Life Extension Magazine September 2003
Inflammation and the aging brain

By Dale Kiefer

Inflammation is now thought to play a role in
pathological conditions ranging from anemia and
allergy to coronary heart disease, psoriasis and
even stroke. From inflamed gums that may
contribute to cardiovascular disease, to playing a
crucial role in fanning the flames of cancer cell
growth, inflammation has been implicated in
many more diseases than was previously
believed.
Recently, inflammation has also been recognized as playing a central
role in the debilitating cognitive decline that characterizes
neurological disorders such as Alzheimer's disease and vascular
dementia. Although mental decline and memory loss have long been
considered inevitable hallmarks of old age, new research suggests
that such inflammation/age-associated decline is avoidable. Indeed,
findings reported by some scientists suggest that early intervention in
low-grade inflammation may offer some protection against these
dreaded brain diseases.
The many guises of inflammation
Inflammation is as familiar as an overworked
muscle, and as common as your latest sunburn.
Parents who have agonized over a child's
escalating fever know that inflammation
occasionally transcends the merely annoying to
become something far more troubling: Fever that
climbs too high for too long can inflict serious,
even life-threatening, damage.
But inflammation, including fever, serves a useful purpose in the
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body. Even sunburn is a result of the body's attempt to repair damage
inflicted by ultraviolet radiation. In fact, inflammation is an ingenious
adaptation that allows the body to defend against clear and present
dangers.
For instance, when virulent bacteria invade, they
thrive precisely at the body's normal temperature
of 98.6 ºF (37 ºC). Once established, they pour
toxins into the bloodstream, while continuing to
proliferate exponentially. The immune system
mounts a defense, but cellular defenders may be
thwarted or simply overwhelmed. In response,
the body turns up the furnace. Sensitive to the
slightest temperature increases, pathogens
perish. The body wins the battle. Fever breaks and all is well.
This is just one example of inflammation's beneficial nature. But
some inflammation goes too far. Fever doesn't always vanquish the
invading horde and fade back to a state of disease-free normalcy.
Occasionally the cost of battle is too dear and fever damages the
very body it is defending. Autoimmune diseases provide another
example of inflammation gone awry. The immune system targets the
body's own tissues by its inability to differentiate between some of the
body's proteins and foreign invaders. In essence, the immune system
wages war, against itself. Diseases such as rheumatoid arthritis and
lupus erythematosus are the result. Clearly, inflammation can be a
double-edged sword.
News from the hot zone
The inflammation of most concern, however,
generally goes unnoticed. It is this low-grade
chronic inflammation (as opposed to the acute,
intense inflammation associated with a healing
wound, for instance) that is believed to underlie
the most serious neurodegenerative diseases.
Huntington's disease, for example, is
characterized by chronic brain inflammation
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caused by the immune system's misguided attempts to eliminate a
defective protein that results from a genetic defect. And although their
inflammation triggers are different, diseases such as Alzheimer's,
Parkinson's, amyotrophic lateral sclerosis (Lou Gehrig's disease, or
ALS) and even multiple sclerosis, are also characterized by chronic
inflammation of neural tissues.
Regarding Alzheimer's disease, one research
team noted, "Inflammation is becoming
increasingly substantiated as a contributor to
Alzheimer's disease pathogenesis"1 For this
reason anti-inflammatory drugs, such as the non-
steroidal anti-inflammatory drugs (NSAIDs, e.g.
aspirin, ibuprofen and acetaminophen) and the
newer COX-2-inhibitor class of prescription
drugs, are under investigation as therapies for
this and other inflammation-related diseases.
Inflammation and the brain
To better understand inflammation's role in disease, it's helpful to
comprehend its more benevolent role in keeping the body healthy.
Inflammation is the body's response to a perceived threat. In the case
of an invasion by bacteria, the immune system correctly identifies the
unwelcome entity and attempts to neutralize it. This involves a
complex chain of events and may require the cooperation of a variety
of specialized cells. Their activity is generally beneficial, but the goal
is always the same: to rid the body of intruders and to dispose of
damaged tissue so healing may take place.
Throughout most of the body, cells known as macrophages act as
living soldiers, searching for invaders, and then engulfing and
neutralizing them. In the brain, supporting cells of the glial family,
known as microglial cells, act as scavengers, in much the same
fashion as macrophages. They engulf and eliminate dead neurons
that have been damaged by injury or illness. Unfortunately, they also
secrete harmful neurotoxins and toxic oxygen free radicals in an
attempt to neutralize foreign or undesirable substances.2
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Regrettably, the inflammatory response is occasionally worse than
the stimulus that triggered it in thefirst place. Even when the original
trigger is eliminated, inflammation may become self-perpetuating.
Such, apparently, is the case in neurodegenerative diseases such as
Alzheimer's, Parkinson's, ALS and multiple sclerosis, which are
characterized by a great deal of microglial activity. The presence of
activated microglial cells is an indicator of chronic inflammation.3,4
Alzheimer's and inflammation
Much remains to be elucidated regarding the onset and progression
of Alzheimer's disease, but it seems clear that an inflammation-
provoking protein fragment, a peptide known as amyloid-B, triggers
inflammation. Uninterrupted, the inflammation gradually accelerates,
killing nerve cells and causing a drastic decline in levels of a vital
brain chemical, the neurotransmitter acetylcholine. This downward
spiral of neural degeneration commences with the induction of nearly
undetectable inflammation, progresses to the erosion of memory,
concentration and learning ability and ends with death. Upon demise,
Alzheimer's patients display abnormal spaghetti-like neuritic amyloid-
B plaques and neurofibrillary tangles. Like a battleground littered with
the remains of the combatants, these damaging plaques are
associated with reactive microglial cells, and consist of amyloid-B
protein fragments, immune system proteins such as interleukin-6 (IL-
6)and other components indicating long-term, and ultimately
counterproductive, inflammation.
Microglial cells, which accompany the neuritic plaques of
Alzheimer's disease, are normally dormant. They are activated
only in response to inflammation, thus their presence is a sure
sign of brain inflammation. Although present in large numbers in
the brains of patients with degenerative neurological diseases,
such as Huntington's6 and Alzheimer's diseases, their numbers
are also elevated in otherwise healthy elderly individuals. This
implies that a certain degree of neuroinflammation is an ordinary
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result of nothing more than advanced age.2 Indeed, some
scientists have suggested that cognitive decline begins early in the
aging process and is an inevitable result of advancing age.7
Controlling inflammation, therefore, could presumably benefit
anyone interested in preventing eventual memory loss and
cognitive decline.
Dual pathways to inflammation
Just in the last decade, scientists discovered a key enzyme
produced by the body in response to inflammatory provocations:
cyclooxygenase-2 (better known as COX-2). COX-2 has been
identified as an important link in the inflammation cascade. Unlike
COX-1, COX-2 is only present in the body during inflammation
Research has revealed that cells convert cell membrane
phospholipids to arachidonic acid, which serves as a substrate
that gives rise, in turn, to two powerful and potentially damaging
classes of inflammation mediators, known as eicosanoids: the
prostaglandins and leukotrienes. As one researcher noted,
"Arachidonic acid release and production of eicosanoids are
prerequisites for inflammation"1 The eicosanoids are synthesized
from arachidonic acid by the action of two enzymes that form the
crux of dual inflammatory pathways: cyclooxygenase (COX) and
lipooxygenase (5-LOX).
The COX proteins take two forms: COX-1 and COX-2. The actions
of COX-1 are generally beneficial. But the activity of COX-2 is
generally harmful. COX-2 inserts an oxygen molecule into
arachidonic acid to synthesize prostaglandins, which are powerful
triggers of pain and inflammation. 5-LOX converts arachidonic
acid into inflammatory leukotrienes.
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NSAID medications treat inflammation by
blocking the activity of both the COX-2
enzyme and its more benevolent sibling,
COX-1. But COX-1 is necessary for stomach
lining protection; so interfering with COX-1's
activity can cause gastric disturbances
ranging from simple discomfort to dangerous
bleeding ulcers. For this reason the new
COX-2-inhibitor class of prescription drugs
(e.g. Celebrex and Vioxx) has rocketed to popularity. Their more
selective action effectively relieves inflammation while minimizing
the distressing side effects that are possible with chronic use of
NSAIDs.
Researchers are investigating the possibility that anti-inflammatory
agents, such as the COX-2 inhibitors, may provide viable therapy
not only for Huntington's, but also for other neuro-degenerative
diseases such as Alzheimer's and Parkinson's disease. It's well
documented that the COX pathway generates inflammatory
prostaglandins. But medical research has largely ignored the
potentially damaging effects of 5-LOX, the enzyme that forms the
second branch of the dual arachidonic acid inflammation
pathways. As a recent study reported, 5-LOX might play a
significant role in the pathobiology of aging-associated neuro-
degenerative diseases.8
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indicate that blocking COX-2 while ignoring the effects of 5-LOX
may be counter-productive. In fact, using COX-2 inhibitors to block
the activity of COX-2 may actually cause 5-LOX levels to increase
further, making inflammation worse, rather than better.2 This
"rebound" inflammation is evidently caused by shifting arachidonic
acid toward synthesis of damaging leukotrienes through the 5-
LOX pathway.
An obvious solution to this problem would be the addition of a drug
to the anti-inflammatory regimen that can block 5-LOX.
Fortunately, such substances exist, although they have only
recently come under scrutiny as complements to far more heavily
researched NSAIDs and COX-2 inhibitors.
In one 5-LOX inhibition study, researchers speculated, 'Inhibitors
of the two pathways might have additive, or even synergistic
neuroprotective effects when used in combination.' By study's end,
they had concluded that a 5-LOX inhibitor "significantly potentiated
the effects of three different COX inhibitors."2 Their findings
suggest, quite simply, that while anti-inflammatory therapy with
COX-inhibitors may be neuroprotective, therapy combining both
COX and 5-LOX inhibitors should prove considerably more
effective.
The promise of anti-inflammatory therapy
The feedback loops in the brain do not allow
for simplistic approaches to the treatment of
multi-factorial diseases. Not surprisingly, a
recent study in the Journal of the American
Medical Association found that COX-2
inhibition alone was ineffective in slowing the progression of
clinically diagnosed Alzheimer's disease. It is likely that these
results reinforce a growing body of research that dual
inflammatory pathway inhibition may be needed to fully realize the
promise of anti-inflammatory therapy. While anti-inflammatory
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therapy may slow progression of some diseases, it may be
necessary to begin taking anti-inflammatory agents long before
symptoms appear, in order to prevent or reverse the ravages of
neurodegenerative diseases.
References
1. Paris D, et al. AB vasoactivity: an inflammatory reaction. Ann N Y Acad Sci
(no date provided) pp.97-108.
2. Klegeris A et al. Cyclooxygenase and 5 lipooxygenase inhibitors protect
against mononuclear phagocyte neurotoxicity. Neurobiol of Aging 2002 (23)
787-794.
3. Teismann P, et al. Cyclooxygenase-2 is instrumental in Parkinson's
disease neurodegeneration. PNAS 2003; 100 (9):5473-5478.
4. Pompl PN, et al. A therapeutic role for cyclooxygenase-2 inhibitors in a
transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003;
10.1096/fj.02- 0876fje
5. Scali C, et al. The selective cyclooxygenase-2 inhibitor rofecoxib
suppresses brain inflammation and protects cholinergic neurons from
excitotoxic degeneration in vivo. Neuroscience 2003; 117:909-919.
6. Sapp et al., Early and progressive accumulation of reactive microglial in the
Huntington Disease Brain. Neuropathol Exp Neurol 2001; 60(2): 161-172.
7. Jorm AF, et al. The prevalence of dementia: a quantitative integration of
the literature. Acta Psychiatr Scand 1987; 76: 465-479.
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8. Uz T, et al. Aging-associated up-regulation of neuronal 5- lipoxygenase
expression: putative role in neuronal vulnerability. FASEB 1998; 12: 439-449.
9. Spanbroek R et al. Expanding expression of the 5-lipoxygenase pathway
within the arterial wall during human atherogenesis. PNAS 2003;
100:12381243.