Effect of mTOR Inhibition and Other Metabolism Modulating Interventions on the Elderly

Study Overview
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Brief Summary
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The ability to mount an effective immune response declines with age, leaving the elderly increasingly susceptible to infectious diseases and cancer. Rapamycin, an FDA approved drug to prevent transplant rejection, increases the lifespan and healthspan of mice and ameliorates age-related declines in immune responsiveness, cancer survival, and cognition in laboratory animals. Investigators are conducting a translational trial to test whether rapamycin also improves life functions in humans focusing on elderly persons (aged 70-95).

Detailed Description
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Inhibition of the mTOR pathway by rapamycin (RAPA), an immunosuppressive drug used as adjunct therapy in preventing solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals. Thus, it has been suggested that RAPA could be used therapeutically in humans to slow age-associated pathologies. Indeed, improvements in cognition, control of tumorigenesis, and enhancing certain aspects of immunity have been demonstrated in RAPA treated murine models. Moreover, long-term RAPA delivery in older mice is associated with changes in immune reactivity not evident in younger animals. Investigators propose to expand to a larger cohort of older humans to test the hypothesis that RAPA treatment, even in very old individuals, will result in simultaneous improvement in systems known to be negatively affected by aging. Investigators will focus on the immune system, cognition, and physical parameters of healthy aging, such as walking speed. Investigators will recruit healthy volunteers, aged 75-95 years, and randomize them to either RAPA or placebo, controlling for gender, ethnicity, and age. These groups will be used to address the following specific aims: Aim 1. Assess general parameters of immune health before and after RAPA treatment; these include serum inflammatory cytokines, PBMC subsets (naïve vs memory T cells, TREGS, etc.), and polyclonal T cell activation potential. Aim 2. Test the effects of RAPA treatment on responsiveness to a vaccine challenge; both B cell (antibody) and T cell responses will be assessed. Aim 3. Correlate immune function rejuvenation with cognitive and physical function measures in subjects treated with RAPA or placebo. Aim 4. Collect pilot data on effect of RAPA on cardiovascular function. Cognition will be assessed by three different testing tools (EXIT25, SLUMS, and TAPS). Physical performance will be measured by grip strength and 40 foot timed walks, parameters known to correlate with healthy aging. Measures of cardiovascular function (Substudy D) using MRI of the heart to evaluate diastolic function and brain MRI to analyze cerebral blood flow, with measures of pulse wave velocity and endothelial function using laser doppler flowmetry will be performed. In addition to scoring positive outcomes, investigators will assess whether there are adverse changes in clinical laboratory tests that could compromise the safe use of RAPA therapeutically in older individuals. The long-term goal is to assess whether RAPA is safe to use in an elderly population, while also being efficacious in slowing, or even reversing, the aging process.

Official Title
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Effect of Mammalian Target of Rapamycin Inhibition and Other Metabolism Modulating Interventions on the Elderly: Immune, Cognitive, and Functional Consequences

Conditions
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Aging

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Placebo
* Drug: Rapamycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 70-95 participants will be in good health with all chronic diseases (hypertension, coronary artery disease, etc.) clinically stable. participants must have adequate cognitive function to be able to give informed consent. This will be established by enrolling participants with CLOX 1 scores of ≥10. Exclusion Criteria: unstable ischemic heart disease clinically significant pulmonary disease history of immunodeficiency or receiving immunosuppressive therapy history of a coagulopathy or receiving a medical condition requiring anticoagulation an estimated glomerular filtration rate of <30ml/min uncontrolled hypercholesteremia >350mg/dl; uncontrolled hypertriglyceridemia >500mg/dl diabetes history of skin ulcers or poor wound healing smoking liver disease treatment with drugs known to affect cytochrome P450 3A (diltiazem, erythromycin)

Ages Eligible for Study
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Minimum Age: 70 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapamycin<br>Rapamycin 1mg taken once daily for 8 weeks | Drug: Rapamycin<br>* treatment<br>* Other names: Sirolimus;|
| Placebo Comparator: Placebo<br>Placebo taken once daily for 8 weeks | Drug: Placebo<br>* control<br>|
| Experimental: Rapamycin Alone - Cardiovascular Effects<br>No placebo control; Rapamycin 1mg once daily for 8 weeks | Drug: Rapamycin<br>* No placebo control in this substudy group<br>* Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological Responses | T cell function measured by number of T cells per millimeter cubed. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical Performance | walking speed: Timed 40-foot walk: each participant will perform 3 walks (timed with a stopwatch) at their preferred walking speed over a measured 40-foot path. Results will be averaged for analysis. The faster the walking speed the better the performance. | 8 weeks | 
| Cognitive Function | The Executive Interview (EXIT25) - This test is a brief bedside test that consists of 25 items measuring abilities that include: Executive functioning, Motor sequencing, Spoken alternate sequencing, Verbal fluency, Design fluency, Persistence, Resistance to interference, Reflexes Scoring directions are listed under each of the 25 portions of this test. For each section, the client is given a score of a 0, 1, or 2. A score 0 indicates no impairment, a score of 1 indicates some impairment, and a score of 2 indicates severe impairment. Directions for what qualifies as each score are listed under each section. The points are totaled and criteria are given for severe, moderate, and no impairment. Minimum score is -0- and maximum is 50. A score of 15 or below indicates normal executive functioning, a score of above 15 indicates moderate to severe impairment. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Geriatrics