Biotechnology of Aging
Keith W. Kelley
It's exciting when scientists can apply what they learn from fundamental research on livestock to important medical problems of humans. One of the hottest developments in biotechnology of both livestock and humans is somatotropin or growth hormone, a new genetically engineered protein. As yet, growth hormone has not received approval from the Food and Drug Administration (FDA) for use in the animal food chain. However, recombinant human somatotropin, which received FDA approval in October 1985, is being used to treat about 15,000 children in the United States who were born with a deficiency of growth hormone. With treatment, these children may grow up to four inches per year. In 1989, worldwide sales of somatotropin exceeded $300 million.
Somatotropin has generated much excitement and concern about other potential clinical uses. Somatotropin may help control obesity in middle-aged humans, reverse some aspects of the aging process, improve wound healing in burn patients, augment the physical abilities of athletes, and both improve growth rate and reduce carcass fat in domestic food or animals.
The New England Journal of Medicine reported in 1990 that giving somatotropin to men between 61 and 81 years of age increased lean body mass and reduced body fat. Unfortunately, the long-term effects on human or animal health are not yet known, but somatotropin is known to affect several activities of cells of the immune system.
Aging's Effects on the Human Immune System
Rapid growth of the aging population and the enormous accompanying costs of health care make research about aging everyone's concern. In the United States, nearly 30 million people are over age 65, and this number will double within the next 30 years.
By the year 2000, 5 million Americans will be over age 85. Nearly 40 percent of those over 85 require daily assistance from relatives or professional caregivers to maintain normal, daily activities.
As a group, the elderly have an increased incidence of respiratory, neoplastic, arthritic, and cardiovascular diseases, and a higher incidence of mortality from bacterial infections due to gram-negative sepsis. Among the aged, influenza and pneumonia are the fourth leading cause of death; tuberculosis occurs most often and leads to the highest death rate among the elderly. Infectious endocarditis causes over 50 percent of deaths when it occurs in people over age 60. Fifteen percent of the aged population suffer from urinary tract infections. The elderly also have an impaired ability to develop fevers following infection. It is generally believed that the increase in disease prevalence is related to aberrations that occur in regulation of the immune systems of the aged.
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Somatotropin, Aging, and the Immune System
Five years ago, immunologists, muscle biologists, and veterinarians working within the College of Agriculture discovered an important link in aged animals between the immune system and somatotropin. For years it has been known that the size of the thymus gland in both humans and animals decreases with age. It is also now recognized that human somatotropin secretion declines as we age. Maximal size of the thymus gland coincides with maximal secretion of somatotropin at puberty; by age 60, only fatty remnants of the thymus gland remain.
This process was thought to be irreversible. We postulated that giving somatotropin in the form of hormone- secreting pituitary cells might permit the thymus gland to grow again in aged animals. We also tested the possibility that this regenerated thymus gland might augment certain aspects of the immune response that deteriorate during aging.
Results from these experiments were amazing. As expected, we could detect only remnants of the thymus gland in control rats equivalent to 54 year-old humans. But aged rats that had been implanted with hormone-secreting pituitary cells were able to regenerate their thymus glands to the point of being indistinguishable from those of young rats. Furthermore, the immune response which normally declines with age (as assessed by the growth of T lymphocytes) was significantly improved (see figure). T lymphocytes, cells that are derived from the thymus gland, are required for most immune responses.
We have now shown that the real cellular target for the action of somatotropin may be the macrophage, a type of phagocytic cell in the immune system that eats bacteria and kills tumor cells with toxic chemicals. Because secretion of growth hormone declines in older humans and animals, these data suggest that genetically engineered somatotropin may be useful in delaying or preventing the age-related change in various immune functions. Experiments are evaluating these possibilities, but research on aging is quite expensive. For example, scientists pay as much as $150 for a two-year-old rat - rats can live up to three years under excellent management conditions. The enormous costs of conducting aging research, which requires between 50 and 100 rats per study, limit the number of experiments that can be run.
Somatotropin and the Immune System of Livestock
The experiments with aged rats provided
the impetus to study whether somatotropin affects the immune system of farm
animals. Initial experiments concentrated on pigs' phagocytic cells, such
as macrophages and neutrophils, which are critically important for destroying
many types of bacterial and fungal pathogens. Using genetically engineered
porcine somatotropin that has already been proven to increase growth rate
and reduce carcass fat, we showed that this protein increases the capability
of macrophages to produce a free radical known as superoxide anion. This
molecule plays an important role in the killing of bacteria by porcine phagocytic
cells. We have now shown in humans (University of Illinois faculty and graduate
students) and in pigs and cattle that recombinant somatotropin increases
the secretion of superoxide anion by another type of phagocytic cell, the
polymorphonuclear neutrophil. In pigs, these somatotropin-treated neutrophils
are also more efficient in killing Escherichia coli in vitro.
All the experiments described above were conducted by adding recombinant porcine somatotropin to phagocytic cells in a test tube, so it is not known if similar results will be obtained if this genetically engineered version of somatotropin is administered directly to pigs. New data from scientists at the University of Guelph in Canada, however, show that injecting recombinant bovine somatotropin into lactating dairy cows increases a number of immune responses.
Summary
New techniques in molecular biology can potentially revolutionize animal agriculture. Somatotropin is the first genetically engineered protein that has been extensively tested and shown to increase a number of economically important traits in dairy cattle, pigs, and sheep. Research conducted at the University of Illinois has shown that this same molecule might also be one of the important keys to understanding why we age and how to augment the immune response of both humans and livestock.
Keith W. Kelley, professor of immunophysiology, Department of Animal Sciences
