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LE Magazine September 1999
Continued from Eat Less - But Do
Eat Lots of Blueberries
Other lectures and poster presentations also suggested that lipoic acid
reduces oxidative stress in the mitochondria of the heart
muscle, and raises the levels of ascorbate and glutathione in
the heart and liver mitochondria. The restoration of ascorbate
levels was particularly striking: supplemental lipoic acid was
able to restore cardiac ascorbate levels in old rats to those
found in young rats.
Since lipoic acid functions as a mitochondrial coenzyme
essential for the oxidation of the alpha-keto acids in the
energy-producing Krebs cycle, its importance for efficient
energy production by the mitochondria seems obvious. It is
probably by increasing mitochondrial energy output that lipoic
acid is able to lower blood glucose levels and the formation
of harmful glycation products. Lipoic acid is thus emerging as
an extremely important anti-aging agent.
(Parenthetically, there was also a lecture on the decrease
of glycation products with the use of a "glyconutritional."
The speaker would reveal only that the product contains a
substantial amount of mannose and fucose.)
Deprenyl (selegiline) and its new close analog rasagiline
are of great interest because they not only slow down aging,
but may produce life span extension. Both deprenyl and
rasagiline selectively increase the activity of antioxidant
enzymes superoxide dismutase (SOD) and catalase, especially in
dopamine-producing regions of the brain. The lecture given by
Dr. Kitani revealed that rasagiline (and thus probably also
deprenyl) also increases SOD and catalase activity in the
heart and the kidneys. Interestingly, the lower dose was more
effective than the higher dose. Rasagiline does not seem to
offer any advantages over deprenyl, a drug used by some
anti-aging researchers. Dosage is obviously crucial.
Still other ways to protect the aging brain were mentioned,
such as anti-inflammatories (let us hope that the new COX-2
inhibitors such as Celebrex and Vioxx will prove much safer
than nonselective NSAIDs such as ibuprofen and aspirin). Since
inflammation-related damage to the brain starts to show up
already in midlife, one should not wait until old age to begin
a preventive anti-inflammatory treatment.
Estrogen replacement in
postmenopausal women has also been shown to help prevent Alzheimer's
disease. In fact, like many other phenolic compounds,
estrogens are potent antioxidants. A sufficient dose of
estrogen can totally prevent lipid peroxidation in brain cell
membranes. However, like most antioxidants, estrogens need to
be recycled back to their antioxidant state, or else they can
act as pro-oxidants. Here glutathione appears to play a
critical role. Hence a woman taking estrogen replacement
should be aware of the need to keep her glutathione levels as
high as possible. This can be accomplished by taking lipoic
acid, N-acetyl-cysteine
(NAC), and anthocyanins such as those contained in blueberries
and bilberries.
Besides their antioxidant effects, estrogens also increase
the release of acetylcholine, activate various methylating
enzymes, act to prevent the formation of the amyloid plaque,
decrease the production of pro-inflammatory cytokines, and
much more. The benefits of estrogen replacement for brain
health are beyond question: the higher the dose and the longer
the duration of supplementation, the greater the protection
against dementia. The point is to supplement estrogen in a safe way. Taking
glutathione-raising supplements is a very important step
toward making estrogen replacement safer.
It is possible that men can obtain similar neuroprotective
benefits from testosterone replacement, since the male brain
converts a significant portion of testosterone into estradiol.
In fact, older men have higher estradiol levels than women of
the same age who are not taking hormones. This has been cited
as one factor that may explain the dramatic female prevalence
of Alzheimer's disease. Since 40% of women over 80 (and over
50% of women over 90) suffer from this terrible disorder, at
an enormous cost to society, spreading information about the
many ways to prevent it or at least delay Alzheimer's
disease is of enormous importance.
Antioxidants such as vitamins C and E have been documented to
protect the brain. However, it turns out that the bioflavonoid
called quercetin, present in onions, apples, and especially in
ginkgo biloba, is particularly effective, as are anthocyanins
(bilberry extract and blueberries are a rich source of
anthocyanins). Anthocyanins have been found to be more
protective against free radical damage induced by the
beta-amyloid protein than vitamins C and E. As Dr. Bruce Ames of
Berkeley pointed out, gamma tocopherol is needed for
scavenging nitrogen free radicals, such as the dangerous
peroxinitrite radical.
Speaking of nitrogen, a new class of synthetic antioxidants
called nitrones is also showing great promise. Nitrones react
with free radicals to form nitroxides, which are further
converted to harmless compounds. Besides acting as
antioxidants, nitrones also have a significant
anti-inflammatory effect. In animal studies, they have been
shown to help prevent cognitive dysfunction and extend
longevity.
Using a variety of antioxidants seems more effective in
protecting the brain than relying on any single
antioxidant.
Finally, heat shock proteins also appear to prevent damage
to the neurons. After a discussion of various ways to protect
the brain against aging, including calorie restriction and
neuroprotective agents, one conference participant asked,
"Wouldn't it be cheaper to just give the animals a sauna every
day or every other day?" Indeed it would. It was quickly
pointed out, however, that calorie restriction, a particularly
effective way of slowing down brain aging, also provides a
multitude of benefits that are difficult to replicate in any
other way. Nevertheless, regular sauna remains a very
promising and much underutilized anti-aging treatment.
Osteoporosis does not discriminate between the
sexes
Barbara Drinkwater, a public health expert at the Pacific
Medical Center, debunked some popular myths about osteoporosis.
The number one myth is that only postmenopausal women lose
bone density, and thus only women need to worry about
osteoporosis. In fact, older men are the fastest growing
population at risk for osteoporosis. Thirty percent of all hip
fractures occur in men. Though typically men are affected at a
later age than women, due to a more gradual decline in their
sex hormones, male spinal bone loss starts already in middle
age, and is significant enough to eventually result in the
phenomenon of a stooped "little old man." Thus it is not just
the proverbial "little old lady" who suffers from
osteoporosis.
The saddest fact is that 80% of osteoporosis victims are
undiagnosed and go untreated. Furthermore, surveys have shown
that 90% of women think that taking calcium is enough to
prevent osteoporosis. Another large percentage of women
believe that exercise alone can save their bones, and that the
best bone-building exercise is walking. To test this
hypothesis, a 12-month study examined the effect of a one-hour
lunchtime walking program on bone density. Unfortunately, the
results were negative. However, it was also found that active
women have 6% more bone density.
Weight lifting is known to produce an increase in bone
mass. Nevertheless, it is premenopausal women who respond
faster to stress on the bone, again pointing to the importance
of hormones in bone building. There is simply no escaping the
conclusion that the most reliable way to prevent osteoporosis
is hormone replacement. But this is not the end of the story.
The most exciting finding suggests that hormone replacement
therapy combined with the right exercise gives the best
results: it makes it possible for older women to have bones
comparable in mass and strength to those of women in their
20s. This is an example of how an age-related degenerative
disorder, once regarded as part of "normal aging," can be
entirely prevented and even reversed.
Another way in which exercise has an additive effect is by
preventing fractures through developing and preserving a
better sense of balance, and thus making falling down less
likely. Estrogen replacement likewise improves the sense of
balance.
Biphosphonates are an important development for those women
who have reasons to avoid estrogen replacement. It is
possible, however, that only hormones can maintain the
viability of bone cells (osteocytes) responsible for the
microarchitecture and resilience of the bone tissue. There is
also evidence suggesting that a combination of hormone
replacement therapy and biphosphonates has a greater effect on
bone density than either one alone.
Unfortunately many women still seem unaware that the
dramatic loss of bone mass after menopause is due to the loss
of hormones, rather than to sudden dietary calcium deficiency.
Only 30% of postmenopausal women choose to stay on hormone
replacement therapy for more than one year. Typically these
are educated women ("exclusively," one conference participant
commented), rather than women with the highest risk factors
for heart disease and/or osteoporosis.
Perhaps the introduction of designer estrogens, such as
raloxifene, will change all that. Though it is not as
effective as standard hormone replacement therapy, raloxifene
has proven to dramatically diminish the risk of breast cancer
as well as to sustain bone mass. On the other hand, raloxifene
has side effects such as hot flashes and blood clots. There is
also a theoretical possibility that by interfering with the
action of estradiol in the brain, raloxifene might lead to
depression and maybe even hasten neurodegeneration. Note that
a significant percentage of tamoxifen users complain of
depression. And, like tamoxifen, raloxifene may also raise the
risk of cataracts and other eye damage. It must be emphasized,
however, that this is only a theoretical speculation. We
simply do not have the data on long-term effects of
raloxifene. In terms of benefits for bone and the
cardiovascular system, it is clearly second-rate compared with
standard hormone replacement therapy. Women would appreciate
other options with proven safety.
A disappointing feature of this lecture was the lack of any
mention of the effects of vitamins D, E and K, magnesium, boron, zinc, anti-inflammatory fatty
acids, and soy estrogens on bone health. Ipriflavone, a
chemically transformed soy phytoestrogen also known by the
brand name of Ostivone, has now been documented to prevent
bone loss. It is also possible that natural soy
phytoestrogens, if taken in a sufficient dose, might have
benefits for preserving bone mass.
Centenarians: all in the genes?
An ongoing study of centenarians was the topic of this year's
Hayflick lecture. Dr. Eugenia Wang of McGill University in
Montreal presented her data on Taiwanese centenarians. Using
advanced genetic techniques, she focused especially on the
genes involved in apoptosis-the self-destruction of cells that
the body wishes to eliminate. These apoptotic genes may be a
significant determinant of longevity, since the survival of
dysfunctional cells is detrimental to the organism.
Another genetic determinant of longevity is the APOE-2
allele (an allele is a normal variant of a gene). The APOE
gene seems to govern the susceptibility to cardiovascular
disease and Alzheimer's disease. It is actually a gene coding
for the cholesterol transport apolipoprotein E. APOE-2 is
twice as frequent in centenarians. Jeanne Calment, who lived
to be 122, was found to have APOE-3, which is also regarded as
a beneficial allele. These alleles developed late in the human
evolution. A fascinating speculation is that perhaps here we
are seeing "the grandmother effect": the grandchildren of
long-lived grandmothers may have had a survival advantage due
to a healthy older woman being available to take care of them
(especially if the mother should die in childbirth).
The link between APOE-4 allele and susceptibility to Alzheimer's
disease is so strong that it might be worthwhile to seek
developing gene therapy for those carrying it. One conference
participant, however, claimed that if you eliminate or
significantly inhibit inflammation, Alzheimer's disease would
not develop. Inflammation can be elimination or sufficiently
inhibited by using NSAIDs such as ibuprofen (the new selective
NSAIDs such as Celebrex promise to work as well with greater
safety), quality fish oil, polyphenols and/or estrogen replacement.
Antioxidants are also promising, especially vitamin E, though it should be
pointed out that antioxidants often have an anti-inflammatory
effect, and this is certainly true of high doses of vitamin
E.
The debate over the relative importance of genes vs.
environment is by no means over. Currently, scientists lean to
the view that about 40 - 50% of one's life expectancy is
determined by one's genes. According to Dr. Wang, it seems
that there are 20 "master genes" that promote longevity. Her
goal is to identify those genes.
Sharing her less formal observations of centenarians, Dr.
Wang commented on their striking mental sharpness even at a
very old age. As an example, she showed an intricate pair of
baby booties made from scratch by a Taiwanese woman aged 100.
The same woman also smoked until the age of 76, and chewed
carcinogenic bitter nuts. Apparently centenarians tend to be
remarkably resistant to cancer.
In her future research, Dr. Wang plans to also examine
various behavioral traits associated with centenarians, such
as optimism and social connectedness.
Continuation
of Report
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