As people get older, there are changes in their cells and tissues that may affect their ability to function. This can lead to increased death and age-associated disorders, like heart disease, cancer, and Alzheimer's disease. Studies in animal models have been able to identify drugs that slow the aging process, leading to a longer, healthier life. This study is focused on one such family of drugs, called mTOR inhibitors, and the investigators' goal is to test two of these drugs, Rapamycin (Sirolimus) and Everolimus (Afinitor), in healthy older adults to find a dose and dose timing that can be used to safely inhibit mTOR to the levels seen in young healthy persons. The investigators expect that the dose that works well in women may differ from the one that is best in men, so it is important to include both sexes in this research.

The study will be done in three parts, each with different human subject groups. Participants may only enroll in one of the sub-studies.

Sub-study 1: Determining target mTOR activity values in YOUNG untreated subjects (ages 20-30 years): NOTE: This aim of the study is not a clinical trial, so this population will not be included in participant flow or included as an arm in the study.

This study defines "best dose" as the choice of drug, dose, and frequency that will come closest to restoring the "youthful" levels of mTOR activity in an older individual. The investigators first need to measure mTOR activity in young untreated subjects to define these target "youthful" mTOR activity levels.

Sub-study 2. Finding the most effective drug, dose, and timing for dosing for oral dosing of the mTOR inhibitor drugs in older adults (65-90 years):

Healthy older persons will be recruited for a short-term (6 week treatment plus 4 week follow-up) dose-finding study. The most effective, but safe dose will then be tested in a larger number of subjects in Sub-study 3. Importantly, the best drug and dose regimen for females may differ from the one determined for males so the cohort will include both sexes.

Sub-study 3. Placebo controlled trial testing of DAILY (sustained) vs. INTERMITTENT mTOR inhibition in older human males and females:

Sub-study 3 will enroll healthy older persons (65-90 yrs) for a long-term clinical trial (6 months of treatment plus 6 months of follow-up) with 3 test groups:

i) best DAILY dose/drug; ii) best INTERMITTENT dose/drug/interval, and iii) PLACEBO (a pill that looks identical to the medicine, but has no drug in it).

This study will help find out what effects, good and/or bad, Rapamycin or Everolimus have on older people who take the drug for a longer period of time. The safety of Rapamycin and Everolimus in humans has been tested in prior research studies; however, some side effects may not yet be known in healthy older persons. By completing the entire study, the Research Team hopes to learn more about how older human subjects can best be treated using these drugs (mTOR inhibitors) to help them live longer, healthier lives.

Inclusion Criteria:

Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2):

1. Age ≥65 to 90 years
2. Men and women
3. In good health with all medical problems stable.
4. Community-dwelling
5. Agreement to adhere to Lifestyle Considerations throughout study duration.
6. Ability of participant to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2):

1. Resident of nursing home or long-term care facility
2. Subjects with diabetes or currently taking glucose lowering medications
3. History of moderate-severe heart disease (New York Heart Classification greater than grade II) or pulmonary disease (dyspnea on exertion upon climbing one flight of stairs or less; abnormal breath sounds on auscultation); Moderate to severe valvular heart disease
4. Active cancer or history of cancer treatment within the last 5 years
5. Chronic inflammatory condition, autoimmune disease, or infectious processes (e.g., active tuberculosis, HIV, rheumatoid arthritis, systemic lupus erythematosus, acute or chronic hepatitis B or C)
6. History of a coagulopathy or any medical condition requiring anticoagulation (except low dose ASA)
7. Renal insufficiency with an estimated glomerular filtration rate of <30ml/min
8. Uncontrolled hypercholesterolemia >350mg/dl or uncontrolled hypertriglyceridemia >500mg/dl
9. Anemia or abnormal blood cell counts: hemoglobin level <9.0g.dl; white blood count <3500/mm3; neutrophil count <2000/ mm3; platelet count <125,000/mm3
10. History of skin ulcers or poor wound healing
11. Active tobacco use (within 6 months)
12. Diagnosis of any disabling neurologic disease such as Parkinson's Disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, cerebrovascular accident with residual deficits (muscle weakness or gait disorder), severe neuropathy, diagnosis of dementia or Clox1 score less than 10 at the time of screening visit, cognitive impairment due to any reason such that the patient is unable to provide informed consent
13. Liver disease
14. Systemic treatment with an immunosuppressant (prednisone, etc.) within the year prior to enrollment
15. Treatment with drugs known to affect cytochrome P450 (CYP3A4), i.e., diltiazem, erythromycin.
16. Patients with history of recent (within 6 months) myocardial infarction or active coronary disease
17. Patients with history of recent (within 6 months) intestinal disorders
18. History of severe head trauma, brain injury, brain surgery, inflammation of the brain, or history of seizure disorder
19. History of Long-Covid (PASC) within one year
20. Acute Covid19 or Covid19 infection within the last 6 months
21. Unwilling to forgo grapefruit juice consumption.
22. Participation in mTORi study within the prior year. (Note: participants in AIM 1 will be excluded from participating in AIM 2 of the proposed trial.)
23. Allergic to RAPA or EVERO
24. Allergic to lidocaine
25. Recreational drug use
26. Donated blood over a two-month period prior to study initiation.
27. Currently using cannabidiol (CBD) or tetrahydrocannabinol (THC) or any preparation contained these, or related, substances.
28. Currently using hormone replacement or modulating therapies.

De-identified Individual participant data (IPD) that underlie results in a publication.

At the time of publication in a peer review journal

Blinding will only occur in Aim 2 (Sub-study 3). Randomization will be done by the research pharmacy providing the investigational drug.