A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
| Status: | Recruiting |
|---|---|
| Conditions: | Healthy Studies, Endocrine, Diabetes |
| Therapuetic Areas: | Endocrinology, Other |
| Healthy: | No |
| Age Range: | 30 - 70 |
| Updated: | 10/15/2017 |
| Start Date: | September 1, 2017 |
| End Date: | July 31, 2018 |
| Contact: | Mark Burge, MD |
| Email: | mburge@salud.unm.edu |
| Phone: | 5052724658 |
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.
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.
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.
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.
Inclusion Criteria:
- Adults with prediabetes (defined as an A1c of 5.7-6.4%)
- BMI between 27 and 40 kg/m2 (inclusive).
Exclusion Criteria:
- Prior treatment with metformin or other diabetes medications,
- Pregnancy,
- Significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for women, > 1.4 mg/dl for
men),
- Severe hepatic dysfunction (aspartate amnotransferease [AST] or alanine
aminotransferase [ALT] > 3 times the upper limit of normal),
- Ongoing alcohol or substance abuse,
- Inflammatory bowel disease,
- Ongoing glucocorticoid therapy,
- Or inability to render informed consent.
We found this trial at
1
site
900 Camino de Salud
Albuquerque, New Mexico 87131
Albuquerque, New Mexico 87131
Phone: 505-272-4658
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