Glutathione and Fuel Oxidation in Aging
Condition: Aging
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Glutathione is an important antioxidant protein which protects cells from harmful oxidative
      stress. Elderly humans are known to have elevated oxidative stress and deficiency of
      glutathione, but it is not known whether there is deficient synthesis of glutathione in
      muscle tissue of elderly humans.

      Mitochondria are engines of cells where food consumed is burned to make energy. Under normal
      conditions the fuel of choice in the fasted state is fat, but fasted elderly humans are not
      able to oxidize fat as well as healthy young humans. Elderly humans also have the highest
      incidence and prevalence of being overweight and obese, and have increased storage of fat in
      liver and muscle.

      This study will help determine whether

        1. elderly humans have diminished synthesis of glutathione in the skeletal muscle, and
           whether this can be improved by supplementing cysteine and glycine (and not an
           isonitrogenous placebo) in the diet;

        2. improving muscle glutathione concentrations can also improve fuel oxidation in aging;

        3. improvement of intracellular glutathione concentrations will be associated with a change
           in total body fat content
    

Detailed description: 
      Subjects will be recruited by written informed consent on forms approved by the Institutional
      Review Board of Baylor College of Medicine at the time of approval of the full protocol.
      Subjects taking an nonvitamin supplements or lipid lowering medications will stop this 4
      weeks before the screening labs and for the entire duration of the study. Fasted subjects
      will have screening labs (blood count, HbA1c, lipid profile, liver profile, blood urea
      nitrogen, Creatinine, thyroid stimulating hormone, free t4, cortisol) followed by an oral
      glucose tolerance test, measures of muscle strength by dynamometry, tests of function
      (including a 6-min walk test) and body composition scans to measure total body fat. On
      another occasion, fasted subjects will be undergo stable isotope infusions and other studies
      in the metabolic research unit to measure concentrations of amino-acids and glutathione in
      red blood cells and muscle tissue, glutathione synthesis rates in muscle and red cells,
      plasma and whole-body mitochondrial fatty-acid oxidation, Kreb's cycle function, urine urea
      nitrogen, plasma reactive oxygen species and F2-isoprostanes, genes of glutathione synthesis
      and fuel oxidation. Elderly subjects will also have magnetic resonance spectroscopy scan for
      liver and muscle fat content.

      Young subjects will be given dietary cysteine and glycine for 2-weeks and be restudied
      2-weeks later. They are then released from the study.

      Elderly subjects will be studied for 16 weeks. They will be assigned to receive either
      cysteine plus glycine, or alanine in a randomized, double-blinded study design. The studies
      described above will be repeated after 2 weeks and 16 weeks. Subjects will have monthly
      measures of liver profile, lipid profiles, BUN and creatinine and glutathione.
    

Intervention name(s): Glycine, cysteine (as n-acetylcysteine), alanine
Intervention type(s): Dietary Supplement
Intervention description(s): Young controls will receive cysteine plus glycine for 2 weeks
The elderly subjects will be randomized in a double-blinded design to receive either cysteine plus glycine OR alanine for a period of 4 months
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine; Glycine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Glutathione deficiency in aging; Impaired mitochondrial fatty-acid oxidation in aging