Everolimus Aging Study (EVERLAST)

University of Wisconsin (UW)

Status and phase: Active, not recruiting; Phase 2

Conditions: Aging; Insulin Resistance

Treatments: Drug: Everolimus 0.5 MG once per day; Drug: Placebo once per day; Drug: Placebo once per week; Drug: Everolimus 5 MG once per week

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05835999

Protocol Version 4/30/2025 (Other Identifier)

1U01AG076941-01 (U.S. NIH Grant/Contract)

A534255 (Other Identifier)

2021-1519

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 106 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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:

  • impaired fasting glucose (100-125 mg/dL)
  • HbA1c (5.7-6.4 percent)
  • glucose 2 hours after a 75 gram oral glucose tolerance test (140-199 mg/dL)
  • previous diagnosis of prediabetes in the past year

• 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:

  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

• 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.

  • Note: Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy.

Inclusion Criteria: Younger Adults aged 18-35 (No intervention)

• Free overt chronic disease

Exclusion Criteria:

• Pregnancy or breastfeeding
• Heart disease
• Cerebrovascular disease
• Cancer or less than 5 years in remission
• Chronic respiratory disease
• Chronic liver disease
• Diabetes
• Alzheimer's
• Chronic kidney disease
• For those undergoing muscle biopsy: problems with bleeding, on medication that prolongs bleeding time
• Taking azathioprine (Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), dexamethasone (Decadron, Dexpak), methotrexate (Rheumatrex, Trexall), prednisolone (Orapred, Pediapred, Prelone), prednisone (Sterapred), sirolimus (Rapamune), and tacrolimus (Prograf) or other medications proposed to lower the immune system. Daily use of high potency topical corticosteroids used on greater than or equal to 10% of body surface area will not be eligible. Nasal sprays or inhaled corticosteroids will be reviewed on a case-by-case basis.
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors
• Taking strong CYP3A4 activators
• Taking daily NSAIDs with the exception of baby asprin (81 mg)
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity and may increase everolimus exposures and should be avoided during treatment
• Subjects who are not willing to restrict the use of St. John's Wort (Hypericum perforatum) because it may decrease everolimus exposure unpredictably
• Subjects who are not willing to avoid blood donations 8 weeks prior to the first visit and 8 weeks after the last visit
• For those undergoing MRI, contraindications with MRI which could include metal on your body
• Low white-blood cell count (<4,000 cell/µL)
• History of stomatitis or ulcers in the mouth
• Those on glucose lowering drugs
• Participating in intensive exercise training program (high to moderate intensity exercise greater than 150 minutes per week) or planning to start new exercise program during study period
• Tobacco use
• Allergies to lidocaine or everolimus
• Subjects currently enrolled in other clinical trials. Subjects may be eligible after a washout period that will be reviewed on a case by case basis.
• Individuals with limited English proficiency
• Subjects who are planning to have elective surgery 12 weeks prior to or during the intervention

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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106 participants in 4 patient groups, including a placebo group

Daily Everolimus (0.5 mg/day) and Weekly Placebo

Experimental group

Description:

Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks

Treatment:

Drug: Placebo once per week

Drug: Everolimus 0.5 MG once per day

Daily Placebo and Weekly Everolimus (5mg/week)

Experimental group

Description:

Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks

Treatment:

Drug: Everolimus 5 MG once per week

Drug: Placebo once per day

Daily Placebo and Weekly Placebo

Placebo Comparator group

Description:

Once daily placebo and once weekly placebo taken orally for 24 weeks

Treatment:

Drug: Placebo once per week

Drug: Placebo once per day

Young Adult Reference Group

No Intervention group

Description:

Baseline testing only