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NF-kappaB, a critical key to life extension?


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#1 VinceG

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Posted 26 October 2008 - 10:08 PM


Emerging research is increasingly pointing to the role of the nuclear cell signaling factor NF-kB in maintaining health and even to organ renewal. A host of very-recent studies point to the crucial role of NF-kB inhibition for enabling apoptosis of both cancer and arthritic cells. Apparently, both cancers and serious inflammation shut down the apoptosis mechanisms that could enable seriously impacted cells to clear themselves out of existence. Inhibition of NF-kB allows the apoptosis mechanisms to work and the affected tissues to heal. For example, see
http://news.bio-medi...3921-1/ <br />The researchers here speculate that NF-kB inhibition could be useful for curing or reducing the impact of arthritis. Other researchers say the same with respect to cancers.

Even more interesting is a recent seminal study that shows that NF-kB is a master regulator of a programmed aging process. See http://genesdev.cshl...ract/21/24/3244. The study indicates that in multiple mammalian tissues (including skin fibroblasts, kidney, cortex, kidney medulla, abdominal muscle, skeletal muscle, and brain), aging involves continuing changes in expression of hundreds of genes. And, further, NF-kB signaling appears to be a major regulator of gene expression related to the aging progress. In fact, by inhibiting NF-kB cell signaling the researchers were able to cause the epidermal tissue of old mice to revert to the state of very young mouse tissue, both in observable characteristics and in genetic expression profile.

Finally and yet even more exciting to me, pouring over the research literature day and night in the last two days, I have discovered that 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.

I have written this up in more detail in my Anti-aging Firewalls paper yesterday by writing new sections featuring a 13th theory of aging - Programmed Genetic Changes. At http://www.vincegiul...ngfirewalls.htm. There are two sections to look at, one describing the theory, the other the firewall regimen. I am continuing to delve into this area and hope to have more to report soon.

#2 100YearsToGo

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Posted 26 October 2008 - 11:18 PM

Emerging research is increasingly pointing to the role of the nuclear cell signaling factor NF-kB in maintaining health and even to organ renewal. A host of very-recent studies point to the crucial role of NF-kB inhibition for enabling apoptosis of both cancer and arthritic cells. Apparently, both cancers and serious inflammation shut down the apoptosis mechanisms that could enable seriously impacted cells to clear themselves out of existence. Inhibition of NF-kB allows the apoptosis mechanisms to work and the affected tissues to heal. For example, see
http://news.bio-medi...13921-1/ <br />The researchers here speculate that NF-kB inhibition could be useful for curing or reducing the impact of arthritis. Other researchers say the same with respect to cancers.

Even more interesting is a recent seminal study that shows that NF-kB is a master regulator of a programmed aging process. See http://genesdev.cshl...ract/21/24/3244. The study indicates that in multiple mammalian tissues (including skin fibroblasts, kidney, cortex, kidney medulla, abdominal muscle, skeletal muscle, and brain), aging involves continuing changes in expression of hundreds of genes. And, further, NF-kB signaling appears to be a major regulator of gene expression related to the aging progress. In fact, by inhibiting NF-kB cell signaling the researchers were able to cause the epidermal tissue of old mice to revert to the state of very young mouse tissue, both in observable characteristics and in genetic expression profile.

Finally and yet even more exciting to me, pouring over the research literature day and night in the last two days, I have discovered that 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.

I have written this up in more detail in my Anti-aging Firewalls paper yesterday by writing new sections featuring a 13th theory of aging - Programmed Genetic Changes. At http://www.vincegiul...ngfirewalls.htm. There are two sections to look at, one describing the theory, the other the firewall regimen. I am continuing to delve into this area and hope to have more to report soon.



Nice Vince,

The theory of aging, exclusively because of accumulated damage, is showing some accumulation of damage. Recently we saw other potential evidence of programmed aging in C. Elegans Worms controlled by the ELT-5. ELT 6 and ELT-3 transcription factors. Eating berries won't help. It appears the intelligent designer (if there is such thing) wanted us dead all along.

Edited by 100YearsToGo, 26 October 2008 - 11:22 PM.


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#3 Mind

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Posted 27 October 2008 - 12:21 AM

It still seems to be a chicken and egg scenario. Does NF-kB signaling/expression change due to a master program or because of accumulating damage. Or another way to think about it, would clearing out the damage and repairing nuclear & mito mutations bring NF-kB signaling/expression back to a youthful level. I think their is great promise in pursuing many angles.

Whatever the cause of the change in NF-kB signaling/expression with age, if we can reliably and safely inhibit it and get some rejuvenation it would be a great step forward.

#4 100YearsToGo

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Posted 27 October 2008 - 01:44 AM

It still seems to be a chicken and egg scenario. Does NF-kB signaling/expression change due to a master program or because of accumulating damage. Or another way to think about it, would clearing out the damage and repairing nuclear & mito mutations bring NF-kB signaling/expression back to a youthful level. I think their is great promise in pursuing many angles.

Whatever the cause of the change in NF-kB signaling/expression with age, if we can reliably and safely inhibit it and get some rejuvenation it would be a great step forward.



Perhaps you can not nock out NF-Kappa B completely and be safe for long.
It looks like it is involved in the response to many pathogenic signals, as it activates a variety of other genes encoding immunologically proteins.
Perhaps suppressing NF-Kappa B should be only done for a limited period. A knock out NF-Kappa B mouse would prove this but it appears it is not technically possible because it does not survive the embryo phase.


Here is a word of warning by the authors of the study:

"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."

http://www.futurepun...ves/004828.html

About the chicken and egg. If one reads the study:

"We identified all genes that changed with NF-B blockade in old skin and then tested whether any
of the induced transcriptional patterns were not observed in young skin.
To identify genes that changed upon 4-OHT addition, we carried out a two-class comparison with
SAM between old EtOH- and 4-OHT-treated samples, obtaining 276 genes (FDR < 0.05).
Unsupervised hierarchical clustering of these 276 genes across all old and young samples revealed
that the young samples were intermixed with 4-OHT-treated old samples,
indicating that NF-B blockade induced an expression pattern that was not distinct from young skin"

It is NF Kappa B that causes the gene expression to change with advancing age. And suppressing it brings it back to its young self. But you correctly pointed out that we don't know what causes the NF-Kappa B expression to increase.
It could be a program it could be damage. Exposing young tissues to extreme oxidative stress
and measuring NF-Kappa B could give an answer to this.

Anyway, where is my curcumin bottle? Nah... don't have any!

Edited by 100YearsToGo, 27 October 2008 - 02:43 AM.

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#5 100YearsToGo

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Posted 27 October 2008 - 02:14 PM

Hey where is Vince? Is he making some curcumin lotion?

We probably just need to keep NF-kappa B levels down but not totaly eliminate it. Youthfull tissues have minimum levels while old tissues are full of it. B.T.W. I was wrong on the berries keep eating them. NF-Kappa B over expression is also caused by oxidative stress (and a host of other things like allergens).

"Reactive oxygen species (ROS) were shown to be crucial intermediates in the activation because antioxidants strongly decreased NF-(kappa)B activation."

http://findarticles....is_/ai_n9044019

This is also probably why you need to keep taking your Alpha Lipoic Acid

http://www.ncbi.nlm....3?dopt=Abstract

http://grande.nal.us...p;therow=260543

Edited by 100YearsToGo, 27 October 2008 - 02:19 PM.


#6 VinceG

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Posted 27 October 2008 - 03:05 PM

It still seems to be a chicken and egg scenario. Does NF-kB signaling/expression change due to a master program or because of accumulating damage. Or another way to think about it, would clearing out the damage and repairing nuclear & mito mutations bring NF-kB signaling/expression back to a youthful level. I think their is great promise in pursuing many angles.

Whatever the cause of the change in NF-kB signaling/expression with age, if we can reliably and safely inhibit it and get some rejuvenation it would be a great step forward.



Perhaps you can not nock out NF-Kappa B completely and be safe for long.
It looks like it is involved in the response to many pathogenic signals, as it activates a variety of other genes encoding immunologically proteins.
Perhaps suppressing NF-Kappa B should be only done for a limited period. A knock out NF-Kappa B mouse would prove this but it appears it is not technically possible because it does not survive the embryo phase.


Here is a word of warning by the authors of the study:

"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."

http://www.futurepun...ves/004828.html

About the chicken and egg. If one reads the study:

"We identified all genes that changed with NF-B blockade in old skin and then tested whether any
of the induced transcriptional patterns were not observed in young skin.
To identify genes that changed upon 4-OHT addition, we carried out a two-class comparison with
SAM between old EtOH- and 4-OHT-treated samples, obtaining 276 genes (FDR < 0.05).
Unsupervised hierarchical clustering of these 276 genes across all old and young samples revealed
that the young samples were intermixed with 4-OHT-treated old samples,
indicating that NF-B blockade induced an expression pattern that was not distinct from young skin"

It is NF Kappa B that causes the gene expression to change with advancing age. And suppressing it brings it back to its young self. But you correctly pointed out that we don't know what causes the NF-Kappa B expression to increase.
It could be a program it could be damage. Exposing young tissues to extreme oxidative stress
and measuring NF-Kappa B could give an answer to this.

Anyway, where is my curcumin bottle? Nah... don't have any!

With respect to rejuvinating effects of NF-kappaB inhibition being long lasting: I think the Adler/Chang analysis and result of being able to return skin cells on old mice back to an youthful phenotype and genetic expression profile via NF-kappaB inhibition is of a breakthrough nature. On the other hand, something else might come into play if the experiment were tried on humans even though the genes involved may be identical. Mice and other members of murine species have very long telomeres. Cell senescence in aged mice is thought to come about as a result of mitochondrial signaling, not telomere shortening. I conjecture that the transformation of tissues to a younger pheotype via Nf-kappaB observed by Adler et al does not affect cell telomere lengths. If this is so, then such transformation applied to tissues of old folks like me would possibly result in young-looking tissues with relatively short telomeres. This means the tissues could be subject to rapid subsequent aging as telomere-related cell senescence sets in, and could be vulnerable to neoplastic transformation. It might be that combining NF-kappaB inhibition with telomerase activation could permanantly reset the tissues to a youger state. At that point the NF-kappaB inhibition could be stopped or let up in order to allow tht substance to exercise whatever positive evolutionary roles it has. Normal aging would start again. This is all cojecture now, but wonderful grist for future research. What an exciting time this is! By the way, as I research the supplements in my anti-aging firewalls regimen, I have this morning added two more to the list of NF-kappaB inhibitors: DHEA and glusocosamine. This brings the number of inhibitors on the list up to thirty-two, and I am still counting. What a coincidence that almost all those substnces put on the list for other anti-aging reasons turn out to be NF-kappaB inhibitors. Or is it coincidence? Vince

#7 VinceG

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Posted 27 October 2008 - 03:25 PM

Hey where is Vince? Is he making some curcumin lotion?

My friends keep telling me I should be, but alas I am just an aged research scholar, studying like crazy to keep young and now starting to share what I am learning.

We probably just need to keep NF-kappa B levels down but not totaly eliminate it. Youthfull tissues have minimum levels while old tissues are full of it. B.T.W. I was wrong on the berries keep eating them. NF-Kappa B over expression is also caused by oxidative stress (and a host of other things like allergens).

Yep - I fill the bottom of my cereal bowl with blueberries every morning. And yeah, NF-Kappa B more fits the profile of Darth Vader than Princess Leah does. And me, it seems I am auditioning for the Obe-Wan-Kanobi role.

"Reactive oxygen species (ROS) were shown to be crucial intermediates in the activation because antioxidants strongly decreased NF-(kappa)B activation."

The recent work on NF-kappa-B fits in very nicely with the oxidative damage, the inflammation and the tissue glycation theories of aging.


http://findarticles....is_/ai_n9044019

This is also probably why you need to keep taking your Alpha Lipoic Acid

Absolutely true, and I argue another thirty-one supplements on the anti-aging firewalls list. These all work through somewhat different channels and we can't rely on just one or two to do the job.
http://www.ncbi.nlm....3?dopt=Abstract

http://grande.nal.us...p;therow=260543



#8 aikikai

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Posted 27 October 2008 - 03:43 PM

What is SENS stand-point regarding NF-kappa? I have read de Greys books and texts, but nothing of importance is mentioned regarding NF-kappa.
I am not a strong believer in the damage theory causing the aging, as it seems that extremely healthy (antioxidant users) people doesn't seem to get much older or have a much younger appearance.

Edited by aikikai, 27 October 2008 - 03:46 PM.


#9 100YearsToGo

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Posted 27 October 2008 - 05:02 PM

With respect to rejuvinating effects of NF-kappaB inhibition being long lasting: I think the Adler/Chang analysis and result of being able to return skin cells on old mice back to an youthful phenotype and genetic expression profile via NF-kappaB inhibition is of a breakthrough nature. On the other hand, something else might come into play if the experiment were tried on humans even though the genes involved may be identical. Mice and other members of murine species have very long telomeres. Cell senescence in aged mice is thought to come about as a result of mitochondrial signaling, not telomere shortening. I conjecture that the transformation of tissues to a younger pheotype via Nf-kappaB observed by Adler et al does not affect cell telomere lengths. If this is so, then such transformation applied to tissues of old folks like me would possibly result in young-looking tissues with relatively short telomeres. This means the tissues could be subject to rapid subsequent aging as telomere-related cell senescence sets in, and could be vulnerable to neoplastic transformation. It might be that combining NF-kappaB inhibition with telomerase activation could permanantly reset the tissues to a youger state. At that point the NF-kappaB inhibition could be stopped or let up in order to allow tht substance to exercise whatever positive evolutionary roles it has. Normal aging would start again. This is all cojecture now, but wonderful grist for future research. What an exciting time this is! By the way, as I research the supplements in my anti-aging firewalls regimen, I have this morning added two more to the list of NF-kappaB inhibitors: DHEA and glusocosamine. This brings the number of inhibitors on the list up to thirty-two, and I am still counting. What a coincidence that almost all those substnces put on the list for other anti-aging reasons turn out to be NF-kappaB inhibitors. Or is it coincidence? Vince



There appears to be a relationship between NF-Kappa B and telomerase activation. The Tert sub unit is essential for telomerase activation in mice. (A Tert nock out mouse did not produce telomerase). NF-Kappa B regulates transcription of Tert. Houston we have a problem?

http://www.jbc.org/c...ct/275/47/36671

#10 Mind

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Posted 27 October 2008 - 05:39 PM

The recent work on NF-kappa-B fits in very nicely with the oxidative damage, the inflammation and the tissue glycation theories of aging.


Just a random thought that popped into my head. Has anyone considered that damage is being mistaken for the "aging program" (in humans anyway). Damage accumulation (including mtDNA and nuclear DNA mutations) begins from day one. The damage accumulates up until a point (around or shortly after puberty) where different gene regulation and cell maintenance takes over to protect the body from further decay. Instead of growth (which would only exacerbate the rate of damage accumulation and lead to a quicker death) cell and organ systems switch over to maintenance which leads to a slower deterioration over time. Maybe NF-kappa-B is just one of the first or master gene regulatory systems (or one of the most sensitive) to "feel" the effects and react to damage.

I don't know if this fits well into evolutionary theory of aging, like I said it just popped into my head. Also there is the quandary of apparently ageless animals. I wonder what happens to their NF-kappa-B system (or analogue).

#11 100YearsToGo

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Posted 27 October 2008 - 09:14 PM

The recent work on NF-kappa-B fits in very nicely with the oxidative damage, the inflammation and the tissue glycation theories of aging.


Just a random thought that popped into my head. Has anyone considered that damage is being mistaken for the "aging program" (in humans anyway). Damage accumulation (including mtDNA and nuclear DNA mutations) begins from day one. The damage accumulates up until a point (around or shortly after puberty) where different gene regulation and cell maintenance takes over to protect the body from further decay. Instead of growth (which would only exacerbate the rate of damage accumulation and lead to a quicker death) cell and organ systems switch over to maintenance which leads to a slower deterioration over time. Maybe NF-kappa-B is just one of the first or master gene regulatory systems (or one of the most sensitive) to "feel" the effects and react to damage.

I don't know if this fits well into evolutionary theory of aging, like I said it just popped into my head. Also there is the quandary of apparently ageless animals. I wonder what happens to their NF-kappa-B system (or analogue).


The body and or the program gets damaged causing aging? As you said it probably doesn't fit well with the evolutionary theory of aging. Why would the tortoise live longer if it is subjected to the same damages that we suffer? It is almost certainly because evolution has given it a better way (program) to respond to those damages. In that sense we have a "bad" program. The question if there is a subroutine in our program that kills us by aging us, is relevant, because we could take it out. If the whole program is just badly designed, because for instance it does not replace parts that gets damaged fast enough, or good enough, then we have a bigger problem. Rewriting the whole thing is more difficult than taking a subroutine, a la NF-Kappa-B, out.

Yes I know..totally off topic. But you started it :)

#12 bkaz

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Posted 28 October 2008 - 08:16 AM

Hello Vincent, great ANTI-AGING FIREWALLS website!

I have a suggestion on overall evolutionary explanation of ageing, interested in your opinion.
It seems that body/evolution can repair/ dispose of practically every kind of damage, but the cost/benefit changes as the scale gets bigger:

- damaged proteins/organelles recycling by lysomes & such, probably upregulated by CR / mimetics,
- damaged cells' apoptisis & replacement by stem cells, when lysosomal recycling becomes less metabolically efficient than cellular recycling,
- damaged body disposal (death) & replacement by offspring, if cellular recycling becomes less metabolically efficient than "body" recycling.

This interpretation means that aging & death, of either cells or bodies, is not inevitable. Rather, as the damage accumulates, there comes a point when cellular/organismal reproduction is simply less expensive, from evolutionary point of view, than repairing them. In the same way that you can maintain an old car forever, but at some point it becomes more expensive that manufacturing a new one. This explains a longer life span in species with more expensive reproduction / maturation process: longer growth for larger animal (whales & elephants), "expensive" shell in turtles, long learning in humans.
Of course, proper learning gets ever longer, & the food costs nothing now, but evolution doesn't know yet, so we still age & die.
So, I agree with you. Theoretically, we can cure ageing simply by upregulating repair/replacement mechanisms we already have, - we don't have to worry about metabolic expense anymore. Blocking TN-kB seems to be a very general way to upregulate apoptosis, thanks for pointing it out.
BTW, I see you're big on carnosine, you don't think Beta-Alanine works as well?
Boris.

#13 VinceG

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Posted 29 October 2008 - 08:01 PM

With respect to rejuvinating effects of NF-kappaB inhibition being long lasting: I think the Adler/Chang analysis and result of being able to return skin cells on old mice back to an youthful phenotype and genetic expression profile via NF-kappaB inhibition is of a breakthrough nature. On the other hand, something else might come into play if the experiment were tried on humans even though the genes involved may be identical. Mice and other members of murine species have very long telomeres. Cell senescence in aged mice is thought to come about as a result of mitochondrial signaling, not telomere shortening. I conjecture that the transformation of tissues to a younger pheotype via Nf-kappaB observed by Adler et al does not affect cell telomere lengths. If this is so, then such transformation applied to tissues of old folks like me would possibly result in young-looking tissues with relatively short telomeres. This means the tissues could be subject to rapid subsequent aging as telomere-related cell senescence sets in, and could be vulnerable to neoplastic transformation. It might be that combining NF-kappaB inhibition with telomerase activation could permanantly reset the tissues to a youger state. At that point the NF-kappaB inhibition could be stopped or let up in order to allow tht substance to exercise whatever positive evolutionary roles it has. Normal aging would start again. This is all cojecture now, but wonderful grist for future research. What an exciting time this is! By the way, as I research the supplements in my anti-aging firewalls regimen, I have this morning added two more to the list of NF-kappaB inhibitors: DHEA and glusocosamine. This brings the number of inhibitors on the list up to thirty-two, and I am still counting. What a coincidence that almost all those substnces put on the list for other anti-aging reasons turn out to be NF-kappaB inhibitors. Or is it coincidence? Vince



There appears to be a relationship between NF-Kappa B and telomerase activation. The Tert sub unit is essential for telomerase activation in mice. (A Tert nock out mouse did not produce telomerase). NF-Kappa B regulates transcription of Tert. Houston we have a problem?

http://www.jbc.org/c...ct/275/47/36671

We indeed have a problem, not only in mice. There is also some evidence that increase in telomerase activity after low-dose radiation is due to upregulation of NF-kappa B. Seems like there is a tradoff between telomerase activation and NF-kappa B inactivation. Can't do both at once. We have known for some time that resveratrol, curcumin and several other of the NF-kappa B inhibitors also inhibit telomerase expression so this should not be too surprising. My conjecture stated previously is supported by this finding: that that the transformation of tissues to a younger pheotype via NF-kB inhibition observed by Adler et al does not (positively) affect cell telomere lengths and any such transformation would result in tissues that are old according to the telomere-length biomarker, if the original tissue was from an old animal or person. That is, the telomeres would stay as short as they started out to be or get even shorter. In any event it appears that NF-kB inhibition and telomerase activation has to take place in different time frames. That is what I am doing now: I take the 36 NF-kB in my anti-aging firewall regime mornings and evenings, and I take tje Astral Fuit telomerase promoter mid-day. At this point I am not sure whether this periodicity of separation is optimal or even sufficient.

#14 VinceG

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Posted 29 October 2008 - 08:11 PM

The recent work on NF-kappa-B fits in very nicely with the oxidative damage, the inflammation and the tissue glycation theories of aging.


Just a random thought that popped into my head. Has anyone considered that damage is being mistaken for the "aging program" (in humans anyway). Damage accumulation (including mtDNA and nuclear DNA mutations) begins from day one. The damage accumulates up until a point (around or shortly after puberty) where different gene regulation and cell maintenance takes over to protect the body from further decay. Instead of growth (which would only exacerbate the rate of damage accumulation and lead to a quicker death) cell and organ systems switch over to maintenance which leads to a slower deterioration over time. Maybe NF-kappa-B is just one of the first or master gene regulatory systems (or one of the most sensitive) to "feel" the effects and react to damage.

I don't know if this fits well into evolutionary theory of aging, like I said it just popped into my head. Also there is the quandary of apparently ageless animals. I wonder what happens to their NF-kappa-B system (or analogue).


The body and or the program gets damaged causing aging? As you said it probably doesn't fit well with the evolutionary theory of aging. Why would the tortoise live longer if it is subjected to the same damages that we suffer? It is almost certainly because evolution has given it a better way (program) to respond to those damages. In that sense we have a "bad" program. The question if there is a subroutine in our program that kills us by aging us, is relevant, because we could take it out. If the whole program is just badly designed, because for instance it does not replace parts that gets damaged fast enough, or good enough, then we have a bigger problem. Rewriting the whole thing is more difficult than taking a subroutine, a la NF-Kappa-B, out.

Yes I know..totally off topic. But you started it :)

Good discussion and I agree with you. Clearly all animals have genetic programs that interact with their environments to detemine their lifespans. Perhaps if we run the NF-Kappa-B subroutine less frequently and alternate it with running the telomerase-activation subroutine, and modify a few other subroutines such as those related to mitochondril damage, we might live a bit longer. And perhaps even live a lot longer.

#15 100YearsToGo

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Posted 29 October 2008 - 11:18 PM

We indeed have a problem, not only in mice. There is also some evidence that increase in telomerase activity after low-dose radiation is due to upregulation of NF-kappa B. Seems like there is a tradoff between telomerase activation and NF-kappa B inactivation. Can't do both at once. We have known for some time that resveratrol, curcumin and several other of the NF-kappa B inhibitors also inhibit telomerase expression so this should not be too surprising. My conjecture stated previously is supported by this finding: that that the transformation of tissues to a younger pheotype via NF-kB inhibition observed by Adler et al does not (positively) affect cell telomere lengths and any such transformation would result in tissues that are old according to the telomere-length biomarker, if the original tissue was from an old animal or person. That is, the telomeres would stay as short as they started out to be or get even shorter. In any event it appears that NF-kB inhibition and telomerase activation has to take place in different time frames. That is what I am doing now: I take the 36 NF-kB in my anti-aging firewall regime mornings and evenings, and I take tje Astral Fuit telomerase promoter mid-day. At this point I am not sure whether this periodicity of separation is optimal or even sufficient.


Maybe we should not try to inhibit NF-Kappa B. But try to normalize its activation.
We know this:

(1)NF-Kappa B seems to be permanently activitated in old
tissues and this leads to the activation of numerous genes that are associated with aging.
2) NF-Kappa is activated as part of the immune response to bacteria, Fungi, Virus
3) The body has increasing ROS activity and DNA damage as we age
4) Interestingly NF-Kappa B is activated by ROS and DNA damage

"Previous reports have indicated that antioxidants abolish NF-kappa B activation in response
to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation"

http://www.mitochond...008 SENSITIVITY

http://mutage.oxford...stract/gen056v1
http://www.ncbi.nlm....pubmed/18485515

I carefully suggest the following:

The abnormal over activation of NF-Kappa B in aged individuals is caused by ROS activity and DNA damage.
A "better" way to normalize NF-Kappa B activity would be to take supplements to fight ROS activity and DNA damage a la alpha lipoic acid.

"Just" inhibiting NF-Kappa B, would do will change gene expressions to youthfull status but will keep
the ROS overactivity and DNA damage. When you stop inhibiting NF-Kappa B you will return to your "old" self.
That is, with high ROS acivity, DNA damage and bad gene expressions.

#16 VinceG

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Posted 30 October 2008 - 06:47 PM

Hello Vincent, great ANTI-AGING FIREWALLS website!

I have a suggestion on overall evolutionary explanation of ageing, interested in your opinion.
It seems that body/evolution can repair/ dispose of practically every kind of damage, but the cost/benefit changes as the scale gets bigger:

- damaged proteins/organelles recycling by lysomes & such, probably upregulated by CR / mimetics,
- damaged cells' apoptisis & replacement by stem cells, when lysosomal recycling becomes less metabolically efficient than cellular recycling,
- damaged body disposal (death) & replacement by offspring, if cellular recycling becomes less metabolically efficient than "body" recycling.

A good simple theory. Now with a vastly complex knowledge-centered society, for societal survival it is efficient to extend the period before body recycling way past the child-rearing ages, thus the stuff us longevity folks are concerned with.

This interpretation means that aging & death, of either cells or bodies, is not inevitable. Rather, as the damage accumulates, there comes a point when cellular/organismal reproduction is simply less expensive, from evolutionary point of view, than repairing them. In the same way that you can maintain an old car forever, but at some point it becomes more expensive that manufacturing a new one. This explains a longer life span in species with more expensive reproduction / maturation process: longer growth for larger animal (whales & elephants), "expensive" shell in turtles, long learning in humans.

Of course, proper learning gets ever longer, & the food costs nothing now, but evolution doesn't know yet, so we still age & die.

Yes insofar as biological evolution goes. But cultural evolution has created longevity research and, for that matter, this forum.

So, I agree with you. Theoretically, we can cure ageing simply by upregulating repair/replacement mechanisms we already have, - we don't have to worry about metabolic expense anymore. Blocking TN-kB seems to be a very general way to upregulate apoptosis, thanks for pointing it out.

Yep, along with telomerase activation, possibly another fundemental chunk of the puzzle.

BTW, I see you're big on carnosine, you don't think Beta-Alanine works as well?

Possibly Boris. I have never looked at it, but will now.

Vince

Boris.



#17 bkaz

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Posted 31 October 2008 - 12:01 PM

So, I agree with you. Theoretically, we can cure ageing simply by upregulating repair/replacement mechanisms we already have, - we don't have to worry about metabolic expense anymore. Blocking TN-kB seems to be a very general way to upregulate apoptosis, thanks for pointing it out.

Yep, along with telomerase activation, possibly another fundemental chunk of the puzzle.

I suspect that telomerase is more of a symptom, its' expression is probably inhibited by accumulated damage. Otherwise it would be an easy, metabolically cheap fix for evolution.
Apoptosis, on the other hand, is metabolically expensive, - you have to dispose of all the junk & then replace the cell. If we reduce the amount of damage by replacing old cells, organelles, & proteins, it will probably upregulate telomerase & other mechanisms controlling stem cell division.
So, I think main pathways for rejuvenation are upregulating apoptisis, lysosomes, & chaperone proteins. The last two are the only ones that would work for neurons, & maybe heart muscles.


BTW, I see you're big on carnosine, you don't think Beta-Alanine works as well?

Possibly Boris. I have never looked at it, but will now.
Vince


Boris.

#18 VinceG

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Posted 09 December 2008 - 03:23 AM

We indeed have a problem, not only in mice. There is also some evidence that increase in telomerase activity after low-dose radiation is due to upregulation of NF-kappa B. Seems like there is a tradoff between telomerase activation and NF-kappa B inactivation. Can't do both at once. We have known for some time that resveratrol, curcumin and several other of the NF-kappa B inhibitors also inhibit telomerase expression so this should not be too surprising. My conjecture stated previously is supported by this finding: that that the transformation of tissues to a younger pheotype via NF-kB inhibition observed by Adler et al does not (positively) affect cell telomere lengths and any such transformation would result in tissues that are old according to the telomere-length biomarker, if the original tissue was from an old animal or person. That is, the telomeres would stay as short as they started out to be or get even shorter. In any event it appears that NF-kB inhibition and telomerase activation has to take place in different time frames. That is what I am doing now: I take the 36 NF-kB in my anti-aging firewall regime mornings and evenings, and I take tje Astral Fuit telomerase promoter mid-day. At this point I am not sure whether this periodicity of separation is optimal or even sufficient.


Maybe we should not try to inhibit NF-Kappa B. But try to normalize its activation.
We know this:

(1)NF-Kappa B seems to be permanently activitated in old
tissues and this leads to the activation of numerous genes that are associated with aging.
2) NF-Kappa is activated as part of the immune response to bacteria, Fungi, Virus
3) The body has increasing ROS activity and DNA damage as we age
4) Interestingly NF-Kappa B is activated by ROS and DNA damage

"Previous reports have indicated that antioxidants abolish NF-kappa B activation in response
to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation"

http://www.mitochond...008 SENSITIVITY

http://mutage.oxford...stract/gen056v1
http://www.ncbi.nlm....pubmed/18485515

I carefully suggest the following:

The abnormal over activation of NF-Kappa B in aged individuals is caused by ROS activity and DNA damage.
A "better" way to normalize NF-Kappa B activity would be to take supplements to fight ROS activity and DNA damage a la alpha lipoic acid.

"Just" inhibiting NF-Kappa B, would do will change gene expressions to youthfull status but will keep
the ROS overactivity and DNA damage. When you stop inhibiting NF-Kappa B you will return to your "old" self.
That is, with high ROS acivity, DNA damage and bad gene expressions.

Actually, it turns out that the same best antioxidants for reducing ROS overactivity and DNA damage also inhibit NF-kappa B. See my discussion of this in http://www.vincegiuliano.com/ Among the thirty six firewall substaces that are NF-kappa B inhibitors listed there can be found virtually all the most popular antioxidants. Free radicals initiate a chain of signaling that causes unbinding of NF-kappa B already in the cell cytoplasm and its traslocation into the cell's nucleus where it binds to DNA and creates all kinds of havoc. See http://www.pubmedcen...gi?artid=295415 So, antioxidants reduce the numbers of such radicals and therefore inhibit nuclear NF-kappa B.

Edit: removed multiple posts

Edited by niner, 09 December 2008 - 03:53 AM.


#19 zoolander

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Posted 09 December 2008 - 04:36 AM

Vince,

Have you thought about redox signalling in controlling NF-KB. ROS activates NF-kB

Here's a diagram I drew for my thesis

Posted Image



NAC (N-acetyl cysteine) inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. (1)
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#20 Guest_Shinigami_*

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Posted 27 December 2008 - 01:42 PM

It still seems to be a chicken and egg scenario. Does NF-kB signaling/expression change due to a master program or because of accumulating damage. Or another way to think about it, would clearing out the damage and repairing nuclear & mito mutations bring NF-kB signaling/expression back to a youthful level. I think their is great promise in pursuing many angles.

From what I've read, I don't think there is a "master program" that changes the expression of NF-kB. NF-kB seems to be intended to be activated for a short time (8 hours to 3 days) in order to clear infectious agents or aid in tissue remodelling for injured tissue. It seems that in a number of pathologies (I'm thinking of COPD in particular) the NF-kB pathway is erroneously activated much longer than intended, either because the immune system fails to clear the infection entirely, or the tissue is damaged to a point that it becomes difficult to restore it to a normal state.

Note also that the actual function of NF-kB may well depend on how damaged the tissue is: if the NF-kB responds to a low level of oxidative stress, it activates the immune system to eliminate the source of the problem before returning to a normal state, if the NF-kB reponds to a high level of oxidative stress, it may invoke the death pathway (the source of the problem may be the incorrect functioning of the cell itself (due to excessive accumulated damage (like cancer-cells?)), and NF-kB thus invokes an apoptosis response).

(The correctness of this information depends on whether my memory and brain have correctly inferred conclusions from the numerous abstracts/papers I have read on this complex subject.)

Perhaps you can not nock out NF-Kappa B completely and be safe for long.
It looks like it is involved in the response to many pathogenic signals, as it activates a variety of other genes encoding immunologically proteins.
Perhaps suppressing NF-Kappa B should be only done for a limited period.

I think you are very correct on this. Maybe we should only try to inhibit NF-kB when the pathway goes out of control due to positive self-feedback.

Also there is the quandary of apparently ageless animals. I wonder what happens to their NF-kappa-B system (or analogue).

This is a very interesting remark. It seems NF-kB is more than a subprogram, but rather a major regulator of which the actual effect depends on quite a few other variables. Maybe the NF-kB pathway in these animals has a more intelligent design which enables them to conquer cancer more effectively and recover more effectively from certain types of tissue damage? Maybe the designer of these animals was smart enough to eliminate one potential cause of tissue damage thereby allowing him to optimise the NF-kB better for the other types of problems NF-kB is intended to respond to? I don't know much about the ageless animals, but it seems to me that tortoises and giant fish with a thick hide may be less prone to physical injury than quite a few non-ageless animals. This is obviously all speculation.

We indeed have a problem, not only in mice. There is also some evidence that increase in telomerase activity after low-dose radiation is due to upregulation of NF-kappa B. Seems like there is a tradoff between telomerase activation and NF-kappa B inactivation. Can't do both at once. We have known for some time that resveratrol, curcumin and several other of the NF-kappa B inhibitors also inhibit telomerase expression so this should not be too surprising. My conjecture stated previously is supported by this finding: that that the transformation of tissues to a younger pheotype via NF-kB inhibition observed by Adler et al does not (positively) affect cell telomere lengths and any such transformation would result in tissues that are old according to the telomere-length biomarker, if the original tissue was from an old animal or person. That is, the telomeres would stay as short as they started out to be or get even shorter. In any event it appears that NF-kB inhibition and telomerase activation has to take place in different time frames. That is what I am doing now: I take the 36 NF-kB in my anti-aging firewall regime mornings and evenings, and I take tje Astral Fuit telomerase promoter mid-day. At this point I am not sure whether this periodicity of separation is optimal or even sufficient.


Maybe we should not try to inhibit NF-Kappa B. But try to normalize its activation.
We know this:

(1)NF-Kappa B seems to be permanently activitated in old
tissues and this leads to the activation of numerous genes that are associated with aging.
2) NF-Kappa is activated as part of the immune response to bacteria, Fungi, Virus
3) The body has increasing ROS activity and DNA damage as we age
4) Interestingly NF-Kappa B is activated by ROS and DNA damage

"Previous reports have indicated that antioxidants abolish NF-kappa B activation in response
to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation"

http://www.mitochond...008 SENSITIVITY

http://mutage.oxford...stract/gen056v1
http://www.ncbi.nlm....pubmed/18485515

I carefully suggest the following:

The abnormal over activation of NF-Kappa B in aged individuals is caused by ROS activity and DNA damage.
A "better" way to normalize NF-Kappa B activity would be to take supplements to fight ROS activity and DNA damage a la alpha lipoic acid.

"Just" inhibiting NF-Kappa B, would do will change gene expressions to youthfull status but will keep
the ROS overactivity and DNA damage. When you stop inhibiting NF-Kappa B you will return to your "old" self.
That is, with high ROS acivity, DNA damage and bad gene expressions.

I carefully totally agree with your suggestion. Maybe the right way to fight ROS is to upregulate the prior phases of response to oxidative stress, for example by improving the Phase II response (Nrf2, ...), or even better, improving the Phase I response (GSH, ...). I would like to grab this opportunity to shamelessly advertise the related thread: Posted ImageThe Nrf2 - NF-kappaB interest thread.

Actually, it turns out that the same best antioxidants for reducing ROS overactivity and DNA damage also inhibit NF-kappa B. See my discussion of this in http://www.vincegiuliano.com/ Among the thirty six firewall substaces that are NF-kappa B inhibitors listed there can be found virtually all the most popular antioxidants. Free radicals initiate a chain of signaling that causes unbinding of NF-kappa B already in the cell cytoplasm and its traslocation into the cell's nucleus where it binds to DNA and creates all kinds of havoc. See http://www.pubmedcen...gi?artid=295415 So, antioxidants reduce the numbers of such radicals and therefore inhibit nuclear NF-kappa B.

This may also indicate a relation with the phase II reponse (see the Nrf2-NF-kB interest thread).

#21 100YearsToGo

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Posted 28 December 2008 - 01:30 AM

It still seems to be a chicken and egg scenario. Does NF-kB signaling/expression change due to a master program or because of accumulating damage. Or another way to think about it, would clearing out the damage and repairing nuclear & mito mutations bring NF-kB signaling/expression back to a youthful level. I think their is great promise in pursuing many angles.

From what I've read, I don't think there is a "master program" that changes the expression of NF-kB. NF-kB seems to be intended to be activated for a short time (8 hours to 3 days) in order to clear infectious agents or aid in tissue remodelling for injured tissue. It seems that in a number of pathologies (I'm thinking of COPD in particular) the NF-kB pathway is erroneously activated much longer than intended, either because the immune system fails to clear the infection entirely, or the tissue is damaged to a point that it becomes difficult to restore it to a normal state.

Note also that the actual function of NF-kB may well depend on how damaged the tissue is: if the NF-kB responds to a low level of oxidative stress, it activates the immune system to eliminate the source of the problem before returning to a normal state, if the NF-kB reponds to a high level of oxidative stress, it may invoke the death pathway (the source of the problem may be the incorrect functioning of the cell itself (due to excessive accumulated damage (like cancer-cells?)), and NF-kB thus invokes an apoptosis response).

(The correctness of this information depends on whether my memory and brain have correctly inferred conclusions from the numerous abstracts/papers I have read on this complex subject.)

Perhaps you can not nock out NF-Kappa B completely and be safe for long.
It looks like it is involved in the response to many pathogenic signals, as it activates a variety of other genes encoding immunologically proteins.
Perhaps suppressing NF-Kappa B should be only done for a limited period.

I think you are very correct on this. Maybe we should only try to inhibit NF-kB when the pathway goes out of control due to positive self-feedback.

Also there is the quandary of apparently ageless animals. I wonder what happens to their NF-kappa-B system (or analogue).

This is a very interesting remark. It seems NF-kB is more than a subprogram, but rather a major regulator of which the actual effect depends on quite a few other variables. Maybe the NF-kB pathway in these animals has a more intelligent design which enables them to conquer cancer more effectively and recover more effectively from certain types of tissue damage? Maybe the designer of these animals was smart enough to eliminate one potential cause of tissue damage thereby allowing him to optimise the NF-kB better for the other types of problems NF-kB is intended to respond to? I don't know much about the ageless animals, but it seems to me that tortoises and giant fish with a thick hide may be less prone to physical injury than quite a few non-ageless animals. This is obviously all speculation.

We indeed have a problem, not only in mice. There is also some evidence that increase in telomerase activity after low-dose radiation is due to upregulation of NF-kappa B. Seems like there is a tradoff between telomerase activation and NF-kappa B inactivation. Can't do both at once. We have known for some time that resveratrol, curcumin and several other of the NF-kappa B inhibitors also inhibit telomerase expression so this should not be too surprising. My conjecture stated previously is supported by this finding: that that the transformation of tissues to a younger pheotype via NF-kB inhibition observed by Adler et al does not (positively) affect cell telomere lengths and any such transformation would result in tissues that are old according to the telomere-length biomarker, if the original tissue was from an old animal or person. That is, the telomeres would stay as short as they started out to be or get even shorter. In any event it appears that NF-kB inhibition and telomerase activation has to take place in different time frames. That is what I am doing now: I take the 36 NF-kB in my anti-aging firewall regime mornings and evenings, and I take tje Astral Fuit telomerase promoter mid-day. At this point I am not sure whether this periodicity of separation is optimal or even sufficient.


Maybe we should not try to inhibit NF-Kappa B. But try to normalize its activation.
We know this:

(1)NF-Kappa B seems to be permanently activitated in old
tissues and this leads to the activation of numerous genes that are associated with aging.
2) NF-Kappa is activated as part of the immune response to bacteria, Fungi, Virus
3) The body has increasing ROS activity and DNA damage as we age
4) Interestingly NF-Kappa B is activated by ROS and DNA damage

"Previous reports have indicated that antioxidants abolish NF-kappa B activation in response
to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation"

http://www.mitochond...008 SENSITIVITY

http://mutage.oxford...stract/gen056v1
http://www.ncbi.nlm....pubmed/18485515

I carefully suggest the following:

The abnormal over activation of NF-Kappa B in aged individuals is caused by ROS activity and DNA damage.
A "better" way to normalize NF-Kappa B activity would be to take supplements to fight ROS activity and DNA damage a la alpha lipoic acid.

"Just" inhibiting NF-Kappa B, would do will change gene expressions to youthfull status but will keep
the ROS overactivity and DNA damage. When you stop inhibiting NF-Kappa B you will return to your "old" self.
That is, with high ROS acivity, DNA damage and bad gene expressions.

I carefully totally agree with your suggestion. Maybe the right way to fight ROS is to upregulate the prior phases of response to oxidative stress, for example by improving the Phase II response (Nrf2, ...), or even better, improving the Phase I response (GSH, ...). I would like to grab this opportunity to shamelessly advertise the related thread: Posted Image[url="http://"http://www.imminst.org/forum/index.php?showtopic=26556""]The Nrf2 - NF-kappaB interest thread[/url].

Actually, it turns out that the same best antioxidants for reducing ROS overactivity and DNA damage also inhibit NF-kappa B. See my discussion of this in http://www.vincegiuliano.com/ Among the thirty six firewall substaces that are NF-kappa B inhibitors listed there can be found virtually all the most popular antioxidants. Free radicals initiate a chain of signaling that causes unbinding of NF-kappa B already in the cell cytoplasm and its traslocation into the cell's nucleus where it binds to DNA and creates all kinds of havoc. See http://www.pubmedcen...gi?artid=295415 So, antioxidants reduce the numbers of such radicals and therefore inhibit nuclear NF-kappa B.

This may also indicate a relation with the phase II reponse (see the Nrf2-NF-kB interest thread).


Thanks for your input. I have returned the courtesy in your Posted Image[url="http://"http://www.imminst.org/forum/index.php?showtopic=26556""]The Nrf2 - NF-kappaB interest thread[/url].
B.T.W nice name, Shinigami = the Japanese God of Death. Are you on the right forum? ha ha.

#22 sthira

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Posted 06 June 2016 - 08:40 AM

VinceG from anti-aging firewalls posted this thread more than 7 years ago back in 2008.

He wrote that the following substances may be supplemented to help block expression of NF-kB or limit 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.

So I'm wondering what we've learned since then? Is Vince is still around today or here on Longecity, did he take these substances, did they block this pathway, did they slow aging, what's up? Any progress here in >7years time?
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#23 normalizing

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Posted 06 June 2016 - 08:16 PM

good bump. but checking vince last visit status, its march of 2015 and judging by his old man picture avatar, he might have passed away


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#24 joelcairo

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Posted 06 June 2016 - 08:22 PM

Assuming VinceG is Vince Giuliano, he's alive and well and still posting at the Anti-Aging Firewalls blog.


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#25 pamojja

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Posted 06 June 2016 - 08:38 PM

A recent interview here:

 

https://selfhacked.c...rative-disease/

 

http://www.anti-agingfirewalls.com/


Edited by pamojja, 06 June 2016 - 08:52 PM.


#26 DareDevil

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Posted 11 March 2017 - 07:59 AM

Refreshing our cells and repairing damage is key to having young tissues, as well as looking young again. Telomere lengthening is key to staying young longer, by breaking the cell replication barrier. Doing alternating treatment between DNA repair/inflammation reduction using NF-kB inhibitors and in a separate treatment taking telomerase activation drugs and telomere lengthening peptides, we may reach both highly sought results of age reversal and life extension.

 

"Agents that inhibit protein kinases, protein phosphatases, proteasomes, ubiquitnation, acetylation, methylation, and DNA binding steps have been identified as NF-κB inhibitors." (paraphrased)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955987

 

 

Multiple pathways to inhibiting Nuclear Factor-kappaB activation:

Attached File  NF-kB Activation.jpg   120.9KB   0 downloads

 
 

List of small molecules acting as inhibitors of NF-kB pathway:

* not to be taken with Epitalon or teleromase activators

 

https://www.ncbi.nlm...port=objectonly

 
 
Which of these molecules are most effective at reducing ROS and DNA damage as well as inhibiting NF-kB as well as safe and affordable supplements? A short-list is needed.
 
Cheers,
 
DareDevil

Edited by DareDevil, 11 March 2017 - 08:34 AM.


#27 DareDevil

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Posted 11 March 2017 - 10:16 AM

An illustration of NF-κB and Aging:

 

Attached File  NF-κB and Aging.jpg   83.12KB   0 downloads

 

The following company displays a list of NF-kB inhibitors:

 

http://www.invivogen...tion-inhibitors

 

Suggestions as to effective combinations and dosage are welcome!

 

DareDevil


Edited by DareDevil, 11 March 2017 - 10:35 AM.


#28 MikeDC

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Posted 11 March 2017 - 03:05 PM

Sirt1 regulate NF-kB. Most of the NF-kB inhibitors are sirt1 activators.
Niagen (Nicotinamide riboside) is the most effective sirt1 activator
And life extension.

Everything related to aging traces back to NAD+.
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#29 zorba990

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Posted 12 March 2017 - 08:47 PM

Vitamin c inhibits NF-kB

http://www.jimmunol....ent/165/12/7180


and reactivation of the gene that allows us to produce it again will not only extend life, but also eliminate the high(er) blood sugar problem that long term calorie restriction is showing.

https://www.lewrockw...we-live-longer/
"Mammals who make their own vitamin C can live 8-10 times beyond their age of physical maturity. Mammals without this ability have a difficult time reaching 3-4 times. Researchers believe the reinstallation of the gulonolactone oxidase enzyme in humans would extend the lifespan to hundreds of years. "

I have a feeling I will have to self fund such an idea as there seems to be little interest...

Edited by zorba990, 12 March 2017 - 08:57 PM.

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#30 MikeDC

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Posted 12 March 2017 - 10:14 PM

High dose vitamin C actually shortens life. Too much antioxydent will prevent natural response to stress such as exercise. So the longevity genes such as sirt1 will be depressed.
http://mobile.nutrai...ter-Animal-data
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