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Sciencedaily: Skin Aging Reversed In Mice


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#1 resveratrol

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Posted 03 December 2007 - 11:56 PM


http://www.scienceda...71129183833.htm

Skin Aging Reversed In Mice By Blocking Action Of Single Protein

ScienceDaily (Dec. 3, 2007) — Researchers at the Stanford University School of Medicine have reversed the effects of aging on the skin of mice, at least for a short period, by blocking the action of a single critical protein.

The work could one day be useful in helping older people heal from an injury as quickly as they did when they were younger, said senior author Howard Chang, MD, PhD, assistant professor of dermatology. However, Chang and his colleagues warned their finding will likely be useful in short-term therapies in older people but not as a potential fountain of youth.

The work backs up the theory that aging is the result of specific genetic changes rather than accumulated wear and tear, Chang said. What's more, those genetic changes can be reversed even late in life.

"The implication is that the aging process is plastic and potentially amenable to intervention," Chang said. The results will be published in the Dec. 15 issue of the journal Genes and Development.

The work came about thanks to existing data from experiments using microarrays, which detect the activity of all genes in a cell. In past experiments, researchers have found a large number of diverse genes that become either more active or less active in older people.

Chang and graduate student Adam Adler, the study's first author, searched through this existing data to see if those age-related genes had anything in common. It turned out that their activity gets dialed up or down with the help of the protein called NF-kappa-B.

Chang said people had long known that NF-kappa-B winds its way into a cell's nucleus to control which genes were active. What they didn't know is that many of those genes regulated by the protein have a role in aging.

Chang and Adler tested whether blocking the activity of NF-kappa-B in the skin of older mice for two weeks had a youthful effect. "We found a pretty striking reversal to that of the young skin," Chang said.

First they looked at the genetic changes resulting from blocking NF-kappa-B. After two weeks, the skin of 2-year-old mice had the same genes active as cells in the skin of newborn mice-a striking difference when compared with the skin of a normal 2-year-old mouse. The skin looked more youthful too. It was thicker and more cells appeared to be dividing, much like the skin of a younger mouse.

Chang and Adler caution that their findings aren't likely to be the source of the long-sought fountain of youth. That's because they don't know if the rejuvenating effects of NF-kappa-B are long-lasting. Also, the protein has roles in cancer, the immune system and a range of other functions throughout the body. Suppressing the protein on a long-term basis could very well result in cancers or other diseases that undermine its otherwise youthful effect.

"You might get a longer lifespan but at the expense of something else," Chang said.

Instead, the researchers believe their work could point to a way of helping older people heal more quickly after surgery or boost organ function during illness. These short-term applications aren't as likely to risk side effects that could accompany blocking such a critical protein.

The work was supported by grants from the American Cancer Society, the National Institutes of Health, the National Cancer Institute and the California Breast Cancer Research Program.

Other Stanford researchers who participated in the work are graduate student Tiara Kawahara and Jennifer Zhang, PhD, who was a postdoctoral scholar.



#2 Fredrik

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Posted 04 December 2007 - 01:47 PM

Fortunately we already have a topical commercialised drug that inhibits the protein NF-Kb and treats aging skin, in both humans and mice!

Tretinoin (all-trans retinoic acid), one of the two FDA approved creams and gels (tazarotene is the other retinoid) to treat aging skin greatly reduce UV-induced expression of AP-1 and NF-Kb in human skin.

NF-Kb controls the skin degrading enzymes collagenase and elastase. It only takes 10-15 minutes of daylight (less than 1 minimal erythema dose) every other day to activate these metalloproteinases, so that is why daily sunscreen and retinoids is the most effective intervention we currently have to prevent photoaging. These MMPs remains elevated for up to a week if one does not use a retinoid.

NF-kb inhibition is one of several mechanisms which retinoids treats, and even prevents aging skin. The others are stimulation of collagen synthesis and inhibition of excessive melanin deposition that causes mottled hyperpigmentation.

"And tretinoin might do more than simply repair wrinkles: it might also stop them happening in the first place. Voorhees refuses to discuss his findings with journalists, but in his Nature paper he reported how several dozen male and female volunteers received a single, quick mild dose of UV-B—about twice the intensity needed to trigger barely perceptible skin reddening—on their bare buttocks.

The researchers then sliced off both the irradiated portions of skin and the adjacent, non-irradiated patches, and compared them. In less than a day after irradiating the buttocks, the levels of three enzymes that degrade collagen and elastin had increased roughly fourfold in the skin samples.

Within just 15 minutes, the levels of AP1 and NF-kB, proteins that switch on the genes for those enzymes, had more than doubled. When tretinoin was applied before irradiation, however, the increase in AP-1 and NF-kB, and in the collagen and elastin-chewing enzymes was greatly reduced."It's a very interesting result," says Christopher Griffiths, professor of dermatology at the University of Manchester. "It's saying that tretinoin might not just repair photodamage, but actually prevent it in the first place."

The skin researchers suspect that tretinoin, a type of retinoid, causes these molecular changes by seeping into the skin and binding to retinoid receptors in cells that, once activated, have profound effects on gene regulation. The widespread presence in the body of the receptors—they are found in many sites besides the skin—reflects the importance of the naturally occurring retinoids such as vitamin A."

http://www.newscient...-cosmetics.html

And the letter to NATURE by the researchers:

Nature 379, 335 - 339 (25 January 1996); doi:10.1038/379335a0

Molecular basis of sun-induced premature skin ageing and retinoid antagonism
GARY J. FISHER, SUBHASH C. DATTA, HARVINDER S. TALWAR, ZENG-QUAN WANG, JAMES VARANI*, SEWON KANG & JOHN J. VOORHEES
Departments of Dermatology and *Pathology, University of Michigan Medical School, Kresge 1, R6558, Ann Arbor, Michigan 48109–0528, USA

DAMAGE to skin collagen and elastin (extracellular matrix) is the hallmark of long-term exposure to solar ultraviolet irradiation1–3, and is believed to be responsible for the wrinkled appearance of sun-exposed skin4,5. We report here that matrix-degrading metalloproteinase messenger RNAs, proteins and activities are induced in human skin in vivo within hours of exposure to ultraviolet-B irradiation (UVB). Induction of metalloproteinase proteins and activities occurred at UVB doses well below those that cause skin reddening.

Within minutes, low-dose UVB upregulated the transcription factors AP-1 and NF-KB, which are known to be stimulators of metalloproteinase genes6,7. All-transretinoic acid, which transrepresses AP-1 (ref. 8), applied before irradiation with UVB, substantially reduced AP-1 and metalloproteinase induction. We propose that elevated metalloprotein-ases, resulting from activation of AP-1 and NF-KB by low-dose solar irradiation, degrade collagen and elastin in skin. Such damage, if imperfectly repaired, would result in solar scars, which through accumulation from a lifetime of repeated low-dose sunlight exposure could cause premature skin ageing (photoageing).

Edited by fredrik, 04 December 2007 - 04:45 PM.


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#3 resveratrol

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Posted 04 December 2007 - 06:53 PM

:thumb:

#4 resveratrol

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Posted 05 December 2007 - 03:42 PM

Chang said people had long known that NF-kappa-B winds its way into a cell's nucleus to control which genes were active. What they didn't know is that many of those genes regulated by the protein have a role in aging.

Chang and Adler tested whether blocking the activity of NF-kappa-B in the skin of older mice for two weeks had a youthful effect. "We found a pretty striking reversal to that of the young skin," Chang said.

First they looked at the genetic changes resulting from blocking NF-kappa-B. After two weeks, the skin of 2-year-old mice had the same genes active as cells in the skin of newborn mice-a striking difference when compared with the skin of a normal 2-year-old mouse. The skin looked more youthful too. It was thicker and more cells appeared to be dividing, much like the skin of a younger mouse.


This article reminded me of a great LEF write-up on nuclear factor kappa beta (NF-kB). It seems to be popping up everywhere these days.

http://www.lef.org/m..._nuclear_01.htm

Edited by resveratrol, 05 December 2007 - 03:54 PM.


#5 drunkfunk

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Posted 08 May 2008 - 05:03 PM

i wonder, what they used to block nf-kappa-b?
could someone point me in a direction?

#6 VictorBjoerk

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Posted 09 May 2008 - 10:40 PM

this is amazing....

#7 Hedgehog

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Posted 09 May 2008 - 11:04 PM

Here is the article

http://www.pubmedcen...bmedid=18055696

Here is the Stanford lab

http://changlab.stan...ublication.html

#8 drunkfunk

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Posted 10 May 2008 - 09:50 PM

4-OHT and an ethanol vehicle?
that's all there is to the fountain of youth?

#9 niner

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Posted 17 May 2008 - 08:43 PM

4-OHT and an ethanol vehicle?
that's all there is to the fountain of youth?

That, and a 4-OHT-responsive, NFKB inhibiting element inserted in your genome.




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