We have constructed a cDNA library from senescent (24-month-old) rat liver mRNA and, by differential screening, have selected clones corresponding to mRNA species with increased abundance in aging rats. Direct sequencing of the inserts indicated that most of the clones (9 of 10) contained sequences coding for T-kininogen, also called major acute-phase protein, cysteine protease inhibitor, or thiostatin. Nuclear elongation experiments showed that the increase in mRNA concentration was controlled at the transcriptional level. RNase mapping and Si analysis indicated that the age-dependent induction operated preferentially at one of the three transcriptional start sites of the gene(s). The acute-phase reaction (inflammation) is known to also induce these genes at the level of transcription; however, two of the three start sites are induced by inflammation. Transcription from one of these sites was induced by both phenomena, aging and inflammation.During the past few years, major efforts have been made to understand developmental processes at the molecular level. Although many researchers have directed their efforts toward an understanding of the changes in gene expression that accompany early development, surprisingly little is known about the molecular changes that occur as the ultimate result of development, namely, senescence.We are particularly interested in the process of aging as well as the factors that might be able to affect this process. The phenomenon of aging is the result of an interplay of various components, both extrinsic (such as nutritional status or physical exercise) and intrinsic. The intrinsic processes can in turn be subdivided into two distinct classes: random events, which are usually triggered by extrinsic events such as UV irradiation or free-radical formation, and programmed events, which are inherently associated with the developmental pathway of the species in question. These programmed events include, for example, the changes in gene expression associated with the loss of hormonal balance (32,34). We are directing our efforts toward an understanding of the programmed changes in gene expression and metabolism that are normally associated with the process of aging.It has been observed for some time that aging is accompanied by an overall deregulation of gene activity (10,29,30,45). At the same time, several investigators have reported changes in the transcriptional activity of specific genes in several organisms (14,34,35,41,46,47). In many cases, transcriptional activity is reduced during aging because of the dependence of some genes on hormonal control. One such example is the extinction of expression of the a2U-globulin gene in aging animals (34). In this case, it has been shown that the gene is turned off not only because of a diminishing level of several controlling hormones but also because the receptors for these hormones appear to diminish with age (33). In addition, a recent report has shown that in aging animals, the a2U-globulin genes are detached from the nuclear matrix (28)....