LONGECITY

http://www.scienceda...30501131845.htm


Hypothalamus: Brain Region May Hold Key to Aging

While the search continues for the Fountain of Youth, researchers may have found the body's "fountain of aging": the brain region known as the hypothalamus. (Credit: © James Steidl / Fotolia)

May 1, 2013 — While the search continues for the Fountain of Youth, researchers may have found the body's "fountain of aging": the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan.

The paper was published today in the online edition of Nature.
"Scientists have long wondered whether aging occurs independently in the body's various tissues or if it could be actively regulated by an organ in the body," said senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. "It's clear from our study that many aspects of aging are controlled by the hypothalamus. What's exciting is that it's possible -- at least in mice -- to alter signaling within the hypothalamus to slow down the aging process and increase longevity."
The hypothalamus, an almond-sized structure located deep within the brain, is known to have fundamental roles in growth, development, reproduction, and metabolism. Dr. Cai suspected that the hypothalamus might also play a key role in aging through the influence it exerts throughout the body.
"As people age," he said, "you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer." Over the past several years, Dr. Cai and his research colleagues showed that inflammatory changes in the hypothalamus can give rise to various components of metabolic syndrome (a combination of health problems that can lead to heart disease and diabetes).
To find out how the hypothalamus might affect aging, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). "Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map," he said.
In the current study, Dr. Cai and his team demonstrated that activating the NF-κB pathway in the hypothalamus of mice significantly accelerated the development of aging, as shown by various physiological, cognitive, and behavioral tests. "The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn -- all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan," he said.
Conversely, Dr. Cai and his group found that blocking the NF-κB pathway in the hypothalamus of mouse brains slowed aging and increased median longevity by about 20 percent, compared to controls.
The researchers also found that activating the NF-κB pathway in the hypothalamus caused declines in levels of gonadotropin-releasing hormone (GnRH), which is synthesized in the hypothalamus. Release of GnRH into the blood is usually associated with reproduction. Suspecting that reduced release of GnRH from the brain might contribute to whole-body aging, the researchers injected the hormone into a hypothalamic ventricle (chamber) of aged mice and made the striking observation that the hormone injections protected them from the impaired neurogenesis (the creation of new neurons in the brain) associated with aging. When aged mice received daily GnRH injections for a prolonged period, this therapy exerted benefits that included the slowing of age-related cognitive decline, probably the result of neurogenesis.
According to Dr. Cai, preventing the hypothalamus from causing inflammation and increasing neurogenesis via GnRH therapy are two potential strategies for increasing lifespan and treating age-related diseases. This technology is available for licensing.



Story Source:

The above story is reprinted from materials provided by Albert Einstein College of Medicine.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

• Guo Zhang, Juxue Li, Sudarshana Purkayastha, Yizhe Tang, Hai Zhang, Ye Yin, Bo Li, Gang Liu, Dongsheng Cai. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 2013; DOI: 10.1038/nature12143

Inflammation is key to aging and evidently it can be reduced by manipulating the Hypothalamus.

http://news.yahoo.co...-191717771.html

Well, here you go... Now we need to "just" find how to apply this knowledge to a working therapy, which I suspect - would work to at least a decent degree.

Maybe a key to the puzzle, but I suspect it is a whole lot more complicated than the headline proclaims.

The hypothalamic-pituitary-adrenal axis is the keystone of the emerging fields of psychoneuroimmunology and mind-body medicine.

Deactivation of the HPA axis in meditation is what is thought to be responsible for the nootropic and anti-aging effects of meditation.

Here's an interesting article about the relationship between psychological activity and physiological aging markers: http://mindblog.deri...-makes.html?m=1

This is potentially bad news for people on testosterone replacement therapy.

If GnRH is directly anti-brain-aging, given that TRT shuts down GnRH, we might see accelerated aging in people on TRT.

Godot, read again. It's the opposite of what you say.

If we have to inject GnRH into our hypothalami (wow, I can't believe the Firefox spellchecker bought that!), this is probably a nonstarter, but would it be sufficient to inject GnRH somewhere a little more accessible?

This is potentially bad news for people on testosterone replacement therapy.

If GnRH is directly anti-brain-aging, given that TRT shuts down GnRH, we might see accelerated aging in people on TRT.

Godot, read again. It's the opposite of what you say.

Well that's why one should use HCG in addition too... Or so I understand at this moment. (GnRH is a HCG releasing hormone. HCG helps to keep that neurogenesis happening (?).. so injected HCG reaches various places in a body by blood, and braing isn't an exception I guess...).

This is potentially bad news for people on testosterone replacement therapy.

If GnRH is directly anti-brain-aging, given that TRT shuts down GnRH, we might see accelerated aging in people on TRT.

Godot, read again. It's the opposite of what you say.

Well that's why one should use HCG in addition too... Or so I understand at this moment. (GnRH is a HCG releasing hormone. HCG helps to keep that neurogenesis happening (?).. so injected HCG reaches various places in a body by blood, and braing isn't an exception I guess...).

No, HCG actually suppresses GnRH even further. It does not replace GnRH. It mimics luteinizing hormone, but that's something very different from GnRH.

Hmm... well what about injections of GnRH then? Would it make it to the brain through blood?

I believe DAA works by stimulating GnRH. I can say from experience that DAA works at a few grams once per day....at least for old guys like me..

DAA is also an exitotoxin. In fact, a closely related molecule with similar effect on neurons that is also an exitotoxin, N-Methyl-D-aspartic acid., is used in animal models to create brain damage.

DAA is also found naturally in the brain, at non-toxic levels. However, the whole idea behind DAA supplementation is to create a supraphysiological concentration of DAA in the brain, at which point all bets are off regarding safety, and there are no safety studies.

So what I am saying is that if you think DAA will be neuroprotective via the secondary effect of GnRH stimulation (if any), you are more likely to be wrong than right at this point.
Edited by viveutvivas, 02 May 2013 - 11:01 PM.

Everything you've stated about DAA is simply unfounded speculation. Almost everything is toxic at some level. Nobody is suggesting to megadose DAA. I have no idea where you came up with the idea of megadosing DAA anymore than suggesting to megadose almost any substance discussed on this forum. I know you supplement testosterone....does that mean you medadose it?

I've supplemented DAA at 2-3 grams once per day almost non-stop for the last 4 or 5 years and have had nothing but positive results. From my experience, it most definitely is safer and has less sides than supplementing testosterone. And in spite of your claims, I can absolutely guarantee that at 56, I am healthier than you in spite of using modest doses of DAA daily for the last 5 years or so. My body works and works very well unlike your body on testosterone replacement.

Everything you've stated about DAA is simply unfounded speculation. Almost everything is toxic at some level. Nobody is suggesting to megadose DAA. I have no idea where you came up with the idea of megadosing DAA anymore than suggesting to megadose almost any substance discussed on this forum. I know you supplement testosterone....does that mean you medadose it?

I've supplemented DAA at 2-3 grams once per day almost non-stop for the last 4 or 5 years and have had nothing but positive results. From my experience, it most definitely is safer and has less sides than supplementing testosterone. And in spite of your claims, I can absolutely guarantee that at 56, I am healthier than you in spite of using modest doses of DAA daily for the last 5 years or so. My body works and works very well unlike your body on testosterone replacement.

It is your claim that DAA is safe that is unfounded speculation, since there are no safety trials for DAA.

You don't know me. You don't know my current state of health or what I'm on. In any case I never claimed to be in better health than you and I don't see what our comparative health has to do with the price of eggs. Of all people, those of us who participate in these forums should know that how someone happens to feel is a very blunt indicator of internal state. Of all people, those of us who participate here should know how unreliable anecdotal accounts like yours are. I was trying to warn people in general to be careful.

We don't know what your brain looks like without opening it up, do we? Who knows if someone supplementing DAA like you might be at higher risk of early Alzheimer's, for example.

As for megadosing, of course you are megadosing. Or do you think a normal diet contains anything close 3 grams of DAA per day, or even of the same order of magnitude? And isn't the idea of DAA supplementation to raise levels of DAA in the brain above what they would be in a normal person of your age?

I have seen several people complain of side effects from DAA in various unrelated forums. Their complaints are most often that DAA takes away their sex drive, which is what one would expect if hypothalamic neurons are being damaged. This is also speculation, and these are anecdotal accounts. However, out of an abundance of caution, we should always take anecdotal accounts of possible harm more seriously than anecdotal accounts of benefit because, well, harm is harmful.
Edited by viveutvivas, 03 May 2013 - 01:07 AM.

Everything you've stated about DAA is simply unfounded speculation. Almost everything is toxic at some level. Nobody is suggesting to megadose DAA. I have no idea where you came up with the idea of megadosing DAA anymore than suggesting to megadose almost any substance discussed on this forum. I know you supplement testosterone....does that mean you medadose it?

I've supplemented DAA at 2-3 grams once per day almost non-stop for the last 4 or 5 years and have had nothing but positive results. From my experience, it most definitely is safer and has less sides than supplementing testosterone. And in spite of your claims, I can absolutely guarantee that at 56, I am healthier than you in spite of using modest doses of DAA daily for the last 5 years or so. My body works and works very well unlike your body on testosterone replacement.

You don't know me. You know nothing of my current health or what I'm on, but in any case I never claimed to be in better health than you and I don't see what our comparative health health has to do with the price of eggs. Of all people, those of us who participate in these forums should know that how someone happens to feel is a very blunt indicator of internal state. Of all people, those of us who participate here should know how unreliable anecdotal accounts like yours are. I was trying to warn people in general to be careful.

We don't know what your brain looks like without opening it up, do we? Who knows if someone supplementing DAA like you might be at higher risk of early Alzheimer's, for example.

As for megadosing, of course you are megadosing. Or do you think a normal diet contains anything close 3 grams of DAA per day, or even of the same order of magnitude? And isn't the idea of DAA supplementation to raise levels in the brain above what they would be in a normal person?

I have seen several people complain of side effects from DAA in various unrelated forums. Their complaints are most often that DAA takes away their sex drive, which is what one would expect if hypothalamic neurons are being damaged.

It is your claim that DAA is safe that is unfounded speculation, since there are no safety trials for DAA.

Your claims are simply wrong on many fronts.

1) I do know you from your almost 1700 posts on this forum. I know that in spite of being 10 or 15 years younger than me, you suffer from a myriad of ailments. I am in perfect health. I rarely go to the doctor because I'm never sick and I feel as good now as 20 years ago but they have began health screenings at work in recent years and ALL my health markers come back in the ideal range and are better than most of the kids half my age. I don't believe you are in any position to lecture me on health and in particular, my health. It 56, I still actively weight lift, bike, and mountain climb. The mountain climbing season is upon us in Colorado which has more (53) 14,000 ft peaks than any other place in North America but I have difficulty finding partners and often go alone because even kids half my age simply can't keep up . If I talk the talk, you can rest assured that I've walked the walk. I also work a very mentally demanding job where mistakes are not forgiving, often 12 hours a day and I am also as mentally sharp now as 20 years ago and every bit as sharp if not sharper than most of the kids I work around. And the point is, if DAA has had any adverse effect, I would certainly have noticed after 5 years...but to the contrary, it seems to be keeping my hormones at a much younger level.

2) As for megadosing and supraphysiological levels of DAA in my brain, again it's your unfounded speculation. And you're confused about the the claim of needing to raise DAA to supraphysiological levels in order for it to work. Is that how you supplement testosterone? To raise T to supraphysiological levels in order for it to work? No, of course not. You supplement T to restore supposedly healthy youthful levels (although I don't know how healthy it is to bypass all the built in biology to achieve that with supplementing hormones directly). And that is what I'm doing...simply restoring youthful levels of DAA in my brain so that I feel like I have the hormones of a 30 year old instead of the typical 56. And if restoring youthful levels of DAA is harmful....than we would have burned up our brain when we were young with the youthful levels of DAA. I'm sure my hormones are more naturally balanced (like somebody half my age) in comparison to people tinkering with hormone therapy.

3) And what does diet have to do with DAA? I bet you're taking more T than anybody gets in their diet too. All supplements are taken above levels in dietary amounts....that is why they are called supplements. If supplements weren't taken above diet amounts, then there would be no need to ever supplement anything. Do you think younger people have higher natural levels of DAA because of diet?

4) And as for Alzheimer's, I'm not worried and plan on a working a long time. I still feel at the top of my game. In spite of 5 years of DAA.

5) And in respect to anecdotal reports of loss of sex drive....comes from the bodybuilding forums where you have dumb 17 year old kids who really are megadosing DAA. That is no different than dumb 17 year old kids megadosing T and other steroids. Just because a kid is shooting a gram of T a week...does that make T bad for you? Just like T, DAA is something a kid shouldn't be messing with and doesn't need to mess with because they already have raging hormones. Nothing good comes from trying to fix what isn't broken. But being 50 years old is a different story. That is why a person's supplement regime should be age based. Anyway, at 56, my sex drive is as good as it's ever been...and my girlfriend is 10 years younger...and I only mention that because she wouldn't be sticking around if it wasn't.

6) And as far as safety testing, I've just successfully completed the 5 year phase 1 and am starting the 10 year phase 2. How long do I need to go to prove my brain isn't blown out? My goal is 100 and I believe I have a fair shot. Is that good enough?

Triptorelin is a somewhat easily available GnRH agonist prescribed for chemical castration in cases of androgen-dependant cancers such as prostate cancer (at high repeated doses it shuts off the hypothalamus GnRH production), some bodybuilder also have used it off label successfully to restart their HPTA after a steroid cycle (with a single 100mcg shot or two)...

Hebbeh> After all you've said now I'm eager to know what else are you taking? :D As if that's true - something is working well for you.

C60/EVOO and resveratrol baby! Seriously it's a combination of being blessed with good genetics and maximizing my potential through lifestyle with strict healthy diet, exercise, and maintaining a lean fit body. You get out of life what you put into it. Persistence and effort pays off. Live the life you want.

I just read an article on this and was going to start a thread, but you beat me to it. It seems nf-kb inhibitors not only make you live longer but can also help with cancer. I am looking for a safe preferably natural inhibitor to take. http://www.businessw...ls-aging#r=most popular
Edited by Laylo, 03 May 2013 - 04:13 PM.

I also endorse this:

http://www.anti-agin...w-applications/

So is the hypothalamus the culprit in sufferers of progeria?

Hebbeh, fuck you. You don't know me. I am not on TRT any more, for your information, but bringing up my health unsolicited for an ad hominem smear is really low, and your boasts about your own do not mean shit. Lots of idiots and assholes are in great health, as you are proving.

Don't tell me where I got anecdotal reports of loss of sex drive from DAA. The reports I am referring to are from several sites, but mostly a members-only site where the people in question took similar doses as you take and are over 35 and mostly responsible.

DAA in gram amounts is megadosing by any possible standard, and your claim of an N=1 safety trial is laughable.

Triptorelin is a somewhat easily available GnRH agonist prescribed for chemical castration in cases of androgen-dependant cancers such as prostate cancer (at high repeated doses it shuts off the hypothalamus GnRH production), some bodybuilder also have used it off label successfully to restart their HPTA after a steroid cycle (with a single 100mcg shot or two)...

I wonder if the GnRH in this rodent study caused chemical castration and if that was the reason they were in better health. After all, human castrates do tend to live longer.
Edited by viveutvivas, 03 May 2013 - 08:48 PM.

Hebbeh, fuck you. You don't know me. I am not on TRT any more, for your information, but bringing up my health unsolicited for an ad hominem smear is really low, and your boasts about your own do not mean shit. Lots of idiots and assholes are in great health, as you are proving.

Don't tell me where I got anecdotal reports of loss of sex drive from DAA. The reports I am referring to are from several sites, but mostly a members-only site where the people in question took similar doses as you take and are over 35 and mostly responsible.

DAA in gram amounts is megadosing by any possible standard, and your claim of an N=1 safety trial is laughable.

Triptorelin is a somewhat easily available GnRH agonist prescribed for chemical castration in cases of androgena-dependant cancers such as prostate cancer (at high repeated doses it shuts off the hypothalamus GnRH production), some bodybuilder also have used it off label successfully to restart their HPTA after a steroid cycle (with a single 100mcg shot or two)...

I wonder if the GnRH in this rodent study caused chemical castration and if that was the reason they were in better health. After all, human castrates do tend to live longer.

Nice. You started the bullshit with your unprovoked and unfounded claims against me. I set the record straight with the truth.

ahh crap I just posted the same damn article just today to find someone had already done it for me haha. I had a similar theory that the lack of testosterone in eunuchs might be the reason for longer lifespan.. same for women...

nf-kb inhibitors might be efficacious in stress related disorders due to the overactive hpa axis. In fact reduction of stress may be why it increases lifespan.

Metformin apparently blocks NF-kB:

http://www.lef.org/w...d-for-metformin
Anti-inflammatory mechanism found for metformin

March 29, 2013. In an article appearing on March 23, 2013 in the journal Aging Cell, researchers at the University of Montreal report that metformin, a drug used to treat diabetes, decreases the production of inflammatory cytokines which, when produced in excess, result in damaging inflammation that increases the risk of cancer and other diseases.

Dr Gerardo Ferbeyre of the University’s department of biochemistry and his associates discovered that metformin inhibits the expression of genes that code for a number of inflammatory cytokines observed during cellular senescence. "Cells normally secrete these inflammatory cytokines when they need to mount an immune response to infection, but chronic production of these same cytokines can also cause cells to age,” Dr Ferbeyre explained. “Such chronic inflammation can be induced, for example by smoking."

"We were surprised by our finding that metformin could prevent the production of inflammatory cytokines by old cells."

The researchers uncovered evidence that metformin blocks the activity of a transcription factor known as nuclear factor kappa-beta (NF-kB), which is involved in inflammation. "The genes that code for cytokines are normal, but a protein that normally triggers their activation called NF-kB can't reach them in the cell nucleus in metformin treated cells", Dr Ferbeyre observed. "We also found that metformin does not exert its effects through a pathway commonly thought to mediate its antidiabetic effects."

"This is an important finding with implications for our understanding on how the normal organism defends itself from the threat of cancer and how a very common and safe drug may aid in treatment of some cancers and perhaps slow down the aging process,” he added. “It remains that determining the specific targets of metformin would give us an even better opportunity of profit from its beneficial effects. That's what we want to figure out next."

VinceG made an interesting post on NF-kB inhibitors in an older previous thread:

http://www.longecity...life-extension/

"... no less than thirty of the substances in my anti-aging firewalls regimen block expression of NF-kB or limits its binding activity: resveratrol, pycnogenol, curcumin, green tea (EGCG), ashwagandha (withania somnifera), astragalus and astragaloside IV, gingo biloba extract, vitamin C, boswellia, allicin, alpha-lipoic acid, vitamin E, Vitamin D-3, vitamin B-6, folic acid, grape seed extract, avena sativa, co-enzyme Q-10, EPA/DHA, carnosine, lycopene, folic acid, melatonin, quercetin, grape seed extract, l-carnitine, stinging nettle and benfotiamine. It is as if an overall objective of the firewall supplement program was to inhibit expression of NF-kappaB. So far I have found only one substance in the firewall regimen that activates NF-kappaB. This is phosphatidylcholine. If the mouse experiments show the same results for humans (the genes are the same), the firewalls regimen might possibly be tweaked to produce age reversal in several human organs..."
Edited by blood, 15 June 2013 - 08:40 AM.

Everything you've stated about DAA is simply unfounded speculation. Almost everything is toxic at some level. Nobody is suggesting to megadose DAA. I have no idea where you came up with the idea of megadosing DAA anymore than suggesting to megadose almost any substance discussed on this forum. I know you supplement testosterone....does that mean you medadose it?

I've supplemented DAA at 2-3 grams once per day almost non-stop for the last 4 or 5 years and have had nothing but positive results. From my experience, it most definitely is safer and has less sides than supplementing testosterone. And in spite of your claims, I can absolutely guarantee that at 56, I am healthier than you in spite of using modest doses of DAA daily for the last 5 years or so. My body works and works very well unlike your body on testosterone replacement.

Didnt you consider to cycle DAA ? I read numerous cautions to cycle it and really suprised to see that you use it without breaks for years.
Is it still as effective as on the beginning ?

I see no reason to cycle it......it works very well for me. Any suggestions to cycle are not based on science but based on speculation. It's like creatine too....some claim it has to be cycled but there is no science behind that and it works continuously. I don't cycle my C60/EVOO either....most things don't need to be cycled and in most cases cycling is more detrimental than useful. Get your body tuned and keep it there.