Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 8 • December 2012

Improved Cognition in Aged Animals

Inhibition of NFkappaB, Master Regulator of Pro-inflammatory Signaling Pathway, Delays DNA Damage-induced Cell Senescence in Mouse Model of Accelerated Aging

The evidence continues to accumulate that chronic inflammation is a major underlying factor in many age-related diseases, such as atherosclerosis, arthritis, cancer, diabetes, osteoporosis, dementia, vascular diseases, obesity, and metabolic syndrome disorders (eg., insulin resistance) and possibly in aging itself.1–4 As a result, the investigation of anti-inflammatory effects of foods, nutrients, and food constituents (phytochemicals) has intensified. This is great news for those of us who would like to live as long as possible in as good condition as possible and also provides an important alternative to the FDA-controlled pathway to medical therapies and to the part of the American medical system that has become seriously dysfunctional as a result of extensive political micromanagement fostered by vested interests.

A new study1 reports on the effects of NFkappaB inhibition in a mouse model of accelerated aging, the XFE progeroid syndrome, caused by a defect in DNA repair. As DNA repair is a major factor in aging and is known to decline with age, this is a good model to study for anti-aging treatments. NFkappaB is a transcription factor, controlling the expression of a large number of genes, that is activated by cellular damage, stress, and inflammation. The authors’ basic premise for the study was that the cellular response to damage may be the key driver to aging.1

“NFkappaB was identified as the transcription factor most associated with mammalian aging, based on patterns of gene expression.” “Furthermore, chronic activation of NFkappaB is observed in numerous age-related diseases, including muscle atrophy, multiple sclerosis, atherosclerosis, heart disease, both type 1 and 2 diabetes, osteoarthritis, dementia, osteoporosis, and cancer. However these studies do not demonstrate a causal relationship between NFkappaB activation and aging.” (several citations were provided here)

As an example of some evidence in support of NFkappaB being causal in aging processes, the authors mention a study in which the depletion of NFkappaB in the skin of transgenic mice reversed age-related gene expression and histologic changes.

The researchers studied the XFE progeroid mice because the pattern of aging in these mice shows progressive degenerative changes that correlate strongly with natural aging. The overall results of the study showed that genetic or pharmacologic inhibition of NFkappaB activation delayed the onset of numerous aging-related symptoms and pathologies. “Inhibition of IKK/NF-kappaB activity reduced cellular senescence and oxidative damage, including DNA and protein damage, revealing that cellular stress responses promote further cellular damage. Our findings strongly suggest that inhibitors of the IKK/NF-kappaB pathway may delay damage and extend healthspan in patients with accelerated aging and chronic degenerative diseases of old age.”

Part of the study1 involved examination of the activity of NFkappaB in aging wild type mice with normal DNA repair. The mice were genetically treated so that a “reporter” gene under the control of NFkappaB would indicate when NFkappaB was activated. The older wild type mice had more cells expressing the reporter than young wild type mice, indicating increased NFkappaB activity with age. Similar to natural aging, NFkappaB activity increased with age in the XPE progeroid syndrome mice. The increase in the progeroid mice was greater than the increase in the wild type mice, though, with 2.5 fold increase in kidney, 2.5 fold increase in pancreas, 1.7 fold increase in muscle, and 4-fold increase in liver as compared to the wild type mice. The researchers identified the p65 subunit of NFkappaB as the predominant subunit contributing to this increased activity.

Liver cells of progeroid mice showed “profound” cellular senescence. Inhibition of NFkappaB and reduced expression of the p65 subunit extended healthspan by “dramatically” reducing the numbers of senescent liver cells.

The authors conclude that “these studies demonstrate that spontaneous endogenous DNA damage can activate NFkappaB” and that “[c]hronic inhibition of IKK/NFkappaB activation is sufficient to delay the onset of aging symptoms and chronic aging-related diseases that arise spontaneously in DNA repair-deficient [] mice that model a human progeroid syndrome. Moreover, inhibiting NFkappaB activation reduces ROS production and oxidative damage to lipids and DNA. This demonstrates a direct causal role for NFkappaB in driving aging-related changes in response to cellular damage by promoting continued damage.”

Natural Products That Inhibit NFkappaB

We have written about NFkappaB inhibitors in previous newsletters. As interest in minimizing inflammation produced by disease-associated increased expression of NFkappaB with natural products is continuing unabated, here are a couple of 2012 papers on the subject.

In one of the new papers,5 turmeric (the yellow colored curry spice containing curcumin, curcuminoids, and other constituents) was reported to inhibit NFkappaB and NFkappaB regulated gene products as well as inducing death receptors leading to suppression of tumor cell proliferation.

The turmeric study was performed on tumor cell lines, including human myelogenous leukemia, human colon adenocarcinoma, pancreatic cancer, human breast cancer, and human multiple myeloma cells. As the authors of the paper noted, much more work has been published on curcumin, which is just one component of turmeric and a minor one at that, than on turmeric itself. They were interested in whether there were differences in the effects of curcumin and turmeric in their cell culture studies. In fact, they cited a study in which other researchers had found that curcumin-free turmeric extract inhibited DMBA-induced mammary tumorigenesis in rats, thus suggesting that other constituents of turmeric have anticancer activities.

NFkappaB is known to play an important role in the survival and proliferation of cancer cells, their resistance to chemotherapy, and bone loss associated with carcinogenesis.5 The results showed that turmeric significantly inhibited the activation of both constitutive and inducible NFkappaB exhibited in breast, pancreas, and multiple myeloma cells, among others. Turmeric also suppressed the activation of STAT3, another pro-inflammatory transcription factor contributing to the development of various types of cancer, including (as observed in this study) multiple myeloma, pancreatic, colorectal, and breast. Turmeric also inhibited the expression of some STAT3- and NFkappaB-regulated proteins, including Bcl-2 and cIAP1, two proteins associated with increased survival of cancer cells, and cyclin D1 and c-Myc, two proteins associated with cancer cell proliferation. Turmeric also potentiated the cytotoxic effects of some chemotherapeutic chemicals.

Moreover, turmeric was found by these researchers5 to be more potent in inhibiting growth of various cell lines, such as breast cancer, than was curcumin. Turmeric is very inexpensive and has been used extensively and in large quantities as a cooking spice for thousands of years. The yellow color of curry is due to the contained turmeric. Because of its strong flavor, we take most of our supplemental turmeric in capsules.

A Natural Form of Boswellic Acid Inhibits NF-kappaB

Another natural NFkappaB inhibitor was tested for whether itcould affect the development of atherosclerosis in apoE-/- mice treated with bacterial lipopolysaccharide (LPS) to mimic a systemic infection.6 This NFkappaB inhibitor, acetyl-11-keto-beta-boswellic acid (AKbetaBA), was isolated from African frankincense and purified to >99.9% purity.

As reported here,6 extracts of Boswellia oleogum resins (also called frankincense) have been used in traditional medicine as anti-inflammatory remedies and in clinical pilot trials to treat patients with rheumatoid arthritis or inflammatory bowel diseases with what were described as “promising results.”6 In the mouse study, the AKbetaBA reduced atherosclerotic lesion size and inhibited NFkappaB in atherosclerotic lesions of the LPS-challenged ApoE-/- mice. It also inhibited plasma levels of prothrombotic and proinflammatory factors in the LPS treated ApoE-/- mice, but had no effect on plasma levels of triglycerides or cholesterol or on plasma levels of autoantibodies against oxidized LDL or cytokines produced by lymphocytes in the blood, liver, and spleen of the animals.

The authors6 conclude that “herbal therapies and plant resins from species of the Boswellia family might represent an alternative for classical medical treatments for chronic inflammatory diseases such as atherosclerosis.”


  1. Tilstra et al. NFkappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest 122(7):2601-12 (2012).
  2. Chung et al. Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Res Rev 8:18-30 (2009).
  3. Tilstra et al. NFkappaB in aging and disease. Aging Dis 2(6):449-65 (2011).
  4. Franceschi et al. Inflamaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92-105 (2007).
  5. Kim et al. Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-kappaB and NF-kappaB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitizaation, and suppressed osteoclastogenesis [which cause bone resorption]. Mol Nutr Food Res 56:454-65 (2012).
  6. Cuaz-Perolin et al. Antiinflammatory and antiatherogenic effects of the NFkappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged apoE-/- mice. Arterioscler Thromb Vasc Biol 28:272-7 (2008).

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