Genetics: Gene Expression

Age-dependent changes in the expression of specific genes have been found in virtually all organisms and tissues that have been tested. These changes have been found to occur at all levels, ranging from the initiation of gene transcription to the posttranslational modification of proteins. In many cases, it has been difficult to decipher which changes in gene expression are responsible for aging phenotypes, as opposed to which changes are responses (whether adaptive or maladaptive) to primary age-related changes in tissues, cells, or molecules.

Despite the many age-related changes in gene expression that have been documented, some general principles and common themes have emerged. First, the expression patterns of many genes do not change with age. This fact has been established by the use of cDNA microarrays, which can assess the levels of mRNA corresponding to hundreds or thousands of genes in a single experiment. The microarray analyses indicate that, at most, only a few percent of the genes expressed by a given tissue or cell type show an age-dependent increase or decrease in mRNA levels.

Second, in many instances, aged cells or tissues appear to be in a chronically stressed state. The origin of this stress is not clear, but may include exogenous or endogenous oxidative damage or subacute inflammation. Whatever the origin, aged cells and tissues frequently show changes in gene expression that appear to be an adaptive response to stress. In mouse liver, for example, a transcription factor that activates the expression of genes encoding acute-phase proteins increases with age. The acute-phase response is invoked when tissues are inflamed or oxidatively stressed. Similarly, some heat-shock proteins are modestly but constitutively elevated in aged organisms (e.g., Drosophila), tissues (e.g., mouse liver), and cells (e.g., senescent human fibroblasts). The heat-shock response is induced by stresses that cause damaged or misfolded proteins to accumulate. The idea that some age-related changes in gene expression are adaptive is supported by microarray analyses of cells and tissues from calorically restricted animals. Caloric restriction extends the life span of many organisms. It also reverses some, but certainly not all, age-related changes in gene expression.

Finally, some aged cells and tissues fail to mount an adequate stress response and therefore are hypersensitive to stress-induced damage or death. Perhaps the best example of this is the heat-shock response. Heat and other stresses induce high levels of heat-shock proteins in young cells and tissues. In aged cells and tissues, by contrast, heat and other stresses fail to induce high levels of heat-shock proteins. The heat-shock response is due to transcriptional activation of the heat-shock genes by a specific transcription factor. Aged tissues and cells apparently contain adequate amounts of the transcription factor. However, for reasons that are not understood, the transcription factor fails to bind the heat-shock gene promoter element in aged cells and tissues.