Frontiers in Endocrinology · Jun 12, 2026

Time-restricted eating versus calorie restriction for improving biomarkers of age in adults with overweight or obesity and incipient fatty liver disease: protocol for the ENSATI randomized controlled parallel groups trial

By Celada-Guerrero JA, Rubio-Gordón L, Jiménez-Perez Y et al.

INTRODUCTION: The increasing global lifespan has shifted the primary objective of geroscience from merely extending lifespan to maximizing health span. Biological aging is a gradual, time-dependent process marked by progressive cellular deterioration that culminates in increased vulnerability, frailty, morbidity, and mortality. Understanding the mechanisms that accelerate or decelerate this deterioration is crucial for developing effective interventions. Diet is recognized as the leading modifiable behavioral risk factor influencing the global burden of noncommunicable diseases and mortality. Therefore, nutritional interventions constitute a highly practical and scalable strategy for promoting healthy aging. METHODS: The ENSATI trial is a randomized, open-label, controlled study with three parallel arms: active dietary counseling control, 25% calorie restriction, and time-restricted eating (14-hour fasting/10-hour eating window) over six months, followed by six months of post-intervention monitoring. A total of 177 adults aged 50-70 years with overweight/obesity and incipient fatty liver disease will be enrolled. ANALYSES: Primary outcomes include changes in body composition (dual X ray densitometry), hepatic fat (elastography) and metabolism (indirect calorimetry). Secondary outcomes encompass glucose regulation (continuous glucose monitoring), gut microbiome profiles, molecular biomarkers of aging (epigenetics, autophagy, immunosenescence), alongside psychological, cognitive, sleep, and dietary assessments using validated tools. Analyses will follow an intention-to-treat approach, with per-protocol sensitivity analyses and sex-stratified models. Mixed-effects models adjusted for potential confounders will assess intervention effects. DISCUSSION: Current TRE and caloric restriction studies are limited by short durations, small samples, and poor control of energy intake, often lacking molecular biomarkers of aging. ENSATI overcomes these gaps through a 12-month, adequately powered, randomized, multi-arm design with rigorous dietary monitoring and comprehensive molecular and physiological profiling, enabling a more rigorous exploration of the relative contributions of caloric intake versus chronobiological effects on obesity and aging. ETHICS AND DISSEMINATION: This study was approved by IMDEA Ethics Committee (IMF PI-057). All participants will provide written informed consent. The findings will be disseminated in peer-reviewed scientific journals and at scientific conferences.

doi.org/10.3389/fendo.2026.1849550 Open access PubMed 42369048 Interventions