Genomic Outcomes of Metformin
| Status: | Completed |
|---|---|
| Conditions: | Cognitive Studies, Cognitive Studies, High Blood Pressure (Hypertension), Obesity Weight Loss, Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 65 - 79 |
| Updated: | 12/15/2018 |
| Start Date: | August 3, 2016 |
| End Date: | November 15, 2018 |
Medical scientists have found that people with diabetes who take the drug Metformin have less
age-related disease than those taking other treatments and researchers believe it may prevent
numerous diseases and conditions that effect older people. In addition, metformin extends
lifespan in some animal models of human disease. The purpose of this study is to see if
taking Metformin causes changes in blood cells consistent with improved health and longevity
in people who do not have diabetes. In this study Metformin will be compared to placebo. A
placebo is a substance, like a sugar pill, that is not thought to have any effect on a
participants disease or condition. In this study participants will either receive the active
study medication, Metformin or placebo which is not active. Placebos are used in research
studies to see if the drug being studied really does have an effect.
age-related disease than those taking other treatments and researchers believe it may prevent
numerous diseases and conditions that effect older people. In addition, metformin extends
lifespan in some animal models of human disease. The purpose of this study is to see if
taking Metformin causes changes in blood cells consistent with improved health and longevity
in people who do not have diabetes. In this study Metformin will be compared to placebo. A
placebo is a substance, like a sugar pill, that is not thought to have any effect on a
participants disease or condition. In this study participants will either receive the active
study medication, Metformin or placebo which is not active. Placebos are used in research
studies to see if the drug being studied really does have an effect.
The number of older adults is projected to increase dramatically by 2050. Aging-related
diseases and conditions still seriously compromise the quality of life among most older
adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan
and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide
antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over
one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents
type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing
insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain
unclear, although a number of potential mechanism such as activation of AMP-activated protein
kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been
proposed. The fact that metformin treatment in persons with type-2 diabetes has been
associated with reduced risk of other aging-related diseases and conditions, including
cardiovascular disease, cancer and cognitive decline supports the possibility of the
beneficial effects of metformin on healthy aging. It is imperative to capitalize on these
leads to extend health span among older adults.
To translate animal findings to human intervention trials, appropriate aging biomarkers are
needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular
features that mediate effects of both genetic and environmental factors on aging-related
functional decline and disease. The roles of monocytes have been implicated in development of
many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative
disease. In a cross-sectional association study of 1,200 monocyte samples, we identified
1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were
over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of
decline in those functions with age. Both autophagy and oxidative phosphorylation are
considered as key contributors to the aging process, and their dysfunctions have been linked
to aging-related diseases. Changes in these aging-related omic biomarkers may be early
indicators of cellular damage or disruption that eventually leads to age-related
dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention
may also provide molecular insight for personalizing treatment. The investigators propose a
pilot study to examine changes in aging-related omic profiles after 3 months of metformin
treatment in 35 monocyte samples from older adults using a randomized, double-blind,
placebo-controlled crossover study design.
Our overarching goal of the pilot study is to evaluate the utility of using the aging-related
omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic
intervention trials through the following specific aims. Although this pilot study does not
have sufficient power to definitively test all the aims, it will provide essential
preliminary data for developing a full scale research program.
- Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and
related functional changes in human monocytes,
- Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in
human monocytes,
- Aim 2: To investigate the longitudinal relationship between transcriptional and
functional changes in human monocytes during the metformin treatment and
- Aim 3: To test the effects of the metformin treatment on frailty and other aging-related
physical and cognitive measures and investigate the longitudinal relationship between
these changes and transcriptional changes.
A randomized, double-blind, placebo-controlled crossover trial in 30 participants using
metformin and matching placebo will be used. In the absence of a treatment by sequence
interaction effect, this design can increase study power for evaluating treatment effects by
allowing each participant to be his/her own control. The period effect may be minimum because
the primary outcomes, methylation and transcriptional measures, are relatively stable
overtime.
diseases and conditions still seriously compromise the quality of life among most older
adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan
and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide
antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over
one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents
type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing
insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain
unclear, although a number of potential mechanism such as activation of AMP-activated protein
kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been
proposed. The fact that metformin treatment in persons with type-2 diabetes has been
associated with reduced risk of other aging-related diseases and conditions, including
cardiovascular disease, cancer and cognitive decline supports the possibility of the
beneficial effects of metformin on healthy aging. It is imperative to capitalize on these
leads to extend health span among older adults.
To translate animal findings to human intervention trials, appropriate aging biomarkers are
needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular
features that mediate effects of both genetic and environmental factors on aging-related
functional decline and disease. The roles of monocytes have been implicated in development of
many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative
disease. In a cross-sectional association study of 1,200 monocyte samples, we identified
1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were
over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of
decline in those functions with age. Both autophagy and oxidative phosphorylation are
considered as key contributors to the aging process, and their dysfunctions have been linked
to aging-related diseases. Changes in these aging-related omic biomarkers may be early
indicators of cellular damage or disruption that eventually leads to age-related
dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention
may also provide molecular insight for personalizing treatment. The investigators propose a
pilot study to examine changes in aging-related omic profiles after 3 months of metformin
treatment in 35 monocyte samples from older adults using a randomized, double-blind,
placebo-controlled crossover study design.
Our overarching goal of the pilot study is to evaluate the utility of using the aging-related
omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic
intervention trials through the following specific aims. Although this pilot study does not
have sufficient power to definitively test all the aims, it will provide essential
preliminary data for developing a full scale research program.
- Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and
related functional changes in human monocytes,
- Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in
human monocytes,
- Aim 2: To investigate the longitudinal relationship between transcriptional and
functional changes in human monocytes during the metformin treatment and
- Aim 3: To test the effects of the metformin treatment on frailty and other aging-related
physical and cognitive measures and investigate the longitudinal relationship between
these changes and transcriptional changes.
A randomized, double-blind, placebo-controlled crossover trial in 30 participants using
metformin and matching placebo will be used. In the absence of a treatment by sequence
interaction effect, this design can increase study power for evaluating treatment effects by
allowing each participant to be his/her own control. The period effect may be minimum because
the primary outcomes, methylation and transcriptional measures, are relatively stable
overtime.
Inclusion Criteria:
- Age 65 - 79
Must meet criteria from one or more of the following groups:
Group 1 (Can have 1 or 2 of these, but not all 3)
- History of coronary artery disease (MI/heart attack, stroke, heart failure, or
peripheral artery disease)
- Cancer, with no active treatment in the last year
- MCI (MoCA >18<26 -inclusive of 1 point if <12 years of education Group 2
- Decline physical function (walking speed < 1 m/s) Group 3 (Either or both)
- Abdominal obesity (>88cm women, >102cm men) AND hypertension (treated or resting blood
pressure >140/90
- Abdominal obesity (>88cm women, >102cm men) AND hyperlipidemia (treated or fasting
total cholesterol >240 English literacy Willing to provide informed consent
Exclusion Criteria:
- eGFR <45
- Type 2 diabetes (HbA1c>6.5) or type 1 diabetes
- Any tobacco or nicotine product use in the past year
- Low vitamin B12 Levels (< 300 pg/mL)
- Self-reported severe difficulty or inability to walk 400m or climb 10 steps (from Q 2
and 19 on PAT-D)
- Self-reported difficulty or inability to perform basic ADL functions (from Q 10, 13,
14, 16 on PAT-D)
- Excessive alcohol use (>14 drinks/week)
- Cancer requiring treatment in past year (except skin)
- Dementia - diagnosed and/or MoCA score <18
- Parkinson's or other neurological disease
- Chronic liver disease or cirrhosis
- End stage renal disease or on dialysis
- Rheumatic conditions (Rheumatoid arthritis, lupus, and any other autoimmune disease
the -PI deems them to be ineligible for)
- Thyroid problems the PI deems them to be ineligible for
- Gout
- Involved in another interventional study
- Hemoglobin <8 or diagnosed with anemia
- Recent unintentional weight change (+/- 10 lbs. in the last 12 months)
- BMI <18.5
- Likely to not follow the protocol
- PI deems unfit to participate
- Already taking Metformin or any other drug intended to treat diabetes
We found this trial at
1
site
Winston-Salem, North Carolina 27157
Principal Investigator: Jingzhong Ding, PhD
Phone: 336-713-8561
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