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| ID | Type | Description | Link |
|---|---|---|---|
| 1U01AG076941-01 | U.S. NIH Grant/Contract | View source | |
| A534255 | Other Identifier | UW Madison | |
| Protocol Version 6/5/2026 | Other Identifier | UW Madison |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks. Participants aged 18-35 will not receive the intervention and can expect to be on study for up to approximately 8 weeks.
Pharmacological inhibition of mechanistic target of rapamycin (mTOR) has been repeatedly demonstrated to extend lifespan and prevent or delay several age-related diseases in diverse model systems. However, the risk of potentially serious side effects in humans have thus far prevented the long-term use of the mTOR inhibitor rapamycin as a therapy for aging and age-related diseases. Therefore, it remains unknown whether rapamycin or rapamycin analogs (rapalogs) can safely improve healthy aging in humans.
The objective of this project is to determine if 24 weeks of daily low dose (0.5 mg/day) or weekly intermittent (5 mg/week) treatment with the rapalog everolimus can safely improve physiological and molecular hallmarks of aging in middle-aged to older insulin resistant adults who are at high risk for nearly every age-related condition.
Using a double-blinded, randomized, placebo-controlled clinical trial, the investigators will perform a battery of gold-standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve 4 inter-related domains of physiological aging: metabolic, cardiac, cognitive, and physical function. The investigators will also assess the incidence of adverse events and changes from baseline blood chemistry, blood cell counts, lipids, glucose, and insulin.
To comprehensively examine the molecular target specificity and the impact on mechanisms of aging by everolimus, the team will evaluate mTORC1 and mTORC2 signaling, assess mitochondrial bioenergetics, and perform a multi-omics approach (epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics) in blood and/or muscle biopsy samples.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Daily Everolimus (0.5 mg/day) and Weekly Placebo | Experimental | Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks |
|
| Daily Placebo and Weekly Everolimus (5mg/week) | Experimental | Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks |
|
| Daily Placebo and Weekly Placebo | Placebo Comparator | Once daily placebo and once weekly placebo taken orally for 24 weeks |
|
| Young Adult Reference Group | No Intervention | Baseline testing only |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus 0.5 MG once per day | Drug | Everolimus is considered an mTOR kinase inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| Metabolic Function: Change in peripheral insulin sensitivity | Change (pre to post) in peripheral insulin sensitivity measured by glucose disposal rate relative to circulating insulin during a dual tracer 75g oral glucose tolerance test (OGTT). | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac Function: Change in fractional shortening velocity | Cardiac Function will be assessed by measuring the change in fractional shortening velocity determined during the echocardiogram. | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Cognitive Function: Change in cerebral blood flow |
| Measure | Description | Time Frame |
|---|---|---|
| Physical Function: Change in cardiorespiratory fitness | Change in cardiorespiratory fitness defined as the VO2peak obtained during a graded exercise test on a stationary bicycle. | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Physical Function: Change in maximal knee extensor muscle power |
Inclusion Criteria: Adults aged 55-80 years old
Free of overt chronic disease
Willing to provide informed consent
Willing to comply with all study procedures and be available for the duration of the study
Able to use and be contacted by the telephone
Ability to take oral medication
Insulin Resistant defined by HOMA-IR greater than or equal to 1.5 or prediabetic defined as:
Not planning to change diet or physical activity status
Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), clinical chemistry and urinalysis
Females of childbearing potential must have a negative urine pregnancy test before DEXA and before the oral glucose tolerance test (OGTT). A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
Women of childbearing potential in sexual relationships with men must use an acceptable method of contraception from 30 days prior to enrollment until 4 weeks after completing study visits. Males must agree to avoid impregnation of women during and for four weeks after completing study visits through use of an acceptable method of contraception.
Inclusion Criteria: Younger Adults aged 18-35 (No intervention)
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Adam Konopka, PhD | University of Wisconsin, Madison | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Wisconsin-Madison | Madison | Wisconsin | 53705 | United States |
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Data from this study may be requested from other researchers years after the completion of the study endpoints by contacting Dr. Adam Konopka or the NIA BioBank Repository.
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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This is a randomized, placebo-controlled, double-blind, 24-week clinical trial using everolimus in middle-aged to older adults. This study will follow a "double-dummy" design where participants will be randomized 1:1:1 in a double-blinded fashion to one of three groups: 1) everolimus once daily (0.5 mg/day) plus placebo once weekly, 2) placebo once daily plus everolimus once weekly (5mg/week) or 3) placebo once daily and placebo once weekly. The double dummy design preserves the double-blind for both placebo versus everolimus and for daily versus weekly dosing schedules. Everolimus and placebo will be over encapsulated to be indistinguishable from one another.
There will also be a group of young, healthy individuals who will complete baseline testing only and not the intervention. This group allows the determination if everolimus changes any molecular and physiological outcomes in older adults toward that of a young, healthy reference group.
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| Everolimus 5 MG once per week | Drug | Everolimus is considered an mTOR kinase inhibitor |
|
| Placebo once per day | Drug | No therapeutic effect |
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| Placebo once per week | Drug | No therapeutic effect |
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Change in blood flow in posterior cingulate, medial temporal lobe (hippocampus and parahippocampus) and inferior frontal cortex assessed by brain MRI (4D Flow, Arterial Spin Labeling). |
| 0 (pre-intervention) and 24 weeks (post-intervention) |
| Safety: Number of Participants with Adverse Events | Safety will be measured in part by reporting the number of participants with adverse events. | up to 36 weeks |
| Safety: Change in concentration of blood metabolites/enzymes | Safety will be measured in part by reporting the change in the blood concentration of metabolites and enzymes as assessed by a complete metabolic panel | 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention) |
| Safety: Changes in concentration of blood lipids | Safety will be measured in part by reporting the changes in the concentration of blood lipids. | 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention) |
| Safety: Changes in number of blood cells | Safety will be measured in part by reporting the changes in the number of blood cells as determined by blood cell count with differential | 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention) |
| Safety: Changes in HbA1c (%) | Safety will be measured in part by reporting the changes in the percentage of glycosylated hemoglobin (Hba1c (%)) | pre-intervention baseline, post-intervention up to 24 weeks |
| Safety: Changes in concentration of insulin | Safety will be measured in part by reporting the changes in fasting blood insulin concentration | 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention) |
| mTOR signaling: Change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 as assessed by immunoblotting and immunoprecipitation. | mTOR signaling will be assessed by measuring the change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 via immunoblotting in muscle and/or peripheral mononuclear blood cells (PMBCs). | pre-intervention baseline, post-intervention up to 24 weeks |
Change in maximal knee extensor muscle power obtained using dynamometry |
| 0 (pre-intervention) and 24 weeks (post-intervention) |
| Physical Function: Change in maximal knee extensor muscle strength | Change in maximal knee extensor muscle strength assessed by one repetition maximum (1-RM) | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Cognitive Function: Change in memory | Change in memory will be measured using the Montreal Cognitive Assessment (MoCA Test). Max score of 30. Score of 26 and above is considered normal. | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Cognitive Function: Change in learning | Change in learning via the California Verbal Learning Test-III: learning slope for trials 1-5 and long delay retention (score range 0-16, where higher scores are better). | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Cognitive Function: Change in executive function | Change in executive function will be measured using the Executive function as indexed by: the Delis-Kaplan Executive Function System Trails Test, and Color-Word Interference Test (score range 0-19, where higher scores are better). | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Metabolic Function: Change in hepatic insulin sensitivity | Change in hepatic insulin sensitivity as assessed by suppression of endogenous glucose production during the dual tracer, 75g oral glucose tolerance test (OGTT) | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Metabolic Function: Change in glucose variability | Glucose Variability will be assessed via continuous glucose monitoring during three occasions during weeks 0, 12, and 24 by measuring the change in range, total standard deviation, mean daily differences (MODD), and the overall net glycemic action over a 4-h and 8-h period (CONGA4; CONGA8). | 0 (pre-intervention), 12, and 24 weeks (post-intervention) |
| Metabolic Function: Change in estimates of fasting insulin resistance | Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Metabolic Function: Change in whole body insulin sensitivity. | Change in Matsuda Index where a higher value indicates greater insulin sensitivity | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Metabolic Function: Change in insulin sensitivity and glucose clearance | Change in oral glucose insulin sensitivity (OGIS) index where a higher value indicates greater insulin sensitivity | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Change in whole blood DNA Methylated positions | Change in differentially methylated positions in whole blood samples as assessed by whole-genome sequencing | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Change in skeletal muscle transcriptome | Transcriptomics: Change in skeletal muscle transcripts assessed via RNA sequencing | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Change in concentration of lipid species | Lipidomics: Change in the concentration of lipid species in blood and/or skeletal muscle as assessed by liquid chromatography mass spectrometry | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Change in skeletal muscle protein abundance | Proteomics: Change in abundance of skeletal muscle proteins as assessed by mass spectrometry. | 0 (pre-intervention) and 24 weeks (post-intervention) |
| Change in the concentration of metabolites | Metabolomics: Change in concentration of blood and/or skeletal muscle metabolites as assessed by liquid chromatography mass spectrometry | 0 (pre-intervention) and 24 weeks (post-intervention) |