The Summer 2020 Issue of Nutraceuticals Now is now available.
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Evidence is growing that this extensively studied compound has an important role in supporting brain health and preventing cognitive disease. Here, a look at the current science.
Over the years hundreds of studies have investigated roles for BioPQQ, with the strongest evidence pointing to its cell signaling, antioxidant and anti-inflammatory properties. To date, the most promising research suggests that these properties enable BioPQQ to play a role in preserving and improving cognitive function, both in animals and humans. In addition, more research is needed to confirm early encouraging findings that the compound may also support heart health and aid in the management of stress, sleep, and fatigue.
The compound is found in vegetables, fruits, eggs, dairy products and some fermented foods, as well as in human and animal tissue; concentrations are especially high in human breast milk.1,2 There is no evidence that humans and animals can synthesize BioPQQ, so external sources of the compound, such as foods and dietary supplements, may be important in maintaining tissue levels
BioPQQ®: A higher standard
BioPQQ® is a natural source of pyrroloquinolone quinone, derived by a patented fermentation process by the Mitsubishi Gas Chemical Company (MGC) following highest standards for purity. It is manufactured to food-grade standards and is the only supplement of its kind that has been approved for New Dietary Ingredient (NDI) status by the U.S. Food and Drug Administration.
With MGC’s commitment to pioneer an effort for more clinical data and research, BioPQQ is also the most widely studied. Its safety has been evaluated in several published animal and in vitro human toxicity studies—including a battery of genotoxicity tests.3,4 In clinical trials in humans ranging from 8 to 24 weeks, no side effects or adverse biochemical and functional liver test findings have been reported.
Since 1980, hundreds of studies have been conducted with MGC-sourced PQQ (PubMed.gov database). At the time of this writing, BioPQQ is the only food-grade supplement of its kind that has been tested in humans.
The importance of higher brain functioning to quality of life
Mental function is a critical component of maintenance and improvement of quality of life, especially in the elderly. A decline in an individual’s cognitive status, and the reduction in their abilities to perform activities of daily living, can strongly influence their perception of their own quality of life.
In the elderly, the burden of oxidative stress—a process increased in the brain with aging—can impair memory, learning and other higher brain functions. Excessive amounts of reactive oxygen species (ROS), combined with declines in the antioxidant system, can contribute to neurodegenerative diseases, including Alzheimer’s Disease and other dementias.
Antioxidant substances and food ingredients that remove active oxygen have been shown to improve brain function in memory and learning. BioPQQ has robust antioxidant effects,5 significantly higher than both Vitamin C and Vitamin E—potentially protective for neurons in the brain, which are susceptible to lethal damage from oxidative stress. Besides acting as an antioxidant, research suggests that BioPQQ can facilitate nerve regeneration.6,7
By potentially stimulating Nerve Growth Factor (NGF), BioPQQ may help nerves in the brain and other organs grow or recover after being damaged8,9 It has been shown to inhibit neurotoxicity and to promote mitochondrial biogenesis10 — energizing cellular activity, particularly in the brain.
In vitro and animal data in cognitive function and disease
In vitro studies performed with BioPQQ suggest several mechanisms by which cognitive functions may be improved. The compound was found to affect the cell signaling pathways associated with oxidative metabolism11,12,13 a key factor in cellular aging processes, and in mitochondrial biogenesis—the production and growth of new mitochondria,14,15 the energy-generating “powerhouses” of cells.
This function of BioPQQ, as a “mitochondrial booster,” is an especially promising area of further study; research is currently underway to better understand its mechanism in detail.16,17,18
In other in vitro studies, BioPQQ inhibited cell death of cultured neuroblastoma cells, with greater effects at higher doses.19 BioPQQ was also effective in preventing the formation of cytotoxic amyloid fibrils associated with neurodegenerative diseases,20,21 and enhanced the synthesis of nerve growth factor, a key protein involved in the development and health of neurons.22,23
Animal data also provide support for the effects of BioPQQ on improving cognition. One study24 compared cognitive functions in old rats who were given either vitamin E or BioPQQ for two weeks, measured by performance on the Morris water maze test. The results showed higher learning rates and improved memory retention in rats treated with either Vitamin E or BioPQQ, when compared with untreated controls.
Another study25 used the Morris water maze test to evaluate cognitive responses to experimentally-induced oxidative stress. Young rats were treated with BioPQQ, a combination of BioPQQ and CoQ10 (ubiquinone, also in the quinone family), or a placebo for 9 weeks, and exposed to hyperoxia conditions. In comparison to controls, memory retention increased significantly in the rats given BioPQQ either alone or in combination, 5 days after hyperoxia conditions. Memory retention was even higher in the combination-treated group after 7 days of hyperoxia. The results suggested that BioPQQ may have protective effects in the brain against oxidative stress-induced neurogenerative damage.
Highlights from Human Studies
Three recent, well-designed clinical studies have evaluated the efficacy of BioPQQ® alone or in combination with CoQ10 in middle-aged and elderly populations.
Pyrroloquinoline Quinone Disodium Salt Improves Higher Brain Function (Koikeda T et al.) 26
A 6-month placebo-controlled, double blind parallel study was conducted with 65 middle-aged-to-elderly healthy Japanese subjects (22 men, 45 women) 45-65 years old, who self- reported forgetfulness, or were identified as forgetful by a close relative.
Subjects were screened using a Japanese version of RBANS, a standard neuropsychological battery to assess mild cognitive impairment, with components to assess delayed and immediate memory, attention, language, and visual-spatial awareness. Those individuals who scored between 29-52, indicating mild impairment, were selected. Those who had prior diseases or took medications, foods, herbs or supplements that could affect results (such as anticoagulants or MAO inhibitors, DHA, or gingko biloba) were excluded.
The subjects were randomized to receive a 4-capsule daily regimen: either BioPQQ 20 mg (n=22), BioPQQ 20 mg and CoQ10 300 mg (n=21) or placebo (n=22). Throughout the 6-month study period, the subjects maintained their usual eating and exercise habits. RBANS testing was administered at baseline and again at weeks 8, 16, and 24.
While all three groups experienced similar, significant improvement in total RBANS scores by the end of the study, the BioPQQ + CoQ10 group experienced significantly greater improvement in short-term memory scores (p<0.003). For those subjects given BioPQQ alone, there was a trend toward short-term memory improvement.
When data was stratified to compare individuals with low and high memory scores at baseline, the BioPQQ + CoQ10 treatment in the lower-scoring group (n=32) had significantly greater improvements at 8 and 16 weeks, compared to placebo (see Figure 1).
This suggests that the beneficial effects of BioPQQ on short-term memory are more pronounced in people with lower memory scores.
BioPQQ was also associated with improvements in higher brain functioning, an important measure of quality of life in elderly people. At week 16, differences in visual-spatial awareness were significantly better in the BioPQQ group versus the placebo group.
There were no reported side effects in any treatment group during the 6-month study period, suggesting that BioPQQ was well tolerated, with or without CoQ10.
Summary: The results suggest that BioPQQ, alone or combined with CoQ10, is safe and useful in improving higher brain function—and indicate its potential in preventing or reversing higher brain function decline cause by aging and oxidative stress.
Effect of Pyrroloquinoline Quinone (BioPQQ) on Mental Status of Middle-Aged and Elderly Persons (Nakano M et al.)27
This 3-month, double-blind, placebo-controlled parallel trial involved 71 healthy, middle-aged adults (29 men, 42 women, ages 45-65) with no cognitive abnormalities. After dividing subjects into three groups—which were selected to ensure an equal balance of cognitive function and gender in each—the groups were randomized to receive either BioPQQ 20 mg (n=22), BioPQQ 20 mg and CoQ10 300 mg (n=24) or placebo (n=23).
During the 12-week study period, subjects took their treatment or placebo supplement daily after breakfast and followed their usual lifestyle habits. They kept diaries to note any adverse experiences and were given regular medical examinations by a physician.
To assess mental status, two standard tests were administered at baseline and at the end of the study (see “How Mental Status was Assessed,” below, for details).
Verbal Memory Test – This protocol measured the ability of subjects to recall seven unrelated words, read aloud. The subjects were first asked to repeat each word immediately after hearing it (free recall), then they were assessed by the number of words that could not be recalled until hints were given (cued recall). Then the subjects were given an interventional task and word recall tests were repeated: the number of words that could be retrieved 5 minutes after task performance (self-retrieval), then the number of words recalled post-task, but with prompts (cued retrieval). The greater the number of words recalled, the higher the mental status score.
The Stroop Color and Word Test – This assessment of executive function is often used as part of the process to determine the presence of mild cognitive impairment, or dementias such as Alzheimer’s disease. It consisted of four subtests, each requiring more complex information processing skills. The test-taker first reads aloud a list of 70 words that spell out different colors, printed in black ink (step 1), then names the color of 70 circles printed in differently-colored inks (step 2). In step 3, the test-taker reads aloud 70 color words spelled out in the wrong-color ink; in step 4, the highest level, the test-taker states the color of those 70 words, regardless of the color spelled out by the words.
In the Verbal Memory tests, the groups treated with BioPQQ (with or without CoQ10) showed a tendency toward improvement in the evaluation measures, though differences between the groups were not significant.
When the data were further analyzed to compare end-of- study responses to the higher levels of the Stroop Test (step 4, which required higher cognitive functioning and higher mental processing speed), the differences between the groups were more pronounced.
Both BioPQQ-treated groups experienced reductions in response time during these more difficult cognitive challenges. Those receiving BioPQQ alone had response time reductions by a mean of 5 seconds, although the difference was not significant compared with placebo (p<0.182). Those treated with the BioPQQ + CoQ10 regimen had increased their mental processing speed significantly, reducing their average time to respond by a mean of 7.3 seconds, versus just 2.0 seconds in the placebo group (p<0.009).
Overall the treatment regimens were well tolerated, with no side effects reported in any group. (Two participants withdrew from the study, for personal reasons.)
Summary: The findings indicate that BioPQQ had a mental status-improving effect that was enhanced by the addition
of CoQ10. Major improvements were seen in higher level executive functions such as attention, information recognition, and processing, while effects on verbal memory were positive but less pronounced. Additionally, BioPQQ was found to be safe, with no reported side effects.
Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQTM) on Cognitive Functions (Itoh et al. 28)
This randomized, double-blind, placebo-controlled study looked at the effects of BioPQQ on standard measures of cognitive function in healthy elderly adults. The subjects (14 men, 27 women) were randomly assigned to receive either BioPQQ
(20 mg/day) or placebo. Ages of the test subjects was similar in both groups; the mean age in the BioPQQ group was 58.6 years; in the placebo group, 58.4 years.
The test subjects took a daily 2-piece BioPQQ capsule or an identical placebo, each day after breakfast for 12 weeks. They continued with their usual eating and exercise patterns. They were given internal and physical examinations at the beginning and end of the study period, along with two tests to evaluate their cognitive status—the Stroop and Reverse Stroop test, and the Touch M evaluation system (see “How Cognitive Functioning was Measured,” below).
The Stroop and Reverse Stroop test – This test series is designed to examine selective attention ability. In each test, subjects had to choose and check one color name or patch that corresponded to a sample color name or ink color, from a list of five choices. From these results two scores were calculated: Stroop Interference Ratios (SIs) and Reverse Stroop interference Ratios (RIs). Low scores on both indicate high attention ability
For elderly individuals, these scores tend to be higher, indicating reduced attention ability. In previous tests to determine average scores covering each generation from ages 7 to 92, mean SIs rose from 8.20 to 40.9, and RIs, from -10.89 to 23.30. Of the two scores, SIs values are considered more useful measures, as RIs can be affected by differences in sensory sensitivity to color, which can be lower in elderly people.
Touch M – This evaluation system measures visual-spatial cognitive functioning and working memory using a laptop tablet. A series of targets are presented on the tablet screen, and scoring is determined by how accurately the test taker is able to reproduce the order of the targets’ appearances. Studies have shown that Touch M scores generally decline after age 60; a score of 70 indicates a decline in brain functions.
The Stroop test results were equivocal, showing no significant decrease in SIs or RIs over the course of the study period. RI scores declined slightly in the placebo group, suggesting an improvement in cognition; however, this artifact that may be attributed to the placebo group’s slightly higher performance at baseline when compared with the treatment group.
An additional analysis of the SIs revealed more definitive findings, when data from three “outlier” study participants were removed from the study. Those participants (one from the BioPQQ group and two from the placebo group) had baseline SIs scores that were more than 2 standard deviations from the mean SIs for all participants, which likely contributed “noise” to the data analysis.
In the additional analysis, the researchers found that there was a significant difference between the changes in SIs among the groups. In the BioPQQ group, mean SIs dropped 0.9 points, while the mean score increased 5.2 points in the placebo group (p <0.05). (See Figure 2).
In the Touch M analyses, mean scores in the BioPQQ group had a tendency to rise by the end of the study period (from a mean of 72.4 to 77.6) while scores in the placebo group remained relatively unchanged (from a mean of 74.8 to 72.2). These differences were not significant (p > 0.1); however, when the data were stratified to divide the groups by higher and lower baseline scores (> 70 points vs. < 70 points), the lower-initial-scoring subgroup of BioPQQ recipients had experienced significant improvement in cognitive function over the course of the study, with their scores increasing from a mean of 58.1 to 71.5 points (p <0.01). There were no significant differences between the higher-initial-scoring group of BioPQQ recipients, suggesting that the effects of BioPQQ were most pronounced in individuals with lower cognitive scores at baseline.
There were no side effects or abnormal blood or urinary findings in either group over the course of the study.
Summary: The results suggest that BioPQQ can be safely used to help prevent a reduction of cognitive functioning in elderly people, especially in the areas of attention and working memory.
Conclusion: A Well-Documented Path in Brain Health Treatment Potential
By all measures, BioPQQ is the most widely studied supplement of its kind, with growing database of laboratory and animal data, and several well-designed clinical trials in humans. The evidence suggests that BioPQQ is exceptionally well tolerated, and may have significant antioxidative and neurogenerative benefits for brain health. This well-documented path suggests that BioPQQ may play an important role in the prevention, management – and even possible reversal – of neurodegenerative factors contributing to cognitive disease.