9 replies to this topic

[prophets]

http://www.scienceda...91118143217.htm

Scientists Find Molecular Trigger That Helps Prevent Aging and Disease


New research has unraveled a molecular puzzle to determine that within certain parameters, a lower-calorie diet slows the development of some age-related conditions such as Alzheimer's disease, as well as the aging process. (Credit: iStockphoto)

ScienceDaily (Nov. 18, 2009) — Researchers at Mount Sinai School of Medicine set out to address a question that has been challenging scientists for years: How does dietary restriction produce protective effects against aging and disease? And the reverse: how does overconsumption accelerate age-related disease?

An answer lies in a two-part study led by Charles Mobbs, PhD, Professor of Neuroscience and of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine, published in the November 17 edition of the journal PLoS Biology. The study examines how dietary restriction and a high-caloric diet influence biochemical responses.

Dr. Mobbs and his colleagues unraveled a molecular puzzle to determine that within certain parameters, a lower-calorie diet slows the development of some age-related conditions such as Alzheimer's disease, as well as the aging process. How the diet is restricted -- whether fats, proteins or carbohydrates are cut -- does not appear to matter. "It may not be about counting calories or cutting out specific nutrients," said Dr. Mobbs, "but how a reduction in dietary intake impacts the glucose metabolism, which contributes to oxidative stress." Meanwhile, a high calorie diet may accelerate age-related disease by promoting oxidative stress.

Dietary restriction induces a transcription factor called CREB-binding protein (CBP), which controls the activity of genes that regulate cellular function. By developing drugs that mimic the protective effects of CBP -- those usually caused by dietary restriction -- scientists may be able to extend lifespan and reduce vulnerability to age-related illnesses.

"We discovered that CBP predicts lifespan and accounts for 80 percent of lifespan variation in mammals," said Dr. Mobbs. "Finding the right balance is key; only a 10 percent restriction will produce a small increase in lifespan, whereas an 80 percent restriction will lead to a shorter life due to starvation."

The team found an optimal dietary restriction, estimated to be equivalent to a 30 percent caloric reduction in mammals, increased lifespan over 50 percent while slowing the development of an age-related pathology similar to Alzheimer's disease.

The first part of the study looked at C. elegans, a species of roundworm, that were genetically altered to develop Alzheimer's disease-like symptoms. Dr. Mobbs and his team reduced the roundworms' dietary intake by diluting the bacteria the worms consume. In these types of roundworms, human beta amyloid peptide, which contributes to plaque buildup in Alzheimer's disease, is expressed in muscle, which becomes paralyzed as age progresses. This model allowed researchers to readily measure how lifespan and disease burden were simultaneously improved through dietary restriction.

The researchers found that when dietary restriction was maintained throughout the worms' adulthood, lifespan increased by 65 percent and the Alzheimer's disease-related paralysis decreased by about 50 percent.

"We showed that dietary restriction activates CBP in a roundworm model, and when we blocked this activation, we blocked all the protective effects of dietary restriction," said Dr. Mobbs. "It was the result of blocking CBP activation, which inhibited all the protective effects of dietary restriction, that confirmed to us that CBP plays a key role in mediating the protective effects of dietary restriction on lifespan and age-related disease."

In the second part of study, Dr. Mobbs and his team looked at the other end of this process: What happens to CBP in a high-calorie diet that has led to diabetes, a disease in which glucose metabolism is impaired? Researchers examined mice and found that diabetes reduces activation of CBP, leading Dr. Mobbs to conclude that a high-calorie diet that leads to diabetes would have the opposite effect of dietary restriction and would accelerate aging.

Dr. Mobbs hypothesizes that dietary restriction induces CBP by blocking glucose metabolism, which produces oxidative stress, a cellular process that leads to tissue damage and also promotes cancer cell growth. Interestingly, dietary restriction triggers CBP for as long as the restriction is maintained, suggesting that the protective effects may wear off if higher dietary intake resumes. CBP responds to changes in glucose within hours, indicating genetic communications respond quickly to fluctuations in dietary intake.

"Our next step is to understand the exact interactions of CBP with other transcription factors that mediate its protective effects with age," said Dr. Mobbs. "If we can map out these interactions, we could then begin to produce more targeted drugs that mimic the protective effects of CBP."

[JLL]

Well this is in roundworms.

Quote

How the diet is restricted -- whether fats, proteins or carbohydrates are cut -- does not appear to matter.

I thought it did matter -- in fact, a reader just posted three studies on my blog showing that cutting carbs or fat does not lead to lifespan extension.

[prophets]

i dont post this cuz i necessarily think it is 100% right.  merely cuz it is likely a piece of a puzzle.

i also think protein restriction does matter, more than carbs/fats.

edit:

keep in mind every scientist/study is going to want to shout from the rooftops, "We have discovered the most important thing about human aging!".... so w/e, i take it with grain of salt, but add it to the laundry list of things to look for in designing a diet/supplement regimen.

Edited by prophets, 19 November 2009 - 04:20 PM.

[maxwatt]

Resveratrol induces CREB binding protein via cAMP.   What else does?

[Blue]

maxwatt, on Nov 19 2009, 11:16 AM, said:

Resveratrol induces CREB binding protein via cAMP.   What else does?

Shown in humans?

[niner]

maxwatt, on Nov 19 2009, 05:16 PM, said:

Resveratrol induces CREB binding protein via cAMP.   What else does?

It activates CREB, but I don't know about the binding protein.

Quote

J Pharmacol Exp Ther. 2005 Aug;314(2):762-9. Epub 2005 May 5.  Free Full Text Available
Resveratrol-mediated activation of cAMP response element-binding protein through adenosine A3 receptor by Akt-dependent and -independent pathways.

Das S, Tosaki A, Bagchi D, Maulik N, Das DK.

Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA. ddas@neuron.uchc.edu

A recent study documented a role of adenosine A(3)-Akt-cAMP response element-binding protein (CREB) survival signaling in resveratrol preconditioning of the heart. In this study, we demonstrate that resveratrol-mediated CREB activation can also occur through an Akt-independent pathway. Isolated rat hearts were perfused for 15 min with Krebs-Henseleit bicarbonate (KHB) buffer containing resveratrol in the absence or presence of adenosine A(3) receptor blocker MRS-1191 [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicar-boxylate], phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], mitogen-activated extracellular signal-regulated protein kinase inhibitor PD098059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], or a combination of LY294002 and PD098059. All hearts were subsequently subjected to 30-min ischemia followed by 2-h reperfusion. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis, and ventricular recovery. Resveratrol phosphorylated both Akt and CREB that was blocked by MRS-1191, which also abolished cardioprotective abilities of resveratrol. LY294002 completely inhibited Akt phosphorylation but partially blocked the phosphorylation of CREB. Inhibition of PI3-kinase also partially blocked resveratrol's ability to precondition the heart. PD098059 partially blocked the phosphorylation of CREB and resveratrol-mediated cardioprotection. Preperfusing the hearts with LY294002 and PD098059 together completely abolished the phosphorylation of CREB, simultaneously inhibiting resveratrol-mediated cardioprotection. The results indicate that resveratrol preconditions the hearts through adenosine A(3) receptor signaling that triggers the phosphorylation of CREB through both Akt-dependent and -independent pathways, leading to cardioprotection.

PMID: 15879002

[ihatesnow]

http://www.immortalh...-aging-disease/

[warner]

from the ScienceDaily link to original Zhang et al.

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How CBP-interacting transcriptional complexes would act to increase lifespan and reduce age-related pathologies remains to be fully elucidated. An important role for the protective effects of CBP HAT activity is implicated by the observation that HDAC inhibitors, which effectively amplify HAT activity, increase lifespan, an effect completely dependent on cbp-1 (enhanced by bDR, which increases CBP activity, and completely blocked by cpb-1 RNAi). Since HAT activity, by increasing histone acetylation, presumably enhances transcriptional flexibility, decreased cbp expression with age may contribute to age-related loss of adaptive capacity [40], in particular in learning and memory [41]. On the other hand, HDAC inhibitors increase lifespan less than does dietary restriction, suggesting that increased HAT activity only partly accounts for the mechanisms by which cbp induction by DR increases lifespan. Since cbp-1 RNAi also blocks effects of bDR on expression of genes regulating metabolic pathways, we hypothesize that the protective effect of CBP is mediated through these metabolic effects, particularly through a shift from glycolysis to fatty acid oxidation [14], as previously reported [42] (SOD isoforms do not appear to play a role in lifespan extension with at least some protocols of DR [43]). Since glucose produces a transcriptional profile opposite that of DR [14], these studies also suggest that down-regulation of the same CBP transcriptional complex implicated here may play a role in the development of age-related diseases such as Huntington's disease [44], Alzheimer's disease, and diabetic complications.

and from reference [14]:

Quote

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types.  Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose.  Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose.  The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression.  First, metabolites induce the machinery of their own metabolism.  Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis.  When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic activity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate.  According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

Which I think highlights one of the most effective things one can do to reduce one's rate of aging:  Get yourself a blood glucose meter and modify your diet to keep postprandial (after-meal) blood glucose levels in the range that is normal for non-insulin resistant young adults (about 80 to 120 mg/dl).  And what you'll find is that, if you're the least bit insulin resistant, then this will require restricting carb intake (or taking a drug if you're already too diabetic).

Edited by warner, 01 January 2010 - 08:38 PM.

[baden-baden]

http://brainier.net/?p=404

About CREB.

Quote

Neutralizing “O-GlcNAc” significantly increases the size of neurons and long-term memory



A sugar produced by the body, O-GlcNAc (O-linked beta-N-acetylglucosamine), nicknamed “Oh-Glick-Nack” - not to be confused with sucrose or table sugar, attaches itself in a potentially harmful manner to more than 200 proteins, including several involved in the regulation processes of addiction to certain molecules and in securing the long-term storage of memory (1). This binding makes the protein involved less active or inactive.
One of them, the “CREB” protein (2) - CREB-binding protein, also known as CREBBP or CBP, is thus neutralized by O-GlcNAc, preventing the transcription of genes related to memory. The researchers blocked the possibility of the O-GlcNAc – CREB linking in mice, and, then, observed a development of long-term memory faster than the control mice (mice without the “treatment”). Under the microscope, neurones without O-GlcNAc have dendrites and axons two to three times longer and more numerous than the neurons with CREB proteins linked to the O-GlcNAc sugar.
The blocking of O-GlcNAc would allow a particularly significant improvement of long-term memory. The question is what molecules to use in order to safely neutralize O-GlcNAc. Especially if, as developed in the study, this manipulation has anticancer properties and can limit the size of tumors in mice with cancer.

(1) Blocking “oh-glick-nack” may improve long-term memory, American Chemical Society
(2) http://en.wikipedia....binding_protein

Author: A.E. / All Rights Reserved. / Copyright Brainier.net.

See this also, much recent (but in french):
http://amplicog.fr/2...e-de-vie-video/

>>>>Metformin activates--> aPKC activates --> CREB activates --> Neurogenesis.

[treonsverdery]

well it would be nifty to see if there were natural variants of the human CBP gene to see if those variations were linked to different human longevity types. There are  at the paper

Variation in the CBP gene involved in epigenetic control associates
with cognitive function
Stella Trompet a,b,∗, Anton J.M. de Craen a, J. Wouter Jukemab,c, D. Pons b,
P. Eline Slagboom d, D. Kremer d, Eduard L.E.M. Bollen e, Rudi G.J. Westendorp a


The intron 4CT and intron 3AC polymorphisms in the CBP gene were associated with better cognitive performance at
baseline and during follow-up. Furthermore, the haplotype with the variant alleles of these two polymorphisms also showed a protective effect
on cognitive function in all cognitive domains (all

p < 0.03). Genetic variation in the CBP gene is associated with better cognitive performance
in an elderly population. Future research is necessary to investigate the effect of these polymorphisms on the expression of CBP levels and
how these polymorphisms affect the gene expression mediated by CBP.


is at the paper http://www.lumc.nl/r...16020537421.pdf


wikipedia lists a number of CREB genes, creb1 has a bunch of haplotypes

CREBs that activate CBP varying amounts could also be longevity genes