What causes the early-onset and slowly progressing elevations
of GFAP during aging? One factor may be diet-sensitive
changes in oxidative load. Caloric restriction, which slows
many aging changes in rodents [20,26], also attenuates the
increase of GFAP expression during aging at the RNA and
protein levels [25]. GFAP transcription is sensitive to oxidative
stress, as mediated by an NF-1 response element (unpublished).
Because caloric restriction decreases the load of
oxidized proteins and lipids and increases the redox balance
(GSH:GSSG), we can then consider a pathway of cellular
aging in the brain in which the early-onset and slowly progressing
accumulations of oxidative changes stimulate GFAP
transcription and, gradually, or at some threshold level, reduce
the astrocytic support of neuronal functions.
These studies of adult-derived astrocytes differ from most
prior work that employed neonatal astrocytes. The age of origin
is cogent because adult- and neonatal-derived astrocytes
differ in secreted growth factors [37]. However, young adult
(shown here) and neonatal astrocytes [29] have similar E2-
dependent wounding responses in vitro which model the in
vivo repression of GFAP by E2 after lesion [9,35].
The reversibility of impaired neurite outgrowth by GFAP
manipulations may be a basis for therapeutic interventions.
Neurite outgrowth after spinal cord injurywas improved only
in mice carrying the double GFAP- and vimentin-knockout