Commentary on "Application of Exogenously Regulatable Promoter Systems to Transgenic Models for the Study of Aging"

Abstract

RANSGENIC (and knockout) mouse technology has been an important research tool for many years now. However, the application of this innovative approach in modem molecular biology to the study of aging has lagged far behind. Recent exceptions have been the telomerase knockout mouse, the Alzheimer's mouse model, and the growth hormone overexpressing mouse. The problems associated with any rodent aging study plague work with transgenic animals in aging research. They are related to the maintenance of a pathogen-free, controlled environ­ ment over the duration of an experiment that lasts some three years. Such problems are not encountered in other disciplines. However, there are more serious technical issues in transgenic aging research. In this issue (pp. B30-B40), Morgan and his colleagues in San Antonio highlight these difficulties, and they thor­ oughly discuss some solutions. They correctly couch the issue in terms of expression of the gene at the right time and the right place. This can be achieved using either trans­ genic or knockout methods or a combination of the two. Particular emphasis is placed on the timing of expression after maturation of the animal. Three expression systems are discussed: tetracycline, RU486, and ecdysone inducible systems. Their relative virtues and limitations are pre­ sented. Each of these expression models was first described in tissue culture. The good news is that the first two of these have finally some history in vivo. As the authors point out, each approach has some draw­ backs, both real and potential. For example, induced ex­ pression with the tetracycline system may be difficult in the brain due to problems with penetration of the blood brain barrier by the antibiotic. However, this problem may be overcome with lipophilic inducers. Some data on long term toxicity of the inducers is available, suggesting there may be few difficulties encountered from this direction. Never­ theless, the critical experiments have not yet been done. The lifetime cumulative effects of the drugs have not been studied. The authors, however, provide useful strategies for protocols that limit exposure of the animals. We all now await an aging study utilizing these inducible expression systems. This will be the acid test of this methodology.