The objective of RAP PAC is to identify safe and effective weekly dose(s) for the mTOR inhibitors sirolimus and everolimus that intervene on the underlying fundamental biology of aging. Participants who are 55-89 years old that are free of overt chronic diseases will be assigned to either 6 weeks of sirolimus or everolimus (5 mg, 10 mg, or 15 mg once per week). The investigators will complete the everolimus arm first and then subsequently complete the sirolimus arm of the study. Total time on study would be up to 17 weeks to complete baseline and follow up visits.

The mTOR inhibitor rapamycin and rapamycin analogs (rapalogs) extend healthspan and/or lifespan in multiple model systems. However, the risk of adverse events and dose limiting toxicities in humans have thus far precluded the long-term prophylactic use of mTOR inhibitors as a therapy for aging and age-related diseases. The pharmacokinetics and pharmacodynamics (PK/PD) data for mTOR inhibitors in older adults is currently unknown and has prevented the identification of a safe dosage that could maximize health-span extension and minimize adverse effects.

RAP PAC will identify a recommended phase 2 trial dose for sirolimus and everolimus in older men and women by performing a phase 1, dose finding study that evaluates PK/PD, safety and tolerability, and mTOR signaling using conventional as well as novel approaches. Overall, the investigators will pair comprehensive molecular and pharmacologic approaches to evaluate PK/PD in humans and identify dosing regimens that safely inhibit mTOR complex 1 (mTORC1) to intervene in the biology of aging.

Inclusion Criteria:

• Middle-age adults 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 telephone
• Ability to take oral medication
• Not planning to change diet or physical activity status
• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), and clinical chemistry
• 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

Exclusion Criteria:

• Heart disease (history, abnormal ECG)
• Cerebrovascular disease (history)
• Cancer or less than 5 years in remission (history)
• Chronic respiratory disease (history, FEV1/FVC < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, abnormal blood liver panel, ALT >104 IU/L, AST >80 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, OGTT ≥ 200 mg/dl at 2 hrs.)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine>1.4, eGFR≤60 ml/min/1.73m2)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• 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
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem
• Taking strong CYP3A4 activators such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
• Taking daily NSAIDs such as ibuprofen, naproxen, aspirin and others, with the exception of baby aspirin (81mg)
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, cannabidiol (CBD) and other foods/substances 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
• 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 or nicotine use
• Allergies to lidocaine, sirolimus, 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

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.