A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
Condition: PreDiabetes; Aging
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Interventional
Phase: Phase 3

Summary: 
      The goal of this pilot and feasibility study is to investigate the effects of a short course
      of metformin therapy on a surrogate marker of cellular senescence and autophagy among adult
      patients with prediabetes. The overall hypothesis is that metformin will have beneficial
      effects on longevity and quality of life by inducing autophagy downstream of activating
      adenosine monophosphate-activated protein kinase (AMPK) and inhibiting mechanistic target of
      rapamycin (mTOR) through potential effects of reduced inflammation, reduced degeneration of
      muscle and tendon tissue, antineoplastic effects, reduced obesity and hyperglycemia,
      preserved cardiovascular functions, and/or the prevention of neurodegeneration (such as
      age-associated dementia). This pilot study will address the following aim:

      Demonstrate that metformin therapy will increase cellular autophagy as an inverse correlate
      of aging as measured by increases in Microtubule-associated protein 1A/1B-light chain 3 (LC3)
      scores.

      Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body
      composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy
      and aging.

      Primary outcome: Increased levels of LC3 in leukocytes.
    

Detailed description: 
      Anti-aging medicine is a burgeoning field. Accumulating evidence implicates the cellular
      process of autophagy as a primary mechanism of normal aging and the diseases associated with
      it. Autophagy is a process of "cellular recycling" and is known to affect a spectrum of
      health and disease states associated with aging, including inflammatory disorders, metabolic
      syndrome, type 2 diabetes, cardiovascular disease, cancer, and neurodegeneration. The
      dynamics of autophagy are controlled by autophagy-related genes and by one of the central
      regulators of metabolism, AMPK (the target of metformin). Autophagy also affects stem cells
      and cellular senescence. When the process of autophagy fails, the result is a state of
      chronic inflammation and degeneration in many organ systems.

      Numerous studies have documented the metabolic benefits conferred by the glucose lowering
      agent metformin. In animal models, metformin has been shown to increase both lifespan and
      health-span, and a clinical trial (NCT02432287) is currently ongoing to determine whether
      this effect translates to humans, with additional investigation into how the medication
      alters the adult human transcriptome. In vitro studies demonstrate metformin's ability to
      mitigate aging- and disease-related inflammation, oxidative damage, and diminished autophagy.
      Additionally, there are numerous cohort, case-control and meta-analysis studies confirming
      metformin's reduction in cancer-related death via hypothesized activity in the relevant mTOR,
      human epidermal growth factor receptor 2 (HER2), micro-Ribosomal Nucleic Acid (miRNA) and
      transcription growth factor alpha (TGF-alpha) pathways and processes. As such, the National
      Institutes of Health (NIH) has issued an Funding Opportunity Announcement (FOA) parent
      announcement PA-17-073 (https://grants.nih.gov/grants/guide/pa-files/PA-17-073.html) to
      solicit additional clinical studies that will evaluate metformin's effects on aging and
      age-related conditions.

      The long term goal of this study is to develop a Phase III study in response to this FOA
      using leucocyte LC3, transcription factor EB (TFEB) scores, total DNA methylation and
      galectin-3 to gauge the magnitude of metformin's effects on autophagy and cellular senescence
      as proxies for aging in adults with prediabetes. This study will provide preliminary data for
      such a proposal, and it will fill a knowledge gap regarding the use of validated biomarkers
      in this arena. It will also contribute significantly to the anti-aging literature. The
      primary objective of this proposal is to validate the autophagy-related experimental design
      by using leucocyte LC3 as a marker of autophagy and cellular senescence in humans.

      Aim: Demonstrate that metformin therapy will increase cellular autophagy as an inverse
      correlate of aging as measured by increases in LC3 scores.

      Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body
      composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy
      and aging.

      Primary outcome: Increased levels of LC3.

      FUTURE DIRECTIONS Confirmation of improvement in markers of autophagy resulting from
      treatment with metformin will justify the submission of grant proposals for more definitive
      clinical trials examining the effect of metformin on actual clinical outcomes (as opposed to
      surrogate measures) in pursuit of a potential Food and Drug Administration (FDA) indication
      for metformin as an anti-aging therapy.
    

Intervention name(s): Metformin; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Total daily dose titrated up to 1500 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.; Total daily dose titrated up to 1944 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.
Other intervention name(s): Glucophage; Calcium Carbonate
Intervention MeSH terms: Metformin; Calcium Carbonate
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a double-blind, approximate placebo-controlled trial of 12 weeks of metformin vs. CaCO3 (Placebo) among adult patients with prediabetes.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Autophagy