Wednesday, July 26, 2006

NF Kappa B and Aging

The Life Extension Magazine has an interesting article on NF Kappa B and its relationship to aging. Previous Al Fin postings on NF Kappa B here, and here, provide more background for understanding this important transcription factor.

From the LEF Magazine article:

The ubiquitous presence of NFkB throughout the inflammation-cancer cycle suggests that the next breakthroughs in cancer treatment will likely center on the inhibition of NFkB and its actions. As scientists learn more about NFkB and the complex systems that regulate it, they also learn more about the wide array of substances that can inhibit its dangerous actions. For example, the anti-inflammatory drug ibuprofen inhibits not only the COX-2 enzyme but also NFkB,12 and has a well-established safety record. This drug, as well as many natural inhibitors of NFkB, will therefore play an important role in controlling the inflammatory components of tumor formation and growth.

Because the NFkB factors are active in both the cancerous cells and inflammatory cells in tumors, nutrients or drugs that can inhibit NFkB show tremendous promise as anti-cancer or cancer-preventive agents.8 Scientists believe that the combination of NFkB inhibition with drugs or cytokines that induce cancer cell death has great promise in fighting cancer.13

Because the NFkB system is also involved in producing healthy immune responses, there are concerns about its long-term inhibition. While NFkB seems to be most profoundly involved in cancer at the stages of promotion and progression,8,14 it may be possible to use inhibitors for relatively short periods. Another potential use for such inhibitors would be in combination with chemotherapy or radiation treatments, as a means of controlling the associated inflammation and enhancing the effects of those treatments.8

....Herbs and spices from around the world have long been sought for their pleasing flavors and healing qualities. Even today, these plant extracts are valued worldwide for promoting health and fighting disease. Scientists are discovering that many of these natural agents act through the universal mechanism of inhibiting the over-expression of NFkB.

Curcumin is a compound found in a number of South Asian spices, most prominently in turmeric, a component of curry seasoning.

Curcumin has well-established antioxidant and anti-inflammatory effects.35,36 The extent to which curcumin exerts these effects by inhibiting NFkB is becoming increasingly clear.37 Curcumin acts directly within the cell’s nucleus and also acts on substances that activate NFkB. For example, it binds iron and copper in brain tissue, reducing the activation of NFkB that is associated with the production of amyloid beta proteins in Alzheimer’s disease.35

Strong evidence suggests that curcumin may fight the following inflammatory diseases:

* Colitis. Dietary curcumin supplements strongly suppressed NFkB activation in a rat model of colitis,38 resulting in both decreased tissue wasting and colonic inflammation. When curcumin was given to experimental animals before the induction of colitis, there was reduced NFkB activation and less visible damage to the colon.39 This effect was accompanied by reduced activity of several enzymes involved in inflammation in the gut.
* Liver disease. The development of alcoholic liver disease, resulting in chemical hepatitis and eventually cirrhosis, has recently been associated with NFkB-mediated gene expression. When laboratory rats were fed sufficient alcohol to produce alcoholic fatty liver with liver cell inflammation and necrosis, dietary curcumin inhibited NFkB activation, preventing both the microscopic and biochemical changes associated with alcoholic liver disease.40 In an experimental model of non-alcoholic fatty liver degeneration (which induces substantial oxidative stress), investigators found that dietary curcumin significantly reduced inflammation and the release of inflammatory modulators through NFkB inhibition.41
* Chronic neurodegenerative diseases. NFkB-induced inflammation involving brain glial cells is thought to be one mechanism contributing to the formation of amyloid beta proteins, which are characteristic of Alzheimer’s and other degenerative brain diseases.42 In several recent studies, curcumin has been shown to reduce the glial cell expression of inflammatory mediators.43,44 Curcumin likewise has been shown to reduce amyloid beta formation in animal models by inhibiting NFkB.45,46
* Arthritis. Curcumin’s inhibition of NFkB reduces the degenerative changes to arthritic joints.47,48 Just this year, curcumin was shown to enhance the anti-inflammatory effects of the COX-2 inhibitor drug celecoxib.49 This is an important finding, since COX-2 inhibitors have adverse effects on the cardiovascular system. This caused scientists to propose that co-treatment with curcumin could reduce the dose of selective COX-2 inhibitors required to achieve significant relief from inflammation.
* Cancer. Curcumin has been found to suppress, retard, and even reverse cancer development at each stage of the disease.50 By inhibiting NFkB, curcumin reduced expression of proteins needed by cancer cells for proliferation (the promotion stage) and for invasion and metastasis (the progression stage).51 Curcumin also reduces cancer progression by increasing cell death in cancer cells, thereby depriving them of the “immortality” they need to survive and invade other tissues.52,53 This has allowed curcumin to be effective in highly chemotherapy-resistant cancers;54 it has also been shown to increase the effect of chemotherapy in animal models of advanced human cancer.51

....Capsaicin, the main ingredient in red pepper, has both anti-inflammatory and anti-cancer effects.81-83 Red pepper compounds have long been used to manage inflammatory joint conditions.37 Capsaicin inhibits the induction of two inflammation-provoking enzymes in stimulated macrophage immune cells.82 This effect is attributable to its inhibition of NFkB activation.83 Capsaicin also induces cell death in many cancers by modulating NFkB.81 Like curcumin, capsaicin inhibits the growth of adult T-cell leukemia cells by impairing NFkB activation.84 Capsaicin further impairs cancer progression by reducing levels of vascular endothelial growth factor, thus depriving growing cancers of nutrients.85

Clove extract (eugenol) inhibits NFkB-mediated expression of inflammatory cytokines.86,87 Like capsaicin, eugenol inhibits NFkB activation in stimulated macro-phage immune cells,87 reducing their synthesis of COX-2 and inflammatory cytokines.86 Oil of cloves has been used in dental care for centuries, and eugenol is now widely used to promote healing and prevent excessive inflammation after root canal surgery.88,89

Ginger extracts exert anti-inflammatory activity and stimulate cancer cell death by inhibiting NFkB.90-92 Ginger reduces expression of the key inflammatory enzymes COX-1 and COX-2.93 Topical application of ginger extract inhibits skin inflammation in a mouse model92 by inhibiting NFkB.91 A ginger extract was shown to enhance tumor cell death and down-regulate production of tumor invasion factors by preventing activation of NFkB.90

Basil and rosemary extracts, which contain ursolic acid, reduce cancer cell proliferation and tumor progression through NFkB inhibition.94-96 By inactivating NFkB, ursolic acid prevents initiated cells from reproducing and also triggers tumor cell death.95 This compound further down-regulates molecules that are required for tumor invasion and metastasis.96 Ursolic acid works through its effects on NFkB to induce resting macrophage immune cells, and thus to participate in tumor cell destruction in the early stages of cancer.97 Ursolic acid derivatives that inhibit NFkB have been shown to suppress pro-inflammatory enzyme expression in mouse models of inflammation.98 This effect has been associated with reduced cardiac fibrosis (scar tissue) in the heart tissue of diabetic mice.94

Garlic has now been shown to exert its anti-inflammatory and immunomodulatory effects by inhibiting NFkB.37,99 Garlic extracts lowered NFkB activity by up to 41% in human blood and kidney cells that had been exposed to an inflammation-provoking challenge, thus reducing the expression of certain cytokines.100 These effects may be linked to the observation that a garlic compound inhibits damage to endothelial cells lining blood vessels and reduces atherosclerotic changes.101 Garlic’s inhibition of NFkB leads to reduced production of chemicals that cause lipid peroxidation, and this could provide further protection from atherosclerosis.102 NFkB inhibition is credited for garlic’s ability to protect liver cells from auto-immune damage in an animal model,103 as well as induce cell death in leukemia.104

Pomegranate fruit extract protects cells against the effects of ultraviolet B radiation by inhibiting ultraviolet light-stimulated NFkB activation.105 Pomegranate fruit extract also prevented chemically induced skin cancers in mice through NFkB-mediated effects on both cancer initiation and promotion.106 Blockade of NFkB by pomegranate fruit extract has shown promise in osteoarthritis by inhibiting the production of protein-digesting enzymes and inflammatory cytokines.107 Pomegranate wine reduced the activation of NFkB in vascular endothelial cells by inflammatory mediators or biomechanical stresses,108 thus protecting against atherosclerosis.109

Scientists have discovered that by controlling our DNA, nuclear factor-kappa beta (NFkB) plays a central role in determining our health and longevity. By integrating signals of inflammation, NFkB appears to be the common link between such diverse conditions as heart disease, cancer, and arthritis.

Agents that control NFkB’s influence within the human body—such as omega-3 fatty acids, phytoestrogens, curcumin, garlic, licorice, ginger, rosemary, and pomegranate—hold great promise in fighting many diverse diseases and in promoting long and healthy lives.
More at Source.

While the LEF article over-simplifies the role of NF Kappa B, it is a helpful first look for non-scientists, at a very important transcription factor involved in cancer, inflammation, and ultimately life extension.

Curcumin, garlic, and ginger are all quite safe and proven to be helpful in several degenerative conditions of middle age and senescence. It is currently not known how much of their beneficial effects come from their effect on NFKB.

Labels: , ,

Wednesday, July 12, 2006

SENS Challenge: Debating Aubrey de Grey

There is ongoing and lively debate at Technology Review concerning the "SENS Challenge", with a prize of US $20,000 at stake. The challenge was issued a year ago, with the $20,000 prize offered to anyone who could prove that SENS was "unworthy of learned debate."

Technology Review has provided links to the entire debate (scroll down). Most of the entries failed to approach the level of serious consideration by the challenge judges, however one entry by Preston Estep was considered well enough argued to be awarded a $10,000 grant, which had nothing to do with the prize money for the challenge.

Links from other challengers are also provided on the TR SENS Challenge page, along with Aubrey de Grey's rebuttals, and the counter-rebuttals by the challengers. Finally, Preston Estep posted a strong protest to the judges' decision.

At the MPrize website, the editors correctly proclaim that SENS has withstood the challenges so far, and the $20,000 prize remains unclaimed. The $10,000 award to Estep is briefly discussed there as well.

The real debate is taking place as you read this, on the discussion forum of Technology Review, and other websites. A quick blog search query brought up a large number of news and blog reports on the decision of the judges. Start at the TR SENS Challenge page, and follow the links.

No one is staking his life that SENS is correct in every detail. That level of perfection is not necessary for SENS to have a profound positive impact on anti-aging research. It is only necessary that the SENS theories help lead to positive results, either directly or indirectly, for the theories to have been worthwhile in the long run.

There are backwaters of science that need to be shaken up from time to time. Gerontology had certainly become one of those backwaters. The entry of SENS into the arena has been like a splash of cold water to the face, and like a breath of fresh air, simultaneously.

Technology Review is to be congratulated for helping to stimulate this lively debate, and for furthering interest in this incredibly important field of study.

Labels: ,

Newer Posts Older Posts