Journal of Neuroscience Research 70:258 –263 (2002)
Perspective
Age-Related Decline in Neurogenesis: Old
Cells Or Old Environment?
Galynn Zitnik1 and George M. Martin1,2*
1
Department of Pathology, University of Washington, Seattle, Washington
2
Department of Genome Sciences, University of Washington, Seattle, Washington
As the baby boom generation ages, the numbers of
patients afflicted with various age-related pathologies of
the brain will increase, creating a tremendous burden on
the health care segment of the economy as well as great
human suffering. Observations that neurogenesis contin-
ues in the adult brain (Kaplan and Hinds, 1977; Notte-
bohm, 1985; Eriksson et al., 1998) and may be part of a
normal repair process has led to ideas for therapeutic
interventions, such as: transplantation of healthy neural
stem/precursor cells and induction of neurogenesis in situ
(reviewed by Magavi and Macklis, 2001). Unfortunately,
age-related changes in the brain may limit therapeutic
success. Transplantation of young neural progenitors or
stem cells may not succeed in repairing damaged brains if
the environment of the recipient brain is hostile to survival
and differentiation due to aging (Sykova, 2001). Induction
of neurogenesis in situ may be thwarted by the inability of
the resident neural stem/progenitor cells to respond due to
aging (Armstrong and Barker, 2001). If we are to effi-
ciently exploit adult neurogenesis for therapeutic ends, we
must understand the effect of aging on the component
parts of neurogenesis. Do age-related changes occur in the
stem/progenitor cells present in the brain or do age-
related changes occur in the local and systemic environ-
ments that allow these cells to proliferate and differentiate
when needed?
DEFINITION OF TERMS
Neural stem cells are defined as cells that are capable
of producing additional undifferentiated stem cells as well
as progeny that go on to differentiate into several cellular
phenotypes: neurons, glial cells and oligodendrocytes.
Neural progenitor cells are defined as cells with a limited
replicative potential that are committed to the neuronal
lineage. Neural progenitors are derived from neural stem
cells either during fetal development or in the adult.
Neurogenesis, the production of new neurons, depends
upon neural stem cells and neural progenitors being
present and responsive to induction. Neurogenesis can be
assessed in vitro (Fig. 1) or in vivo.
ADULT NEUROGENESIS AND AGING
Evidence that cell proliferation occurs in the adult
brain is often based upon labeling with 5-bromo-2⬘-
© 2002 Wiley-Liss, Inc.
deoxyuridine (BrdU), a thymidine analog. BrdU is incor-
porated into DNA during replication and repair, and can
subsequently be detected by immunohistology using an
antibody against BrdU. In response to criticism that BrdU
incorporation might be detecting DNA repair in postmi-
totic neurons instead of cell division in progenitors or stem
cells, Cooper-Kuhn and Kuhn (2002) investigated this
question in 8-week-old Wistar rats. After labeling with
BrdU, brains were fixed at defined time intervals. Immu-
nohistological analysis of the granule cell layer of the
dentate gyrus of the hippocampus revealed that BrdU
positive cells co-expressed markers for mitosis, progeni-
tors, immature and mature neurons in that sequence with
increasing time after BrdU labeling. BrdU positive cells
were not found to co-localize with cells undergoing ap-
optosis, and irradiation, which stimulates DNA repair,
caused a decrease in BrdU labeling. The authors con-
cluded that incorporation of BrdU is a reliable method for
detecting cells undergoing mitosis, and can be used to
detect both neural stem and progenitor cells.
BrdU labeling has indicated that cell division takes
place in at least two regions of the adult brain: the dentate
gyrus of the hippocampus and the subependyma surround-
ing the anterior lateral ventricle. Using adult Wistar rats
(8 –10 weeks old) and adult CD1 mice (6 – 8 weeks old),
Seaberg and van der Kooy (2002) carefully dissected out
tissue from each region, extracted cells and tested these
cells for self-renew in tissue culture. In both species of
rodent the cells derived from the dentate gyrus exhibited
a limited ability for self-renewal whereas the cells derived
from the subependyma exhibited more proliferative po-
tential, suggesting that the dentate gyrus contains only
Contract grant sponsor: Alzheimer’s Disease Research Center, University
of Washington; Contract grant sponsor: NIA/NIH; Contract grant num-
ber: AG019711.
*Correspondence to: G.M. Martin, University of Washington, Seattle
98995. E-mail: gmmartin@u.washington.edu
Received 24 April 2002; Accepted 28 May 2002
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/jnr.10384

progenitors and the subependyma contains both progeni-
tors and stem cells.
In the dentate gyrus of the hippocampus age-related
changes have been observed. Using highly polysialylated
neural cell adhesion molecule (NCAM-H) as a marker for
newly generated granule cells and BrdU as a marker for
newly synthesized DNA, Seki and Arai (1995) compared
neurogenesis in the dentate gyrus of Wistar rats 35 days to
18 months of age. Immunohistology showed that the
numbers of newly generated granule cells decreased with
increasing age. Using a double labeling protocol consisting
of BrdU and either anti-NeuN (neuron-specific nuclear
protein) or anti-calbindin-D28k (an intracellular protein
with high affinity for calcium), Kuhn et al. (1996) com-
pared 6-month-old Fischer 344 rats with 12- and
27-month-old rats. Immunohistology revealed a reduction
in the differentiating progeny of granule cells with increas-
ing age. That this phenomenon was not limited to rats was
shown by Kempermann et al. (1998) who compared
8-month and 20-month-old C57Bl/6 mice and found that
BrdU labeling in the dentate gyrus of the hippocampus
decreased with increasing age.
In the forebrain subependma age-related changes
have been observed by Tropepe et al. (1997). When 2–
4 month and 23–25 month-old SW/COBS mice were
compared, the older mice exhibited a 50 – 60% decrease of
BrdU positive progenitor cells. Sequential labeling with
BrdU and tritiated thymidine revealed lengthening of the
cell cycle in the older mice. When cells were isolated from
the subependyma and proliferative potential was assessed
in tissue culture, however, no age-related decrease was
observed, suggesting a lack of aging in the neural stem
cells.
Additional insights were gained from transplantation
studies that introduced fetal or embryonic neural stem cells
into aged brains. Hodges et al. (2000) injected condition-
ally immortalized hippocampal cell lines derived from
mouse embryos into the ventricles of 22-month-old
Sprague-Dawley rats. Qu et al. (2001) injected primary
neural stem cells derived from human fetuses into the
ventricles of 24-month-old Fischer 344 rats. Both kinds of
cells migrated widely throughout the recipient brains,
differentiating into neurons and astrocytes, and both pro-
cedures resulted in significant improvements in the ability
of the aged rats to remember the location of a submerged
platform in the water maze tests. The possible mechanism
by which memory was enhanced, however, remained
ambiguous: did the donor cells augment deficient resident
neural stem/progenitor cells or did neurotrophic factors
released by the donor cells improve the aged environ-
ment?
Specifically addressing possible age-related changes
in the host environment, Zaman and Shetty (2002) freshly
isolated rat fetal hippocampal cells (prelabeled in utero
with BrdU), then injected these cells into the ventricles of
Fischer 344 rats of three ages: young adult, middle-aged
adults (12–14 months) and old adults (11–24 months).
Thirty days after transplantation, absolute graft cell survival
Age-Related Decline in Neurogenesis 259
was determined by immunostaining for BrdU and stereo-
logical cell counting methods. When the hippocampi
were undamaged approximately 18 –25% of donor cells
survived at all ages of recipient. When hippocampi were
first damaged with kainic acid (KA), however, then given
fetal hippocampal cells, an age-related change in absolute
graft cell survival was revealed: an average of 72% survived
in young brains vs. 30% in middle-aged and old brains.
The failure to observe a further decline in the brains of old
as compared to middle-aged host brains raises the question
that the decrements in middle-aged brains could be related
to maturation rather than aging. Additional experiments,
however, did support continued decrements into old age.
Graft cell survival could be improved by incubation of the
freshly isolated fetal hippocampal donor cells for 3 hr in
the presence of brain-derived neurotrophic factor
(BDNF), neurotrophin-3 (NT-3) and caspase inhibitor
before transplantation to KA damaged brains. Survival
increased in middle-aged rats to 51% and in old rats to
63%. The authors speculated that damage to brain tissue
stimulates the release of neurotrophic factors. As an animal
ages this response to damage becomes impaired, so that
transplanted cells experience a less supportive environment
in the middle-aged and old brains. This age-related defi-
ciency could be overcome to an extent by artificially
supplying the neurotrophic factors.
Another damaging treatment that reveals age-related
changes in the brain is transient forebrain ischemia, a
model for stroke (Yagita et al., 2001). Wistar rats were first
subjected to ischemia, then injected with BrdU to label
proliferating cells. When hippocampal tissue was fixed
1 day after BrdU labeling, ischemic animals exhibited an
increase in labeled cells in the subgranular zone of the
hippocampus when compared to control animals: a 5.7-
fold increase for young adults (3– 4 months old) and a
10.6-fold increase for old adults (24 months old). When
hippocampal tissue was fixed 28 days after BrdU injection,
the number of nuclei still labeling with BrdU could be
compared to the number at Day 1, assessing the survival of
the labeled cells during that period of time. In young adult
tissue 65.5% of the labeled cells survived, whereas in old
adult tissue only 15.3% remained. Double staining for
BrdU and NeuN showed that 71.6% of the surviving cells
had differentiated into neurons. The authors suggested
that although both young and old tissues responded to
ischemia with increased incorporation of BrdU, the
younger brains retained a higher number of such cells,
reflecting a higher survival rate of such cells and suggesting
that the young brains provided a more supportive envi-
ronment for survival. These authors postulated that an
age-related increase in glucocorticoids might be inhibiting
survival of the transplanted cells.
Global approaches to improving memory or stimu-
lating neurogenesis in old animals have provided a number
of interesting results. Nichols et al. (2000) review the
evidence that increases in glucocorticoids with increasing
age may cause synaptic loss, and inhibit production of
newly born granule neurons. Lichtenwalner et al. (2001)
260 Zitnik and Martin
Fig. 1. Mouse cell positive for neuron-specific marker MAP2. MAP2
is a microtubule-associated protein that promotes tubulin polymeriza-
tion and is involved in neurite outgrowth. In the mature neuron,
MAP2 is present in the soma and dendrites of the neuron. Using a
transgenic line of mice, C57BL/6-TgN(ACTbEGFP)1Osb (The Jack-
son Laboratory, Bar Harbor, ME), that constitutively expresses green
fluorescent protein (GFP) in every cell of the body, newborn mouse
brains were dissociated into single cells. In serum-free medium con-
taining growth factors, these cells were grown as unattached neuro-
spheres for 19 days. At that time the growth factors were removed and
the cells were allowed to attach to polyethylenimine coated sterile
coverslips. After an additional 38 days in which the cells migrated out
from the neurospheres and differentiated into a variety of cell pheno-
types, the cells were fixed with 4% paraformaldehyde and permeabil-
ized with Triton X-100. MAP2 was visualized using a mouse mono-
clonal antibody (clone AP-20; Sigma-Aldrich Inc., St. Louis, MO)
followed by counterstaining (red color) with Alexa Fluor 568 signal-
amplification kit for mouse antibodies (A-11066; Molecular Probes,
Eugene, OR). The nucleus was stained with DAPI (purple).

and Aberg et al. (2000) suggest that decreases in levels of
IGF-I in the aged brain may be responsible for decreased
neurogenesis. Mayo et al. (2001) report that infusions of
the neurosteroid, pregnenolone sulfate (PREG-S), will
reverse memory impairments in aged rats. Nicolle et al.
(2001) and Manev et al. (2000) discuss the possible role of
oxidative stress in increasing neuronal vulnerability in aged
hippocampal neurons. Lee et al. (2000), Mattson (2000),
and Duan et al. (2001) describe the effects of dietary
restriction (the only intervention known to increase lifes-
pan) on neural progenitor/stem cells: an increase in newly
generated neural cells in the adult brain, an increase in
expression of neurotrophic factors such as BDNF, and an
increase in the resistance of neurons to dysfunction and
apoptosis. None of these studies directly address our orig-
inal question, however, because both neural progenitor/
stem cells and support cells may be changed by any of these
experimental manipulations.
Nearly half the total cells in the brain are astrocytes,
star-shaped glial cells that support the proliferation, sur-
vival and maturation of neurons. Studying differentiation
in vitro, Song et al. (2002) have shown that co-culture of
astrocytes derived from the adult hippocampus with adult
neural stem cells promotes neuronal fate commitment,
whereas co-culture of astrocytes derived from the adult
spinal cord does not promote neurogenesis from the same
stem cells. These data suggest that astrocytes play an active
role in controlling neurogenesis, and that astrocytes in
different areas of the central nervous system have distinct
characteristics in this regard. With increasing age the ratio
of glial cells to neurons increases, resulting in gliosis (re-
viewed in Cotrina and Nedergaard, 2001). With increas-
ing age, might astrocytes also lose the ability to stimulate
neurogenesis?
In summary, the results of many experiments are
consistent with the hypothesis that old brains are less able
to support proliferation and differentiation of neural pro-
genitor cells, but no data have been gathered as to whether
intrinsic age changes occur in the neural progenitors
themselves. The picture is even less clear concerning neu-
ral stem cells.
ADULT NEUROGENESIS AND DEMENTIA
OF THE ALZHEIMER TYPE
What is the relationship between age-changes in
neurogenesis and dementia of the Alzheimer type (DAT)?
Do the disease processes involved in neurodegeneration
cause defects in neurogenesis or do defects in neural stem/
progenitor cells contribute to DAT?
Mutations in the Presenilin-1 (PS1; PSEN-1) gene is
a significant cause of early-onset familial Alzheimer disease
(Selkoe, 1998). Presenilin protein is thought to be part of
a complex of proteins involved in the cleavage of amyloid
precursor protein-C terminal fragments (APP-CTF) to
produce the beta-amyloid peptides that accumulate during
the pathogenesis of DAT (reviewed in Esler and Wolfe,
2001).
Knock-out mice lacking a functioning presenilin-1
gene exhibit greatly reduced numbers of neural progenitor
Age-Related Decline in Neurogenesis 261
cells at 9.5 days of gestation, and later in gestation the brain
exhibits hemorrhages and cerebral cavitation (Shen et al.,
1997). These mice also have gross skeletal malformations
and die within minutes of being born. Handler et al.
(2000) subsequently determined that the reduced number
of neural progenitor cells was caused by premature differ-
entiation. Normally during early neurogenesis, most pro-
genitor cells would continue to cycle producing an ex-
pansion of the progenitor population. When PS1 function
is missing the premature differentiation of neural progen-
itor cells severely depletes this pool of progenitors, which
are not available when needed later in development. These
data suggest that PS1 may be necessary for the mainte-
nance of undifferentiated neural progenitor cells during
development.
A clever technique that allows the study of PS1
knockout mice while avoiding the perinatal lethality is the
production of conditional knockout (cKO) mice. Tsien et
al. (1996) inserted loxP sequences into the genome of
embryonic stem (ES) cells so that they flanked part of the
PS1 gene, but did not interfere with the normal expression
of the gene. The ES cells were used to generate homozy-
gous mice, which were then crossed with a second mouse
line transgenic for Cre recombinase under the control of
the ␣-CaMKII (Ca2⫹/calmodulin-dependent protein ki-
nase II) promoter. The activity of this promoter is re-
stricted to the forebrain and starts about 4 weeks after
birth. Therefore, in the hybrid animals the Cre recombi-
nase is expressed after birth, catalyzing recombination be-
tween the loxP recognition sequences, and deleting part of
the PS1 gene only in some cells of the forebrain. This
efficient deletion occurs in postmitotic neurons. Compar-
ing control and cKO mice, Feng et al. (2001) found that
basal levels of neurogenesis as assessed by BrdU incorpo-
ration were not significantly different; however, when the
mice were exposed to an enriched environment known to
stimulate neurogenesis (Kempermann et al., 1997) a dif-
ference was revealed. The cKO mice increased neurogen-
esis 37% less than the control mice.
To test the correlation between memory and neu-
rogenesis, Feng et al. (2001) subjected both control and
cKO mice (10 –17 months old) to various behavioral
experiments. A significant difference between the two
groups was found only with the cued fear conditioning
test. In this test, mice are given a one-time shock paired
with a tone, then 15 days later the mice are exposed to the
tone without shock. The cKO mice exhibited more freez-
ing responses than the controls, leading the authors to
suggest that neurogenesis in the hippocampus is correlated
with the stability of memory in the hippocampus. Newly
generated neurons in the dentate gyrus make new syn-
apses, but the cells live only 3 weeks (Cameron et al.,
1993; Hastings and Gould, 1999). Three weeks is about
the time that memory is stored in the hippocampus before
being transferred elsewhere in the brain. Production of
new neurons during this time period actually degrades the
resident memory traces in the hippocampus. In the cKO
mice, the absence of neurogenesis allows the hippocampal
262 Zitnik and Martin
memory of the conditioned fear response to be retained,
whereas in the control mice normal neurogenesis allows
new memories to take the place of old.
Additional evidence that PS1 is important in adult
neural progenitor cells comes from Wen et al. (2002).
Two-month-old C57B16/DBA F1 hybrid mice were
prelabeled for 4 hr with BrdU and 24 hr later the brains
were fixed and prepared for histology. Co-staining for
BrdU and a marker of early neuronal differentiation was
observed in only 11–14% of BrdU labeled cells. Co-
staining for BrdU and a marker of mature neurons or
astrocytes was not observed. But co-staining for BrdU and
nestin (a marker for immature neural progenitors) was
observed in 70% of BrdU labeled cells. These data indicate
that not enough time had passed at fixation for the pro-
liferating cells of the hippocampus to differentiate into
neurons or glia. Double immunofluorescent staining for
BrdU and PS1 revealed an average of 64% of all BrdU
labeled cells were also PS1 positive. These data suggest that
PS1 expression is common in undifferentiated neural pro-
genitor cells of the adult brain.
In summary dominant mutations in the gene for PS1
are associated with early-onset familial DAT. PS1 is ex-
pressed in neural progenitor cells and may be necessary for
maintenance of the undifferentiated state. Might muta-
tions in PS1 lead to a deficit of or premature differentia-
tion of neural progenitor cells in DAT?
EXPERIMENTAL APPROACHES
The most thoroughly studied of all adult stem cells
are hematopoietic stem cells (HSCs). Insights gained from
the study of these adult stem cells can be used to guide
experiments with neural stem cells. Globerson (2001) and
Schlessinger and Van Zant (2001) have reviewed the ev-
idence for age-related changes in HSCs. Extensive trans-
plantation studies from young into old and old into young
have established a consensus: basal hematopoiesis is main-
tained throughout life, but the ability to respond to stress
decreases with age and cells derived from aged donors
exhibit some alterations in their ability to differentiate.
Similar experiments should be conducted with adult
neural stem cells; i.e., the transplantation of stem cells from
elderly animals into young animals and vice versa with
suitable controls. Such experiments would provide data
concerning: 1) numbers of stem cells that can be isolated
from old tissue vs. young tissue, 2) the ability of the stem
cells from elderly animals to proliferate and migrate in the
environment provided by the young brain, and 3) the
extent to which stem cells from elderly animals retain the
ability to differentiate into various cell phenotypes. Vari-
ations on this theme would include damaging the brains of
the young hosts to elicit neurotrophic factor release and
assessing the ability of the stem cells derived from elderly
animals to repair such damage. If deficits are identified in
the old neural stem cells, pretreatment with growth factors
or hormones could be attempted to determine if such
deficits can be reversed.
Are similar experiments feasible using neural stem
cells with mutations for familial DAT? Palmer et al. (2001)
reported recently the successful extraction of neural stem
cells from postmortem human brains 2–20 hr after death.
Embryonic and fetal human neural progenitors have been
successfully transplanted into rat brain where the human
cells migrate and differentiate (Aleksandrova et al., 2001;
Qu et al., 2001; Englund et al., 2002). Adult human neural
precursors have been transplanted to adult rat spinal cord
where remyelination was elicited (Akiyama et al., 2001).
Therefore, it might be possible to extract neural stem cells
from postmortem samples of human dentate gyrus, from
patients with familial DAT, age-matched controls and
young controls. After characterization of proliferative and
differentiation potential in vitro, the cells could be char-
acterized further by transplantation into young rat brains
with and without damage, to test for proliferative and
differentiation potential in vivo. If deficits are identified in
neural stem cells from patients with DAT, experimental
analysis to identify the metabolic bases for such deficits
would follow with the eventual goal of generating rational
protocols for intervention.
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