Nutrition and Age-Related Fertility Solutions

I.  Purpose

This paper investigates existing evidence to support a specific dietary composition and/or key nutrients, or antioxidants that may positively influence egg quality in advanced reproductive-aged women. An exploratory search was conducted to unearth evidence-based nutrition for egg quality especially in women 40 to 50 years of age.

II. The Natural Process of Age-related Fertility Decline 

Around 35 years of age, egg quality and quantity begin to decrease as a natural process of aging (Mikwar et al, 2020). The term advanced maternal age denotes the higher risk for genetic defects, abnormal chromosomes, and miscarriage in aging eggs according to the American College of Obstetricians and Gynecologists (ACOG) Committee Opinion (ACOG, 2014). With more women waiting longer to have children in their 40s (US DHHS, 2018) for a variety of personal reasons, the quantity and quality of their eggs become an issue for women when trying to conceive (TCC). Although, there are numerous medical and environmental variables that affect a woman’s reproductive ability, those issues are beyond the discussion of this paper.  The relationship between nutrition and egg quality is in early stages of development, there is data suggesting specific patterns of eating and certain key nutrients may help (Koga et al. 2020). Dietary composition, macronutrient patterns, and micronutrients of interest will be highlighted in pursuit of understanding how to improve egg quality in advanced maternal-aged women.

III.  Biochemical Processes that Disrupt Egg Quality

Although the quantity of the female egg is in nature’s control, there is emerging research in the area of improving egg quality and thereby improving maternal outcomes (Mikwar et al, 2020). Most intriguingly, there are obvious reasons why eggs may age prematurely, and the process is similar to a premature aging of our body systems. The relationship between nutrition and reproduction is provided in a recent review by Koga et al, 2020.  The main findings of the review show that when older women seek reproductive treatment that the aging oocyte is the greater cause of problems than organic factors (Koga et al, 2020, abstract). Factors that cause cellular aging include oxidation, glycation, and chronic inflammation, for which there is a large body of evidence supporting the rationale for these processes (Koga et al, 2020).

In Section IV, the rationale for dietary patterns and nutrients is discussed to support improved egg quality; some evidence is weaker or stronger depending on the study rigor and type of study. Less weight is given to observational or epidemiological studies that have uncontrolled variables, but these studies do provide insight by following different cohorts through a long period of time, some lasting 20 years or more. Pre-clinical animal models do not solidly support claims but may be suggestive of a mechanism of action (MOA) and give reason to design more studies. Heavy weight is given to clinical studies that are randomized placebo-controlled trials that are adequately powered and where the study has been repeated several times to rule out statistical errors. However, randomized trials on diets are difficult to perform because of the many variables including medical history and can be easily flawed.

Scientists have linked molecular biological processes to functional or anatomical changes leading to diseases such as aging however. Data on oxidative stress and chronic inflammation, glycation, and mitochondrial function have provided a large volume of information to support a probable positive role of antioxidants in egg health.  (Liguori et al, 2018; Singh, 2001; Roth 2018). A brief description of these processes will help in the understanding that although not all nutrients and nutritional components have been fully substantiated to improve egg quality, it is plausible that down-playing certain negative metabolic processes such as glycation and oxidation through strategic dietary choices can support egg quality.

A.  Oxidation – Cycle of Oxidative Stress and Inflammation

Free radicals are produced when highly reactive atoms or molecules react with one or more unpaired electron(s) in their external shell and are formed when oxygen interacts with certain molecules. These radicals can be produced in cells by losing  or accepting a single electron; these are referred to as oxidants or reductants (Liguori et al, 2018, page 759, col 2). The molecules will easily attach themselves to other molecules by scavenging and searching creating a cycle of electron stealing to make an even number and thereby, initiating an inflammatory state that creates a vicious circle in which chronic oxidative stress and inflammation feed each other, and consequently, increases the associated age-related morbidity and mortality (Liguori et al., 2018, page 759, col 2).   The terms reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced by all aerobic cells and play an important role in aging as well as in age-related diseases (Liguori et al, 2018, Page 757, bottom half of page). 

A health-forward focus is to reduce free radical production and oxidative process through diet. There are numerous other reasons for oxidative stress and inflammation that may promote premature aging including environmental pollutants, chemicals, and stress. 

B.   Glycation – Advanced Glycation End-Products (AGEs)

Glycation is the non-enzymatic process where there is covalent attachment of a sugar to a protein or lipid (Lima & Baynes, 2013).This is different from glycosylation which is the enzymatic process that is (energy) ATP-dependent to attach sugars to protein or lipid and necessary for the functioning of mature protein. Cross-links in tissue protein are known as advanced glycation end products (AGEs) and irreversible. AGEs accumulate gradually with age in long-lived extracellular proteins, such as collagen. Increased rates of formation of AGEs in tissue proteins during hyperglycemia and oxidative stress or inflammation are implicated in the pathophysiology of aging, diabetes and other chronic diseases (Lima & Baynes, 2013; Singh, 2001). Sugars involved in glycation are glucose, fructose, and other derivatives of simplified sugars.  

C.   Mitochondria – Compromised Energy Function

Optimal energy production is required for oocyte and embryo development (Babayev & Seli, 2015). If compromised, mitochondrial abnormalities have devastating reproductive consequences (Babayev & Seli, 2015; Mikwar et al, 2020; Roth, 2018). The review by Roth et al explains the pattern of DNA damage and apoptosis (cell death) when lactating cows experience heat and environmental stress. This is explained when antioxidants counteract ROS derived from mitochondrial metabolism and reduce the damage to the cell. If an imbalance between the amounts of antioxidants and ROS is produced, with more ROS, it then leads to oxidative stress. Oxidative stress creates lipid peroxidation which affects the integrity of the cell membranes. It also creates RNA, DNA, and protein oxidation, which leads to enzymatic degradation by nucleases and proteases and initiates cell death. Further DNA is prone to mutations because it lacks protective histones and is close to the inner mitochondrial membrane. Finally, oxidative stress has been related to telomere shortening and senescence (Rodriquez-Valera and Lambarta, 2020 Intro, 4^th para)In summary, when reactive oxygen species (ROS) production or the number of oxidants become disbalanced with antioxidant capacity, it affects optimal mitochondrial functioning. Improvements of oocyte mitochondrial function via intake of compounds that boost mitochondrial activity may have clinical benefits.

IV.  Plausible Role of Nutrition to Improve Egg Quality

Dietary habits over the last 100 years are accompanied by a concurrent downward trend in the fertility rates for women over the age of 35. The following studies investigate diets, foods, and nutrients where the most conclusive evidence to date is documented in the literature to support improved egg quality in advanced maternal age.

A.  Dietary Composition and Feeding Intervals

Traditionally and still applicable, whole diets comprised of specific macronutrient ratios (carbohydrate, protein, and fat) have been used  to control insulin resistance.  Controlling blood glucose levels is important in mitochondrial function as discussed in the previous section.

Three online fertility clinics were shown to support High Fat, Low Carbohydrate diet without proper substantiation and promoting an inappropriate one size-fit all approach. This may be interpreted as a non-prescriptive ketogenic diet. Ketogenic diets do reduce inflammation across the board however, the specific foods allowed in this diet approach do not support oocyte quality or the dietary information that follows in this report.

·       High Fat Diet – .Gonella et al 2022 disputes the High Fat diet in the context of oocyte and follicular quality thoroughly explains this through a biochemical process however, but promotes the Mediterranean diet – rich in omega-3 fatty acids.

·       Ketogenic Diet  - There is no known data or clinical trial to support the ketogenic diet (high fat, very low carbohydrate diet) in oocyte quality of any age. However, there is data surrounding fertility treatments that do warrant this dietary parameter, but it is not discussed here. A blanket ketogenic diet generally consists of animal proteins and may contain saturated/trans fats that contradict with the recommendations for plant-based proteins and complex carbohydrates containing high amounts of antioxidants (not characteristic of a ketogenic diet). 

·       Low Carbohydrate Diet - McGrice and Porter 2017 share systematic review data on the effect of Low Carbohydrate diet on Fertility hormones and outcomes in overweight and obese women. Seven studies fulfilled the inclusion criteria and were included in the evidence synthesis. Interventions were diverse and included a combination of low carbohydrate diets with energy deficit or other co-treatments. Study quality was rated as positive for six studies, suggesting a low risk of bias, with one study rated as neutral. Of the six studies which reported changes in reproductive hormones, five reported significant improvements post intervention. The findings of these studies suggest that low carbohydrate diets warrant further research to determine their effect. These randomized controlled trials should consider the effect of carbohydrates (with or without energy deficit) on hormonal and fertility outcomes.

Future studies should apply control and differentiation for types of carbohydrates – complex vs simple.

·       Lower Caloric diet – Selesniemi et al, 2011 proposed that lowering calories by 40% or a calorie restriction (CR) in a mouse model would improve chromosomal stability with success.  It was confirmed that the ovulated oocytes of aged female mice previously maintained on CR or lacking PGC-1α are comparable to those of young females during prime reproductive life. This study was more complex that explained here and incorporated genetic features beyond this exploration, but worth mentioning as an additive thought.

·       Mediterranean Diet – Muffone et al 2022 a systematic review and meta-analysis to determine whether greater adherence to the Mediterranean Diet (MD) can improve fertility markers and outcomes in infertile men and women. While this was not aimed specifically at egg quality in advanced age maternal women, some form of dietary pattern must be modeled that is optimal while TCC.. {Eleven studies met the inclusion criteria  (n = 13 157 women and 1338 men). Greater adherence to the MD was associated with live births (I² = 83.16%; odds ratio [OR], 0.652; 95%CI, 0.408–3.194), pregnancy rate (I² = 93.83%; OR, 1.192; 95%CI, 0.349–4.325), sperm concentration >15 × 10⁶/mL (I² = 32.97%; OR 2.862; 95%CI, 1.583–5.174), and sperm count > 39 × 10⁶/mL (I² = 48.1%; OR, 2.543; 95%CI, 1.319–4.904); however, in an inconsistent scenario regarding the meta-analysis.} Authors say evidence is insufficient to support their clinical application even though it indicates sperm improvement and a possibility of better pregnancy outcomes.

The Mediterranean diet is best supported overall because it includes specific guideline and since women will need some kind of guidance on a general dietary pattern to follow, the MD is a viable dietary pattern for women TTC to follow whether or not it directly impacts egg quality; it is a logical approach for which to base a diet on. The Lower Calorie diet (40% lower) is very logical but without specific food guidance. Here, a MD with caloric mindfulness might be recommended. There is no apparent benefit of ketogenic diet (High Fat, Very Low Carbohydrate Diet) on egg quality as far as the current data shows.

·       Meal Intervals – Research aimed at improving insulin resistance has shown that meal intervals are effective in controlling glucose levels more so than the meal content. Spreading out meals to be smaller and more frequent has been the dietary advice of nutritionists to prevent a rapid surge of glucose into the bloodstream.

It is plausible that controlling glucose levels and preventing insulin resistance would prevent glycation and AGEs from damaging viable eggs.

B.  Macronutrients

1. Complex and Simple Carbohydrates

·       Chavarro et al 2007 From the abstract – “evaluated whether the amount or quality of carbohydrate in diet is associated with ovulatory infertility. In total, 18,555 married, premenopausal women without a history of infertility were followed as they attempted a pregnancy or became pregnant during an 8-year period. Diet was assessed two times during follow-up using a validated food-frequency questionnaire and prospectively related to the incidence of infertility due ovulatory disorder. During follow-up, 438 women reported ovulatory infertility. Total carbohydrate intake and dietary glycemic load were positively related to ovulatory infertility in analyses adjusted for age, body mass index, smoking, parity, physical activity, recency of contraception, total energy intake, protein intake and other dietary variables. The multivariable-adjusted risk ratio (RR) (95% confidence interval (CI)) of ovulatory infertility comparing the highest-to-lowest quintile of total carbohydrate intake was 1.91 (1.27-3.02). The corresponding RR (95% CI) for dietary glycemic load was 1.92 (1.26-2.92). Dietary glycemic index was positively related to ovulatory infertility only among nulliparous women. Intakes of fiber from different sources were unrelated to ovulatory infertility risk. The amount and quality of carbohydrate in diet may be important determinants of ovulation and fertility in healthy women.”

This high-quality study with women is remarkable in that overall, glucose from carbohydrate substrates can play a viable role in fertility issues. This data can be applicable when keeping with to the Mediterranean-style pattern, while incorporating the correct ratio of carbohydrates, and correct selection of proteins and fats (below) into the diet.

Carbohydrates such as processed white bread, cake mix, cookie dough, ultra-processed snack crackers should be avoided. Sugars include: sucrose (granulated/powdered sugars), glucose (simple) syrup, high fructose corn syrup, dextrose, maltodextrin, honey. Less desirable carbohydrates also include white rice and white potatoes as a source of high glycemic index (GI) foods. The GI is a good tool for women TCC to utilize.

2. Protein

These findings are not specifically related to advanced maternal age – but mentioned out of totality for a preferred diet in general for women TCC.

·       Chavarro et al 2008 states that “replacing animal sources of protein, in particular chicken and red meats, with vegetable sources of protein may reduce the risk of infertility due to anovulation. Since this is, to our knowledge, the first report of this relationship in humans, these results should be confirmed. It is also important to clarify which biological mechanisms are responsible for this association.” 

The above study needs further confirmation, however, recommended protein sources would include plant-based protein including soy, lentils, and beans as the highest sources for protein. [BM opinion: Until a clear mechanism can be confirmed, it seems reasonable to include fish, especially fatty fish and lean poultry as a part of the usual intake].  

3. Fats and Omega 3 Fatty Acids

Western diets have changed largely in the past 100 years with omega-6 to omega-3 fatty ratio traditionally consumed at 1:1 ratio, and now very different with ratios as high as 25:1. This dietary shift has been hypothesized to be a reason for downward shift in fertility rates for women over the age of 35. Studies were proposed to investigate omega-3 fatty acid dietary enrichment as an option to delay oocyte aging and improving quality at advanced maternal age.

·       Nehra K et al 2012 studied mice receiving High Coconut Oil (deficient in essential fatty acids), Soy, and DHA diets. Their findings hold that omega-6 fatty acids are detrimental to the reproductive success of advanced maternal age. The results of this study were based on 2.1% of total calories in the form of omega-3 fatty acid docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid (LCP) and provided at a ratio of 20:1 [DHA / AA (arachidonic acid) (an omega-6 long-chain polyunsaturated fatty acid)] was safe for murine models. Oocyte quality was measured by spindle apparatus and mitochondrial dynamics (last para discussion).  [2.1% of a 2000 calorie diet is 42 calories or 4.5g – self calculated].

·       Kermack et al 2020, a study in humans investigated whether a dietary intervention that included an increase in marine omega-3 fatty acid (DHA), olive oil and vitamin D alters the fatty acid composition human follicular fluid.  The experimental group (55 couples) consumed olive oil for cooking, an olive-oil based spread, and daily supplement drink enriched with vitamin D and long-chain omega 3s – DHA, and eicosapentoenoic acid (EPA). The control group (56 couples) received placebo equivalents. The follicular fluid was significantly higher with EPA and DHA in the experimental group. This is the first report of dietary intervention altering fatty acid composition but more research needs to be done to see if this intervention improves oocyte quality.

It has been found that high fat diets (>35% calories from total diet) have a negative effect on dysregulation of gene expression  - one study in mice tried to see oocytes could be rescued with DHA and EPA-rich diets, but was not successful (Hohos et al, 2020). This is mentioned because ketogenic diets are used in certain fertility situations, and if not properly designed, they can be very high in saturated fats, and low in the long-chain polyunsaturated fats (LCPs) (DHA and EPA).

·       Abodi et al 2022 was a systematic review to investigate the current evidence on the effect of a dietary intervention that includes omega-3 FAs or a dietary assessment focused on their intakes among women undergoing assisted reproductive technology procedures to improve oocyte and embryo quality. While only a few studies were found to be eligible, the positive impact of omega-3 on key parameters for female fertility is encouraging and supported by biologic plausibility. Despite the heterogeneity, the emerging results pave the way for future intervention studies to strengthen the evidence on the relationship between nutrition and fertility.

Nutrient Omega - 3	RDA/ AI*	UL	Experimental Level	Comments
Alpha Linolenic Acid (ALA)	1.4g*	ND	4.5g mice	5g/d probably safe. Fish oils are usually come in 1000 mg (1g) doses with DHA and EPA
Docosahexaenoic Acid (DHA)	ND	ND
Eicosapentaenoic Acid (EPA)	ND	ND

Alpha-linolenic acid (ALA) is an essential fatty acid found mainly in plant oils such as flaxseed (7.26 g/1 tbsp), soybean, canola oils (1.28 g/1 tbsp), and chia seeds (5.06 g 1 oz) and walnuts (2.56g/ 1 oz). The body converts only small amounts of ALA to DHA and EPA, so getting more LCPs)  is desired; they are found in salmon (1.24g/ 3 oz), and seafood. Supplements are usually the means for increasing to high enough levels.

Dietary Reference Intake 31-50 y Pregnancy:

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

C.  Micronutrients

1. Selenium (trace mineral)

Selenium is an antioxidant trace mineral that functions through selenoproteins and is found to regulate both thyroid hormone actions and the redox status of vitamin C and other molecules to attenuate the effects of oxidative stress (IOM, DRI, 2006).

·       Yang H et al 2019 (mouse study) reports that selenium deficiency (or marginal levels) can negatively impact the fertility and reproduction in females, particularly those of an advancing age, and that the selenium supplementation (inorganic and organic) can substantiate ovarian function and overall reproductive efficiency in aging females. This trial would need to be done in humans to fully substantiate findings.

·       Mintziouri et al, 2020 (human and animal) notes that as oxidative stress can seriously impair male, and possibly also female reproductive functions, it can be speculated that the antioxidant properties of selenium could constitute one of the pathways by which this element is involved in fertility. Specifically, there are strong indications that selenium influences the growth, maturation, and replication of oocytes, but the full mechanism has not been fully elucidated. The data are still insufficient to recommend routine assessment of selenium status in men and women seeking fertility. Nevertheless, the existing evidence, despite being of limited quantity and somewhat low quality, suggests that selenium supplementation (< 200 mcg/d) is possibly beneficial in men through its improvement of sperm motility. Well-designed, randomized control studies are still needed. The toxic daily limit has not been evaluated in this report and 200 mcg should be used with caution. Mintziouri et al, 2020 assessed evidence from observational and interventional studies in humans and animals on the role of selenium in fertility.  Although it is not specifically targeted in results for older women, it adds value and identifies that more studies are needed to be conclusive.

·       Selenium dependent glutathione peroxidase appears to have effectiveness in endometriosis – a marker of oxidative stress, as shown an in-vitro fertilization study – details not included in this scope.

Selenium plays many roles in the body that may help the egg to thrive and survive that have not been demonstrated in clinical trials. Selenium may also have a role in reducing elevated insulin in the blood but it is inconclusive and studies provide differing results. Recommending selenium prenatally to support egg quality through its role as an antioxidant is an acceptable approach however, but it is not one specifically targeted for advanced maternal age.

Care should be exercised with selenium excesses since it can be toxic. There is controversy over whether selenium excesses may increase the risk of neurotoxin effects such as inhibition of prostaglandin D synthase in the brain. Selenomethionine is a good form for supplementation and 55 mcg/day is recommended for preconception in woman.

Rich food sources include Brazil nuts (544mcg/1 oz, 6-8 nuts), meat and seafood (30-47 mcg/3 oz serving), oatmeal (13 mcg/1 c), macaroni, enriched (37 mcg/1c). Most foods contain some amounts of selenium but regional soils play a big role in absorption. Vegetarians have lower selenium levels than non-vegetarians, this is  an interesting clinical point because of the marked increased in plant-food popularity.

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Selenium	60 mcg	400 mcg	Unknown in humans	Food sources preferred over supplements

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

2. Zinc (trace mineral)

·       Garner et al 2021 (not specific to advanced maternal age) A review notes an adequate supply of zinc is necessary for the oocyte to form a fertilization-competent egg as dietary zinc deficiency or chelation of zinc disrupts maturation and reduces the oocyte quality. He further notes that in mice, a lack of zinc in the diet (3–5 days preconception) or during in vitro maturation severely impairs fertility in mice though combined disruption of meiosis, fertilization, preimplantation, and post-implantation development. Likewise, in humans, dietary zinc deficiency severely impairs reproduction.

Zinc deficiency is common in many parts of the world among pregnant women and in disadvantaged populations in the USA (Wuelher et al, 2005).

The richest food sources of zinc are oysters (32 mg/3 oz), red meat (3.8 mg/3 oz), breakfast cereals, fortified (2.3 mg/serving), pumpkin seeds (2.2 mg/1oz) and other nuts.

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Zinc	11mg	40 mg	Unknown in humans	Vegans should supplement

Dietary Reference Intake 31-5-y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

3. Inositol (Myo-inositol or D-chiro inositol) – (Vitamin B8)

Although not technically a vitamin, inositol can sometimes be referred to as vitamin B₈. Inositols are sugar-like compounds that are easily obtained from the diet and act as second messengers of the insulin-signaling pathway that exerts insulin-sensitizing and lowering blood glucose and promoting hepatic glycogen synthesis. d-chiro-inositol has been widely used as a treatment for pathologies associated with insulin resistance, e.g., polycystic ovary syndrome (PCOS) and diabetes (Lopez-Gombero et al, 2020 Intro, 3^rd para). This is significant because it may keep glycation and AGEs in check.

Myo- or d-chiro-inositol forms have been milestones for understanding their physiological regulation of inositols confer antioxidant properties and can help fight the effects of free radicals in the body. The myo-inositol form appears to help egg quality as the study below shows, however, there is conflicting information with the forms of inositol and further probing is necessary.

This work presents a critical review of inositol actions on insulin signaling, oxidative stress, and endothelial dysfunction, and its potential for either preventing or delaying cognitive impairment in aging and neurodegenerative diseases (Lopez-Gambero et al, 2020).

For information purposes, a review of the literature showed that women with polycystic ovarian syndrome (PCOS)  were helped with myo-inositol and that myo-inositol also helped egg quality. This prospective, longitudinal, cohort study did not relate to women of advanced maternal age, but mentioned that more research could yield improved results in the future.

·       Unfer et al, 2011 studied the effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in- vitro fertilization cycles for poor oocyte quality. Forty-six women were treated with 4g/day myo-inositol and 3g/day melatonin for 3 months and underwent IVF cycle. There were 13 pregnancies and 4 evolved in spontaneous abortion. The treatment with myo-inositol and melatonin improves ovarian stimulation protocols and pregnancy outcomes in infertile women with poor oocyte quality. 

Myo-inositol is found abundantly in foods such as cantaloupe, citrus fruit, and many fiber-rich foods such as beans, brown rice, corn, sesame seeds, and wheat bran. Care must be taken not to take very high doses of myo-inositol since it can block the absorption of zinc, calcium and iron. 

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Myo-inositol	ND	ND	4g/d	10-12g probably safe. May cause stomach upset. Low level supplementation could be recommended but plentiful in a varied diet

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

4. Folate/Folic Acid (Vitamin B9)

Folate is an essential vitamin responsible for producing red and white blood cells in bone marrow, producing DNA and RNA, ad transforming carbohydrates into energy.  It is particularly important during periods of rapid growth and development such as pregnancy.

·       Ebisch et al 2007 is a review of zinc and folate in female reproduction and suggests that folate is also important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development.

·       Holis et al 2013 used data collected from the National Down Syndrome Project (NDSP), a case-control study of infant born with trisomy 21 and tested the hypothesis that the lack of maternal folic acid supplementation around the time of conception increases the risk of chromosome 21 nondisjunction and that this risk may vary depending on the origin of the meiotic error.  They observed an association between MII nondisjunction errors and lack of folic acid supplementation before conception among mothers who were ≥35 years of age.  There was no association among young mothers with either MI or MII errors. Findings raise two questions: 1) Why is folic acid supplementation associated with only MII errors in older mothers? and 2) Can the restriction of the effect of folic acid to MII errors explain conflicting results from other studies? In conclusion, the lack of folic acid supplementation is associated with MII errors in the aging oocyte, but these observations need to be confirmed in an independent sample with folate status around time of conception and biomarkers of folate pathway to confirm the findings. 

The food richest in folate are beef liver (215 mgc/3 oz), black-eyed peas (105 mcg/ ½ c) brussels sprouts (78 mcg/ ½ c), cooked spinach (131 mcg/ ½ c), asparagus (4 spears 89 mcg), and orange juice (35 mcg/ ¾ c), avacado (59 mcg/ ½ c). Fortified foods that contain the folic acid form of the vitamin are cereals, bread, pasta, rice, and cornmeal (90-100 mg/s).

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Folate/Folic Acid (DFE)	600 mcg	1000 mcg	Not available	Typical pre-natal supplementation levels advised

Dietary Reference Intake 31-50 Pregnancy Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND No data]

5. Coenzyme Q10 (CoQ10) (Vitamin B10)

Coenzyme Q10, (Vitamin Q) is not an essential vitamin, meaning that some is synthesized in the body, although it is in insufficient quantities and more needs to be obtained by food or supplements. The chemical name, ubiquinone, helps to increase body energy production or ATP and has been shown in studies to treat various human diseases (Shukla & Dubey, 2018). The most applicable function of CoQ10 is a powerful antioxidant that reduces normal signs of aging by preventing damage caused by free radical and oxidative stress (Shukla & Dubey, 2018). The reduced form of CoQ10, ubiquinol, protects biological membranes from lipid peroxidation by recycling vitamin E (Rodriquez-Valera and Lambarta, 2020, p4.)

·       Akarsu et al, 2017 demonstrated that a high follicular fluid CoQ10 level is associated with optimal embryo morphokinetic (specific embryo development) parameters and higher pregnancy rates.

·       Ben-Meir et al, 2015 was an animal study that successfully treated aged dams with known stimulators of mitochondrial bioenergetics, CoQ10, alpha lipoic acid, and resveratrol. The CoQ10 arm significantly improved ovulation rates in this model.  

·       Bentov et al, 2016 looked at the use of coenzyme Q-10 supplementation of 600 mg/day for 2 months up to the day of ooctye retrieval had inconclusive outcomes for advanced age women with infertility because ROS prolonged exposure was insufficient and failed to show significant difference between the groups – this study ended prematurely. Author surmises that the dose and duration of the treatment were based on mice studies and humans require longer exposure or high doses to achieve benefits.

·       Xu et al, 2018 was a randomized controlled trial seeking high quality embryos for a primary outcome. This CoQ10 group of young women who took a pretreatment of 200 mg three times a day orally, for a period of 60 days in an open label fashion had increased number of retrieved oocytes, higher fertilization rate and more high-quality embryos. More research is needed to determine whether there is an effect on clinical treatment endpoints. This is the only known quality clinical trial completed but it is in young women.

CoQ-10 has been pegged a promising, non-pharmacologic treatment, economical, and safe. There is a need for more quality designed clinical trials to fully assess this intervention.

Our bodies make some Q10 and so it is not an essential vitamin. Foods containing the highest amounts of CoQ-10 per 100g are organ meats (beef heart 11.3 mg), (liver 3.9 mg), (chicken hearts 9.2 mg), (mackerel  6.75 mg) and (trout 0.85 mg). Supplement is the best bet to assure a level reached in the treatment groups – 200mg (3 times per day).

Nutrient-Component	DRI / AI*	UL	Experimental Level	Comments
Coenzyme Q-10	ND	ND	600 mg/d humans	200 mg/TID

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

6. Vitamins A, C, D and E (Antioxidant vitamins)

Vitamin A – It is speculated that Vitamin A or its metabolites are essential for proper oocyte maturation because of its’ antioxidant capability. Cow and mice studies have shown beneficial effects with enhancing mitochondrial membrane potential activity, lowering ROS levels, and decreasing apoptosis. More work needs to be done to assess the role in improving oocyte quality. Rich sources of vitamin A are organ meats ( liver - 6582 mcg/ 3oz), sweet potato (1 whole - 1403 mcg (beta-carotene form and not toxic), spinach (573 mcg/ ½ c), carrots (459 mg/ ½ c).

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Vitamin A (RAE)	770 mcg	3000 mcg	Animal studies – no known effective human recommendation	Food recommended over supplementation

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

Vitamin C – No clear benefit has been seen to improve oocyte quality. Vitamin C is found in fruits and vegetables and easily acquired through diet.

Vitamin D – Supplementation and optimal vitamin D levels decrease both maternal and fetal risk for complications and adverse events. There was not enough evidence at the time of this writing to recommend for increased egg quality in any aged women, however.  Vitamin D is hard to obtain from food, but can be acquired through sunlight and supplementation. Few foods contain vitamin D however a 100g portion of fatty fish like salmon and trout contains approximately 14-16 mcg vitamin D. Other fish that have some amounts of vitamin D are mackerel, oysters, anchovies, sardines (1-2 mcg/ 3 oz). Foods that are fortified with vitamin D are cow’s milk, dairy products, and orange juice.

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Vitamin D	5mcg/20 IU	50 mcg/2000 IU	No value established	50-75 mcg / 2000-3000 IU is probably safe. Check with doctor. Supplementation is recommended.

Dietary Reference Intake Women:  31-50yr Pregnant women

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

Vitamin E is an essential fat-soluble vitamin and antioxidant. Its main role is protection of cell membranes from oxidative damage. Although some studies were conducted, they do not clearly support oocyte quality improvement in advanced maternal age. Foods particularly high in vitamin E are: Wheat germ 20 mg/ 1 Tbsp,  sunflower seeds 10 mg/ 1oz, almonds 7.3 mg/ 1 oz.

Nutrient	DRI / AI*	UL	Experimental Level	Comments
Vitamin E (TE)	15 mg	1000 mg	Not established	Supplementation may not be necessary since easily obtained from diet

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

D.    Other Bioactive Components

1. Resveratrol

Polyphenols are secondary metabolites of plants. Resveratrol is a natural polyphenol that is synthesized by several plant in response to pathogens. It is found in grapes, red wine, peanuts and several medicinal plants. Resveratrol has anti-aging, antioxidant, anti-inflammatory and insulin-sensitizing properties; thus acting in numerous pathological ways to reduce oxidation.

·       Di Emidio et al 2014 Resveratrol may improve age-related decline in ovarian function through the activation of sirtuin 1 (SIRT1), a molecule that protects mitochondrial function from oxidative stress and whose levels are undetectable in aged ooctyes in mice.

·       Chen et al 2010 Resveratrol prolonged ovarian lifespan in rats

·       Lui et al 2013 Mice treated with resveratrol for 12 months exhibited a higher number of follicles and control and improved the number and quality of oocytes, as evidenced by spindle morphology and chromosome alignment.  Telomerase activity, length, and age-related gene expression in the ovaries of mice supplemented with resveratrol resembled those of younger mice.

·       Lui et al 2018 included human resveratrol supplementation in in-vitro maturation (IVM) of aged immature oocytes and demonstrated improved oocyte maturation rate and quality as evidenced by improved mitochondrial immunofluorescence intensity and a reduced proportion of oocytes with abnormal spindle morphology and irregular chromosomal disposition. However, results were with 1.0 μm (infrared radiation) resveratrol for IVM medium and this information is not applicable in term of dietary intake.

·       A triple-blinded RCT comparing 800 mg/day of resveratrol to placebo with PCOS group increased high quality oocytes 81.9% v 69.1; p=0.002%.

·       An un-related study by Semba et al 2014 investigated whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and morality in humans in the Chianti area of Italy and it did not have a substantial influence. Therefore, supplementing with 800 mg/day as noted above may not be recommended due to the negative effects on the endometrium, but useful to downplay insulin sensitivity.

Additionally to note, resveratrol’s insulin sensitizing effect may be useful in polycystic ovarian syndrome (PCOS), but the anti-inflammatory properties may inhibit the inflammatory-related process of decidualization leading to decreased endometrial receptivity. Although resveratrol may have potential to benefit women with diminished ovarian function, its teratogenicity has not been ruled out. Alternative procedures to avert the negative consequences could be recommended for the future. At this time, it should be avoided during the luteal phase and pregnancy. It is unknown what effects this bioactive may have in general on aging oocytes of advanced reproductive age. 

Resveratrol can be found in red or purple grapes, grape juice (0.17-1.30 mg/ 5 oz) and red wine (5 mg/glass). Peanuts blueberries, cranberries, cocoa, dark chocolate and pistachios contain some resveratrol in smaller amounts.

Bioactive	DRI / AI*	UL	Experimental Level	Comments
Resveratrol	ND	ND	800 mg/day – human safety concerns	Not recommended for supplementation Mechanism unknown and questionable safety

Dietary Reference Intake Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

2.  Melatonin

Melatonin is synthesized from the amino acid tryptophan, almost exclusively by the pineal gland. It is released into the blood according to the circadian cycle, and its production is restricted to nighttime. The mitochondria may have amounts of melatonin and an important role in reducing oxidative stress. Its antioxidant properties come from its superior free radical scavenging, as well as its capacity to upregulate the expression of antioxidant enzymes and a spectrum of stress-responsive genes (Lopez-Gamber et al, 2020, Sect 2.3, 1^st para). Melatonin supplementation has been proposed as a treatment for poor oocyte quality due to its antioxidant effect in oocytes and granulosa cells.

·       Takasaki et al, 2003 studied 3mg/day of melatonin (from the previous cycle until the day of triggering) and found improved oocyte quality with previous IVF failure due to poor oocyte quality. However, improvement was evidenced only in the number of degenerated oocytes retrieved and not in the number of mature oocytes obtained.

·       Other clinical trials had varying results depending on various IVF situations that are too complex for this review – but the point is they were met with mixed conclusions because of variables that need further control.

·       Espino et al, 2019 A randomized pilot study (small sampling) aimed at assessing whether exogenous melatonin ameliorated oxidative stress and improved in-vitro fertilization (IVF) success rates in IUI. Thus, 3 mg/day or 6 mg/day of melatonin were given to IUI patients for a period spanning from the first appointment to control ovarian stimulation until the day of follicular puncture. Our results indicate that melatonin supplementation, irrespective of the two doses tested, ameliorated intrafollicular oxidative balance and oocyte quality in IUI patients, and that this translated into a slight increase in the rate of pregnancies/live births. Larger clinical trials in populations with different backgrounds are encouraged to corroborate the usefulness of melatonin.

Melatonin can be obtained by consumption of wine, beer, walnuts but much more research is needed to understand specific mechanisms of action. Melatonin’s safety is well-documented around 0.5 – 3 mg/day as a sleep aid, however formal safety parameters are not known. Some foods also contain melatonin such as goji berries, eggs, milk (warm milk is a known sleep aid), fish and nuts.

Bioactive	DRI / AI*	UL	Experimental Level	Comments
Melatonin	ND	ND	3 mg/d – documented safety	10 mg/day probably safe

Dietary Reference Intake 31-50 y Pregnant Women: 

[RDA – Recommended Daily Allowance; AI – Adequate Intake; UL – Tolerable Upper Level; ND – No data]

3. Other Antioxidant Components

This study successful study demonstrated the use of alpha-lipoic acid, citric acid, and L-carnitine – all antioxidants in protecting aging ooctyes in mice.

·       Li-Feng et al 2017 in a mouse study demonstrated the protective effect of antioxidants on the pre-maturation aging of mouse oocytes. Antioxidants – citric acid, alpha-lipoic acid, and L-carnitine successfully improved oocyte maturation after pre-maturation aging. Antioxidants improved normal spindle formation and chromosome configuration during oocyte aging. They also prevented DNA damage in oocytes during aging. This study, although a mouse design, was replicated three times and demonstrates that antioxidants can protect oocytes from damages caused by aging. Antioxidant quantification in mouse could not be transferred to human doses.

ALA can be found in yeast, organ meats like liver and heart, spinach, broccoli. ALA from food does not produce a noticeable effect in the body. It is surmised, this would need to be in a supplemental form. ALA is noted not be taken during pregnancy. Not enough data is known to supplement ALA in women TCC and should be used with a doctor’s recommendation.

4. Antioxidant-rich Foods

It would be exhaustive to examine every food rich in compounds that serve in an antioxidant capacity in particular for improving egg quality for advanced maternal aged women. However, armed with the understanding of the body processes discussed earlier in Section 3, it is plausible and certainly a good safety net to advise on eating foods particularly rich in the many bioactive components that serve as antioxidants to safe-guard the health of the egg.  There are no quality dietary studies that have specifically demonstrated outcomes of a high antioxidant diet in the population of interest, because such food studies are extremely difficult to control for. However, consuming anti-oxidant foods is good all-around advice that “may support egg quality”.

Although no evidence, it is worth mentioning that carbonyl compounds from common foods such as  burnt particles (including burnt toast) and charred food (crispy barbequed food) could potentially promote AGE’s and care should be taken to follow-up with antioxidants to minimize damage to cells (oocytes).  Chai et al 2012 supports carbonyl compounds from common foods as a culprit in AGE promotion.  Although speculative, it makes sense to avoid as a precautionary measure.

·       Carlson et al, 2010 – This article is a database of the richest antioxidant foods (about 3000), too much to list here. Here are a few that stand out. https://doi.org/10.1186/1475-2891-9-3 This extensive list can serve as a good source of information.

Other naturally occurring antioxidants include flavonoids, tannins, phenols and lignans. Some examples of immensely rich foods in antioxidants are teas (green tea), botanicals, and spices (allspice, clove, oregano).  

V.   Summary of Data

Fertility nutrition specific to the egg quality in advanced maternal age women is still evolving. The evidence related to oocyte quality is supported by numerous studies and the metabolic processes responsible for eventual cell death are also supported by a large body of evidence dating back decades. The evidence of key nutrients, nutrient components, and foods playing a role in improving egg quality, is indeed plausible with science to support their roles. A positive assertation cannot be made on some nutrients without clinical trials linking dietary data directly to human oocyte or egg quality. In a clinical practice, recommending such foods or antioxidants outlined in this report are viable and responsible recommendations for “supporting egg quality”. From an industry perspective, claims would need to be carefully reviewed and fully substantiated outlining the clinical evidence at levels shown to produce the results or from the product.

VI.  References

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APPENDIX

Professional Organizations 

The American College of Obstetricians and Gynecologists (ACOG) is the premier professional membership organization for obstetrician–gynecologists. https://www.acog.org/ 

American Society of Reproductive Medicine (ASRM)  is a nonprofit, multidisciplinary organization for advancement of the science and practice of reproductive medicine. The society has its headquarters in Washington, D.C and its administrative office in Birmingham, Alabama. https://www.asrm.org/

Resolve -The National Fertility Organization is a non-profit patient advocacy organization. https://resolve.org

Opinion Leaders and U.S. Influencers

Opinion leaders are subject matter experts in the stages of life, nutrients or ingredients. There are several subject matter experts identified from the reference section that were positively identified who could serve as single nutrient or subject matter contributors to your initiative.

There are select research centers in the U.S. identified as leaders in oocyte investigation.

·       Palm Beach Center for Reproductive Medicine – Wellington, Florida

·       Center for Human Reproduction – New York, New York

·       University of Rochester School of Medicine and Dentistry – Rochester, New York

The following influencers have not been vetted, but for information only.

·       Aimee Eyvazzadeh, MD, MPH – The Egg Whisperer https://draimee.org 

·       Nazameen Hoffaifar, MD – Influencer Resolve organization (not on LinkedIn)

·       Halle Teccom MBA, MPH – Influencer Resolve organization (not on LinkedIn)