Role of Metformin on Muscle Health of Older Adults

Hospitalizations for disease, injury, and/or surgery in older adults are likely to impair
physical mobility and, therefore, the older adults capacity to be physically active both
during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted
as the "new normal", ultimately increasing the risk of skeletal muscle and metabolic
dysfunction (e.g. insulin resistance and sarcopenia).

Muscle atrophy and insulin resistance are an unfortunate consequence with disuse in older
adults. We have observed with our bed rest studies in healthy older adults that in addition
to muscle and metabolic changes, we notice increased skeletal muscle inflammation, impaired
glucose uptake signaling and an upregulation of enzymes related to de novo ceramide
biosynthesis. The accumulation of ceramide, a toxic lipid intermediate, can disrupt glucose
homeostasis and impair muscle growth. Metformin treatment has been shown to improve insulin
sensitivity and attenuate muscle loss in insulin resistant adults through a mechanism that
may involve ceramide synthesis. Metformin used as a preventive strategy to maintain muscle
and metabolic health during a period of physical inactivity in older adults has not been
investigated.

Therefore, we have proposed to conduct a clinical study in older adults to test whether
metformin treatment during bed rest will attenuate insulin resistance, muscle loss and
accumulation of ceramides. These findings will be foundational for future development of
treatments to prevent insulin resistance and muscle atrophy in inactive older adults.

Inclusion Criteria:

- Age between 60-75y

- Ability to sign informed consent

- Free-living, prior to admission

Exclusion Criteria:

- Personal history of cardiovascular disease

- Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, HbA1c ≥6.5%)

- Evidence of kidney disease or failure (defined as serum creatinine > 1.5mg/dL)

- Vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled
hypertension, obesity, diabetes, hypercholesterolemia > 250 mg/dl)

- Risk of Deep vein thrombosis including family history of thrombophilia, Deep vein
thrombosis, pulmonary emboli, myeloproliferative diseases including polycythemia
(Hb>18 g/dL) or thrombocytosis (platelets>400x103/mL)

- Use of anticoagulant therapy (e.g., Coumadin, heparin)

- Uncontrolled hypertension (e.g. systolic pressure >160 or a diastolic blood pressure >
100)

- Cancer or history of successfully treated cancer (less than 1 year) other than basal
cell carcinoma

- Currently on a weight-loss diet or body mass index > 30 kg/m2

- Inability to abstain from smoking for duration of study

- HIV or hepatitis B or C*

- *Subjects excluded due to positive screening results, including HIV, hepatitis B
or hepatitis C, will be immediately scheduled for counseling and follow-up
testing as needed, and will be advised to consult their primary physician.

- Recent anabolic or corticosteroids use (within 3 months)

- Subjects with hemoglobin or hematocrit lower than accepted lab values

- History of stroke with motor disability

- A recent history (<12 months) of GI bleed

- Depression [>5 on the 15 items Geriatric Depression Scale (GDS)]

- Liver disease (the ratio of serum aspartate aminotransferase to serum alanine
aminotransferase 2 times above the normal limit, hyperbilirubinemia) History of
respiratory disease

- Currently taking estrogen products

- Recent travel history as defined by 4 hours of travel by airplane in the last week

- Any other condition or event considered exclusionary by the PI and faculty physician