The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
2 • March 2008
Motif Maps from Microarrays Reveal Enforcement of
Aging by Continual NF-kappaB Activity
A group of scientists has published a paper on age-dependent gene expression in humans and mice. On p. 3244, the authors say, “. . . we identify the transcription factor NF-kappaB as a major regulator of gene expression programs associated with mammalian aging. . . . Here we provide evidence for widespread involvement of NF-kappaB in mammalian aging and demonstrate a reversal of many features of aging upon acute blockade of NF-kappaB in aged skin.”
We have written about NF-kappaB
before [Life Extension News, December 2006, published in Life Enhancement, February 2007], as it is importantly involved in the regulation of innate and adaptive immunity, inflammation, apoptosis, and (as suggested by in vitro studies) regulation of cell senescence. Excess NF-kappaB activity is also involved in the induction of muscle atrophy, insulin resistance, and neurotoxicity (as in Alzheimer’s disease). An earlier paper reported on NF-kappaB constitutive activation (always turned on) in an animal model of aging.
Since an NF-kappaB knockout mouse would suffer from embryonic lethality, the authors used a sophisticated technique to allow site-specific inducible or inhibited NF-kappaB activity in mouse skin, but not in other tissues. These animals had normal development, lifespan, and age-dependent induction of NF-kappaB activity in the skin.
They used a compound, 4-OHT (4-hydroxytamoxifen), that inhibited NF-kappaB activity. “Upon NF-kappaB blockade in old skin, expression of 225 of these 414 genes [differently expressed in old as compared to young skin] (54%) was reduced to expression levels indistinguishable from those of the young samples. . . . No gene was significantly altered by 4-OHT treatment that was not also reciprocally altered by aging (FDR<0.05 cutoff).” Markers of cell senescence (SA-beta-gal, p16INK4a) that were induced in aged skin were significantly decreased upon NF-kappaB blockade.
“Interestingly,” the authors note, “seven NF-kappaB target genes identified in this study possess homologs that extended lifespan when inactivated in C. elegans.”
As we wrote in our earlier article, there are a number of natural products that suppress NF-kappaB activity (not necessarily by the same mechanism), as reported in Reference 3, including alpha-lipoic acid, astaxanthin, capsaicin, curcumin, EGCG (found in green teas), L-ascorbic acid, alpha-tocopherol, quercetin, resveratrol, silymarin, theaflavin (found plentifully in fermented teas), aged garlic extract, apple juice, blueberry and berry mix, Ginkgo biloba extract, red wine, glucosamine sulfate, melatonin, fish oils, and others. Reference 4 also adds glutathione, aspirin, and others. Reference 5 reports a new study in which cinnamaldehyde, the major component of cinnamon, suppressed age-related inflammatory NF-kappaB activation in rats. [Suggestion: Add three teaspoons of cinnamon to a batch (one container) of LifeByChocolate™ chocolate pudding. Delicious way to get cinnamaldehyde!]
A note of caution: You do not want to inhibit NF-kappaB entirely; if you didn’t have it at all, you’d die. (Remember, the NF-kappaB was knocked out only in the mouse skin because a global knockout would have been embryonically lethal owing to the importance of NF-kappaB in development. The inflammatory activity of which NF-kappaB is an important part is also essential to proper immune activity against bacteria, viruses, and cancer cells.) The idea here is to prevent excessive and chronic activation of NF-kappaB, an important part of the increased inflammatory activity with aging. The substances we take for this and other purposes (below) have not been reported to impair immune activity, increase the risk of cancer (in fact, they generally reduce the risk), or have cytotoxic effects at the doses we use them. But this is still an experiment because there are no data in animals, let alone humans, on such complex combinations of substances.
The fly (or, perhaps, the elephant) in the ointment is that there is limited information on what is a healthy range of NF-kappaB levels, nor is there a readily available lab test that would provide NF-kappaB levels for specific knowledge of your systemic NF-kappaB status. Thus, moderation is essential. The substances that we take that moderate our NF-kappaB levels (though they have many other effects) are the following. Follow the label-recommended dosages. Alpha-lipoic acid (from AGEless™); melatonin (found in Serene Tranquility™ nighttime formulations); vitamin C [from Double C™ and Personal Radical Shield™ (PRS)]; alpha-tocopherol; curcumin (we take turmeric itself, as it contains 40% curcumin; also found in nutritional supplements); quercetin (from PRS); resveratrol (from MealMate™); fermented teas (black, pu-erh, oolong, from ShapeShifter Teas™); green tea (EGCG source, from ShapeShifter Teas™); silymarin; Ginkgo biloba; red wine; fish oils (from Omega-3 HeartFelt™); and cysteine (to increase glutathione levels; from Root Food™).
- Adler et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Devel 21:3244-57 (2007).
- Spencer et al. Constitutive activation of NF-kappaB in an animals model of aging. Int Immunol 9(10):1581-8 (1997).
- Aggarwal et al. Nuclear factor-kappaB: a holy grail in cancer prevention and therapy. Curr Signal Transduc Ther 1:25-52 (2006).
- Garg and Aggarwal. Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 16:1053-68 (2002).
- Kim et al. Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. Biogerontology 8:545-54 (2007).