Aging Aging

368 Andersencapacity of cells is due either to random accumulation of cellular damage or toa genetic preprogrammed process or innate “biological clock.”Replicative senescence of fibroblasts can be prevented by expression of largeT antigen (T Ag) which allows proliferation to continue indefinitely as long asT Ag is expressed. If it is removed, cells enter a postmitotic state. To test atwhat point fibroblasts become dependent on T Ag for continued cell division,embryonic fibroblasts were prepared from transgenic mice expressing a temperature-sensitiveform of T Ag under the control of the interferon promoter(50). When grown in the presence of interferon at 33°C, fibroblasts derivedfrom these animals become immortal. Removal of interferon or switching culturesto 39°C resulted in reduction of functional T Ag and cessation of celldivision. When T Ag levels were reduced while the cells were still dividing,they did not lose proliferative potential. T Ag appeared to be required tomaintain cell division only once the normal mitotic life-span had elapsed. Inaddition, when cells that were immortalized by switching them to growth in thepresence of T Ag were switched back to conditions of no T Ag, they underwentonly the exact number of cell divisions that would have been remaining if theyhad not ever been exposed to T Ag. This suggests that fibroblast replication is aregulated phenomenon and that the biological clock that limits mitotic lifespancontinues to operate in the presence of functional T Ag.7.2. DNA Damage and RepairMice containing a targeted deletion of the Pms2 DNA mismatch repair geneshow a 1000-fold elevation in mutation frequency in all tissues examined comparedto control animals; however, the presence of increased rates of mutagenesisdid not affect life-span (51). This suggests that DNA damage and repair isnot a limiting factor in longevity.8. Examples of Genetically Engineered Mice Constructedto Dissect Cellular Events Involved in Age-Related DiseasesThe use of genetically engineered mice has been invaluable in aiding in theunderstanding of a myriad of age-related diseases. Transgenics and knockoutshave provided us with several valuable animal models that have not onlyallowed the analysis of disease progression but also the testing of new drugtherapies for various disorders associated with aging in the human population.Some selected examples are described briefly in the following sections.8.1. Alzheimer’s DiseaseIn the case of Alzheimer’s disease, several recent transgenic studies havecontributed greatly to our knowledge of how mutations in both the amyloidprecursor protein (APP) and the presenilin genes may contribute to the accu-