Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 4 • September 2011

Inflammatory Exposure via Stimulants of Toll-Like
Receptors in Foods: Possible Effects on Risk of
Disease and Life Expectancy

We have written in earlier newsletters on the hypothesis,1 supported by increasing amounts of data, that exposure to inflammatory stimuli from infections and other sources (including non-infectious sources such as tissue damage2a and oxidative stress2b) contributes importantly to reducing life expectancy. As proposed by Finch and Crimmins,1 the “reduction in lifetime exposure to infectious diseases and other sources of inflammation—a cohort mechanism—has also made an important contribution to the historical decline in old-age mortality.” In a later paper,3 Crimmins and Finch explain: “It is well known that the survivors of birth cohorts with lowered early age mortality due to infections experienced lower mortality throughout adult life.” In the same paper,3 they note that “In highly infectious environments, children are exposed to high inflammation levels, which promote the process of atherosclerosis even without exposure to high-fat diets.” Surprisingly (and in support of the hypothesis that lifelong exposure to inflammation promotes atherosclerosis), they also note3 that “... Fogel showed that cardiovascular disease was twice as prevalent among older Army veterans born before 1845 vs. veterans born in the early 20th century.”

Much has been discovered on the transduction pathways responsible for inflammatory signaling. “A major family of innate immune sensors involved in the induction of inflammatory signaling in response to bacterial products [such as LPS, lipopolysaccharides], the Toll-like receptors (TLRs), has been shown to play a key role in the promotion of [insulin resistance and atherosclerosis].”4

An interesting new paper4 now reports that stimulants of Toll-like receptors TLR-2 and TLR-4 are found abundantly in certain foods (minimally processed vegetables), thus providing another and perhaps unexpected source of exposure to increased inflammation. In the new paper, the authors, explain that “stimulation of TLR2- or TLR4- signaling promotes both atherosclerosis and insulin resistance in mice.” The researchers wanted to learn whether humans might be exposed to ligands (activators) of TLR2 or TLR4.

The authors report:4 “[w]e showed recently that a variety of common foodstuffs can contain relatively high levels of stimulants of TLR2 or TLR4, and that these stimulants were likely to be bacterial lipopeptides and lipopolysaccharides (LPS), respectively. While the highest levels of TLR-stimulants were found in processed meat and dairy products, the fresh fruits and vegetables examined in the previous study tended to contain only very low or undetectable levels of these agents. Since minimally processed vegetables, which are defined as being fresh but otherwise physically altered from their original state, and certain other vegetable products such as bean sprouts and cress can contain a relatively high bacterial load relative to unprocessed vegetables, we here examined the potential of extracts of MPVs [minimally processed vegetables] and related products to stimulate TLR2 and TLR4 signaling using a recently developed quantitative bioassay.”

The MPVs they studied included samples of grated carrot, diced onion, sliced apple, mixed leaf salad, and baby spinach, each packaged under a modified atmosphere) and three classes of other vegetable products they considered to be likely to contain a high microbial load (including bean sprouts, water cress and salad cress). They found, for example, that TLR stimulants were abundant in processed (diced) onion and grated carrot, but undetectable in the whole unprocessed forms. “Stimulants of TLR2 or TLR4 were not detectable in chopped onion or carrot on the day of preparation, but tended to increase with time from 4 days onward when stored exposed to air at 5 degrees C.”4

The authors explain4 that “... certain vegetable products, such as bean sprouts and cress tend to contain a relatively high microbial load even in the absence of processing, as a result of susceptibility of these products to microbial growth ... Alternatively, for those vegetables which are otherwise resistant to microbial growth in the whole or unpeeled form (such as onion and carrot) it is possible that TLR-stimulants accumulate in these products as a result of microbial growth subsequent to the processing and storage of these products.” “This notion is consistent with the well-established principle that damage to the protective outer layers of vegetables markedly diminishes their resistance to microbial growth.”

“As humans are responsive to doses of LPS [lipolysaccharides] at least 250-fold lower than those required to elicit inflammation in mice, it is tempting to speculate that the occasional ingestion of certain MPVs could result in an oral LPS dose sufficient to promote systemic inflammatory signaling in human subjects.”4

The obvious conclusion of the report on Toll-like receptor stimulants in minimally processed vegetables is that one should use these processed veggies, such as chopped onion and diced carrots, soon after preparing them and perhaps avoid minimally processed foods of this type that are stored for extended periods of time. Of course, sterile foods, such as canned and fully cooked, avoid these problems.

Natural Products That Suppress Signaling by Toll-Like Receptors

(click on thumbnail for full sized image)
Mechanism of NF-κB action.
There are also nutrients that provide protection against inflammatory Toll-like receptor signaling. A recent paper5 reports in a study of thirty two patients with severe multiple trauma (mostly from automobile accidents) on the effects of w-3 polyunsaturated fats on inflammatory signaling in peripheral blood mononuclear cells (PBMCs) from the patients. “The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in w-3 PUFA group as compared with control group at 5th and 7th day [after initiation of w-3 PUFA supplementation].” “It was concluded that w-3 PUFA can remarkably decrease the expression of TLR2, TLR4, and some related inflammatory factors in NF-kappaB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that w-3 PUFA may suppress the excessive inflammatory response mediated by the TLRs/NF-kappaB signaling pathway.”

Another paper6 reported that plant proanthocyanidins from cranberries, tea, and grapes “... inhibit LPS interaction with TLR4/MD2, an activity that also mediates the inhibition of LPS- induced NF-kappaB activation.” (The authors explain6 that LPS binding to MD2 is a prerequisite for TLR4 signaling activity and LPS endocytosis [LPS being taken up by cells].)


1. Finch and Crimmins. Inflammatory exposure and historical changes in human life-spans. Science 305:1736-9 (2004).
2a. McDonald et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330:362-6 (2010).
2b. Gill et al. Linking oxidative stress to inflammation: Toll- like receptors. Free Radic Biol Med 48:1121-32 (2010).
3. Crimmins and Finch. Infection, inflammation, height, and longevity. Proc Natl Acad Sci USA 103(2):498-503 (2006).
4. Erridge. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food Chem Toxicol 49:1464-7 (2011).
5. Yi et al. Effect of w-3 polyunsaturated fatty acid on Toll-like receptors in patients with severe multiple trauma. J Huazhong Univ Sci Technolog Med Sci [paper in English] 31(4):504-8 (2011).
6. Delehanty et al. Binding and neutralization of lipopolysaccharides by plant proanthocyanidins. J Nat Prod 70:1718-24 (2007).

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