Effect of mTOR Inhibition and Other Metabolism Modulating Interventions on the Elderly
Condition: Aging
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Rapamycin; Placebo; Rapamycin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): treatment; control; No placebo control in this substudy group
Other intervention name(s): Sirolimus; Sirolimus
Intervention MeSH terms: Sirolimus; Temsirolimus; MTOR Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Geriatrics