Age-Related Changes of Dopaminergic Functions

This summarizes recent findings on several aspects of Parkinson’s disease (PD), which are part of our studies on questions of gene expression in the brain during aging and neurological diseases. Although there is no evidence that age per se determines the onset of PD or that PD is simply accelerated senescence, the strong age-related increase of PD after midlife (Mutch et al., 1986; Ayd, 1961) can not be ignored, and draws attention to the types of age changes and their individual variations that occur in these and other neuronal systems (Finch, 1976, 1987). A particular issue concerns the long-standing assumptions that non-dividing cells such as neurons inevitably suffer senescent involution and age-related loss. This question bears on the often presumed inevitability of PD as a feature of later life, with the presumed generality of nigrostriatal degeneration. While true that few of central neuron types in mammals are formed de novo after puberty or can regenerete after injury (Jacobson, 1978; Rakic, 1985), there is ample evidence to question whether senescent involution generally occurs in most neurons. For Example, two neurosecretory systems show no evidence of general failure up through the average lifespan. The LHRH neurons that maintain sustained elevations of pituitary gonadotropins long beyond menopause (Scaglia et al., 1976) and no loss of these cells occurs in female mice showing major agerelated disturbances of pituitary functions (Hoffman and Finch, 1986; Finch et al., 1984). Moreover, vasopressinergic neurons become progressively more sensitive to osmotic stimuli in elderly men (Robertson and Rowe, 1981). At the molecular level, an analysis of whole brain RNA from male rats across their lifespan did not detect changes in the levels of messenger RNA (polyA+mRNA isolated from polyribosomes) or in its nucleotide sequence complexity, which assays the number of different types of mRNA species (Colman et al., 1980). On the other hand, many types of neurons show statistically significant trends for degenerative changes during aging, particularly in the hippocampus, cerebral cortex, and in monoaminergic projection systems (Coleman and Flood, 1987; Morgan et al., 1987b). In regard to the basal ganglia, the striatum is the only major brain region to show decreases of bulk (ribosomal) RNA during aging in rodents (Chaconas and Finch, 1973; Shaskan, 1977). At a cell level, the changes include alterations in dendritic structure, loss of receptors, decreases in cell body RNA, and to an unknown extent, death of neurons. It is interesting to compare the nucleolar shrinkage, an index of ribosomal RNA transcription, in the substantia nigra and locus ceruleus of neurologically normal humans, since both cell types accumulate neuromelanin with age: the greater nucleolar atrophy of nigra neurons (Mann and Yates, 1979) could indicate selective vulnerability of these cells to age-related damage. Future studies may reveal how many of these changes occur in all individuals. The extent of age-related neuron loss is highly controversial (Coleman and Flood, 1987;Terry et al., 1987), and may be far less general than once thought. Its extent in the basal ganglia is based on a relatively limited number of specimens, even though a large number of neurons were counted in these demanding studies (McGeer et al., 1977).