Holding Back the Years

A creaking back, the aching legs. The realization that climbing a flight of stairs has become hard work. The blush of youth has ripened, only to be replaced with experience, maturity and sometimes sheer tiredness. Along with the nonstop march through the second half of life comes the gradual weakening of once-mighty muscles. Is it any wonder that as the nation ages, those people hitting middle age—and leaving it behind—are asking their doctors for a way to feel young again?

by Alicia Di Rado

en, and even some women, are increasingly seeking testosterone replacement therapy to supplement the body’s declining production of testosterone as it ages, in the hope that the therapy will restore waning strength and energy. And doctors are listening: Physicians wrote about 1.75 million prescriptions for testosterone replacement therapy in 2002, a 170 percent increase from 1999, according to the Institute of Medicine of the National Academy of Science.

The United States Food and Drug Administration has approved testosterone and similar medications for the treatment of weight loss due to known medical or unexplained causes.

Hold on, though, say scientists and policymakers. Before muscling-in on the promise of testosterone, remember the women’s hormone replacement therapy (HRT) controversy.

Millions of women took combinations of the hormones estrogen and progestin for years, ostensibly to battle the discomforts of menopause but also expecting the hormones would protect against disease. That is, until the Women’s Health Initiative study screeched to a well-publicized early halt in 2002 because women on HRT in the study showed increased risk of breast cancer and heart problems.

With that stinging memory, an expert panel from the Institute of Medicine—a private institution that provides national health policy advice under congressional charter—recently cautioned that the use of testosterone therapy is quickly outpacing science’s knowledge about its benefits and risks, especially its effects on the prostate and heart. They urged that researchers conduct small, careful studies to determine testosterone therapy’s effectiveness in treating specific health problems in older men before the therapy goes to broad trials or hits the mainstream.

Fortunately, a team of USC researchers already has taken on the charge.

Faculty members from the Keck School of Medicine of USC and the USC Department of Biokinesiology and Physical Therapy want to uncover the facts: They seek answers to how certain hormones might help not only maintain muscle and strength, but boost many aspects of health.

Hormone power

In the USC Department of Biokinesiology and Physical Therapy’s Clinical Exercise Research Center, a 72-year-old retiree reclines on an exercise machine’s vinyl seat and rests his right foot on the pedal in front of him. With a swift push of his heel, as if stepping on the gas, he sets a flywheel spinning.

That movement tells researchers about the sheer strength of the man’s thigh; it also sets in motion a series of other tests that will unlock secrets held in the tiny fibrous cells that make up human muscle.

The man is participating in HORMA, the Hormonal Regulators of Muscle and Metabolism in Aging study.

Early in 2003, the National Institute of Aging awarded $5 million to a USC-led multi-center research team to investigate what happens to muscle in seniors when certain declining hormones are returned to youthful levels.

The four-year study is examining how testosterone and growth hormone influence muscle and metabolism in those men over age 65.

Levels of both testosterone and growth hormone decline as a person ages, explains Fred Sattler, M.D., professor of medicine at the Keck School of Medicine, professor in the Department of Biokinesiology and Physical Therapy and HORMA’s principal investigator. “We’d like to see if restoring these hormones to youthful levels can boost synthesis of muscle proteins and help maintain muscle strength, power and function,” he says.

The testes and adrenal glands produce testosterone, a steroid hormone. Testosterone is responsible for growth and development of male sexual organs, so men have greater levels of the hormone than women. But testosterone also plays a part in building muscle in both men and women by helping control creation of the tiny fibers that make up human muscle.

At least a quarter of men over age 60 have such low levels of testosterone that they are considered to have hypogonadism, and almost all have levels of testosterone lower than when they were 20 to 30 years of age.

Growth hormone (GH), meanwhile, comes from the pituitary gland and is key to growth and metabolism in both men and women. About 35 percent of men over age 60 are GH-deficient. The researchers hypothesize that GH amplifies the effects of testosterone.

At the same time that testosterone and GH levels decline in the last decades of life, seniors begin to lose their muscle and strength.

Skeletal muscle mass—all the muscles that enable people to move, lift and push—reportedly declines about 15 percent between the third and eighth decades of life, and as much as 30 percent afterward. Muscle seems to be lost in certain areas, such as the thighs, that can especially hurt seniors’ ability to walk across a street, rise from a chair or climb stairs without help.

With loss of independence, seniors often face depression and increased risk for injury, a daunting possibility when one considers the nation’s demographics: The number of Americans older than age 65 will climb to 70 million by 2030.

Keeping seniors strong just might help keep them healthy, and that is where HORMA begins.

Steroid secrets

E. Todd Schroeder, Ph.D., research assistant professor in the USC Department of Biokinesiology and Physical Therapy, is co-investigator and project manager for the multi-center study, which encompasses centers at USC, Charles R. Drew University of Medicine and Science and Tufts University, with collaborators at Washington University in St. Louis. Stanley P. Azen, Ph.D., Keck School professor of preventive medicine, oversees the data-coordinating center for HORMA, which involves more than a dozen USC investigators in all.

Researchers are enrolling 36 healthy men, ages 65 through 90, for the USC portion of the 108-participant study. Men must have low levels of testosterone and another hormone called insulin-like growth factor 1 to participate.

The men are assigned randomly into two groups: one in which participants have their testosterone levels restored to those of a 30-year-old man, and another in which they maintain the typical level of an older man. Besides testosterone, each participant receives one of two doses of GH or a placebo.

Participants get testosterone in the form of AndroGel, an alcohol-based gel. Men administer GH through a nightly injection under the skin.

The study lasts 16 weeks, with follow-up tests another three months later. First, participants undergo a series of initial health assessments, electrocardiograms, chest X-rays and blood tests at USC’s General Clinical Research Center. Then, the participants return for regular evaluations, in which researchers take samples of their muscle tissues, test their endurance while walking and climbing stairs, perform scans and take other measurements to monitor participants’ muscle, fat and general health.

USC researchers will study the big picture: men’s overall muscle strength and size. But they also will scrutinize muscle change on the minuscule cellular level, looking at how muscle protein is metabolized and integrated into muscle. “We’re covering everything from how well the men can climb stairs to the activity of satellite cells in the muscles themselves,” Schroeder says.

Whole-body health

But their studies are about more than just testosterone and muscle.

“We hypothesize that testosterone decreases abdominal and visceral fat and increases insulin sensitivity,” says Schroeder. He is backed by prior studies showing that men who took a short course of a testosterone-like medication lost fat all over their body, but especially in the abdomen. This visceral fat is thought to increase risk for diabetes, high blood pressure and unhealthy levels of certain fats in the blood, which in turn spur heart disease.

“When you improve people’s sense of well-being, strength, physical function and abdominal fat,” Schroeder says, “you improve their quality of life.”

Notes Sattler: “We’re taking studies now to a more metabolic level. The metabolic effects have even more health ramifications outside muscle. And they are less gender-specific.”

The researchers soon will begin small studies to look at hormones and body fat in women as well as men.

And in another study related to HORMA, USC investigators plan to recruit another 36 older men to test the effectiveness of resistance training—exercises using weights—together with testosterone to build muscle and reduce fat.

Past research has shown that men who took a form of testosterone grew stronger in proportion to the amount of muscle they gained, Schroeder says. But younger men taking a form of testosterone who also lifted weights saw their strength far outpace what could be produced from taking testosterone alone.

Schroeder suspects pairing exercise with short-term testosterone therapy may eventually greatly boost strength and physical function in seniors.

“The most potent stimulus to muscle is resistance training, not testosterone,” Schroeder says. “But how can you get people to keep going to the gym? It may be that androgen therapy can give seniors the short-term boost they need to get them on their feet, and then benefits can be maintained through strength training.” n

For more information about HORMA, the Hormonal Regulators of Muscle and Metabolism in Aging study, call (323) 442-2498, or to learn more about any of The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).