In light of caloric restriction studies this is interesting. Recently noted
one claim that caloric restriction paradoxically increases protein turnover
in cells, via the s26 pathway I presume. Perhaps caloric restriction helps
because by enhancing protein turnover proteins are prevented by aggregating,
are not as susceptible to oxidation or nitration. Additionally, I think heat
shock proteins are upregulated via caloric restriction (certainly true of
the brain. Mark Mattson reference somewhere ...) and these also help in
binding denatured proteins and allowing s26 degradation.
Unfortunately there are no animal models of Alz because only humans get it.
A study last year showed that while the gene transcription rates for liver
and kidney are similiar for humans vs primates, in the human brain gene
transcription rates are x3 of our closest relatives. Human brains are in
overdrive, working hard, susceptible to oxidative stress. Increasing protein
turnover would help such busy brains by quickly eliminating nasty proteins
... . Alz, the special price for intelligence.
On the other hand, high caloric intact may correlate with poor health
habits, and some studies have indicated that obesity leads to increased
levels of circulating proinflammatory cytokines which while not causative
certainly won't help in Alz. Ah Neuroscience so many ways to come at the
problems.
Caloric restriction won't stop Alz, just slow it down. Alz is not via
oxidative stress but is via ????
John H.
"Ian Goddard" <igoddard at erols.mom> wrote in message
news:3d5c4934.43222222 at news.erols.com...
> RE:
>http://groups.google.com/groups?selm=3d5b0329.102929276%40news.erols.com>>> 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 bread 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>>> *************************************************************************
>> [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]
>>http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list
_uids=10526115&dopt=Abstract
>> *********************************************************************
>> [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]
>>http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list
_uids=9894871&dopt=Abstract
>> *********************************************************************
>> [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]
>>http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list
_uids=11220789&dopt=Abstract
>> *********************************************************************
>> [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]
>>http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list
_uids=11905999&dopt=Abstract
>> *********************************************************************
>> [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. mattsonm at 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]
>>http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list
_uids=11119686&dopt=Abstract
>> *********************************************************************
>>>http://IanGoddard.net>> "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=->>>
