Rapalog Pharmacology (RAP PAC) Study

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 thestudy

• 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 aftercompleting 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 >80IU/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 serumcreatinine>1.4, eGFR≤60 ml/min/1.73m2)

• Problems with bleeding, on medication that prolongs bleeding time (if subject cannotsafely 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), andtacrolimus (Prograf) or other medications proposed to lower the immune system

• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such asketoconazole, 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

• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice,cannabidiol (CBD) and other foods/substances that are known to inhibit cytochromeP450 and PgP activity and may increase everolimus exposures and should be avoidedduring treatment

• Subjects who are not willing to restrict the use of St. John's Wort (Hypericumperforatum) because it may decrease everolimus exposure unpredictably.

• Subjects who are not willing to avoid blood donations 8 weeks prior to the firstvisit 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 intensityexercise greater than 150 minutes per week) or planning to start new exerciseprogram during study period

• Tobacco use

• Allergies to lidocaine, sirolimus, or everolimus

• Subjects currently enrolled in other clinical trials. Subjects may be eligible aftera 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 theintervention