Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span.

Estrogen treatment during middle-age postpones memory impairments, which depend on the hippocampus. However, estrogen responsiveness diminishes with advanced age. The challenge remains to determine, which processes are important for delaying brain aging and the mechanisms for decreased sensitivity. Estrogen can influence transcription through estrogen receptors (e.g., ERalpha and ERbeta) and membrane effects on rapid signal transduction cascades ultimately influencing the phosphorylation state of transcription factors. In middle-aged animals, the membrane effects involve Ca2+ and G-protein cascades, which rapidly counteract senescent physiology. Moreover, estrogen induces transcription for elements of signal transduction cascades that decline with age. Together, the rapid and genomic influences promote synaptic transmission and cell growth. Thus, interruption of genomic/membrane interactions due to loss of ERs, disruption of the hormone cycle, or uncoupling of the hormone/receptor system associated with extended exposure to estrogen could contribute to a decline in these biological pathways during aging.