RESTOR: PK/PD mTORi Inhibition in Older Adults

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.