Lifespan Extension: Overexpression Strategies in the Mouse and Yeast

2004 senior Scholar Award in aging

The work by my laboratory at the California Institute of Technology is about understanding bits and pieces of the following large problem: how and why cells destroy their own proteins? A related problem is to understand the consequences of having protein destruction machines in every cell of the body for the emergence of specific diseases, and for slow processes such as aging. The grant by the Ellison Medical Foundation supports the latter part of our research. Before describing it, a brief introduction to regulated protein degradation. The mechanisms and functions of this process became understood (still incompletely) over the last 25 years, in part through discoveries in my laboratory. A protein called ubiquitin becomes tightly associated with a variety of other proteins in a cell, thereby causing selective destruction of ubiquitin-linked proteins. (Ubiquitin was called ubiquitin because almost identical versions of this protein were found in fungi, plants and animals, including humans.) The molecular machines inside a cell that link (conjugate, as chemists say) ubiquitin to other proteins are quite elaborate and diverse. The intracellular machinery that ìrecognizesî ubiquitin linked proteins and selectively destroys them is also quite complex. The entire set of these protein-destruction pathways is called the ubiquitin system. Detailed understanding of this system is likely to have a profound impact on the practice of medicine, 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 will be designed to suppress, enhance or otherwise modify various aspects of the ubiquitin system.

In our research into causes and alterations of the aging process, we plan to overexpress, selectively and in a controlled manner, specific components of the mouse ubiquitin system in intact mice, and to determine the effects of such alterations on the rate of aging and related processes. We also plan to use analogous approaches with a much simpler organism, a bakerís yeast. The aim of these projects is to discover molecular circuits that contribute to normal aging, and also to see whether some of the alterations that we plan to introduce would slow down the aging process.

Alexander Varshavsky Ph.D.
California Institute of Technology