Genomic Outcomes of Metformin
Condition: Coronary Artery Disease; Mild Cognitive Impairment; Obesity, Abdominal; Hypertension
MeSH terms: Coronary Artery Disease; Obesity, Abdominal; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Health Services Research