Journal of Neuroimmunology 147 (2004) 141 – 144

www.elsevier.com/locate/jneuroim

Interleukin-6 in the aging brain

J.P. Godbout 1, R.W. Johnson *
Laboratory of Integrative Biology, Department of Animal Sciences, University of Illinois at Urbana-Champaign 61801, USA

Abstract

Astrocytes, microglia, and neurons express the cytokine interleukin-6 (IL-6), which in the brain has been suggested to reduce food intake,
inhibit memory and learning, cause neurodegeneration, and exacerbate sickness behavior induced by other cytokines. Recent evidence
indicates IL-6 levels are increased in brain of healthy aged animals, thus it may play a role in the neurophysiological manifestations of old
age. The purpose of this brief report is to discuss the new evidence that suggests an age-related increase in brain IL-6 and the impact this
inflammatory cytokine may have on ‘‘successful’’ aging.
D 2003 Elsevier B.V. All rights reserved.

Keywords: Aging; Brain; Cytokines; Interleukin-6; Mice; Microglia

1. Introduction 2. Interleukin-6 increases in the aged brain

In the last century, the average life span increased from
47 to 78 years and the elderly population tripled from 4%
to 13%. It is projected that by the year 2025 20% of the
population will be over the age of 65. Unfortunately, most
studies indicate only a modest increase in healthy years
but a far greater increase in years of poor or compromised
physical and mental health. For instance, after 65 the
prevalence of Alzheimer’s disease and dementia doubles
every 5 years so that nearly 50% of all people over 85
have symptoms of Alzheimer’s disease. Furthermore, there
is a gradual withdrawal from social and physical activities
and a decline in cognitive function, even in the absence of
any identifiable disease. Therefore, research concerning
the basic biology of the aging nervous system is critical
to understanding what is necessary for ‘‘successful’’
aging. In this brief review, we discuss the effects of aging
on interleukin-6 (IL-6) expression in the brain and the
impact this inflammatory cytokine may have on successful
aging.
* Corresponding author. 390 Animal Science Lab., 1207 West Gregory
Drive, University of Illinois Urbana, IL 61801, USA. Tel.: +1-217-333-
2118; fax: +1-217-333-8286.
E-mail address: rwjohn@uiuc.edu (R.W. Johnson).
1
Dr. J.P. Godbout is a Ruth L. Kirschstein National Research Service
Award Postdoctoral Fellow.
Interleukin-6 is a 26-kDa cytokine that belongs to a
superfamily of structurally related cytokines that share the
130-kDa glycoprotein receptor component (Taga and Kish-
imoto, 1997). It has diverse biological properties and is
recognized to have a key role in behavior, development,
immunity, inflammation, and metabolism. Ordinarily, the
IL-6 gene is closely regulated in leukocytes, but for reasons
yet to be determined, the control system becomes relaxed or
disengaged with age, so that older adults have high circu-
lating levels of IL-6 compared to younger adults (Wei et al.,
1992; Ershler and Keller, 2000). A recent long-term study of
healthy elderly subjects by Weaver et al. (2002) reports an
age-dependent increase in IL-6 in the plasma, which was
correlated to a modest decline in cognitive ability. Impor-
tantly, lymphoid cells isolated from older adults and mice
spontaneously secreted high levels of IL-6 (Daynes et al.,
1993), indicating that the age-related increase in circulating
IL-6 is not merely a reflection of undiagnosed disease as has
been suggested (Beharka et al., 2001).
The age-related increase in IL-6 production is not re-
stricted to the periphery, as it is now evident that cells in the
CNS respond in a similar way. For instance, the level of IL-
6 in whole brain as well as in the hippocampus, cerebral
cortex, and cerebellum was increased in aged mice com-
pared to juvenile and adult mice (Ye and Johnson, 2001a).
Aging did not appear to increase IL-6 in the hypothalamus.
Similarly, 10-month-old senescence-accelerated mice of the
P8 strain—a murine model for accelerated aging—had

0165-5728/$ - see front matter D 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jneuroim.2003.10.031
142 J.P. Godbout, R.W. Johnson / Journal of Neuroimmunology 147 (2004) 141–144
Fig. 1. Spontaneous expression of interleukin-6 in cultured glial cells
increases with age. (A) Expression of IL-6 in glia cultured from neonate
( < 1-week-old), adult (3-month-old) and aged (24-month-old) mice. The
bars represent the treatment means F S.E. and letters represent significance
( P < 0.05). (B) Total RNA isolated from glia was reverse transcribed and
amplified by PCR using primers specific for IL-6 or GADPH. Respective
PCR products were visualized and quantified by phosphoimaging.
increased IL-6 in the cerebral cortex and hippocampus
compared to age-matched controls (Prechel et al., 1996;
Ye and Johnson, 2001a). Several studies indicate that the
increased IL-6 in the aged brain is centrally produced.
Coronal sections of the cerebral cortex taken from aged
mice spontaneously secreted more IL-6 than sections taken
from younger controls (Prechel et al., 1996; Ye and Johnson,
2001a). Furthermore, competitive quantitative RT-PCR
showed a marked increase in steady-state IL-6 mRNA in
whole brain of healthy aged mice compared to adults (Ye
and Johnson, 1999, 2001a). Studies on glial cells cultured
from aged mice also indicate an age-associated increase in
IL-6 production. Ye and Johnson (1999) established glial
cell cultures from neonate, adult and aged mice that
contained both astrocytes and microglia. The steady-state
level of IL-6 mRNA and spontaneous secretion of IL-6
protein were higher in glial cells cultured from aged mice
than in glia cultured from either adult or neonate mice (Ye
and Johnson, 1999, 2001a,b). Two-color flow cytometric
analysis of IL-6 and MAC-1 (a marker for microglia)
staining showed an age-related increase in IL-6-positive
microglial cells (Ye and Johnson, 1999). Moreover, the
IL-6 mean fluorescence intensity increased as a function
of age, suggesting more IL-6 expression per cell. Brain
endothelial cells, which form the blood –brain barrier, may
also contribute IL-6 to the aged brain. Endothelial cells
cultured from brains of very old rhesus monkeys spontane-
ously released more IL-6 than those isolated from adult and
fetal/neonatal monkeys (Reyes et al., 1999). Collectively,
these studies indicate that the transcription and expression of
IL-6 is increased in the brain with age (Fig. 1).
3. NFnB binding to the IL-6 promoter is increased in the
aged brain
Interleukin-6 gene expression is regulated by a complex
arrangement of several transcription factors including nu-
clear factor nB (NFnB) (Libermann and Baltimore, 1990),
multiple response element (MRE), C/EBPh/NF-IL-6, and
AP-1 (Li and Karin, 1999). The age-related increase in IL-6
gene expression in the brain, however, appears to be under
control of NFnB. Relative to the adult brain, NFnB binding
to the IL-6 gene promoter was increased in brain of aged
mice (Ye and Johnson, 2001a,b). The DNA binding activity
of NF – IL-6, AP-1, and MRE was either unchanged or
decreased in whole brains of aged mice. Moreover, intra-
cerebroventricular injection of nB decoy—a molecule that
competes with the DNA-binding sequences for NFnB—
decreased NFnB DNA binding activity and IL-6 mRNA in
brain of aged mice (Ye and Johnson, 2001a). Parallel studies
with mixed glia cultures from aged mice also revealed
increased NFnB binding to the IL-6 promoter. Incubating
glia from aged mice with nB decoy decreased NFnB
activity, IL-6 mRNA, and IL-6 protein secretion to levels
similar to that in glia from adults (Ye and Johnson, 2001a).
These findings are supported by other studies of age-related
or disease-associated increases in NFnB transcriptional
activity. For example, NFnB DNA binding activity is
increased in the aged rat forebrain and hippocampus
(Korhonen et al., 1997; Toliver-Kinsky et al., 1997) and
in hippocampal and cerebral cortical neurons of Alzheimer’s
patients (Terai et al., 1996). Furthermore, in peripheral
lymphoid organs of aged mice NFnB activation is associ-
ated with chronic inflammation (Spencer et al., 1997;
Poynter and Daynes, 1999).
4. Potential impact of increased interleukin-6 in the aged
brain
It must be noted that it is not at all clear that the age-
related increase in brain IL-6 interferes with successful
aging. While it is possible that IL-6 expression in the aged
brain maintains neuroprotective properties as it does during
development, the majority of evidence indicates otherwise.
The increased expression of IL-6 in the aged brain is
potentially significant because this cytokine can be neuro-
toxic and affects cognitive and motivational systems (Papa-
nicolaou et al., 1998). As evidence of such, increased IL-6 is
found in brain trauma (Woodroofe et al., 1991) and in CNS
infections including HIV and meningitis. Furthermore, the
severity of dementia in Down syndrome and in Alzheimer’s
disease is correlated with increased concentrations of IL-6
(Kalman et al., 1997). In Alzheimer’s disease senile plaques
are surrounded by activated microglia and astrocytes, sug-
gesting that the advancement of the disease is driven in part
by cytokines and neurotoxic factors (McRae et al., 1997).
Interestingly, overexpression of human h-amyloid precursor
protein was not itself acutely neurotoxic, but rather it
induced gliosis and inflammation (Irizarry et al., 1997).
Interleukin-6 is present in these senile plaques (Bauer et al.,
1991) and is also detectable prior to amyloid plaque
formation (Huell et al., 1995). Therefore, inflammatory
 J.P. Godbout, R.W. Johnson / Journal of Neuroimmunology 147 (2004) 141–144
Table 1
Potential defects associated with IL-6 in the brain
Group Finding(s)
Bauer et al. (1991) IL-6 present in Alzheimer plaques
Campbell et al. (1993) Transgenic mice that overexpress IL-6 in
astrocytes develop neurological disease
correlated with IL-6 expression
Fattori et al. (1995) Increases expression of IL-6 in neurons
promotes activation of microglia and
astrocytes
Irizarry et al. (1997) IL-6 induces gliosis and inflammation
Kalman et al. (1997) Severity of dementia in Down syndrome and
Alzheimer’s diseases is correlated with IL-6
concentration
Heyser et al. (1997) Transgenic mice expressing IL-6 in astrocytes
have impaired avoidance learning
Li et al. (1997) IL-6 inhibits long-term potentiation in
hippocampal neurons
Qui et al. (1998) IL-6 enhances the neurotoxic properties of
NMDA
Vaillieres et al. (2002) IL-6 reduces adult neurogenesis in the
hippocampal dentate gyrus
Weaver et al. (2002) Plasma IL-6 levels correlated with cognitive
impairments in aged individuals
cytokines may be primers for later neuropathological
changes present at the end stages of Alzheimer’s disease
(Griffin et al., 1994; Mrak et al., 1995; Lorton et al., 1996)
(Table 1).
Further support for this notion comes from studies where
heightened expression of IL-6 in neurons of transgenic mice
increased the number and size of astrocytes and the number
of ramified microglial cells (Fattori et al., 1995). Further-
more, transgenic mice whose astrocytes overexpressed IL-6
developed neurological disease that was related to the level
of cytokine expression (Campbell et al., 1993). The pro-
gressive neuropathic manifestations of the IL-6 transgene
were closely related to deficits in avoidance learning
(Heyser et al., 1997), which is consistent with a study
showing IL-6 inhibits long-term potentiation in hippocam-
pal neurons (Li et al., 1997). In adult mammals in the
subgranular zone of the hippocampal dentate gyrus, multi-
potent progenitor cells proliferate, migrate into the adjacent
granule cell layer, and differentiate into fully functional
neurons (Gross, 2000). Recent studies suggest that the adult
neurogenesis is important for cognitive function (Gould et
al., 1999; Shors et al., 2001). A recent study showed that
neurogenesis was decreased by 63% in hippocampal dentate
gyrus of adult transgenic mice whose astrocytes overex-
pressed IL-6 (Vallieres et al., 2002). Embryonic cerebral
precursor cells differentiate into astrocytes when cultured in
the presence of IL-6 (Bonni et al., 1997). Thus, IL-6 may
restrain neurogenesis in the aged brain by redirecting
progenitor cells toward a glial cell lineage. Gliosis is
commonly reported in aged brain, especially in the context
of Alzheimer’s disease. Although IL-6 levels in aged brains
do not equate to those in CNS diseases, there is evidence
that chronic exposure to low levels of IL-6 causes changes
in neurons that enhance neurotoxic properties of N-methyl-
143
D-aspartate (NMDA). Chronic IL-6 reduced the number of
granule neurons in culture and enhanced NMDA receptor-
mediated neurotoxicity (Qiu et al., 1998). Therefore, an
increase in IL-6 in the aged brain may predispose individ-
uals to the onset of neurological disease or at least partially
explain the cognitive deficits observed in the elderly.
5. Conclusions
Studies published to date indicate an age-associated
increase in brain IL-6, which is caused by increased binding
of NFnB to the IL-6 promoter. Ongoing studies are inves-
tigating why NFnB activity increases in the aged brain, and
what affect the increased IL-6 has on cognitive and motor
skills. Understanding how and why IL-6 and other inflam-
matory molecules are affected in the brain by aging will be
helpful in increasing the likelihood of successful aging,
which is important given the rapid growth of the elderly
population.
Acknowledgements
This work was supported by NIH Grants RO1 AG16710
and T32 DK59802.
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