X-Message-Number: 27906
Date: Wed, 3 May 2006 21:03:45 -0700 (PDT)
From: Doug Skrecky <>
Subject: CR and brain aging

Message #27888From: "Hare, Tim R"
> While a selection of recent literature wrt CR's impact on brain aging is
> compelling,
Not so compelling, Tim. Caloric restriction has been vastly over-rated as
an anti-aging strategy. Many people are interested in losing body fat, so
as to increase their percieved sexual attractiveness. This deep seated
bias in favour of fat loss has found it's way into the medical journals,
where CR related articles readily find an audience, but where CR's
numerous failures to conform to expectations are often ignored. (see below
for a particularly damning example) Unfortunately (and tellingly) much
more powerful inhibitors of brain aging are mostly neglected. A wise move
would be to forget calories, and focus on dietary quality instead. Your
brain will thank you.

Neurobiol Aging. 1999 Mar-Apr;20(2):177-89.
Life-long diet restriction failed to retard cognitive aging in
Fischer-344 rats.
  Although the beneficial effects of diet restriction on longevity and
the retardation of many somatic age-related processes are well
established, the answer to the question of whether anti-aging effects of
diet restriction extend to the brain and cognitive function remains
unclear. In the present study, the effects of long-term dietary
restriction (60% of ad-libitum calories) on an age-related alteration of
memory and sensorimotor function have been investigated in Fischer 344
male rats at four different ages: 6 months, 12 months, 18 months, and 24
months. A major drop in reference memory of DR and AL rats occurred at the
age of 18 months. The performance deficits in working memory tasks were
observed in both diet groups at the age of 24 months. These results
indicate that diet restriction failed to provide protection against
age-related deficits in memory. Although DR rats outperformed
AL rats in sensorimotor tasks throughout the life-span, the slope of the
declining function in DR rats paralleled those of AL rats, suggesting
that diet restriction failed to alter the rate of aging in sensorimotor
performance, as well.

[While blueberry has an edge over most other foods, a beneficial action
against beta amyloid is common among high ORAC fruits.]

Nutr Neurosci. 2003 Jun;6(3):153-62.
Blueberry supplementation enhances signaling and prevents behavioral
deficits in an Alzheimer disease model.
  Previously, we showed that blueberry (BB) supplementation reversed the
deleterious effects of aging on motor behavior and neuronal signaling in
senescent rodents. We now report that BB-fed (from 4 months of age) APP +
PS1 transgenic mice showed no deficits in Y-maze performance (at 12
months of age) with no alterations in amyloid beta burden. It appeared
that the protective mechanisms are derived from BB-induced enhancement of
memory-associated neuronal signaling (e.g. extracellular signal-regulated
kinase) and alterations in neutral sphingomyelin-specific phospholipase C
activity. Thus, our data indicate for the first time that it may be
possible to overcome genetic predispositions to Alzheimer disease through

J Alzheimers Dis. 2004 Aug;6(4):403-11; discussion 443-9.
Fruit extracts antagonize Abeta- or DA-induced deficits in Ca2+ flux in
M1-transfected COS-7 cells.
  Evidence suggests that there is a selective sensitivity to oxidative
stress (OSS) among muscarinic receptor (MAChR) subtypes with M1, M2 and
M4 showing > OSS than M3 or M5 subtypes in transfected COS-7 cells. This
may be important in determining the regional specificity in neuronal
aging and Alzheimer disease (AD). We assessed the effectiveness of
blueberry (BB) and other high antioxidant (HA) fruit extracts
(boysenberry, BY; cranberry, CB; black currant, BC; strawberry, SB; dried
plums, DP; and grape, GR) on the toxic effects of Abeta 25-35 (100
microM, 24 hrs) and DA (1 mM, 4 hrs) on calcium buffering
(Recovery) following oxotremorine (750 microM) -induced depolarization in
M1AChR-transfected COS-7 cells, and on cell viability following DA (4
hrs) exposure. The extracts showed differential levels of Recovery
protection in comparisons to the non-supplemented controls that was
dependent upon whether DA or Abeta was used as the
pretreatment. Interestingly, assessments of DA-induced decrements in
viability revealed that all of the extracts had some protective
effects. These findings suggest that the putative toxic effects of Abeta
or DA might be reduced by HA fruit extracts.

J Alzheimers Dis. 2004 Feb;6(1):27-30.
Apple juice prevents oxidative stress induced by amyloid-beta in culture.
  Increased oxidative stress contributes to the decline in cognitive
performance during normal aging and in neurodegenerative conditions such
as Alzheimer's disease. Dietary supplementation with fruits and
vegetables that are high in antioxidant potential have in some cases
compensated for oxidative stress. Herein, we examined whether apple juice
could alleviate the neurotoxic consequences of exposure of cultured
neuronal cells to amyloid-beta (Abeta), since at least a portion of the
neurotoxicity of Abeta is due to oxidative stress. Apple juice
concentrate (AJC; 70 degree brix) was diluted into culture medium of
SH-SY-5Y human neuroblastoma cells that had been differentiated for 7
days with 5 microM retinoic acid concurrent with the addition of 20
microM Abeta. AJC prevented the increased generation of reactive oxygen
species (ROS) normally induced by Abeta treatment under these
conditions. AJC also prevented Abeta-induced calcium influx and
apoptosis, each of which results in part due to increased ROS. These
findings suggest that the antioxidant potential of apple products can
prevent Abeta-induced oxidative damage.

[Some vegetables can help too.]

Eur J Pharmacol. 2004 Apr 12;489(3):197-202.
S-Allylcysteine prevents amyloid-beta peptide-induced oxidative stress in
rat hippocampus and ameliorates learning deficits.
  The effects of S-allylcysteine on oxidative damage and spatial learning
and memory deficits produced by an intrahippocampal injection of
amyloid-beta peptide 25-35 (Abeta(25-35)) in rats were investigated. The
formation of reactive oxygen species, lipid peroxidation and the
activities of the antioxidant enzymes superoxide dismutase and glutathione
peroxidase were all measured in hippocampus 120 min after
Abeta(25-35) injection (1 microl of 100 microM solution), while learning
and memory skills were evaluated 2 and 35 days after the infusion of
Abeta(25-35) to rats, respectively. Abeta(25-35) increased both reactive
oxygen species and lipid peroxidation, whereas pretreatment with
S-allylcysteine (300 mg/kg, i.p.) 30 min before peptide injection
decreased both of these markers. In addition, Abeta(25-35)-induced
incorrect learning responses were prevented in most of trials by
S-allylcysteine. In contrast, enzyme activities were found unchanged in
all groups tested. Findings of this work: (i) support the participation
of reactive oxygen species in Abeta(25-35)-induced hippocampal toxicity
and learning deficits; and (ii) suggest that the protective effects of
S-allylcysteine were related to its ability to scavenge reactive oxygen

[DHA from fish, plus a number of spices, including curry, marjoram,
rosemary, sage and tumeric appear to be helpful.]

Neurobiol Aging. 2005 Dec;26 Suppl 1:133-6. Epub 2005 Nov 2.
Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic
anti-oxidant interventions.
  Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes
of aging that share analogous lesions and risk factors, involving
lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD,
sensitive biomarkers are unknown, and high-risk groups are
understudied. To identify potential prevention strategies in AD, we have
focused on pre-clinical models (transgenic and amyloid infusion models),
testing dietary/lifestyle factors strongly implicated in reducing risk in
epidemiological studies. Initially, we reported the impact of
non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which
reduced amyloid accumulation, but suppressed few inflammatory markers and
without reducing oxidative damage. Safety concerns with chronic NSAIDs
led to a screen of alternative NSAIDs and identification of the phenolic
anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in
turmeric that we found targeted multiple AD pathogenic cascades. The
dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited
amyloid, oxidative damage and synaptic and cognitive deficits in a
transgenic mouse model. Both DHA and curcumin have favorable
safety profiles, epidemiology and efficacy, and may exert general
anti-aging benefits (anti-cancer and cardioprotective.).

Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005.
Phenolic anti-inflammatory antioxidant reversal of Abeta-induced
cognitive deficits and neuropathology.
  Both oxidative damage and inflammation have been implicated in
age-related neurodegenerative diseases including Alzheimer's Disease
(AD). The yellow curry spice, curcumin, has both antioxidant and
anti-inflammatory activities which confer significant protection against
neurotoxic and genotoxic agents. We used 22 month Sprague-Dawley (SD) rats
to compare the effects of the conventional NSAID, ibuprofen, and curcumin
for their ability to protect against amyloid beta-protein (Abeta)-induced
damage. Lipoprotein carrier-mediated, intracerebroventricular infusion of
Abeta peptides induced oxidative damage, synaptophysin loss, a microglial
response and widespread Abeta deposits. Dietary curcumin (2000 ppm), but
not ibuprofen, suppressed oxidative damage (isoprostane levels) and
synaptophysin loss. Both ibuprofen and curcumin reduced microgliosis in
cortical layers, but curcumin increased microglial labeling within and
adjacent to Abeta-ir deposits. In a second group of middle-aged female SD
rats, 500 ppm dietary curcumin prevented Abeta-infusion induced spatial
memory deficits in the Morris Water Maze and post-synaptic density
(PSD)-95 loss and reduced Abeta deposits. Because of its low side-effect
profile and long history of safe use, curcumin may find clinical
application for AD prevention.

Mol Cells. 2001 Apr 30;11(2):137-43.
Inhibitory effect of ursolic acid purified from Origanum majorana L on
the acetylcholinesterase.
  We screened 139 herbal spices in search of the acetylcholinesterase
(AChE) inhibitor from natural resources. AChE inhibitors, which enhance
cholinergic transmission by reducing the enzymatic degradation of
acetylcholine, are the only source of compound currently approved for the
treatment of Alzheimer's Disease (AD). Among these herbs, edible plants
and spices, the ethanol extract from Origanum majorana L. showed the
highest inhibitory effect on AChE in vitro. By sequential fractionation
of Origanum majorana L. the active component was finally identified as
ursolic acid (3 beta-Hydroxyurs-12-en-28-oic acid). The ursolic acid of
Origanum majorana L. inhibited AChE activity in a dose-dependent and
competitive/non-competitive type. The Ki value (representing the affinity
of the enzyme and inhibitor) of Origanum majorana L. ursolic acid was 6
pM, and that of tacrine was 0.4 nM. The concentration required for 50%
enzyme inhibition of the active component (IC50 value) was 7.5 nM, and
that of tacrine was 1 nM. This study demonstrated that the ursolic acid
of Origanum majorana L. appeared to be a potent AChE inhibitor in
Alzheimer's Disease.

Mol Cells. 2002 Feb 28;13(1):5-11.
Ursolic acid of Origanum majorana L. reduces Abeta-induced oxidative
  Amyloid beta protein (Abeta) increases free radical production and
lipid peroxidation in PC12 nerve cells, leading to apoptosis and cell
death. The effect of ursolic acid from Origanum majorana L. on
Abeta-induced neurotoxicity was investigated using PC12
cells. Pretreatment with isolated ursolic acid and vitamin E prevented the
PC12 cell from reactive oxygen species (ROS) toxicity that is mediated by
Abeta. The ursolic acid resulted in decreased Abeta toxicity assessed by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),
lactate dehydrogenase (LDH), and trypan blue assay. Thus, treatment with
these antioxidants inhibited the Abeta-induced neurotoxic
effect. Therefore, these results indicate that micromolar Abeta-induced
oxidative cell death is reduced by ursolic acid from Origanum majorana L.

J Pharmacol Exp Ther. 2006 Feb 22; [Epub ahead of print]
The spice sage and its active ingredient rosmarinic acid protect PC12
cells from amyloid-{beta} peptide-induced neurotoxicity.
  Traditional use and clinical reports suggest that the culinary herb
sage (Salvia officinalis) may be effective in patients suffering of mild
to moderate Alzheimer's disease (AD). In this study we evaluated the
effect of a standardized extract from the leaves of Salvia officinalis
(SOE) and its active ingredient rosmarinic acid on Alzheimer amyloid-beta
peptide (Abeta)-induced toxicity in cultured rat pheochromocytoma PC12
cells. Incubation of PC12 cells with Abeta (fragment 1-42) for 24 h
caused cell death and this effect was reduced by SOE, and by its active
ingredient rosmarinic acid. Rosmarinic acid reduced a number of events
induced by Abeta. These include reactive oxygen species (ROS) formation,
lipid peroxidation, DNA-fragmentation, caspase-3 activation and tau
protein hyperphosphorylation. Moreover, rosmarinic acid inhibited p-p38
MAP kinase, but not GSK-3beta activation. These data demonstrate that
neuroprotective effect of sage against Abeta-induced toxicity, which
could validate the traditional use of this spice in the treatment of
AD. Rosmarinic acid could contribute, at least in part, for sage-induced
neuroprotective effect.

[What you drink may have an impact.]

J Neurosci. 2005 Sep 21;25(38):8807-14.
Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor
protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic
  Alzheimer's disease (AD) is a progressive neurodegenerative disorder
pathologically characterized by deposition of beta-amyloid
(Abeta) peptides as senile plaques in the brain. Recent studies suggest
that green tea flavonoids may be used for the prevention and treatment of
a variety of neurodegenerative diseases. Here, we report that
(-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent
of green tea, reduces Abeta generation in both murine neuron-like cells
(N2a) transfected with the human "Swedish" mutant amyloid precursor
protein (APP) and in primary neurons derived from Swedish mutant
APP-overexpressing mice (Tg APPsw line 2576). In concert with these
observations, we find that EGCG markedly promotes cleavage of the
alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage
product, soluble APP-alpha. These cleavage events are associated
with elevated alpha-secretase activity and enhanced hydrolysis of tumor
necrosis factor alpha-converting enzyme, a primary candidate
alpha-secretase. As a validation of these findings in vivo, we treated Tg
APPsw transgenic mice overproducing Abeta with EGCG and found decreased
Abeta levels and plaques associated with promotion of the nonamyloidogenic
alpha-secretase proteolytic pathway. These data raise the possibility
that EGCG dietary supplementation may provide effective prophylaxis for

Eur J Epidemiol. 2000 Apr;16(4):357-63.
Intake of flavonoids and risk of dementia.
  It has been postulated that oxidative stress may play a key role in
dementia. This is substantiated by the recent discovery of the protective
effect of wine. In wine, the flavonoids--powerful antioxidant substances
also contained in tea, fruits and vegetables--have been thought to offer
such protection. We investigated whether flavonoid intake could be
associated with a lower incidence of dementia in a cohort of 1367
subjects above 65 years of age (Paquid). A questionnaire was used to
evaluate their intake of flavonoids and subjects were followed-up for 5
years between 1991 and 1996: 66 incident cases of dementia were
observed. We estimated the relative risk (RR) of dementia according to
tertiles of flavonoid intake using a Cox model. The age-adjusted RR of
dementia was 0.55 for the two highest tertiles compared to the lowest
(95% CI: 0.34-0.90; p = 0.02). After additional adjustment for gender,
education, weight and vitamin C intake, the RR was 0.49 (95%
CI: 0.26-0.92; p = 0.04). We conclude that the intake of antioxidant
flavonoids is inversely related to the risk of incident dementia.

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