Methylglyoxal (MGO) Lowering Cocktail to Reduce Appetite in Obese Individuals

Testing the Impact of a Combination of Dietary Supplements With Multimodal Effects on Longevity Mechanisms on Reducing Body Weight and Delaying Aging

Mechanisms that drive addiction to sugar rich foods are a major driving factor in the pathogenesis of obesity, which has become one of the most significant health care burdens. The molecular underpinnings of these hedonic mechanisms that drive addiction to sugar are poorly understood. The investigators demonstrated that methylglyoxal (MGO) derived Advanced Glycation Endproducts (AGEs) enhance food intake especially under a high sugar diet. The investigators identified a methylglyoxal (MGO) lowering cocktail, Gly-low, a combination of alpha-lipoic acid, nicotinamide, thiamine, pyridoxamine, and piperine that demonstrates a multimodal effect influencing many pathways related to aging including calorie restriction. Glycation lowering (Gly-low) treatment significantly reduces food intake and weight gain in the db/db mice that lack the leptin receptor. The investigators also extended the lifespan of C57BL/6 mice fed with these compounds starting when they were 24 months old. Based on these results, the investigators hypothesized that methylglyoxal (MGO) lowering cocktail of compounds can be given to adults with obesity, specified as body mass index (BMI) >27, to lower serum and urinary markers of insulin resistance, lower boy mass index (BMI), and lower food intake.

Study Overview

• Status: Withdrawn
• Conditions: Obesity; Aging
• Intervention / Treatment: Drug: Gly-low; Other: Placebo

Detailed Description

The aging population in the United States of America and around the world is expected to put enormous pressure on the medical system and thus aging remains the biggest challenge for biomedicine. The current approaches to slow aging or age-related diseases rely on targeting specific pathways for each indication, whereas the cause of aging is multifactorial. Hence, developing drugs that can function in a multimodal fashion to engage multiple pathways involved in aging is likely to be a much more effective approach.

Previous studies have demonstrated that combining mutations in the insulin and tOR (target of rapamycin) pathway can result in a nearly five-fold extension in lifespan. This study proposes to achieve similar effects pharmacologically. A compound mix has been identified utilizing glycation lowering (Gly-low) compounds that alter multiple key pathways involved in aging including the reduction of calorie intake, Nicotinamide adenine dinucleotide (NAD) metabolism, inflammation, glycation stress and increased fat burning. Preliminary findings that have shown significant increases in survival of normal and diabetic mice models fed with Gly-low confirms the efficacy of multimodal benefits of Glycation lowering (Gly-low) compounds. Glycation lowering (Gly-low) compounds were chosen based on their ability to protect neurons against glycation stress and consist of 5 compounds that have been designated GRAS (generally regarded as safe) by the Food and Drug Administration (FDA). Based on these results, the investigators hypothesize that methylglyoxal (MGO) lowering cocktail of compounds can be given to adults with obesity, specified as body mass index body mass index (BMI) >27, to lower serum and urinary markers of insulin resistance, lower body mass index (BMI), and lower food intake. Successful completion of this innovative project will result in a cocktail of compounds that can complement ongoing treatments to reduce obesity and enhance the health and slow age-related diseases.

This is a single center, double-blind, placebo-controlled, randomized trial. 100 subjects will be recruited between the ages of 50 and 70 yrs with a body mass index (BMI)>27. The participant will take 3 Gly-low supplements in pill form orally by mouth once in the morning. Baseline measurements in body mass index (BMI) (height and weight), waist circumference, food intake and dietary behavior (by questionnaire), urine, and serum will be obtained. Body mass index (BMI) will be measured every 12 weeks. The primary endpoints will be measures of physical frailty, based on performance and a clinical frailty index, and cognitive performance based on a cognitive impairment questionnaire, including memory, will be measured after 6 months and 12 months. Urine and serum will be analyzed every 12 weeks for various aging and metabolic markers. Patients will also be monitored for side effects or other compound related issues.

Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered into the study.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Obese (BMI >27) individuals

Exclusion Criteria:

• must be older than 50 years of age or older

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; MGO cocktail containing a combination of alpha-lipoic acid, nicotinamide, thiamine, pyridoxamine, and piperine	Drug: Gly-low; MGO cocktail containing a combination of alpha-lipoic acid, nicotinamide, thiamine, pyridoxamine, and piperine
Placebo Comparator: Control; sugar pill	Other: Placebo; sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body mass index (BMI) from baseline to 1 year	Body Mass Index (BMI) is a calculated from a person's weight in kilograms divided by the square of height in meters.	baseline and one year
Change in frailty from baseline to 1 year	Frailty will be assessed and measured using a questionnaire-based method as well as analyzing the physical performance of the subject in clinic. The Clinical Frailty Scale (CFS) is a judgement-based frailty tool that evaluates specific domains including comorbidity, function, and cognition to generate a frailty score ranging from 1 (very fit) to 9 (terminally ill).	baseline and 1 year
Change of cognition from baseline to 1 year	Cognition will be assessed and measured using a questionnaire-based method. The Clinical Frailty Scale (CFS) is a judgement-based frailty tool that evaluates specific domains including comorbidity, function, and cognition to generate a frailty score ranging from 1 (very fit) to 9 (terminally ill).	baseline to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Marker Glucose for Aging and Insulin Resistance	Blood samples will be collected and analyzed over the course of the study to measure the blood marker glucose in mmol/L associated with aging and insulin resistance.	baseline to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Marker Insulin for Aging and Insulin Resistance	Blood samples will be collected and analyzed over the course of the study to measure the blood marker insulin in ulU/mL associated with aging and insulin resistance.	baseline to 1 year

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Marshall Stoller, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 26, 2021
• First Submitted That Met QC Criteria: October 15, 2021
• First Posted (Actual): October 19, 2021

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 22, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: 20-32631

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No IPD will be shared.

Drug and device information, study documents

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