Aging, Epigenetics, Inflammatory Mediators
Conditions
Keywords
Epigenetic clock
Brief summary
Topical Rapamycin ointment will be applied to participant forearms to test whether epigenetic changes in the skin are elicited.
Detailed description
Rapamycin 8% ointment will be applied topically to one of the participant's forearms and matching placebo to the opposite forearm daily for a total of 6 months. After consenting, screening and randomization of arms, the participants will be monitored at monthly visits until study completion.
Interventions
DRUGRapamycin Topical Ointment
8% topical rapamycin ointment
OTHERPlacebo
Petrolatum ointment containing no active ingredient
Sponsors
National Institute on Aging (NIA)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Randomization will be performed by the compounding pharmacy. Ointment dispensers will be color-coded for left and right arm for each subject.
Intervention model description
Participants will be their own control, either right or left arm will be randomized to treatment or placebo.
Eligibility
Sex/Gender
ALL
Age
65 Years to 95 Years
Healthy volunteers
Yes
Inclusion criteria
* 65-95 years of age. * Good health with all chronic diseases (hypertension, coronary artery disease, etc.) clinically stable. * Selected subjects will be in good health (Per the World Health Organization, good health will be defined as complete physical, mental, and social well-being and not merely the absence of disease or infirmity). * All diseases or infirmities will be clinically stable whether managed by medications or not. * CLOX score of 10 or greater * Women will be postmenopausal * Postmenopausal women taking hormone replacement will be included if they have been on a stable dose for ≥6 months * Live within a 20 mile drive of the UTHSA campus (7703 Floyd Curl Drive, San Antonio, TX)
Exclusion criteria
* Diabetes. * History of skin ulcers or poor wound healing, or keloid formers. * Smoking. * Liver disease. * Coumadin anti-coagulation. * Treatment with drugs known to affect cytochrome P450 3A (diltiazem, erythromycin, etc. - due to role in rapamycin metabolism). * Treatment with an immunosuppressant (prednisone, etc.) within 6 months. * History of recent (within 6 months) Myocardial Infarction or active Coronary Disease. * Hypersensitivity to rapamycin or petrolatum (ointment vehicle) * Arm tattoos or scars in application area
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Epigenetic Markers | Baseline to 6 months | A set of DNA methylation marks that correlate with chronological age will be used to measure rejuvenation of the epigenetic clock due to drug treatment compared to placebo. Using Illumina EPIC arrays, CpG methylation will be assessed and then the predicted age, based on the combined methylation at the set of 391 marks (the epigenetic clock as defined by Dr. Steven Horvath, UCLA), will be determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Inflammatory Marker IL-6 | Baseline to 6 months | A measure of inflammatory markers will include analytes that are affected either by aging or oral rapamycin. Inflammatory markers are measured using Enzyme-Linked Immuno-Sorbant Assays (ELISA). The marker to be measured is IL-6. |
| Change in Inflammatory Marker CRP | Baseline to 6 months | A measure of inflammatory markers will include analytes that are affected either by aging or oral rapamycin. Inflammatory markers are measured using Enzyme-Linked Immuno-Sorbant Assays (ELISA). The marker to be measured is CRP. No data were obtained from this measure due to the low blister fluid volume. |
Countries
United States
Participant flow
Recruitment details
Subjects acted as their own controls, one forearm had rapamycin ointment applied and the other placebo, thus there were 20 participants who had both rapamycin applied to one arm and placebo to the other.
Participants by arm
| Arm | Count |
|---|---|
| Topical Rapamycin Ointment is applied to a color coded area on the subject forearm daily.
Rapamycin Topical Ointment: 8% topical rapamycin ointment to one arm and Petrolatum ointment containing no active ingredient to the opposite arm | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Topical Rapamycin |
|---|---|
| Age, Customized Age 65-92 years | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 4 / 22 | 4 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
Primary
Change in Epigenetic Markers
A set of DNA methylation marks that correlate with chronological age will be used to measure rejuvenation of the epigenetic clock due to drug treatment compared to placebo. Using Illumina EPIC arrays, CpG methylation will be assessed and then the predicted age, based on the combined methylation at the set of 391 marks (the epigenetic clock as defined by Dr. Steven Horvath, UCLA), will be determined.
Time frame: Baseline to 6 months
Population: DNA prepared from the placebo and rapamycin-treated skin sites was analyzed for methylation at specific sites known to change with age.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Rapamycin | Change in Epigenetic Markers | 84.4 years |
| Placebo | Change in Epigenetic Markers | 82.8 years |
Secondary
Change in Inflammatory Marker CRP
A measure of inflammatory markers will include analytes that are affected either by aging or oral rapamycin. Inflammatory markers are measured using Enzyme-Linked Immuno-Sorbant Assays (ELISA). The marker to be measured is CRP. No data were obtained from this measure due to the low blister fluid volume.
Time frame: Baseline to 6 months
Secondary
Change in Inflammatory Marker IL-6
A measure of inflammatory markers will include analytes that are affected either by aging or oral rapamycin. Inflammatory markers are measured using Enzyme-Linked Immuno-Sorbant Assays (ELISA). The marker to be measured is IL-6.
Time frame: Baseline to 6 months
Population: Recovery of blister fluid from some subjects was lower than anticipated so a Luminex-based array assay, which uses much lower sample volumes than ELISAs, was performed and the cytokine levels on the rapamycin treated side were compared to the placebo levels.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Rapamycin | Change in Inflammatory Marker IL-6 | 1.44 pg/ml |
| Placebo | Change in Inflammatory Marker IL-6 | 1.57 pg/ml |