CALERIE Phase II Ancillary: Metabolic
Condition: Aging
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary aim of this NIA sponsored ancillary study of phase 2 CALERIE is to measure
      whether metabolic adaptation lasts up to 2 years in response to a 25% calorie restriction in
      normal-weight and slightly overweight individuals. Energy metabolism (24-hour sedentary and
      sleeping) will be measured in a respiratory chamber. Other measures include the activities of
      the sympathetic nervous and thyroid axes, oxidative stress in lipids, protein and DNA, organ
      size by MRI and echocardiography, and posture allocation (time spent engaging in different
      activities and the energy expended during these activities), and activity temperament (the
      innate predilection for movement). This set of studies will allow assessment of whether the
      previously observed metabolic adaptation in response to 25% caloric restriction is long
      lasting (up to two years), associated with reduced thyroid and sympathetic activities and
      reduced oxidative damage. The studies of organ sizes (liver, spleen, kidney, heart, adipose
      and muscle) by MRI and echo (heart) is essential to determine whether the metabolic
      adaptation is related to decreased organ sizes or improved organ energy metabolism
      efficiency. The above described measures will be performed at baseline and after 1 and 2
      years of a 25% caloric restriction in 50 non-obese humans and in 25 sex-, BMI- and age-
      matched subjects who will not engage in caloric restriction.
    

Detailed description: 
      Hypothesis 1: The decrease in energy expenditure (sedentary and sleeping) will be larger than
      that expected on the basis of loss of fat-free mass and fat mass even after weight
      stabilization. Aim 1: Determine the metabolic adaptation after 1 and 2 years of a 25% CR

      Hypothesis 2: The metabolic adaptation (what is not accounted by a decrease in FM and FFM) is
      not entirely accounted by reduced organ/tissue size (liver, spleen, kidney, heart and brain)
      but is accompanied by reduced activities of the sympathetic and thyroid systems. Aim 2:
      Assess the contribution of organ sizes and activities of the thyroid and sympathetic systems
      to the metabolic adaptation. Results will be compared to in vivo and in vitro oxidative
      phosphorylation (Smith, PI).

      Hypothesis 3: A decrease in markers of oxidative stress to lipid (urinary isoprostanes) DNA
      (strand breaks) in blood and protein (carbonylation and thiol oxidation) in blood and
      skeletal muscle tissue after 1 and 2 years of CR will be observed. Aim 3: Determine the
      changes in oxidative stress after 1 and 2 years of 25% CR by measuring urinary isoprostanes,
      serum carbonyls, DNA damage in nucleated blood cells and protein oxidation (carbonyls and
      oxidation of cysteine residues) in skeletal muscle.
    

Intervention name(s): Caloric restriction
Intervention type(s): Other
Intervention description(s): 25% caloric restriction below baseline energy requirement
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Prevention