As an approach to resolving the circularity of feed-forward
pathways in aging, we developed a heterochronic culture
model in which embryonic neurons (E18) were co-cultured
with primary astrocytes derived from young (3 mo) or old
(24 mo) brain donors. Age increases in GFAP transcription
is a robust phenotype that persists in primary monotypic culture
in the absence of interactions with microglia or neurons
[28]. Note that “aging” in this primary culture model does
not refer to the Hayflick phenomenon of replicative senescence,
which is an outcome of serial culture. This co-culture
model allows study of astrocyte aging apart from effects of
microglia, which also become activated during normal aging
[8,25]. In “wounding-in-a-dish” model with neonatal
astrocytes and E18 neurons, the secretion of extracellular
laminin and neuronal outgrowth were minimal. Antisense-
GFAP markedly increased laminin secretion and neuronal
outgrowth, although decreases in GFAP were modest [6,18].
More robust effects on GFAP were obtained by lowering
GFAP through estradiol, which decreases GFAP transcription
and protein, and enhanced laminin reorganization and
sprouting [29]. These findings implicate elevated GFAP in
attenuating astrocytic production of laminin and other factors
that support neurite outgrowth independently in lesioned
co-cultures.