Biological Effects of Weight Loss In Older, Obese Women

SPECIFIC AIMS A.1. Overview Obesity is associated with a higher level of inflammation and oxidative stress, which in turn are important mediators of sarcopenia, declines in physical functioning, and physical limitations in older adults. Several observational studies and randomized controlled trials (RCTs) suggest that behavioral interventions targeting weight loss through caloric restriction plus exercise (CR +EX) may reduce inflammation and may improve function in obese older adults.3 The mechanisms by which CR +EX may influence physical functioning and sarcopenia (the involuntary loss of skeletal muscle with age) remain largely understudied. It is proposed that CR +EX may avert sarcopenia by reducing inflammation, oxidative damage, and consequent apoptosis of skeletal muscle myocytes.

A.2. Objective of the Pilot Study

The proposed pilot study will lay the groundwork for a RCT of the effects of CR +EX on inflammation, oxidative stress, apoptosis, body composition, intramuscular fat, sarcopenia, muscle strength, and physical functioning in obese older adults. The specific objectives of the proposed study are as follows:

1. Demonstrate the feasibility, acceptability, and efficacy of the proposed intervention, including:

   1. Ability to recruit 40 sedentary, older obese adults with mild to moderate functional disability;
   2. High rate of attendance at treatment sessions (Mean > 75%); and
   3. Good response to treatment (Mean body weight loss > 7%).

2. Evaluate the biological effects of the CR +EX intervention, including changes in:

   1. Inflammation (i.e., tumor necrosis factor-α [TNF- α], interleukin-6 [IL-6], myeloperoxidase [MPO]);
   2. Oxidative stress (RNA and DNA oxidative damage in leucocytes)
   3. Apoptosis (as assessed by caspases and nuclear DNA fragmentation);
   4. Body composition (as assessed by dual x-ray absorptiometry [DXA)] and
   5. Sarcopenia and muscle composition (i.e., fat free muscle and intramuscular fat, as assessed by Magnetic Resonance Imaging [MRI] and Magnetic Resonance Spectroscopy [MRS]).

3. Examine functional changes associated with weight loss including:

   1. Upper and lower extremity muscle strength (as measured by grip strength and isometric and isokinetic ankle and knee strength);
   2. Response to the Short Physical Performance Battery; and
   3. Self-reported disability.
4. Test whether the expected beneficial effects of the CR +EX intervention on physical functioning are mediated by changes in inflammation, oxidative stress, apoptosis, and sarcopenia;
5. Determine the effect size of the CR +EX intervention on the key outcomes so as to provide the basis for sample size calculations for the planning of the larger RCT.

A.3. Research Hypotheses for the Future RCT

The synergistic effects of CR +EX may be effective in reversing the effects of inflammation, oxidative distress, apoptosis, and sarcopenia on both muscle strength and physical functioning in older adults. Thus, the primary goal of this pilot study is to provide support for a future RCT to test the hypothesis that a lifestyle intervention targeting a 7% loss in body weight through CR + EX will produce greater reductions in these outcomes, as compared to a (no weight loss) control condition. The future RCT would be designed to test the following primary and secondary hypotheses:

Primary hypotheses. As compared with a control condition, the CR +EX Intervention will:

1. Decrease inflammation (as measured by TNF-α, IL-6, and MPO);
2. Decrease oxidative stress (as measured by DNA and RNA damage in isolated leucocytes);
3. Decrease the rate of apoptosis (as measured by caspases and DNA laddering);
4. Produce favorable changes in body composition (i.e., a decrease in total fat mass and an increase in appendicular lean mass, as assessed by DXA); and
5. Produce favorable changes in muscle composition (i.e., a decrease in intramuscular fat and an increase in fat-free muscle as assessed by MRI/MRS).
6. Increase muscle strength and performance (as assessed through validated strength measures)