Insulin and Sarcopenia in the Elderly

Our general hypothesis is that a reduced response of muscle protein anabolism to insulin
plays an important role in the loss of muscle mass with aging. Our goal is to determine the
mechanisms underlying the age-related insulin resistance of muscle proteins, which will
allow us to define specific interventions to target this defect and provide the scientific
basis for the prevention and treatment of sarcopenia.

Our previous studies indicate that the response of muscle proteins to the anabolic action of
insulin is impaired in healthy older adults as compared to younger controls, which hampers
the anabolic effect of mixed feeding on muscle proteins. These changes are associated with
an age-related reduction in the vasodilatory response to insulin, which, from our data,
appears to be a potentially important mediator of the physiological anabolic effect of
insulin on muscle proteins. Preliminary data from our laboratory also suggest that in older
subjects a single bout of aerobic exercise may restore the normal response of blood flow,
muscle protein synthesis and anabolism to insulin.

Therefore, we will test in healthy subjects the following specific hypotheses:

1. Insulin-induced increases in blood flow and muscle perfusion are necessary for the
physiological stimulation of muscle protein synthesis and anabolism by insulin.

2. Aging reduces the vascular sensitivity to insulin, which prevents the physiological
increase in blood flow and muscle perfusion in response to insulin, thereby decreasing
the response of muscle protein synthesis and net balance to the anabolic action of
insulin and mixed feeding.

3. Aerobic exercise can restore, in older subjects, the insulin-induced increase in blood
flow and muscle perfusion to youthful levels, thus normalizing the anabolic effect of
insulin and mixed feeding on muscle protein synthesis and net muscle protein balance.

We will use state-of the art stable isotope tracer techniques to measure muscle protein
turnover, and a newly developed method to measure muscle perfusion in young and older
subjects. The results of these studies will allow us to better define the physiological
mechanisms of action of insulin on muscle protein anabolism, advance our knowledge on the
pathophysiology of sarcopenia, and provide the scientific basis for the behavioral and/or
pharmacological treatment of muscle loss with aging.

Inclusion Criteria:

1. Age 18-40 yrs, and 65-85 yrs.

2. Ability to sign consent form (score >23 on the 30-item Mini Mental State Examination,
MMSE)

3. Stable body weight for at least 3 months

Exclusion Criteria:

1. Physical dependence or frailty (impairment in any of the Activities of Daily Living
(ADL), history of falls (>2/year) or significant weight loss in the past year)

2. Exercise training (>2 weekly sessions of moderate to high intensity aerobic or
resistance exercise)

3. Pregnancy or nursing women.

4. Significant heart, liver, kidney, blood or respiratory disease

5. Peripheral vascular disease

6. Diabetes mellitus or other untreated endocrine disease

7. Active cancer

8. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.

9. Alcohol or drug abuse

10. Severe depression (>5 on the 15-item Geriatric Depression Scale, GDS)

11. Potential subjects who have recently donated blood in the past 60 days will be
excluded from participating in the study.