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radual genetic changes may be the source of many, if not all illnesses of aging, including breast cancer, osteoporosis, Alzheimer's disease and arthritis. A study by scientists in The Skaggs Institute for Chemical Biology at TSRI and the Genomics Institute of the Novartis Research Foundation, published recently in Science, concludes that human aging and its associated diseases and conditions can be traced to a gradual increase in cell division errors in tissues throughout the body. This functional change begins slowly in middle age and increases gradually with advancing age. The work received extensive coverage in the international news media.

According to Richard A. Lerner, M.D., an author of the paper, "Mitotic Misregulation and Human Aging," "This represents a radical change in the way people have thought about aging. While scientists have believed that aging is a disease in which cells stop dividing, this study suggests that aging is really a disease of quality control. In this case the manufactured product is a new cell. As we get older, altered gene expression results in cells with diminished function." Dr. Lerner is TSRI President, Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry, and Professor in The Skaggs Institute for Chemical Biology and the Department of Chemistry.

CELL DIVISION ERRORS ARE KEY

Errors in cell division lead to the altered expression of a collection of key genes in the cells. Altered gene expression gradually causes the loss of tissue function which results in aging. Unlike cancers, in which cells are uniformly dysfunctional, aging occurs in a mosaic pattern, at different rates in different parts of the body. "Our research ties the effects of aging into a single package by identifying a common element in aging tissues throughout the body," Dr. Lerner continued.

Dr. Lerner noted that, "The Human Genome Project is biology's particle physics experiment. Because of this massive effort, science is going the way of complexity. To use the power of the genome, we are entering the era of big science; without the extraordinary gift from the Skaggs family, this work could not have been done." The study was funded by The Skaggs Institute for Research.

Dr. Lerner and his co-authors, Drs. Danith H. Ly, David J. Lockhart, and Peter G. Schultz, studied gene regulation in actively dividing cells donated from young, middle and old age patients and those with progeria, a rare genetic disorder characterized by accelerated aging. The authors note that 61 of more than 6000 genes studied showed consistent changes more than two-fold from young to middle age.

More than half of the 61 genes could be grouped into two functional classes; genes whose products are involved in cell cycle progression, and those involved in the maintenance of the extracellular matrix, a scaffolding to which most kinds of cells adhere and which modulates cellular functions. The scientists believe that the multiplicity of genes in these two classes compared to the smaller number of genes involved in other cellular processes may reflect a different level of coordinated regulation between them. This observation is important because it helps scientists to better understand the importance of how genes interact with each other. Some believe that gene interactions may be more important than the effects of individual genes.

GENETIC LINKS TO SPECIFIC AGE-RELATED DISEASES

In addition to outlining the mechanism of aging, the study also revealed a number of genes with altered expression that could be linked to age-related diseases. Some of these include BARD (BRCA­1 associated Ring domain), an essential binding partner of the tumor suppressor BRCA-1; hFRP-1, an analogue of the mutated AT (Ataxia-Telangiecstatia) that is linked to progressive neurodegenerative disease and premature aging; -- crystallin, a heat shock protein that is overexpressed in neurological disorders such as Alzheimer's disease, diffuse Lewy body disease, and Alexander's disease, as well as being implicated in juvenile cataract formation; hyaluronic acid synthase and matrix metalloproteinase, both of which play a role in arthritis; and COX-2, a key enzyme necessary for kidney, heart and ovary function. Altered expression of these genes may contribute to age-related breast cancer, neurodegenerative disease, arthritis and defects in other tissues such as kidney, heart and ovaries.

This is not the first time that Dr. Lerner has collaborated with Dr. Schultz. Their work in converting antibodies into enzymes, permitting the catalysis of chemical reactions considered impossible to achieve by classical chemical procedures, has garnered international attention. In recognition of this scientific achievement, they received the Wolf Prize in Chemistry 1994 and were named California Scientists of the Year in 1996.

The authors note their research is not conclusive and additional studies will be needed before the process of aging can be completely understood in complex organisms, but the mechanisms identified contribute to aging and age-related problems. Dr. Lerner noted, "We need broader analyses of how genes function, how they interact with one another and with the environment. This research will bring us closer to identifying specific genes associated with age-related diseases and potential ways to prevent and/or treat them."