.	Baseline to 12 weeks
Change in total sleep time	Total sleep time (minutes per night) will be estimated from wrist-worn accelerometry recorded over a 2-week monitoring period.	Baseline to 12 weeks
Change in Lower-body muscular performance	Lower body muscular performance measured by chair stand test.	Change from baseline to 12 weeks
Change in Quality of life	Quality of life will be assessed by the Rand Short Form 36 (SF-36). This questionnaire provides an score ranged from 0 to 100. Higher values mean better quality of life.	Changes from baseline to 12-weeks
Change EuroQol Visual Analogue Scale (EQ-VAS) score	The EQ-VAS is a vertical 0-100 scale used in the EuroQol EQ-5D instrument to measure a patient's self-rated, current overall health. It ranges from 0 (worst imaginable health) to 100 (best imaginable health), allowing patients to quantify their perceived health status.	Changes from baseline to 12-weeks
Change in mid-thigh subcutaneous adipose tissue area	Mid-thigh subcutaneous adipose tissue area will be quantified from segmented magnetic resonance imaging (MRI) slices.	Baseline to 12 weeks
Change in mid-thigh intramuscular fat content	Mid-thigh intramuscular fat content will be quantified from segmented magnetic resonance imaging (MRI) slices.	Baseline to 12 weeks
Change in mid-thigh intermuscular fat content	Mid-thigh intermuscular fat content will be quantified from segmented magnetic resonance imaging (MRI) slices.	Baseline to 12 weeks
Change in mid-thigh skeletal muscle cross-sectional area	Mid-thigh skeletal muscle cross-sectional area will be quantified from segmented magnetic resonance imaging (MRI) slices.	Baseline to 12 weeks

Collaborators and Investigators

• Sponsor: Consorcio Centro de Investigación Biomédica en Red (CIBER)
• Collaborators: Hospital General Universitario Gregorio Marañon; Universidad Complutense de Madrid; Universidad de Granada; Universidad Politecnica de Madrid; Instituto Mixto Universitario Deporte y Salud (iMUDS)

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: February 3, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Exercise
• Other Study ID Numbers: AG24_13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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