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July 1995
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Scientists have gained important new insights into the underlying causes of age-related changes in the immune system which lead to decreased immune function and increased vulnerability to infectious diseases in older people. In an article published in the July, 1995, issue of the Journal of Experimental Medicine, John Mountz, M.D., Ph.D., and his colleagues at the University of Alabama at Birmingham, described their research on the role of the fas cell-death gene in age-related T-cell dysfunction in the immune system.
"It has been appreciated for many years that the immune system undergoes changes with age, in humans as well as in experimental animals. However, figuring out the mechanisms that underlie these functional changes has been difficult. This study provides important progress in understanding the molecular basis for age-related immune changes and may provide a basis for designing interventions to alter or prevent these changes," says Dr. Richard Hodes, Director of the National Institute on Aging (NIA), the agency that funded this study.
T-cells, a central part of the immune system, play an important immune regulatory function and are critical components in defenses against cancer as well as a variety of infectious agents (bacterial, viral, fungal). Age-related defects in T-cell function also can contribute to the diminished response to immunization in older adults.
One process which was found to become abnormal in T-cells from aged mice is called apoptosis. Sometimes referred to as programmed cell death, apoptosis is thought to provide a critical step in the regulation of T-cell response by removing cells with defects and by maintaining appropriate levels of T-cells. Apoptosis is necessary for the removal of inactive or senescent T-cells that may accumulate with age, leading to decreases in immune function.
NIA-supported research in the laboratory of Dr. Mountz highlights the role of a gene known as fas. The fas gene product is a cell surface protein involved in signaling the cell to undergo programmed cell death. Dr. Mountz and colleagues discovered that fas-mediated cell death is decreased in aged mice when compared to young adult mice. The age-related decreases in fas-mediated cell death were reversed in mice expressing a genetically engineered copy (called a transgene) of the fas gene, which is expressed in T-cells throughout the entire life span of these mice. Sustained fas expression prevented a number of the detrimental age-related changes in T-cell function that normally occur in old mice. These results suggest that age-related T-cell dysfunction is linked to defective cell death. The findings also show that expression of the fas transgene allows maintenance of fas-mediated cell death and restores T-cell function in aged mice to a level comparable to that of young mice. Thus, this fas "gene therapy" approach prevented age-related changes which contribute to impaired immune function in older mice.
It is not known why the synthesis of the fas gene product becomes defective with age, although recent studies in France and at the National Institutes of Health may yield clues to this mystery. These studies have identified mutations in the fas gene that are associated with autoimmune diseases in humans. The fas gene mutations interfere with gene expression in humans, resulting in accumulation of autoimmune cells, uncontrolled T-cell growth, and impaired fas-regulated apoptosis. These findings point out the crucial regulatory role of fas in apoptosis and in maintaining normal function of the immune system.
Additional research is underway to determine if this exciting research in aging transgenic mice can be applied to prevention of T-cell dysfunction in aging humans. Working with Dr. Mountz at the University of Alabama is Dr. Tom Zhou, and at the Marion Merrell Dow Research Institute in Cincinnati, Ohio, is Dr. Carl K. Edwards III.
The National Institute on Aging, part of the National Institutes of Health, leads the Federal effort supporting basic, clinical, epidemiological, and social research on aging and the special needs of older people.
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