I wrote about blueberries back in September 2009 in the blog entry Blueberries and health – the research case, citing 11 research citations there on their positive health effects. I have long been in the habit of eating a cupful of wild blueberries every morning together with raisin bran and walnuts. However, my mind has been concerned with more exotic longevity things reported in this blog. At the AAAS meeting I was exposed to some interesting new research relating to those little purple critters. In this post I review mostly-new research relating blueberries to cognition, neural inflammation, Alzheimer’s disease, cancer, and cardiovascular health.
Blueberries and microglial activation
I have discussed emerging knowledge about the role of activated microglia in blog entries relating to inflammatory nervous system disorders including Spinal cord injury pain, and New views of Alzheimer’s disease and new approaches to treating it. “Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS)(ref).” Microglia can become activated due to physical injury, toxic assault, the presence of pathogens, or disease conditions such as Alzheimer’s disease. When activated, microglia release pro-inflammatory cytokine signaling molecules like TNF-alpha, NO, IL-1 and IL-6, and this process can excite neurons to further excite the microglia. The loop of mutual excitement can feed on itself contributing to a worsening pathological inflammatory phenotype. It appears that blueberries can help block the process.
The 2007 publication Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microglia was one of the first relating blueberries to microglia. “Sustained microglial activation in the central nervous system (CNS) has been extensively investigated in age-related neurodegenerative diseases and has been postulated to lead to neuronal cell loss in these conditions. Recent studies have shown that antiinflammatory drugs may suppress microglial activation and thus protect against microglial overactivation and subsequent cell loss. Research also suggests that fruits such as berries may contain both antioxidant and antiinflammatory polyphenols that may be important in this regard. Our previous research showed that blueberry extract was effective in preventing oxidant-induced calcium response deficits in M1 (muscarinic receptor)-transfected COS-7 cells. Extrapolating from these findings, the current study investigated the effect of blueberry extract on preventing inflammation-induced activation of microglia. Results indicated that treatments with blueberry extract inhibited the production of the inflammatory mediator nitric oxide (NO) as well as the cytokines interleukin-1beta and tumor necrosis factor-alpha, in cell conditioned media from lipopolysaccharide (LPS)-activated BV2 microglia. Also, mRNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-activated BV2 cells were significantly reduced by treatments with blueberry extract. The results suggest that blueberry polyphenols attenuate inflammatory responses of brain microglia and could be potentially useful in modulation of inflammatory conditions in the CNS.” LPS is an endotoxin often used in laboratory and mouse experiments to elicit powerful immune responses and excite microglia.
The 2010 publication Blueberry supplementation attenuates microglial activation in hippocampal intraocular grafts to aged hosts is one of several that expands on this theme. “Transplantation of central nervous tissue has been proposed as a therapeutic intervention for age-related neurodegenerative diseases and stroke. However, survival of embryonic neuronal cells is hampered by detrimental factors in the aged host brain such as circulating inflammatory cytokines and oxidative stress. We have previously found that supplementation with 2% blueberry in the diet increases graft growth and neuronal survival in intraocular hippocampal grafts to aged hosts. In the present study we explored possible biochemical mechanisms for this increased survival, and we here report decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged hosts fed a 2% blueberry diet. Markers for astrocytes and for activated microglial cells were both decreased long-term after grafting to blueberry-treated hosts compared with age-matched rats on a control diet. Similar findings were obtained in the host brain, with a reduction in OX-6 immunoreactive microglial cells in the hippocampus of those recipients treated with blueberry. In addition, immunoreactivity for the pro-inflammatory cytokine IL-6 was found to be significantly attenuated in intraocular grafts by the 2% blueberry diet. These studies demonstrate direct effects of blueberry upon microglial activation both during isolated conditions and in the aged host brain and suggest that this nutraceutical can attenuate age-induced inflammation.”
In my previous post on blueberries I mentioned a related citation: Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus, “These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.” It was observed that blueberries attenuated the expression of NF-kappaB induced by the neurotoxic kainic acid and augmented the expression of IGF-1. Blueberries can be protective of mental capability when exposed to brain toxins.” While this 2005 document does not mention the role of microglia, their involvement can now clearly by hypothesized.
The mechanisms of action of blueberries appear to be shared by other anthocyanin-expressing flavonoids such as found in other berries. The 2009 publication Flavonoids and brain health: multiple effects underpinned by common mechanisms outlines some of those actions that go along with inhibition of microglial activation. “The neuroprotective actions of dietary flavonoids involve a number of effects within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. This multiplicity of effects appears to be underpinned by two processes. Firstly, they interact with important neuronal signalling cascades leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and differentiation. These interactions include selective actions on a number of protein kinase and lipid kinase signalling cascades, most notably the PI3K/Akt and MAP kinase pathways which regulate pro-survival transcription factors and gene expression. Secondly, they induce peripheral and cerebral vascular blood flow in a manner which may lead to the induction of angiogenesis, and new nerve cell growth in the hippocampus. Therefore, the consumption of flavonoid-rich foods, such as berries and cocoa, throughout life holds a potential to limit the neurodegeneration associated with a variety of neurological disorders and to prevent or reverse normal or abnormal deteriorations in cognitive performance.”
The 2010 publication Blueberry supplementation improves memory in older adults reports on a small human study confirming what we have pretty much known all along. “The prevalence of dementia is increasing with expansion of the older adult population. In the absence of effective therapy, preventive approaches are essential to address this public health problem. Blueberries contain polyphenolic compounds, most prominently anthocyanins, which have antioxidant and anti-inflammatory effects. In addition, anthocyanins have been associated with increased neuronal signaling in brain centers, mediating memory function as well as improved glucose disposal, benefits that would be expected to mitigate neurodegeneration. This study investigated the effects of daily consumption of wild blueberry juice in a sample of nine older adults with early memory changes. At 12 weeks, improved paired associate learning (p = 0.009) and word list recall (p = 0.04) were observed. In addition, there were trends suggesting reduced depressive symptoms (p = 0.08) and lower glucose levels (p = 0.10). We also compared the memory performances of the blueberry subjects with a demographically matched sample who consumed a berry placebo beverage in a companion trial of identical design and observed comparable results for paired associate learning. The findings of this preliminary study suggest that moderate-term blueberry supplementation can confer neurocognitive benefit and establish a basis for more comprehensive human trials to study preventive potential and neuronal mechanisms.” Clearly, larger-scale studies are needed to confirm the results.
Blueberries contain pterostilbene. “Pterostilbene is a stilbenoid chemically related to resveratrol. It is thought to be the key compound found predominantly in blueberries (as well as grapes) that exhibit anti-cancer, anti-hypercholesterolemia, anti-hypertriglyceridemia properties, as well as fight off and reverse cognitive decline. It is believed that the compound also has anti-diabetic properties, but so far very little has been studied on this issue. Additionally, it is also touted as a potent anti-fungal(ref).”
Pterostilbene, inflammation, glycation and diabetes
Pterostilbene is a powerful anti-inflammatory, responsible for some of the effects of blueberries in controlling a range of inflammatory disease conditions. The 2008 publication Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages reports “Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also to induce apoptosis in various types of cancer cells. Here, we investigated the inhibitory effects of pterostilbene on the induction of NO synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS).” Continuing, “Treatment with pterostilbene resulted in the reduction of LPS-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and the dependent transcriptional activity of NFkappaB by blocking phosphorylation of inhibitor kappaB (IkappaB)alpha and p65 and subsequent degradation of IkappaB alpha. Transient transfection experiments using NFkappaB reporter constructs indicated that pterostilbene inhibits the transcriptional activity of NFkappaB in LPS-stimulated mouse macrophages. We found that pterostilbene also inhibited LPS-induced activation of PI3K/Akt, extracellular signal-regulated kinase 1/2 and p38 MAPK. Taken together, these results show that pterostilbene down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFkappaB by interfering with the activation of PI3K/Akt/IKK and MAPK. These results have an important implication for using pterostilbene toward the development of an effective anti-inflammatory agent(ref).” Inhibition of the transcriptional activity of NFkappaB is not only a useful anti-inflammatory strategy but has been proposed as a powerful anti-aging strategy as discussed several times in this blog and in my treatise(ref). See the discussion under the subheading Increase in aberrant NF-kappaB signaling. Thirty nine supplements in my anti-aging combined supplement firewall are inhibitors of NFkappaB. To these can be added blueberries and a number of other phyto-substances in my normal food diet.
Pterostilbene and cancer
A number of recent studies have focused on the anti-cancer properties of pterostilbene. I cite a selected few here.
– The 2010 report Pterostilbene inhibits pancreatic cancer in vitro,
– The 2010 report Dietary intake of pterostilbene, a constituent of blueberries, inhibits the Î²-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats,
– The 2010 report Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis,
– The 2010 report Pterostilbene inhibits lung cancer through induction of apoptosis,
– The 2009 publication Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells,
– The 2009 publication Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells, and
– The 2007 report Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats.
Pterostilbene, inflammation, glycation and diabetes
One of the theories of aging is Tissue Glycation, a process deeply implicated in diabetes. Tissue glycation involves cross linking of tissue proteins with sugars resulting in the formation of Advanced Glycation Endproducts (AGEs). The result of AGEs can be self-propagating systemic or “silent” tissue inflammation. AGEs are recognized by cell RAGE receptors which result in the production of cytokine chemicals that can induce unwanted and potentially deadly inflammation in blood vessels, nerve, liver and other tissues. Atherosclerosis can be a consequence. AGEs are responsible for much bodily mischief related to aging leading to deterioration of function and structure of organs. They play important roles in diabetes, atherosclerosis, vascular disease, kidney failure, and neuropathy including Alzheimer’s disease. The presence of AGEs also appears to negatively impact on immune system functioning. Diabetes in particular appears to have its roots due to glycation and people with high blood sugar levels are particularly susceptible to glycation.
The 2006 publication Wild blueberry (Vaccinium angustifolium) consumption affects the composition and structure of glycosaminoglycans in Sprague-Dawley rat aorta is one of several that speaks to the effects of blueberries on tissue glycation. “Our results demonstrate for the first time that a diet rich in blueberries results in structural alterations in rat aortic tissue GAGs. These changes may affect cellular signal transduction pathways and could have major consequences for the biological function of GAG molecules within the vascular environment.” Other relevant documents include the 2009 publication Seasonal phytochemical variation of anti-glycation principles in lowbush blueberry (Vaccinium angustifolium) and Anti-diabetic properties of the Canadian lowbush blueberry Vaccinium angustifolium Ait.
The previous blog post on blueberries contains a number of additional research citations worth reviewing. One clear conclusion from reading those citations and the citations quoted here is that researchers are taking the anti-inflammatory, brain-health, cancer-fighting, diabetes-fighting and anti-aging properties of blueberries most seriously. Eating blueberries goes far beyond being a health food fad.
Putting it all together
My daily cup of blueberries is an important dietary component of my total anti-aging firewalls regimen, taking its place along with olive oil, walnuts, green tea, garlic and many other healthy foods. In general, I go along with the philosophy expressed in the 2009 publication Grape juice, berries, and walnuts affect brain aging and behavior. “Numerous studies have indicated that individuals consuming a diet containing high amounts of fruits and vegetables exhibit fewer age-related diseases such as Alzheimer’s disease. Research from our laboratory has suggested that dietary supplementation with fruit or vegetable extracts high in antioxidants (e.g. blueberries, strawberries, walnuts, and Concord grape juice) can decrease the enhanced vulnerability to oxidative stress that occurs in aging and these reductions are expressed as improvements in behavior. Additional mechanisms involved in the beneficial effects of fruits and vegetables include enhancement of neuronal communication via increases in neuronal signaling and decreases in stress signals induced by oxidative/inflammatory stressors (e.g. nuclear factor kappaB). Moreover, collaborative findings indicate that blueberry or Concord grape juice supplementation in humans with mild cognitive impairment increased verbal memory performance, thus translating our animal findings to humans. Taken together, these results suggest that a greater intake of high-antioxidant foods such as berries, Concord grapes, and walnuts may increase “health span” and enhance cognitive and motor function in aging.”
I end this note with a speculation relating to my personal health. In the blog post Spinal cord injury pain, I reported on an extremely painful injury to my spine incurred about a year ago while swimming in extremely cold water. I reported how terrible pains were showing up in unrelated parts of my body – e.g. my knee, my back, my hips, and my rotator cuff. A runaway inflammatory condition in my spine was sending out large quantities of cytokines creating debilitating havoc in all those places. My personal diagnosis was microglial over-activation due to injury in my spine, though none of the medical personnel treating me had ever heard of that. They thought my diverse pains were psychosomatic because the painful parts were not direct;y connected to my spine. Finally, I reported how the pains went away when I started taking gabapentin, and how I came across an obscure publication indicating that gabapentin reverses spinal microglial activation in a rat model(ref). Since then, all pains or problems associated with the spinal injury have vanished though I have kept myself on a low dose of gabapentin ever since, just-in-case. What I have to say now is that, having read the research about blueberries and microglia cited above, perhaps blueberries get some or all of the credit for having quenching my activated microglia – instead of or in addition to the gabapentin. About when the accident happened, I had raised my daily blueberry consumption to a small cupful and this may have helped a lot. I will soon phase the gabapentin out completely and see what happens.
Please see the medical disclaimer for this blog.
Wow! This was a real good post. In theory I’d like to write like this too – taking time and real effort to make a good article… but what can I say… I procrastinate a lot and never seem to get something done. Hope you can help me with my writing skills. c:
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