Age changes in signal transduction and gene expression.

Altered regulation of physiological and behavioral processes is an important functional manifestation of aging. Our laboratory has been examining a number of model systems in order to elucidate the mechanisms by which these processes, controlled mainly by hormones and neurotransmitters, change during aging. Two, in which alternations in gene expressions are critical, are loss of striatal dopaminergic motor control and impaired stimulation of hepatocyte DNA synthesis. Loss of striatal D2 dopamine receptors contributes substantially to reduced motor control in the elderly. Such receptor loss is due both to the death of some receptor-containing neurons and decreased expression of the receptor gene in the surviving neurons. Current efforts are focussed on the mechanisms responsible for neuronal death, reduced gene expression and the relationship between the two. In addition, the D2 receptor gene has now been inserted into attenuated adenoviral vectors which elicit expression of functional receptors when injected into the brains of living rats and mice. Stimulation of DNA synthesis by various agents including catecholamines and growth factors is markedly reduced in primary cultures of hepatocytes obtained from aged rats when compared with younger counterparts. Such impairment is not the consequence of receptor loss. Moreover, since very different signal transduction pathways are employed by G protein linked receptors and those mediated by tyrosine kinases, the defect would appear to be at a very functional level. Results to date indicate that increased expression of sdi-1/p21, an inhibitor of cyclin-dependent kinases, is not responsible. However, decreased stimulation of the MAP Kinase pathway, possibly due to elevated levels of MAP Kinase Phosphatase, may also play a role. IN addition, cells of aged rats appear to shift to other growth factor responsive pathways. In summary, altered gene expression during aging may be responsible for some important impairments in signal transduction and corresponding physiological and behavior functions.