Increased Expression of RbAp48 Restores Memory Capacity in Old Mice
Permalink | View Comments (29) | Post Comment | | Posted by Reason

Researchers are making strides in uncovering the low-level details of how memory operates in mammalian brains, just as they are making strides in all areas of biology. Sometimes the process of discovery comes hand in hand with a demonstration of utility, as is the case here. Putting to one side the consequences of an Alzheimer's-like build up of amyloid deposits and its associated neural dysfunction, the research quoted below demonstrates that the rest of the decline in memory function due to old age in mice can be mostly reversed by increasing the levels of one particular protein. This is very interesting, as it suggests that the processes of memory are not greatly inhibited by most of the forms of cellular damage that causes aging, at least in mice, and that this portion of mental decline occurs due to one of the epigenetic responses to that damage.

We might well ask why this came to pass in the course of evolutionary adaptation, but any sort of theorizing on my part would be very speculative at this point, following the party line on antagonistic pleiotropy in the context of aging.

A Major Cause of Age-Related Memory Loss Identified

A team of Columbia University Medical Center (CUMC) researchers [has] found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer's disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer's, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects. To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies.

When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48 inhibition was turned off, the mice's memory returned to normal. The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.

In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. "We were astonished that not only did this improve the mice's performance on the memory tests, but their performance was comparable to that of young mice."

It seems unlikely that what is going on under the hood is simple, even as the result of a single gene change. Researchers still can't fully and comprehensively explain any of the forms of life extension achieved through single gene manipulations, and some of those have been known for more than fifteen years. Altered levels of a single protein can trigger all sorts of sweeping changes in metabolism. I predict that much of the next decade will pass before even a rough sketch of what is going on here is assembled. Fortunately, full understanding isn't required to demonstrate the potential for therapies - it just improves the odds of producing a feasible, useful medical technology.

Here's the paper for those who like to see the original sources:

Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

To distinguish age-related memory loss more explicitly from Alzheimer's disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation.

To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation.

Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.

Comments

Are any human trials going on related to this protein therapy?

Posted by: Robert white at August 29, 2013 9:05 AM

I AM A WOMEN 49 YRS. OLD TERRI GREENE,I HAVE EPILEPSY WITH THREE KIDS 21, 14,11 YEARS OLD. I HAVE SHORT TERM LONG TERM MEMORY LOSS. I WOULD LIKE TO BE A CLINICAL TRAIL PATIENT. WHY DOES IT ALWAYS HAVE TO BE MICE THAT GET THE OPPORTUNITY TO BECOME BETTER. I LIVE IN GRAY,GA 31032 SMALL TOWN OUTSIDE OF MACON,GA. WHY NOT TEST HUMANS FORGET THE MICE.

Posted by: TERRI GREENE at August 29, 2013 10:42 AM

It is important that the factors that influence on RbAp48 were revealed. The study should be done researching for nutritional factors, environmental factors, educational factors, brain –exercise factors including reading, learning, studying etc. When the exact factor/factors which inhibiting the gen will be revealed, and the cured will be prescribed, it will be the biggest relief for humanity.

Posted by: Ruzanna at August 29, 2013 11:06 AM

My wife is starting to forget simple things like what plate we eat A certain
type of food on. or remember where her favorite place to go have lunch is located, and lots of other small things. It would be so wonder full to see her back to normal or close to it. We will do what ever it takes to get their. That RBAp48 sounds so good.

Posted by: Billy W. Callahan at August 29, 2013 12:40 PM

what natural foods contain or stimulate the protein RbAp48

Posted by: Roger Lewis at August 29, 2013 2:51 PM

To Terri Greene
I recommend you go to www.longecity.org become a registered user or member.Its free to become a registered user.

Once you have done that you can browse/ search the forums; there is a tremendous amount of information available and as more is known about restoring memory etc, you'll probably read about it there first or very shortly after.

Reason the author of this site is also a member, as am I.

Mike

Posted by: Mike at August 29, 2013 3:55 PM

To be practical:
Wich type of food or pills contain RbAp48?

Posted by: Gerard at August 30, 2013 5:18 AM

since when has this protein RbAp48 been in the testing? i would also like to know which foods or pill contain RbAp48?

Posted by: angelo at August 30, 2013 5:42 AM

This is animal research only, using gene therapy, and it seems no-one is discussing trials at this point. If there was a good drug candidate the researchers would probably have mentioned it, so I assume a process of drug discovery has yet to take place. The general overview of this sort of research is:

1) find something useful that can be done via gene therapy in animals
2) find or create a drug that affects the gene of interest or the levels of protein it produces in a similar way
3) trial the drug in animals
4) move to human trials

It might take a decade to get from step (1) up to late human trials under the present regulatory regime.

Posted by: Reason at August 30, 2013 6:13 AM

Are there any particular foods or vitamins that one can take to increase the level of RbAp48 protein?

Posted by: Jody Snyder at August 30, 2013 5:47 PM

Notice that no one is answering the simplest question. WHAT NATURAL FOODS CONTAIN RbAp48????????

Are the contributors and article writers 'In" with the big FARMA??? That wuld NOT be a surprise, would it???

Posted by: Bob at August 31, 2013 12:12 AM

It's in red meat.

That's why the liberal media doesn't want you to know. Vegetarians have Alzheimer's and Dementia at a much higher rate. Your brain is made out of bad cholesterol. Wait till all your money goes toward Obamacare and the only foods you can afford are wheat, soybean oil, and corn syrup. You'll be on your knees begging for their pharmacological drugs. Maybe your town can buy Chinese industrial waste with some of that stuff in it and add it to your water supply so you can wash your electric car and water your pesticide-ridden lawn with it.

Don't let political correctness suppress factual correctness.

Posted by: David Rockefeller's honest son at August 31, 2013 4:55 AM

If nature made our brains and not a lab than nature is where we look for the protein RbAp48
when we are running short of it.

Posted by: Diane Celenza at August 31, 2013 8:38 AM

I too would think there would be foods that one could ingest that would help build up this protein in the brain. Are any of them yet known? I saw mentioned that therapies might be implemented. Would these be similiar to ones already used? Such as computer games, word puzzles, etc. or what are the thoughts of the experts on this?

Posted by: Leener at August 31, 2013 6:11 PM

Just wanted to say "THANKS" for research that is being done to help further the longevity and healthiness of the human population. I see it is very time consuming and tedious. Not to mention that even people who read your articles get confused and demand info which you don't already have. I too at first misunderstood that the protein itself was something you could just eat. But like muscles which are protein, it now occurs to me that probably, it is something that needs to be built IN the body from ingested foods that hook up and need to be "exercised" to work. A bit of enlightenment in layman's terms explaining this on the writer's part would save us all some grief.

Posted by: Leener at August 31, 2013 6:28 PM

@Leener: Indeed, asking whether you can eat something to alter levels of RbAp48 in the brain is a symptom of the wrong way of thinking about health, metabolism, and medicine. There is a vast industry out there selling the (almost entirely mistaken) idea that you can eat certain supplements to meaningfully improve health, and public misunderstanding over what is and isn't possible is somewhat a consequence of that.

I would expect that the two lifestyle choices known to improve long-term health and raise at least mean life span - exercise and calorie restriction - will positively impact levels of RbAp48, since they are known to slow age-related memory loss. That seems like a fairly safe bet on the basis of this research.

So you people wanting to know how to take advantage: that's your answer, the same answer as existed before this research was published. Both exercise and calorie restriction have been shown to be beneficial in older people, so it's never too late to do more of both.

But thinking about any specific aspect of your inner biochemistry in terms of "which fruit or supplement will give me more of protein X" is absolutely the wrong way to look at things. It's just playing into the hands of marketing departments in the business of selling lies and wishful thinking. The world, and the human body, just doesn't work that way. If there was some easily available food or natural substance that raised levels of RbAp48 and thus greatly improved memory in old age, be assured that we'd have known about it for centuries.

Human biology reacts to aging in many ways that produce frailty and dysfunction beyond that which would be caused by the cellular damage of aging alone. Many of these changes are thought to have evolved to reduce the risk of cancerous stem cells arising, at the cost of limiting vital tissue maintenance by shutting down the activity of those stem cells - a balance is struck between those things, cancer versus frailty and failing tissues. Who knows why RbAp48 fades out with age, but it will probably turn out to be something similar.

Posted by: Reason at August 31, 2013 8:50 PM

Please put me on an information mailing list. Male age 68. Thanx

Posted by: Guy Moore at September 1, 2013 3:55 PM

Red meat only?


Posted by: Gregre at September 2, 2013 1:22 AM

NESECITO URGENTE CUAL ES MEDICAMENTO PARA AYUDAR CON LA PERDIDA DE LA MEMORIA,, Y LA PROTEINA QUE LE FALTA AL HIPOCANPO,, RbAb48,,, por favor

Posted by: lizeth medina at September 2, 2013 7:18 AM

I am 85 and have those "senior moments". I am a perfect candidate for any upcoming trials! How do we get on a list or stay informed of such? Live near a Medical Center in NH

Posted by: alexandra at September 2, 2013 1:36 PM

To Reason's post; we would not have known about this generations ago. That's why we perform, seek, test and learn. Obviously there is method to increase this protein - the scientists did it in the mice! There are many known fixes, improvements and cures that are withheld from the people. This is driven by the greed of our government and their money makers; pharmacuetical and agrigcultural companies. We might be forgetful but we aren't completely stupid - yet (Rockefeller's post nailed that one!)

Posted by: Karen Stansberry at September 2, 2013 2:09 PM

Is red meat the only thing that will help increase memory. I am 74 and experiencing some short term memory. I would like to know if there is anything else besides red meat that would increse protien.

Thank you.

Posted by: Lucille Caia at September 3, 2013 12:09 PM

The 'red meat' line is inaccurate. You need the RbAp48 on the other side of the brain barrier and the proteins in red meat gets broken down by the digestive tract just like any other proteins. It needs to be assembled and transported somehow. Might be one of the things exercise and socializing does?

Rockefeller's son's argument is just a bunch of political buzz phrases tied together to look like an argument. This is going to take research, analysis, and evidence rather than thinking with your anger management issues like the conservative media wants you to do.

Posted by: Alt at September 5, 2013 9:04 AM

I don't know why Rockefella and Stansberry have to turn this into a political issue. Give us a break.
I have had a memory problem my whole life and may not live long enough to benefit from this research, but celebrate this none the less. Thank you for this site.

Barbara Peterson

Posted by: Barbara Peterson at September 6, 2013 9:49 AM

Bonjour,
de la venue de l'australopitheque jusqu'ˋa la naissance de Néandertal et cromagnon et enfin sapiens sapiens. ˋA l'époque, il n'y avait aucun médecin pour effectuer un trafiquage de l'ADN et de l'ARN,alors que s'est-il passé pour en arriver ˋa nous.

Nos cellules sont des entités ˋa part entiere, elles ont une conscience reliée entre elles et tout ce qui existe dans l'Univers, nous sommes intriqués quantiquement et donc en corrélation comme tout ce qui existe dans les Univers.

Vous devez prendre conscience que vous etes reliés avec tout ce qui peut exister,vous n'etes jamais seul, c'est une impression simplement.

Si vous y croyez, vous pourriez communiquer avec vous-meme, prendre conscience de vos cellules, de votre ADN, de votre puissance ˋa pourvoir vous régénérer. Je ne dis pas que c'est facile, mais c'est faisable.

Je vous conseilles deux livres de....Lyne Mctaggart.

Le lien quantique et la science de l'intention.

Dans ces deux livres,vous découvrirez par des expériences de laboratoire la possibilité de pouvoir agir sur le corps d'une facon physique et spirituelle.

Nous nous pensons incapable de quoi que ce soit face a la maladie, mais au contraire, tout dans la nature prouve que nous pouvons nous régénérer par des techniques différentes, telles que la priere qui en laboratoire a prouvé son efficacité, en priant avec une intention, nous dirigeons des ondes vers quelqu'un ou nous-memes.

Nous pouvons comme un faisceau lazer concentré de l'énergie provenant de nous-memes pour activer des processus que jamais nous aurions crus possibles.

Je conseil vivment la lecture de ces deux livres qui prouvent hors de tout doute que nous pouvons nous guérir nous memes et aussi les autres en prenant conscience d'une facon physique et spirituel ou put importe le nom que l on lui donne.

Posted by: charles at September 21, 2013 3:54 PM

The protein RbAp48 is manufactured by the body for use in the body. Eat a balanced diet, exercise your body, and your brain (this means read, write, do complicated math problems, or word problems)and your body will reward you with more of the good stuff. Otherwise, if you don't have enough then it's your genes that are coded to shut down production. Gene therapy is a long way away. You can't ingest the protein, it will be broken down. I suppose you could inject it but I doubt you could get it refined in a cost effective way.

Posted by: Know at September 26, 2013 11:01 AM

Ifound RbAp48 for sale on the internet I did not call to get more info
I expect it would be the type used in the Mice trial and I would need a device to inject it into my brain I did not understand the quantity factor but it costs like $295.00 I expect that would be one very small injection

Posted by: FON MADDOX at October 8, 2013 8:54 PM

I think the scientist should not forget the most important thing which is to check the medications those people take and compare to what happens to them over the years, including "short memory loss" "macular degeneration" and "extreme depression"
I have noticed in the people that I know those who take medication for
Blood Pressure & Cholesterol at the same time, they all suffer from the above results.

Posted by: Ruby Minas at October 23, 2013 4:03 PM

I am only 50 and have had low protein for several years now. My memory is horrible , so I think I will add me some red meat everyday for awhile and see. As of now my cholesterol has been on the low side so it shouldn't hurt

Posted by: worth a try at January 29, 2014 6:49 PM
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