Exercise and Inflammation in the Elderly (IRIS)

• Adipose tissue and skeletal muscle inflammation [ Time Frame: Before and after the exercise training or weight loss intervention. ] [ Designated as safety issue: No ]
• Body composition and fitness [ Time Frame: Before and after the exercise training or weight loss intervention. ] [ Designated as safety issue: No ]

Persistent low-grade inflammation and impaired fibrinolysis, are independent predictors of several chronic diseases highly prevalent in the older veteran population including CVD, stroke, and diabetes. Inflammation is likely to be a causative underlying mechanism of insulin resistance. Lifestyle changes such as weight loss and physical activity are advocated for the treatment of these chronic diseases and endpoints, and data are emerging which suggest that these treatments may be beneficial, in part, due to their anti-inflammatory effects. Identification of effective therapies that reduce chronic inflammation for veterans is important given the widespread adverse health effects of a chronically elevated inflammatory state.

This study will compare the effects of 6 month randomized trial of aerobic exercise (AEX) vs. weight loss (WL) in older individuals on:

1. adipokine secretion and expression (TNFalpha, adiponectin, PAI-1);
2. adipose tissue and skeletal muscle inflammatory proximal receptor expression (adipoR1, adipoR2, TNFR1, TNFR2 expression) and intermediate signaling pathways (AMPK, IKKalpha, NFkB, JNK activity), and the terminal inhibitory action on IRS-1 tyrosine phosphorylation, IRS-1 phosphorylation (Ser307) and Akt; and
3. whether the changes in ligand concentrations, receptor expression, and signal transduction are associated with changes in peripheral (whole body insulin sensitivity by a hyperinsulinemic-euglycemic clamp), hepatic (hepatic glucose production, HGP), and cell-type specific (insulin stimulated glucose transport in adipocytes) insulin sensitivity.

The prevention and treatment of insulin resistance, the metabolic syndrome, and their CVD complications through exercise and weight loss could improve veterans' health and reduce health care costs. Knowledge of their effectiveness has important implications for the cardiovascular health of veterans given the widespread adverse health effects of chronic inflammation on vascular biology, skeletal muscle function and insulin action.

• Inflammation
• Insulin Sensitivity

• Other: Weight Loss
  6 months of weight loss
• Other: Aerobic Exercise Training
  6 months of aerobic exercise training

• Experimental: Arm 1
  6 months of aerobic exercise training
  Intervention: Other: Aerobic Exercise Training
• Experimental: Arm 2
  6 months of weight loss
  Intervention: Other: Weight Loss

Inclusion Criteria:

1. Male and Female
2. 45-80 yrs of age
3. Non-smoking for one year
4. BMI greater than 20 kg/m2 and less than 50 kg/m2
5. Menopause over 1 year

Exclusion Criteria:

1. Symptomatic heart disease, CAD, CHF, or uncontrolled hypertension (BP over 180/100 mm Hg) unless medically stabilized
2. Currently being treated for active cancer
3. Type 1 diabetes; Insulin or oral agent treatment for diabetes, poorly controlled diabetes FBS over 160 mg/dl
4. Allergic to lidocaine
5. Untreated dyslipidemia with National Cholesterol ATPIII 10 year cardiac risk score greater than 10% (www.nhbli.nih.gov/guidelines/cholesterol/atp3upd04.htm), or receiving TG lowering meds
6. Other systemic disorders that are not medically treated and stable
7. Taking beta-blockers, oral steroids, warfarin or any other medications interfering with fat/muscle metabolism that may not be safely discontinued temporarily for specific procedures (ie for 72 hours prior)
8. Abnormal response to exercise test (ST segment depression greater than 2mm, chest pain, significant arrhythmias, extreme shortness of breath, cyanosis, exercising BP above 240/120mm Hg, or other contraindications to exercise) *requires follow up treatment w/ primary MD for continued participation in study
9. Abnormal liver function
10. Abnormal renal function (BUN above 40 mg/dl, Cr above 2 mg/dl)
11. Chronic pulmonary disease
12. Anemia Hct below 35 mg/dl, platelets below 100,000/cm3
13. MMSE below 24, dementia or unstable clinical depression by exam
14. Aerobically trained with VO2max greater than 2 SD above age-adjusted mean
15. Exercise group only: History of CVA (by medical history) with symptoms limiting the ability to exercise

• University of Maryland
• Johns Hopkins University