ABSTRACT
Replicative aging was first described 40 years ago, when Hayflick (1) reported that normal human lung fibroblasts did not divide indefinitely like cancer cells but rather exhibited a limited ability to proliferate in culture. This paper contradicted the prevailing concept that all cells were immortal, and it was met with great skepticism at the time. Most of the criticism centered on the artificial nature of the in vitro culture environment and the likelihood that inadequate culture conditions were preventing the long-term proliferative capacity of the cells (see Refs. 2 and 3 for recent summaries of these views). As we shall discuss below, this criticism is valid in a variety of culture systems, so that we now must reevaluate some of the data that we had thought reflected replicative aging. However, the identification of telomeric shortening as the mitotic clock that counts cell divisions, the demonstration that telomeres shorten in vivo with donor age, the proof that telomerase can prevent telomeric shortening and immortalize cells, and the observation that most cancer cells have escaped these controls by upregulating/reactivating telomerase have all combined firmly to establish replicative aging as a legitimate in vivo biological process. This chapter will review the development of our current concepts of the mechanisms regulating replicative aging and discuss some of the outstanding issues facing the field.
