03/17/2005 08:00:00

Toward a Longer, Healthier Life

PASADENA, Calif. - The Spanish explorer Ponce de Leon spent a fair amount of his time in 1513 looking for the fountain of youth. The upside was that he discovered Florida. The downside was that the fountain was a myth. Now in two separate awards from the Ellison Medical Foundation, two scientists from the California Institute of Technology are taking a much more scholarly approach to the ravages of aging. Harry Gray, a chemist, has been awarded $970,000 to reveal the structure of a protein and a peptide that underlie two age-related diseases, Alzheimer's and Parkinson's, while biologist Alexander Varshavsky has been awarded $972,000 to conduct a systematic investigation of the genetics and biochemistry of aging.

Gray, the Arnold O. Beckman Professor of Chemistry, notes that approximately one million Americans suffer from Parkinson's, while 4.5 million have Alzheimer's. In order to design a drug to combat these two diseases, a key step is to understand the critical structural differences between normal proteins and the malignant proteins that comprise these diseases.

Both Alzheimer's and Parkinson's are associated with the accumulation in the brain of aggregates of proteins known as fibrils. In Parkinson's, the fibrils are composed of the protein alpha-synuclein, while in Alzheimer's, the fibrils or plaques are composed of the AB amyloid peptide. Alpha-synuclein and AB amyloid peptide are known as "disordered biopolymers," meaning that they do not have well-defined structures. Because of this lack of structure, the traditional tools used by chemists, such as x-ray crystallography and nuclear magnetic resonance spectroscopy, are virtually useless. They are only effective if the peptides and proteins being studied have well-defined structures in crystals or solutions.

Instead, Gray and his colleagues plan to use laser spectroscopic methods developed in Caltech's Beckman Institute to gain new insights into the structures, dynamics, and misfolding of malignant proteins and peptides. One of the most powerful methods they will use will employ an ultrafast camera to obtain distances between atoms in disordered structures that are constantly changing.

"We're very excited about the possibility of applying our laser methods to study proteins and peptides that are involved in disease in older people," says Gray. "We have a chance to identify toxic species that lead to these diseases, and point the way to successful interventions."

For Alexander Varshavsky, the Howard and Gwen Laurie Smits Professor of Cell Biology, it is the causes and alterations of the aging process that interest him. Every cell contains within it a molecular machine to eventually destroy its own proteins, he notes. The mechanisms and functions of this so-called regulated protein degradation became (mostly) understood over the last 25 years, in large part through discoveries in Varshavsky's lab. When a protein called ubiquitin is linked to another protein in a cell, that protein is marked for destruction. The molecular machines inside a cell that link ubiquitin to other proteins, and the intracellular machinery that "recognizes" ubiquitin-linked proteins and destroys them, are elaborate and complex. "Detailed understanding of these protein-destruction pathways will have a profound impact on the practice of medicine," says Varshavsky, "because all kinds of things that go wrong with us, from cancer and infectious diseases, to neurodegenerative syndromes and even normal aging, have a lot to do with either inherent imperfections of the ubiquitin system, or with an overt damage to it in a specific disease." Many clinical drugs of the future, he notes, will be designed to suppress, enhance, or otherwise modify various aspects of the ubiquitin system.

In this research Varshavsky will overexpress, selectively and in a controlled manner, specific components of the mouse ubiquitin system in intact mice, in order to determine the effects of such alterations on the rate of aging. He also plans to use analogous approaches with a much simpler organism, S. cerevisiae, common baker's yeast. His aim is to discover the molecular circuits that contribute to normal aging, and also to see whether some of the alterations that he plans to introduce could slow down the aging process.

The Ellison Medical Foundation is a nonprofit corporation that was established by a gift from Mr. Lawrence J. Ellison to support basic biomedical research to understand aging processes and age-related diseases and disabilities. Through various award mechanisms, including the Senior Scholar and New Scholar award programs, the foundation fosters research by means of grants-in-aid to investigators at universities and laboratories within the United States.