Cellular and molecular mechanisms of impaired dopaminergic function during aging.
One important cause of impaired motor function during aging is deterioration of the dopamine system. Such motor deficits in experimental animals can be closely related to loss of striatal dopamine receptors, and similar observations have now been made in humans. Two mechanisms account for the age-related decrease in striatal dopamine receptor levels: loss of receptor-containing neurons and reduced rates of receptor synthesis. The striatal neurons affected by aging appear to reside in a kainic-acid-sensitive population. Attempts to mimic those death mechanisms which occur in vivo using cultured neurons suggest that large D2-dopamine-receptor-containing cells may be the most vulnerable. Whether dopamine itself, the endogenous neurotransmitter for the cells, may ultimately be toxic to these neurons remains to be determined. The levels of D2-receptor mRNA in the surviving neurons is reduced during aging. This decrement is apparently due to a decreased rate of mRNA biosynthesis. Future experiments must therefore focus on the regulatory elements of this gene in order to determine why its transcription is selectively affected by aging. Finally, various interventions have been shown to delay or reverse the age changes characteristic of the dopaminergic system. Both dopamine receptors and motor function have been manipulated by diet and exercise as well as 6-OH-dopamine lesions and estrogen and prolactin administration. The possibility that such treatments might eventually be utilized therapeutically has become increasingly real as our knowledge of the affected cellular and molecular processes continues to expand.
Roth
G S
GS
Molecular Physiology and Genetics Section, National Institute on Aging, Francis Scott Key Medical Center, Baltimore, Maryland 21224.
Joseph
J A
JA
D000375:Aging / Q000502:physiology*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008967:Molecular Biology; D016472:Motor Neuron Disease / Q000503:physiopathology; D009046:Motor Neurons / Q000502:physiology; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D004298:Dopamine