VITAL: Vaccination, Immunity, Time-restricted Eating, Aging and Lifestyle

Charite University, Berlin, Germany24 enrolled

Overview

The aim of this study is to investigate the effects of a four-week time-restricted eating (TRE) intervention on autophagy, immune function, and vaccine response to a seasonal influenza and COVID-19 vaccines in older healthy subjects.

Aging impairs immune cell autophagy and reduces vaccine efficacy, leaving older adults highly vulnerable to influenza and other infectious diseases. Time-Restricted Eating (TRE), by limiting daily food intake to an 8-hour window without detailed calorie counting, modulates nutrient-sensing pathways (e.g., mTOR inhibition, AMPK activation) and boosts autophagic flux in preclinical models. In a randomized, controlled trial, healthy volunteers aged 60-85 will follow either four weeks of TRE or their usual eating pattern. After that, all will receive a standard seasonal vaccines against influenza and COVID-19 outside of the trial at their general practitioner (min. 2 days and max. 14 days after the stop of intervention). Blood and physiologic measurements at baseline, after four weeks of study intervention will quantify autophagy in immune cells, metabolome/proteome shifts, body composition, blood pressure, and arterial stiffness, among others. At two additional visits after the vaccination (2 weeks and 12-14 weeks after the vaccination), immune responses to the vaccination will be monitored in the blood. The investigators hypothesize that TRE-induced restoration of autophagy and amelioration of immunosenescence will correlate with stronger vaccine responses, offering a simple, low-cost strategy to rejuvenate immunity and improve preventive care in the elderly.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Vaccination Immunosenescence Metabolism

Interventions

TRE: Time-restricted eatingBEHAVIORAL

The daily eating pattern is reduced to 8 h/day. The first meal will be before 10:00 AM.

Eligibility

Sex: ALLMin age: 60 YearsMax age: 85 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Male and female participants, enrolled in a 1:1 ratio * Age 60-85 years * Body mass index (BMI) 20-35 kg/m² * Capacity to give informed consent * Existing health insurance to allow evaluation and treatment of any incidental findings * Usual daily eating window \> 11 hours * First meal of the day before 10:00 AM * Willingness to receive seasonal influenza and COVID-19 vaccination and proof of scheduled appointment * Willingness and ability to follow a prescribed TRE dietary regimen (8-hour daily eating window; 16-hour fast without any caloric intake) * Appointment for simultaneous influenza and COVID-19 vaccination pre-arranged with primary care physician and coordinated with study team to align with TRE intervention Exclusion Criteria: * Any vaccination (especially influenza and/or COVID-19) within 6 months before the intervention start * Vaccinations not related to the study, administered during the study period from V0 to V4 * History of influenza infection within 6 months prior to initiation of the study intervention * History of severe adverse reactions to prior vaccinations * Use of pharmacological weight-loss agents (e.g., semaglutide) * Diabetes mellitus under ongoing pharmacological treatment * Symptoms of systemic inflammatory or autoimmune disease * Immunosuppression (including use of immunosuppressive drugs) * Severe hypertension (systolic \> 180 mmHg or diastolic \> 110 mmHg) * Diseases or functional disorders which, in the opinion of the study physician, preclude participation in the study * Participation in any fasting intervention (e.g., TRE, alternate-day fasting, 5:2, 18:6) within 6 months before enrollment * Participation in another diet or weight-loss program (e.g., intensive athletic training) * Night-shift or rotating-shift work * Severe, active, or unstable medical conditions requiring treatment * Postoperative recovery phase * Antibiotic therapy within 3 months before enrollment * Acute or chronic infections * Therapeutic or medically prescribed special diets * Vegan diet * Current smoker * Weight change \> 2 kg in the month before enrollment * Known substance, drug, or alcohol abuse * Anemia * Claustrophobia * Legal incapacity or any other circumstance that prevents full understanding of the nature, importance, and implications of the study

Locations (1)

Clinical Research Unit, Experimental & Clinical Research Center, Campus Buch, Charité

Berlin, Germany

RECRUITING

Outcomes

Primary Outcomes

Autophagic flux in PBMCs

Change in autophagic flux in peripheral immune cells from baseline (V1) to four weeks (V2), comparing the TRE group versus control, as measured by flow cytometry detection of LC3-II accumulation via antibody staining.

Time frame: Change from baseline to 4 weeks

Secondary Outcomes

Change in body weight

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in body composition (BodPod)

Change in body composition (e.g., fat and lean body mass), assessed via Air Displacement Plethysmography (ADP, BodPod).

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in body composition (BIA)

Change in body composition (e.g., fat and lean body mass), assessed via bioimpedance analysis (BIA).

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in the differential blood count

Change in the differential blood count, assessed with Hematology analyzers.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in blood glucose levels

Change in blood glucose levels, assessed via routine blood diagnostic tests

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in insulin metabolism

Central Contacts

Sebastian Hofer, Dr. rer. nat.

CONTACT

+493094062372 sebastian.hofer@charite.de

Data from ClinicalTrials.gov

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Changes in insulin metabolism parameters, including insulin, IGF-1, C-peptide, ghrelin, leptin, adiponectin, and glucagon, assessed via ELISAs

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Changes in blood ketone body levels

Changes in blood ketone body levels (3-hydroxybutyrate, acetoacetate, acetone), assessed using commercially available assay kits

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in blood lipid profile

Changes in blood lipids assessed via metabolomics and routine blood diagnostic tests

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in liver or renal function

Changes in blood parameters of liver and renal function assessed via routine blood diagnostic tests

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in blood electrolyte levels

Changes in blood electrolyte levels assessed via routine blood diagnostic tests

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in the incidence of clinically diagnosable infections during the study period

Change in the incidence of clinically diagnosable infections during the study period, assessed at study visits by the study physician

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in continuous blood glucose levels

Change in continuous blood glucose levels, assessed with continuous glucose monitors (CGM). CGMs will be applied at V1 and V2 and record continuous glucose levels for 14 days each.

Time frame: CGMs will be applied at V1 and V2 and record continuous glucose levels for 14 days each.

Change in grip strength

Change in grip strength, assessed with a dynamometer. Handgrip strength will be measured using a dynamometer three times sequentially and repeated after 1 hour.

Time frame: Change from baseline to 4 weeks (end of TRE).

Change in metabolic rate

Change in metabolic rate via indirect calorimetry. Indirect calorimetry will be performed to assess energy expenditure as well as carbohydrate and fat oxidation rates. During the procedure, the subject will rest quietly in bed while wearing a ventilated hood. The hood is equipped with an inlet and an outlet valve. Through the inlet valve, the subject receives a constant supply of fresh air, while exhaled air is collected via the outlet valve. Sampling at the rear of the calorimetry device allows determination of gas concentrations in the ambient room air. By calculating the difference, oxygen consumption (VO₂) and carbon dioxide production (VCO₂) in ml/min are determined. These volumes enable the calculation of energy expenditure and substrate oxidation rates. This measurement is performed after a rest period of 30 minutes to determine resting fasting energy expenditure (duration approximately 30 minutes).

Time frame: Change from baseline to 4 weeks (end of TRE).

Change in Sleep Quality

Change in Sleep Quality assessed using a questionnaire for the Pittsburgh Sleep Quality Index \[PSQI\].

Time frame: Change from baseline to 4 weeks (end of TRE)

Change in health-related quality of life

Change in EQ-5D-5L assessed using questionnaires.

Time frame: Change from baseline to 4 weeks (end of TRE)

Change in ChronoType

Change in ChronoType assessed using the Munich ChronoType Questionnaire \[MCTQ\]

Time frame: Change from baseline to 4 weeks (end of TRE)

Change in the Multidimensional Prognostic Index (MPI).

Change in the MPI for geriatric assessment. MPI assessments will be conducted, including documentation of medication and dietary supplement use, medication allergies, nutritional therapies, a range of disease symptoms, social history, activities of daily living (ADL), instrumental activities of daily living (IADL), malnutrition screening, the Short Portable Mental Status Questionnaire (SPMSQ), and the Exton Smith Scale (assessment of decubitus risk), all administered via standardized questionnaires.

Time frame: Change from baseline to 4 weeks

Change in the walking speed.

A 10-meter walk test will be performed to determine walking speed in m/s. For this purpose, the subject will walk from a 0-meter mark to a 10-meter mark upon command. Timing will begin at the 2-meter mark. The procedure will be repeated three times, and the times will be averaged. If the subject's fitness level permits, the procedure will be repeated with the instruction to complete the 10 meters 'as fast as possible while still feeling safe'.

Time frame: Change from baseline to 4 weeks

Change in proteome profiles in plasma and PBMCs.

Change in proteome profiles in plasma and PBMCs, measured by LC-MS mass spectrometry or Olink proteomics.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in metabolite patterns in plasma.

Change in metabolite patterns in plasma, assessed by untargeted (¹H-NMR) and/or targeted (LC-MS) metabolomics.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in metabolite patterns in stool.

Change in metabolite patterns in stool, assessed by untargeted (¹H-NMR) and/or targeted (LC-MS) metabolomics.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in metabolite patterns in urine.

Change in metabolite patterns in urine, assessed by untargeted (¹H-NMR) and/or targeted (LC-MS) metabolomics.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in gut microbiome composition.

Change in gut microbiome composition by metagenomic sequencing of stool.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in immune-cell subset distribution and activation.

Change in immune-cell subset distribution and activation, assessed by scRNA-seq and flow cytometry.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in body fat percentage.

Change in body fat percentage, measured by air-displacement plethysmography.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in office systolic and diastolic blood pressure.

Change in office systolic and diastolic blood pressure (mmHg), measured by non-invasive blood pressure cuff.

Time frame: Change from baseline to 4 weeks

Change in pulse-wave velocity.

Change in pulse-wave velocity (m/s), measured by PulsePen.

Time frame: Change from baseline to 4 weeks

Change in frequency of pro- and anti-inflammatory immune cells.

Change in frequency of pro- and anti-inflammatory immune cells in PBMCs, by flow cytometric immunophenotyping.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in immune-cell function.

Change in immune-cell function (cytokine production, proliferation) after in vitro stimulation of PBMC subsets, by flow cytometry.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in circulating pro- and anti-inflammatory cytokine concentrations in plasma.

Change in circulating pro- and anti-inflammatory cytokine concentrations in plasma, by multiplex cytokine assay.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in expression of senescence markers in immune-cell subsets.

Change in expression of senescence markers in immune-cell subsets, by flow cytometry.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in the hypusination status of eIF5A in PBMCs

Change in the hypusination status of eIF5A in PBMCs by flow cytometry.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in mTOR activity status in PBMCs

Change in mTOR activity status in PBMCs by flow cytometry.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in expression of key autophagy-regulatory genes.

Change in expression of key autophagy-regulatory genes in specific immune-cell types or bulk PBMCs, by qPCR, scRNA-seq, or bulk RNA-seq.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in energy metabolism in immune-cell subsets.

Change in cellular energy metabolism in immune-cell subsets, measured by Seahorse extracellular flux analysis and/or Scenith Assay in isolated immune cells ex vivo.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in coagulation.

Change in coagulation, assessed via e.g., thrombin generation, d-dimers from plasma

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in influenza-specific B- and T-cell responses.

Change in influenza-specific B- and T-cell responses in serum and PBMCs (e.g., ELISpot).

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in SARS-CoV-2 specific B- and T-cell responses.

Change in SARS-CoV-2 specific B- and T-cell responses in serum and PBMCs (e.g., ELISpot).

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in concentration of influenza-specific IgG antibodies.

Change in concentration of influenza-specific IgG antibodies, by ELISA.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in concentration of SARS-CoV-2 specific IgG antibodies.

Change in concentration of SARS-CoV-2 specific IgG antibodies, by ELISA.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in concentration of influenza-neutralizing antibodies.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in concentration of SARS-CoV-2 neutralizing antibodies.

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination

Change in DNA-break profiles in primary B cells.

Change in DNA-break profiles in primary B cells, assessed by SWIBRID (Switch-joint Breakpoint Repertoire Identification).

Time frame: Change from baseline to 4 weeks (end of TRE), 2 weeks and 12-14 weeks after vaccination