Pilot Study of Losartan and N-acetylcysteine as Inhibitors of Muscle Oxidative Stress in Elderly

The general hypothesis is that elderly have diminished nutritive flow to skeletal muscle and impaired capacity for building muscle. In aging populations, this decreased ability to build muscle may represent a tipping point in the progression towards chronic physical frailty and disability. The goal is to examine whether novel pharmacologic therapies can improve nutritive blood flow to the muscles and muscle building in the elderly.

The purpose of this study is 1) to determine if losartan administration will enhance blood flow and 2) to determine if N-acetylcysteine (NAC) will enhance blood flow.

The investigators will study community dwelling, healthy older men and women (60-85 years). Subjects will be randomized to one of three groups:

Experimental Group 1: Placebo losartan and placebo N-acetylcysteine (NAC). Experimental Group 2: losartan (25mg/dose) and placebo N-acetylcysteine (NAC). Experimental Group 3: N-acetylcysteine (NAC) (50 mg/kg/dose) and placebo

Subjects will admit to the clinic on day 1 of the study. Baseline testing consisting of leg blood flow (LBF), contrast enhanced ultrasound, handgrip testing and fatigue questionnaires. After testing is completed the subjects will recieve their first dose of NAC/ losartan/ placebo with dinner. Subjects will be fasted after 10 pm. On day 2, leg blood flow (LBF) will be measured approximately 12 hours post dose 1. Subjects will receive their second dose of NAC/ losartan/ placebo. Leg blood flow will be measured 1 hour and 2 hours post dose 2 of study interventions. The subjects will eat a meal and receive their third dose of the study intervention. Leg blood flow will be repeated at 1 hour and 2 hours post dose 3. Appoximately 30 minutes after dose 3 of the study intervention, handgrip testing will be performed and fatigue questionnaires completed.


Eligibility Criteria:
Inclusion Criteria:

1. Age between 60-85 years.
2. Ability to sign informed consent.
3. Ability to sign consent form.
4. Ability to pass a mini-mental status exam (score \>23 on the 30-item Mini Mental State Examination, MMSE).
5. Free-living, prior to admission.

Exclusion Criteria:

1. Subjects with cardiac abnormalities considered exclusionary by the study physicians (e.g., unstable angina or a cardiology-confirmed ECG that demonstrates cardiac abnormalities such as \> 0.2 mV horizontal or downsloping ST segment depression, frequent arrhythmia's (\> 10 PVC/min), or valvular disease).
2. Subjects with uncontrolled metabolic disease, including liver or renal disease.
3. Subjects with vascular disease characterized by a combination of risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, uncontrolled diabetes, hypercholesterolemia \> 250 mg/dl, claudication or evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal, and pedal arteries.
4. Any history of hypo- or hyper-coagulation disorders. (e.g., Coumadin use or history of DVT or PE).
5. Subjects with chronically elevated systolic pressure \>170 or a diastolic blood pressure \> 100. Subjects may be included if they are taking medication and have a blood pressure below these criteria.
6. Subjects with cancer or recently (6 months) treated cancer other than basal cell carcinoma.
7. Any subject currently on a weight-loss diet or a body mass index \> 33 kg/m2.
8. Inability to abstain from smoking for duration of study.
9. A history of \> 20 pack per year smoking.
10. Subjects with atrial fibrillation, history of syncope, angina, or congestive heart failure.
11. Any subject that is HIV-seropositive or has active hepatitis.
12. Recent anabolic or corticosteroids use (within 3 months).
13. Subjects with low hemoglobin or hematocrit (i.e., lower than accepted lab values).
14. Agitation/aggression disorder.
15. Dementia.
16. History of stroke with motor disability.
17. A recent history (\<12 months) of GI bleed.
18. Alcohol (more than 3 drinks per day) or drug abuse.
19. Polycystic ovary syndrome (PCOS) and/or hyperthecosis.
20. Non-classical adrenal hyperplasia.
21. Cushing's syndrome.
22. Pregnancy.
23. Hyperprolactinoma, hypothyroidism.
24. Lactose intolerance.
25. Subjects with coronary heart or mitral valvular rheumatic heart disease.
26. Subjects with impaired renal function and/or renal artery stenosis.
27. Subjects with pulmonary hypertension.
28. Subjects on any medications known to vasodilate the peripheral arteries.
29. Subjects taking NSAIDs
30. Physical dependence or frailty (impairment of activities of daily living, ADLs).
31. History of falls (\>2/year).
32. Depression (\>5 of the 15 items on the Geriatric Depression Scale (GDS).
33. Subjects suffering malnutrition or with a BMI \< 20 kg/m2 with low albumin or transferrin.
34. Asthma
35. Any other condition or event considered exclusionary by the PI and covering faculty physician.