Aging
Conditions
Keywords
acarbose, aging
Brief summary
The investigators are studying the effects of acarbose on muscle and adipose gene transcription in older adults.
Detailed description
Acarbose, an FDA approved drug for the treatment of type 2 diabetes, has known effects on glucose metabolism. Evidence from mice indicates that acarbose may prolong lifespan. In humans, acarbose improves inflammatory markers and reduces cardiovascular events. Consequently, acarbose is of interest in clinical translational aging research since it may influence fundamental processes that contribute to age-related diseases. The study described herein is an exploratory study to examine the effect of acarbose treatment on the biology of aging in humans. Specifically, the investigators plan to study whether treatment with a 10 week course of acarbose will alter the gene expression profile in adipose tissue and muscle in older adults in pathways that are known to be affected by human aging, in a placebo-controlled crossover study.
Interventions
DRUGAcarbose
see arm description
OTHERPlacebo
See arm description
Sponsors
Glenn Foundation for Medical Research
Montefiore Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
60 Years to 100 Years
Healthy volunteers
Yes
Inclusion criteria
* Male * age \>60 years * impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)
Exclusion criteria
* cancer * heart failure * Chronic Obstructive Pulmonary Disease (COPD) * inflammatory conditions * estimated Glomerular Filtration Rate (eGFR) \<45 * active liver disease * poorly controlled hypertension * epilepsy * recent cardiovascular disease event (last 6 months) * inflammatory bowel disease * history of bariatric or other gastric surgery * cigarette smoking * serious substance abuse. * Treatment with drugs known to influence glucose metabolism * Hypersensitivity to acarbose or any component of the formulation. * Treatment with anti-coagulant medications or anti-platelet drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tissue Gene Expression Using RNA Sequencing (RNA-Seq) | 10 weeks | Difference in gene expression in muscle and abdominal adipose tissue using RNA-Seq were to have been evaluated to assess the effects of absorbed metabolites on tissues. Muscle and adipose are key metabolic tissues that undergo significant age-related changes and play an active role in the pathogenesis of aging. Muscle and abdominal adipose tissue samples were obtained and homogenized with tissue homogenizer. Subsequent mRNA extraction and analysis of gene expression (RNA seq) was conducted using multiplexed 100bp single-end sequencing. Differential expression between samples and after acarbose and after placebo were to have been determined using a negative binomial model approach implemented in the DESeq package. Results were to have been summarized by study arm and subsequently analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum microRNA (miRNA) | At the end of 10 week treatment period (Visit 4) and at 22 weeks (Visit 6) following enrollment | Differences in miRNA expression between acarbose and placebo arms were to have been evaluated. 1 milliliter (mL) of sera collected from the processing of blood samples will be used for miRNA sequencing. miRNA was extracted from the serum samples using miRNeasy kit in accordance with the manufacturer's protocol and miRNA libraries were prepared. Cel-miR-39 mimic was added to each sample before extraction, for normalization, and sequenced using multiplexed single-end sequencing on an Illumina HiSeq2500. miRNA are small, non-coding RNAs that regulate gene expression at a post-transcriptional level. Due to their stability in blood, changes in expression of circulating miRNA may serve as markers for age-related pathologies and investigators have correlated B-lymphocyte miRNA profiles in the plasma associated with exceptional longevity. Read counts were to have been summarized by study arm and statistically analyzed using a Wilcoxon test to compare miRNA expression levels. |
| Fecal Microbiome for 16s Ribosomal DNA (rDNA) Gene Sequencing | At the end of 10 week treatment period (Visit 4) and at 22 weeks (Visit 6) following enrollment | 16s rDNA gene sequence expression levels were to have been assessed following the collection of stool samples. A fecal microbiome stool collection kit was provided to participants for self-collection of samples and returned for treatment and analysis. 16s rDNA sequencing was to have been performed to assess bacterial species clustering. Fecal microbial DNA was extracted from the samples and eluted DNA divided into 1 cubic centimeter (cc) aliquots and shipped for 16s rDNA sequencing. The raw 16s sequence data was converted to taxonomic profiles by grouping 16s sequences into Operational Taxonomic Units (OTUs) based on sequence similarity as well as by generating de-novo OTU generation using a de novo OTU-picking tool. A Basic Local Alignment Search Tool (BLAST) was to have been used to analyze each OTU's representative against a database. Relative abundance plots for visual comparison of microbial abundances were to have been generated, summarized, and reported by study arm. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acarbose First, Then Placebo Participants will take Acarbose three times daily for 10 weeks (titration over 4 weeks, maintenance 6 weeks as per protocol). After a two week washout period, participants will take Placebo three times daily for a total of 10 weeks (titration over 4 weeks, maintenance 6 weeks as per protocol). | 10 |
| Placebo First, Then Acarbose Participants will take Placebo three times daily for 10 weeks (titration over 4 weeks, maintenance 6 weeks as per Protocol). After a two week washout period, participants will take Acarbose three times daily for a total of 10 weeks (titration over 4 weeks, maintenance 6 weeks as per Protocol). | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo First, Then Acarbose | Total | Acarbose First, Then Placebo |
|---|---|---|---|
| Age, Customized 60-81 years old | 10 Participants | 20 Participants | 10 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 3 / 20 | 2 / 20 |
| serious Total, serious adverse events | 0 / 20 | 1 / 20 |
Outcome results
Primary
Tissue Gene Expression Using RNA Sequencing (RNA-Seq)
Difference in gene expression in muscle and abdominal adipose tissue using RNA-Seq were to have been evaluated to assess the effects of absorbed metabolites on tissues. Muscle and adipose are key metabolic tissues that undergo significant age-related changes and play an active role in the pathogenesis of aging. Muscle and abdominal adipose tissue samples were obtained and homogenized with tissue homogenizer. Subsequent mRNA extraction and analysis of gene expression (RNA seq) was conducted using multiplexed 100bp single-end sequencing. Differential expression between samples and after acarbose and after placebo were to have been determined using a negative binomial model approach implemented in the DESeq package. Results were to have been summarized by study arm and subsequently analyzed.
Time frame: 10 weeks
Population: Muscle and abdominal adipose tissue biopsies collected and processed for gene expression data analyses did not yield meaningful data as the results were unable to be differentially expressed and could not be reported. Funding for repeat assays was unavailable and this study was terminated and unable to be published. Funding required to repeat gene expression data analyses is not available and results for this Outcome Measure will never be able to be reported.
Secondary
Fecal Microbiome for 16s Ribosomal DNA (rDNA) Gene Sequencing
16s rDNA gene sequence expression levels were to have been assessed following the collection of stool samples. A fecal microbiome stool collection kit was provided to participants for self-collection of samples and returned for treatment and analysis. 16s rDNA sequencing was to have been performed to assess bacterial species clustering. Fecal microbial DNA was extracted from the samples and eluted DNA divided into 1 cubic centimeter (cc) aliquots and shipped for 16s rDNA sequencing. The raw 16s sequence data was converted to taxonomic profiles by grouping 16s sequences into Operational Taxonomic Units (OTUs) based on sequence similarity as well as by generating de-novo OTU generation using a de novo OTU-picking tool. A Basic Local Alignment Search Tool (BLAST) was to have been used to analyze each OTU's representative against a database. Relative abundance plots for visual comparison of microbial abundances were to have been generated, summarized, and reported by study arm.
Time frame: At the end of 10 week treatment period (Visit 4) and at 22 weeks (Visit 6) following enrollment
Population: Stool samples collected for 16S fecal microbiome analysis were submitted to an external laboratory for processing and analysis; however, results were confounding and uninterpretable. As such, relative abundance plots were unable to be generated. In the absence of relative abundance plots there is no gene expression data to review, summarize, or report. Funding required to repeat fecal microbiome analyses is not available and results for this Outcome Measure will never be able to be reported.
Secondary
Serum microRNA (miRNA)
Differences in miRNA expression between acarbose and placebo arms were to have been evaluated. 1 milliliter (mL) of sera collected from the processing of blood samples will be used for miRNA sequencing. miRNA was extracted from the serum samples using miRNeasy kit in accordance with the manufacturer's protocol and miRNA libraries were prepared. Cel-miR-39 mimic was added to each sample before extraction, for normalization, and sequenced using multiplexed single-end sequencing on an Illumina HiSeq2500. miRNA are small, non-coding RNAs that regulate gene expression at a post-transcriptional level. Due to their stability in blood, changes in expression of circulating miRNA may serve as markers for age-related pathologies and investigators have correlated B-lymphocyte miRNA profiles in the plasma associated with exceptional longevity. Read counts were to have been summarized by study arm and statistically analyzed using a Wilcoxon test to compare miRNA expression levels.
Time frame: At the end of 10 week treatment period (Visit 4) and at 22 weeks (Visit 6) following enrollment
Population: Serum samples collected and pre-processed for microRNA expression level determinations were never sequenced and analyzed due to lack of funding. Since samples were never sequenced and analyzed there is no read count data to summarize and there are no results to report. Funding to sequence samples for analysis is not available and results for this Outcome Measure will never be able to be reported.