Immune Function and Muscle Adaptations to Resistance Exercise in Older Adults

The loss of muscle mass and strength due to aging leads to serious health problems for older adults. Muscle health can be improved by exercise training, but some people improve their strength substantially, whereas others improve little. The reason for this variation is unknown. This study will investigate whether function of the immune system influences how well people respond to exercise. Older Veterans who participate will have their muscle size, strength, and function measured periodically for almost a year. Participants will drink a nutritional supplement or placebo daily and complete a 36 session strength training program. Participants will be vaccinated for tetanus and donate small amounts of blood and muscle tissue during the study so that immune function can be compared to muscle outcomes during training and during a long-term follow-up. The study results should increase the investigators' understanding of the negative effects of aging on muscle and will possibly lead to better strategies for muscle maintenance and rehabilitation for older adults.

Objective: The study will examine the influence of immune function in older adults on improvement of muscle mass, strength, and function by resistance training. The maintenance of those benefits during long term follow-up will also be examined. This objective will be accomplished by a double-blind randomized placebo-controlled trial of a nutritional supplement (Muscle Armor) which evidence suggests can improve immune function, promote muscle growth, and counteract muscle loss. The study premise is that aging results in decreased ability of the immune system to respond to stimuli such as exercise. The study proposes that the supplement will improve muscle health by promoting a shift in immune function of older adults from a pro-inflammatory state towards a state which supports muscle growth and maintenance.

Research Plan: The study will randomize Veterans (age 60-80, N=50) to participate in the supplement or placebo groups in a three phase study. The phases of participation correspond to the three specific aims. Aim 1 will determine if 2-weeks of supplementation improves immune function. Humoral immune function will be assessed as the response to vaccination. Innate immune function will be measured as systemic and cellular responses to acute resistance exercise that the investigators' previous studies indicate are affected by aging. Aim 2 will determine if supplementation during 36 sessions of progressive high-intensity resistance training boosts improvement in muscle size (CT scan), strength, and function (gait and balance). Muscle adaptations at the cellular levels will also be measured. Aim 3 will determine if continued supplementation for 26-weeks after completion of exercise training promotes the retention of the gains in muscle size, strength, and function. Multivariable testing will then be used to compare the results between Aims 1, 2, and 3 to determine whether or not immune function is correlated with muscle adaptation to training or detraining.

Methods: Participants will undergo nine blood draws and five muscle biopsies of the vastus lateralis over the course of the study so that the effects of the supplement on immune function and cellular adaptations to training can be measured. Three of the blood draws will be used to assess the antibody response to the tetanus, pertussis, and diphtheria vaccine. Muscle and blood will be collected before and after a bout of exercise conducted before and after the 2-weeks of supplementation prior to training. Immune function will be measured using the blood based on pro- and anti-inflammatory cytokine levels, the balance between specific T-cell subpopulations, and the proliferative capacity of mononuclear cells. Immune function will be measured in muscle based on macrophage content of specific cytokines and growth factors. The investigators' previous study showed that these muscle measures strongly correlate with size and strength gain after training. Key signaling pathways including nuclear factor-k B and PI3 kinase will also be measured. The fifth biopsy will be collected post-training to measure adaptation at the cellular level based on changes in number of satellite cells and myonuclei and fiber size. Hypotheses related to these measures will be tested with 80% power to detect at least 0.8 standard deviations difference in means between the supplement and placebo groups.

Clinical Relevance: Exercise is clearly able to affect immune function. However, the proposed study will attempt to modulate immune function and determine the effects on exercise outcomes. The study will also examine detraining, an important issue for older adults, that is usually omitted from training studies. Thus, the study will potentially advance the understanding of the mechanisms of muscle gain and loss in older adults, but more importantly, the study will evaluate a nutritional intervention as a complement to exercise for supporting muscle health during aging. Targeting the immune system may be the advantage needed for an older Veteran to successfully maintain or restore the muscle mass, strength, and function that is necessary for personal independence.

Eligibility Criteria:
Inclusion Criteria:

* Veteran
* Age 60-80 years
* Body Mass Index of 18.5 - 29.9 kg/m2

Exclusion Criteria:

* Currently participating in any other research study involving an intervention
* Smokes tobacco products
* Tetanus or TDAP vaccine in previous two years
* Allergic to vaccination
* Seizure in past 3 months
* Guillain-Barre Syndrome in past 3 months
* Takes the medications heparin, plavix / clopidogrel, or coumadin / warfarin
* Allergic to lidocaine
* Significant problem with fainting
* Problems walking or exercising with both legs
* Participated in a weight-lifting program targeting the thighs in last 3 months
* Pains, tightness or pressure in chest during physical activity
* Metastatic cancer or undergoing chemotherapy
* Cerebral aneurysm or intracranial bleed in past year
* End-stage congestive heart failure (NYHA Stage IV)
* Unstable abdominal or thoracic aortic aneurysm (\>4cm)
* Renal disease requiring dialysis
* Allergic to vaccination
* Acute retinal hemorrhage or ophthalmologic surgery in past 3 months
* Bone fractures in the pelvis, legs, or feet in the last 3 months
* Hernia that causes pain during physical activity
* Myocardial infarction or cardiac surgery in past 3 months
* Pulmonary embolism or deep venous thrombosis in past 3 months
* Proliferative diabetic retinopathy or severe nonproliferative retinopathy
* Active suicidality or suicidal ideation
* Systemic bacterial infection
* Taking aspirin in any form and unable/unwilling to discontinue at least 10 days prior to muscle biopsy
* Unwilling to halt concurrent use of amino acid or protein supplements
* Unwilling to halt new use of nutritional supplements
* Unwilling to maintain current normal diet
* Encephalopathy in past 7 days
* Active oral or genital herpes
* Current use of appetite stimulants
* Current treatment for mania or bipolar disorder or taking lithium.
* Diagnosis of a significant cognitive deficit
* Untreated severe aortic stenosis
* Uncontrolled diabetes mellitus (HbA1C\>10)
* Uncontrolled hypertension or hypotension (\>160/100, \<100 systolic)
* Uncontrolled malignant cardiac arrhythmia
* Unstable angina
* Allergic to latex or tape
* Bleeding or clotting disorders
* Taking any non-ASA NSAID and unable or unwilling to discontinue use for 3 days prior to muscle biopsy
* Taking Fish Oil, Gingko, Garlic, Saw Palmetto, Turmeric, or Vitamin E and unable or unwilling to discontinue use for 10 days prior to the muscle biopsy procedure
* Significant problems with chronic pain
* Uncontrolled asthma or allergies
* Taking lactulose, nitrates plus hypertension medications or Viagra
* Liver cirrhosis or other severe liver disease
* History of peripheral artery disease
* Certain Steroid or androgen use in past 3 months
* Other physician judgment
* Significantly abnormal complete blood count (CBC) or prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR)