Pyrroloquinoline quinone (PQQ) is a natural bacteria cofactor found in plants, soil, and interstellar dust. It is critcal for healthy development and reproduction in humans. PQQ has recently gained a reputation for its ability to significantly increase the formation of mitochondria (Zhang, NaturalFactors, Saihara, Chowanadisai). Mitochondria create most of the adenosine triphosphate molecules (ATP energy) needed for folliculogenesis and embryogenesis to correctly take place. I want to emphasis the word “correctly” because this is the issue most women trying to conceive with advanced maternal age face: producing enough energy through ATP to allow for proper oocyte growth and maturation, and correct division and growth of an embryo.

As we age, the mechanisms responsible for ATP production decline. If you are trying to conceive over 35, especially over 40, you need to remedy this natural decline in cellular energy. The good news is PQQ can help you do just that!

PQQ enhances mitochondrial biogenesis

Antioxidants are very important to counteract a high oxidative stress load, especially while trying to conceive over 35 (Gao). Treatment with PQQ improves mitochondrial morphology and motility. The mitochondrial transport system maintains quality control by delivering healthy mitochondria to peripheral sites and returning damaged mitochondria to central sites. However, the process of transporting mitochondria creates elevated levels of reactive oxygen species (ROS). Luckily, in its reduced form, PQQ’s “radical-scavenging activity is 7.4-fold higher than that of vitamin C”! (Jonscher)

deacetylation of the peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α)

PQQ treatment activates the deacetylation of the peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α). Believe me I don’t like that term either, that’s why acronyms exist! Deacetylated PGC-1α is vital because it moves into the nuclei of the cell and activates gene metabolism and mitochondrial oxidative defense (Park, Dai, Chowanadisai, Jonscher). In addition, deacetylated PGC-1a increases Sirtuin 1 (Park). If you read my last article, you should be familiar with the Sirtuin family and NAD(+). If not, check out that article here.

Sirtuin 1 and Sirtuin 3

Healthy Sirt1 and Sirt3 levels are imperative for women of advanced maternal age trying to conceive. Unfortunately, Sirtuin concentrations decline as we age. Gao and colleagues investigated how PQQ leads to improvement of mitochondrial function in auditory cells. They explored the changes in the protein expression of SIRT1 and PGC-1α. Auditory cells were divided into two groups, one group was pre-treated with PQQ before exposure to H202, the other group was not pre-treated. Study results revealed after exposure to H202, in the non-treated group the expression of Sirt1 decreased significantly. In the PQQ-pre-treated group, the expression of SIRT1 recovered from the exposure to H202 (Gao).

Recall that the deacetylation of PGC-1a is important because it allows PGC-1a to move into the nucleus, thus the acetylation of PGC-1α is something we want to avoid. After exposure to H202, the acetylation of PGC-1a increased significantly, while it decreased dramatically in the PQQ-pre-treated group. These results indicate that PQQ treatment increases the expression of Sirt1, Sirt3, and PGC-1a under H202 exposure. Furthermore, this increase enhances NAD(+) activity (Gao, Saihara). If you missed my last post about NAD(+), check that out here:

“PQQ has the potential to protect against oxidative stress-induced premature cellular senescence in auditory cells by enabling the recovery of mitochondrial function by restoring the regulation of SIRT1/PGC-1α, the protein expression of SIRT1, and the deacetylation of PGC-1α, and by facilitating the recovery of mitochondrial biogenesis including the ATP production rate and maximum respiration rate. Restored SIRT1 leads to the mediation of PGC-1α and mitochondrial biogenesis in the auditory cells with oxidative stress-induced premature senescence”

Gao

Treatment of Age-Related Infertility

PQQ has been deemed safe for supplementation (more on that in a bit), yet there has been very few studies conducted on its beneficial effects on the condition of human infertility. Don’t cringe, it’s okay! It has been studied for its effects on many other human ailments. Honestly, there isn’t a huge demand for age-related infertility research…yet! Even though PQQ has not been studied in aged female humans, it has been studied in other aged female mammals.

Animal Studies

The process through which mitochondria create ATP is called oxidative phosphorylation (mt-OXPHOS) (Bergman). The more mt-OXPHOS created, the more ROS created. Remember that ROS form during any process, healthy or unhealthy, that instigates an oxygen molecule. Increased levels of ROS (oxidative stress) have an adverse effect on follicular health. Hoque and colleagues aimed to identify whether PQQ could improve “the negative effects of ROS on mitochondrial functions in FSH-stimulated granulosa cells during the follicular development process” (Hoque).

To test the effectiveness of PQQ, experiments were performed with the granulosa cells from superovulated mice. The cells were pretreated with or without PQQ. The level of oxidative stress and mtDNA damage were significantly increased in the granulosa cells stimulated with FSH-/eCG. Treatment with PQQ reduced the level of oxidative stress and improved mtDNA damage. In addition, the PQQ treated cells had an increase in the expression of mitochondrial genes and membrane potential (Hoque).

Hoque reports: “Accordingly, the proliferation and viability of granulosa cells, numbers of healthy preovulatory follicles and ovulated oocytes and serum estrogen level were significantly improved, while the apoptosis of granulosa cells was reduced.” Moreover, PQQ “significantly increased the number of offspring born per delivery. These results revealed that ROS-associated damage in FSH-stimulated granulosa cells adversely affects their physiology and follicular health during the follicular development process. Treatment with PQQ is a beneficial tool to increase both the number of ovulated oocytes and pups per delivery“

Hoque

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Reynolds wanted to determine if adding PQQ directly to oocyte culture media could decrease spindle abnormalities in obese, aged mice. 50uM PQQ was added to the culture media of half of the oocytes collected, and then cultured overnight for 14-16 hours. The following morning analysis showed that none of the aged oocytes in PQQ media had degenerated, whereas 30% in the control group (no PQQ) degenerated. In addition, there was a 50% reduction in abnormal meiotic spindle development in the aged oocytes that were cultured in PQQ compared with the control! “Supplementing oocyte culture media with the antioxidant PQQ may decrease the incidence of abnormal meiotic spindle development seen not only in aged, but also obese, oocyte” (Reynolds).

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Alkylating Agents (AAs) are commonly used for cancer therapy, but they cause significant damage to female reproductive organs. Dai conducted studies to see whether treatment of PQQ could alleviate damage to ovaries in mice treated with AAs. The PQQ treatment dose was 5mg/kg for three months. Results showed that PQQ treatment partially normalized the disrupted estrous cycle period, increased the ovarian weight and size, and prevented the loss of follicles in mice treated with AAs (Dai). In addition, “PQQ treatment significantly increased the pregnancy rate and litter size per delivery” and promoted pro-mitochondria biogenesis (Dai).

It has been demonstrated that inhibiting the high level ROS caused by AAs could effectively improve the number of follicles in each stage (12, 42). Consistently, in the present study, we found that PQQ could significantly alleviate oxidative damage in ovaries of mice treated with CTX/BUL…PQQ could be potentially used as an agent for preventing ovarian aging and preserving fertility

Dai

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BioPQQ is the form of PQQ that is used in successful human clinical trials. Long conducted a study to determine the effects of different levels of BioPQQ on sperm quality and antioxidative parameters of aging layer breeder roosters. Ninety-six roosters were randomly assigned to 4 treatments (0, 0.5, 1, 2 mg/kg BioPQQ) for 6 weeks (Long).

The administration of BioPQQ “significantly increased semen quality (semen volume, sperm motility, straightness, progressive motility, curvilinear velocity, straight-line velocity, and amplitude of lateral head displacement) and antioxidant capacity… in seminal plasma” (Long). Long concludes that supplementation with 1 mg/kg BioPQQ could increase antioxidant activity and sperm quality in roosters (Long). In addition, there was no significant benefit to increasing the dosage from 1mg/kg to 2mg/kg.

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Fetal and placenta growth, and milk production need a large amount of energy and oxygen (Zhang, 2019). We know that any process that engages an oxygen molecule creates ROS, and an increase in ROS results in oxidative stress. Oxidative stress is a nominal contributor to age-related infertility!

A study by Zhang and colleagues demonstrated “that pregnant sows had elevated oxidative stress during late gestation and lactation, which was responsible for impaired milk production, reproductive performance, and longevity”. Gestating and lactating cows were treated with 20mg/kg BioPQQ daily. Results revealed that sows treated with PQQ had a significant increase in both the number of piglets born and the number born alive (Zhang, 2019).

Zhang reports that maternal BioPQQ supplementation alleviated the inflammatory state of the placenta in gestating sows. Also, it reduced the expression of inflammatory cytokine genes (Zhang, 2019). BioPQQ treatment “also increased antioxidant levels in the placenta, plasma and milk”, and “ raised the concentration of NO [Nitric Oxide] in the plasma and placenta” (Zhang, 2019).

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Steinberg provided evidence that “PQQ improves reproduction performance” in mice and “stimulates neonatal growth. In a pair of experiments, female mice were divided into groups, each group was fed a diet containing a different amount of PQQ: 0, 100, 200, 300, 1000, or 5000 ng PQQ/g. The reproductive outcome of each group was analyzed, as were all surviving offspring until 20 weeks of age. The results are as follows: Groups supplemented with ≥1000 ng PQQ/g diet had 8 pups/litter whereas
groups supplemented with ≤300 ng PQQ/g (PQQ-deficient) diet had 4-5 pups/litter.
Of the pups that surviving to be weaned, 8 of 10 pups supplemented with ≥300 ng PQQ/g survived to weaning, whereas only 4 of 10 pups supplemented with ≤300 ng PQQ/g (PQQ-deficient) survived to weaning. These results suggest that PQQ plays an important roles at multiple stages critical for embryonic and postnatal development (Steinberg).

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Logsdon and colleagues conducted studies to determine whether PQQ supplementation added to mouse embryo culture is beneficial. Embryos were cultured in different concentrations of PQQ, high (2.5 uM) and then low (0.25 uM). Logsdon reports an increase in “mitochondrial activity (n=38) of 2-cell embryos following culture in 0.25 uM PQQ… Blastocyst total cell number was increased when embryos were cultured with PQQ in step one.”(Logsdon). In addition, more embryos from aged females hatched when PQQ was included in culture” (Logsdon). ncreased mitochondrial activity compared to those without PQQ.”  These results suggest that PQQ improves mitochondrial metabolism in early cleavage stages of embryogenesis, and it may provide benefit to blastocyst quality and development (Logsdon).

Supplementation

BioPQQ is the form of PQQ used in studies on humans. It “is created using a natural fermentation process that results in a highly absorbable PQQ disodium salt” (NaturalFactors). Nutrition and Allergies (NDA) stated that PQQ is “a novel food pursuant to Regulation (EC) No 258/97″ that “does not raise safety concerns… At a maximum proposed level of consumption of 20 mg/day (corresponding to 0.29 mg/kg bw per day for a 70‐kg person).” They report a “no‐observed‐adverse‐effect‐level (NOAEL) of 100 mg/kg bw per day from a 90‐day repeated dose oral toxicity study with BioPQQ™” (Turk). NDA concludes PQQ to be “safe under the intended conditions of use” (Turk).

As I mentioned, there is very little information about PQQ and infertility in gerneral, let alone age-related infertility. CNY Fertility promotes PQQ supplementation while trying to conceive over 35 but does not say a dosage:

“There aren’t any clinical studies looking specifically at PQQ for fertility, but the theoretical framework is there and many fertility specialists have already started recommending PQQ alongside CoQ10 as a Batman and Robin type pair for egg and sperm mitochondrial health, energy production, and quality”

CNY

The common dose of BioPQQ being sold is 20mg daily. I take 20mg of BioPQQ daily while I am trying to conceive, and I will continue to take it as an anti-aging supplement after I am done with my journey. I use the following BioPQQ:

Thank you so much for being here,

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