The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No.
3 • August 2006
Interleukin-1beta, a Mediator of Inflammation and Possibly Aging: Protection by Cholinesterase Inhibitors, EPA, and Pomegranate Fruit Extract
Increased expression of the proinflammatory cytokine IL-1beta (interleukin-1beta), as occurs in the aged brain, has been associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. It has been reported that patients with an inherited defect in a certain gene (NALP3) are prone to secrete excess quantities of IL-1beta and IL-18 (another proinflammatory cytokine) and suffer from systemic inflammatory diseases. These patients have a high circulating concentration of proinflammatory factors, including IL-6, serum amyloid A, and C-reactive protein, each of which decreases rapidly upon blockade of the IL-1 receptor1. Elevated IL-6 levels in humans are correlated with increased mortality and reflect IL-1 activity in vivo. IL-1 is released as an important part of the immune response to infection, but excessive or chronic release can cause damaging side effects. IL-lbeta also promotes angiogenesis, tumor growth, and metastasis. Moreover, “IL-1beta expression is increased, in parallel with cell damage, in experimental models of ischemia, excitotoxicity, and traumatic lesions.”
A recent paper reports that peripheral administration of the acetylcholinesterase inhibitors tacrine, rivastigmine, or neostigmine to mice significantly reduced the production of IL-1beta in the hippocampus and blood, along with the reduction of acetylcholinesterase activity. The authors suggest that this might be a mechanism whereby acetylcholinesterase inhibitors improve brain function; in particular, acetylcholine has been shown to inhibit the lipopolysaccharide (bacterial LPS)-induced production of proinflammatory cytokines in the brain, including IL-1, from macrophages and microglia. We have written before on how the benefit of increasing cholinergic function in the brain may also be mediated in the body by the acetylcholine anti-inflammatory pathway operating via the vagus nerve. On page 744 of this paper, the authors also refer to this mechanism: “[r]ecent studies show that in the periphery, cholinergic neurons of the efferent vagus nerve inhibit acute inflammation, providing a rapid, localized, and adaptive anti-inflammatory reflex system. Specifically, ACh [acetylcholine], which is secreted by the vagal efferents, inhibits LPS-induced secretion of tumor necrosis factor-alpha and IL-1beta by macrophages, as well as by microglia, through the alpha7 unit of the nicotinic receptor that is expressed by these cells.” It is interesting to note that the cholinesterase inhibitor galantamine also activates the alpha7 nicotinic receptors.
The cholinesterase inhibitors tested in this study included neostigmine, which does not cross the blood-brain barrier and, therefore, cannot have a direct effect on brain inflammatory activity. However, neostigmine completely blocked the production of IL-1beta in the hippocampus, “suggesting that the peripheral effect of cholinesterase inhibitors contributes to the prevention of IL-1beta overproduction within the brain.” [Emphasis added] These peripheral effects would provide protection to the whole body against damaging inflammation due to excess IL-1beta activity.
In addition to cholinesterase inhibitors, there are two other supplements that provide protection against the effects of IL-1beta that we’d like to mention here: eicosapentaenoic acid (EPA) (in rat brain) and pomegranate fruit extract (in human cartilage cells—chondrocytes—in vitro).
- Dinarello. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83(Suppl):447S-455S (2006).
- Pollak et al. Acetylcholinesterase inhibitors reduce brain and blood interleukin-1beta production. Ann Neurol 57:741-5 (2005).
- Martin et al. Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J Biol Chem 277(37):34239-46 (2002).
- Ahmed et al. Punica granatum L. extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. Nutrition 135:2096-102 (2005). “Taken together, these novel results indicate that PFE [pomegranate fruit extract] or compounds derived from it may inhibit cartilage degradation in OA [osteoarthritis] and may also be a useful nutritive supplement for maintaining joint integrity and function.”