Caloric Intake and Alzheimer's disease
James Michael Howard
Luchsinger, et al., reported that reducing caloric intake may reduce the risk
of Alzheimer's disease "in individuals carrying the apolipoprotein E epsilon4
allele" (Arch Neurol 2002 Aug;59(8):1258-63). Roth, et al., report that
caloric restriction extends "youthful levels of DHEAS" in nonhuman primates
and suggest this may be the case in humans (Science 2202; 297: 811). It is my
hypothesis that DHEA evolved as a consequence of its ability to optimize
transcription and replication of DNA. Therefore, all tissues are dependent
upon DHEA for optimum growth and development and maintenance, especially brain
tissue in humans, the most advanced tissue group. In a study of protection
from oxidative damage, DHEA was effective in the epsilon3/epsilon4 APOE
genotype (Free Radic Biol Med 1999 Sep;27(5-6):544-53). In 1985 I first
suggested that low DHEA could result in Alzheimer's disease. I suggest the
findings of Luchsiner, et al., represent earlier decline of DHEA as a result
of DHEA production in response to caloric intake.
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Ian Goddard
>
>Luchsinger, et al., reported that reducing caloric intake may reduce the risk
>of Alzheimer's disease "in individuals carrying the apolipoprotein E epsilon4
>allele" (Arch Neurol 2002 Aug;59(8):1258-63).
In addition to studies cited in my caloric restriction (CR)
report ( http://iangoddard.net/cr.htm See refs 26-30 & 31-34)
finding neuroprotective effects of CR in animals, the following
abstracts present further evidence pointing to possible causal
mechanisms of CR-induced neuroprotection, and another review.
The hippocampus is a primary target of Alzheimer's disease (AD).
[1] found that caloric restriction reduced damage to hippocampal
neurons in mice bred with an AD-like mutation. "Some cases of AD
are caused by mutations in presenilin-1 (PS1) ... [CR] completely
counteracted the endangering effect of the PS1 mutation."
[2] found that CR "increases resistance of the brain to insults"
similar to those found in neurodegenerative disorders such as AD.
[3] found that CR increases the growth of new cells (neurogenesis)
in the dentate gyrus of the hippocampus, a primary target of AD.
[4] also found that CR increases neurogenesis in the hippocampus.
[5] is an abstract to a review by Mark Mattson, an NIH scientist
who concludes: "Collectively, the available data suggest the that
dietary restriction, and physical and mental activity, may reduce
both the incidence and severity of neurodegenerative disorders in
humans." Another review by Mattson was cited in my previous post:
http://groups.google.com/groups?selm=3d5b0c65.105293614%40news.erols.com
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[1] Brain Res 1999 Sep 18;842(1):224-9
Dietary restriction protects hippocampal neurons against the
death-promoting action of a presenilin-1 mutation.
Zhu H, Guo Q, Mattson MP.
Department of Anatomy and Neurobiology, Sanders-Brown Research Center
on Aging, University of Kentucky, 211 Sanders-Brown Building, 800
South Limestone Street, Lexington, KY 40536, USA.
Alzheimer's disease (AD) is an age-related disorder that involves
degeneration of synapses and neurons in brain regions involved in
learning and memory processes. Some cases of AD are caused by
mutations in presenilin-1 (PS1), an integral membrane protein located
in the endoplasmic reticulum. Previous studies have shown that PS1
mutations increase neuronal vulnerability to excitotoxicity and
apoptosis. Although dietary restriction (DR) can increase lifespan and
reduce the incidence of several age-related diseases in rodents, the
possibility that DR can modify the pathogenic actions of mutations
that cause AD has not been examined. The vulnerability of hippocampal
neurons to excitotoxic injury was increased in PS1 mutant knockin
mice. PS1 mutant knockin mice and wild-type mice maintained on a DR
regimen for 3 months exhibited reduced excitotoxic damage to
hippocampal CA1 and CA3 neurons compared to mice fed ad libitum; the
DR regimen completely counteracted the endangering effect of the PS1
mutation. The magnitude of increase in levels of the lipid
peroxidation product 4-hydroxynonenal following the excitotoxic insult
was lower in DR mice compared to mice fed ad libitum, suggesting that
suppression of oxidative stress may be one mechanism underlying the
neuroprotective effect of DR. These findings indicate that the
neurodegeneration-promoting effect of an AD-linked mutation is subject
to modification by diet.
PMID: 10526115 [PubMed - indexed for MEDLINE]
*********************************************************************
[2] Ann Neurol 1999 Jan;45(1):8-15
Food restriction reduces brain damage and improves behavioral outcome
following excitotoxic and metabolic insults.
Bruce-Keller AJ, Umberger G, McFall R, Mattson MP.
Sanders-Brown Research Center on Aging, Department of Anatomy and
Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Food restriction (FR) in rodents is known to extend life span, reduce
the incidence of age-related tumors, and suppress oxidative damage to
proteins, lipids, and DNA in several organ systems. Excitotoxicity
and mitochondrial impairment are believed to play major roles in the
neuronal degeneration and death that occurs in the brains of patients
suffering from both acute brain insults such as stroke and seizures,
and chronic neurodegenerative conditions such as Alzheimer's,
Parkinson's, and Huntington's diseases. We now report that FR
(alternate-day feeding regimen for 2-4 months) in adult rats results
in resistance of hippocampal neurons to excitotoxin-induced
degeneration, and of striatal neurons to degeneration induced by the
mitochondrial toxins 3-nitropropionic acid and malonate. FR greatly
increased the resistance of rats to kainate-induced deficits in
performance in water-maze learning and memory tasks, and to
3-nitropropionic acid-induced impairment of motor function. These
findings suggest that FR not only extends life span, but increases
resistance of the brain to insults that involve metabolic compromise
and excitotoxicity.
PMID: 9894871 [PubMed - indexed for MEDLINE]
*********************************************************************
[3] J Mol Neurosci 2000 Oct;15(2):99-108
Dietary restriction increases the number of newly generated neural
cells, and induces BDNF expression, in the dentate gyrus of rats.
Lee J, Duan W, Long JM, Ingram DK, Mattson MP.
Laboratory of Neurosciences, Gerontology Research Center, National
Institute on Aging, Baltimore, MD 21224, USA.
The adult brain contains neural stem cells that are capable of
proliferating, differentiating into neurons or glia, and then either
surviving or dying. This process of neural-cell production
(neurogenesis) in the dentate gyrus of the hippocampus is responsive
to brain injury, and both mental and physical activity. We now report
that neurogenesis in the dentate gyrus can also be modified by diet.
Previous studies have shown that dietary restriction (DR) can suppress
age-related deficits in learning and memory, and can increase
resistance of neurons to degeneration in experimental models of
neurodegenerative disorders. We found that maintenance of adult rats
on a DR regimen results in a significant increase in the numbers of
newly produced neural cells in the dentate gyrus of the hippocampus,
as determined by stereologic analysis of cells labeled with the DNA
precursor analog bromodeoxyuridine. The increase in neurogenesis in
rats maintained on DR appears to result from decreased death of newly
produced cells, rather than from increased cell proliferation. We
further show that the expression of brain-derived neurotrophic factor,
a trophic factor recently associated with neurogenesis, is increased
in hippocampal cells of rats maintained on DR. Our data are the first
evidence that diet can affect the process of neurogenesis, as well as
the first evidence that diet can affect neurotrophic factor
production. These findings provide insight into the mechanisms whereby
diet impacts on brain plasticity, aging and neurodegenerative
disorders.
PMID: 11220789 [PubMed - indexed for MEDLINE]
*********************************************************************
[4] J Neurochem 2002 Feb;80(3):539-47
Dietary restriction enhances neurotrophin expression and neurogenesis
in the hippocampus of adult mice.
Lee J, Seroogy KB, Mattson MP.
Laboratory of Neurosciences, National Institute on Aging Gerontology
Research Center Baltimore, Maryland 21224, USA.
The adult brain contains small populations of neural precursor cells
(NPC) that can give rise to new neurons and glia, and may play
important roles in learning and memory, and recovery from injury.
Growth factors can influence the proliferation, differentiation and
survival of NPC, and may mediate responses of NPC to injury and
environmental stimuli such as enriched environments and physical
activity. We now report that neurotrophin expression and neurogenesis
can be modified by a change in diet. When adult mice are maintained on
a dietary restriction (DR) feeding regimen, numbers of newly generated
cells in the dentate gyrus of the hippocampus are increased,
apparently as the result of increased cell survival. The new cells
exhibit phenotypes of neurons and astrocytes. Levels of expression of
brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are
increased by DR, while levels of expression of high-affinity receptors
for these neurotrophins (trkB and trkC) are unchanged. In addition, DR
increases the ratio of full-length trkB to truncated trkB in the
hippocampus. The ability of a change in diet to stimulate neurotrophin
expression and enhance neurogenesis has important implications for
dietary modification of neuroplasticity and responses of the brain to
injury and disease.
PMID: 11905999 [PubMed - indexed for MEDLINE]
*********************************************************************
[5] Brain Res 2000 Dec 15;886(1-2):47-53
Neuroprotective signaling and the aging brain: take away my food and
let me run.
Mattson MP.
Laboratory of Neurosciences, National Institute on Aging Gerontology
Research Center, 5600 Nathan Shock Drive, 21224-6825, Baltimore, MD,
USA. matt...@grc.nia.nih.gov
It is remarkable that neurons are able to survive and function for
a century or more in many persons that age successfully. A better
understanding of the molecular signaling mechanisms that permit such
cell survival and synaptic plasticity may therefore lead to the
development of new preventative and therapeutic strategies for
age-related neurodegenerative disorders. We all know that overeating
and lack of exercise are risk factors for many different age-related
diseases including cardiovascular disease, diabetes and cancers. Our
recent studies have shown that dietary restriction (reduced calorie
intake) can increase the resistance of neurons in the brain to
dysfunction and death in experimental models of Alzheimer's disease,
Parkinson's disease, Huntington's disease and stroke. The mechanism
underlying the beneficial effects of dietary restriction involves
stimulation of the expression of 'stress proteins' and neurotrophic
factors. The neurotrophic factors induced by dietary restriction may
protect neurons by inducing the production of proteins that suppress
oxyradical production, stabilize cellular calcium homeostasis and
inhibit apoptotic biochemical cascades. Interestingly, dietary
restriction also increases numbers of newly-generated neural cells in
the adult brain suggesting that this dietary manipulation can increase
the brain's capacity for plasticity and self-repair. Work in other
laboratories suggests that physical and intellectual activity can
similarly increase neurotrophic factor production and neurogenesis.
Collectively, the available data suggest the that dietary restriction,
and physical and mental activity, may reduce both the incidence and
severity of neurodegenerative disorders in humans. A better
understanding of the cellular and molecular mechanisms underlying
these effects of diet and behavior on the brain is also leading to
novel therapeutic agents that mimick the beneficial effects of dietary
restriction and exercise.
Publication Types:
Review
Review, Tutorial
PMID: 11119686 [PubMed - indexed for MEDLINE]
*********************************************************************
"To lengthen thy life, lessen thy meals." Benjamin Franklin
Caloric Restriction: http://users.erols.com/igoddard/cr.htm
Ongoing CR-monkey-study update: "In the monkeys...those on
reduced feeding since the study started are dying at a rate
that is about half that of the monkeys receiving a full food
ration." Associated Press: Eating less may extend human life.
August 1, 2002 : http://www.msnbc.com/news/788746.asp?0si=-