Oocyte Anti-aging Protocol

Oocyte Anti-Aging Protocol

Female fertility declines with age for two main reasons. The first is the gradual depletion of the ovarian reserve. The second is the progressive decline in oocyte quality. Every woman is born with a finite number of primordial follicles, and this number steadily declines until menopause. At the same time, the remaining oocytes gradually lose their ability to fertilize normally and support embryo development.

For many years, reproductive medicine focused primarily on the number of eggs remaining. Anti-Müllerian hormone (AMH), antral follicle count and basal follicle stimulating hormone (FSH) remain valuable tools for predicting ovarian response to stimulation, but they tell us very little about the biological competence of the oocytes themselves. Two women of the same age with identical AMH levels may have very different IVF outcomes because the quality of their oocytes differs. Oocyte quantity and oocyte quality are related but distinct processes. A low ovarian reserve does not necessarily imply poor egg quality, just as a good ovarian reserve does not guarantee reproductive potential.

Unlike most cells in the body, oocytes are formed before birth and remain arrested in the first stage of meiosis for decades before ovulation. A woman conceiving naturally at the age of 40 is releasing an oocyte that began its developmental journey before she herself was born. During this prolonged period of dormancy, the oocyte is continuously exposed to metabolic stress, reactive oxygen species, DNA damage and the gradual effects of aging. Although repair mechanisms remain active, they become progressively less efficient over time, increasing the likelihood of chromosome segregation errors, failed fertilization, impaired embryo development and miscarriage.

Modern aging biology recognizes that these changes do not occur in isolation. Aging results from the gradual accumulation of several interconnected processes, including genomic instability, epigenetic alterations, impaired proteostasis, mitochondrial dysfunction, chronic inflammation, defective autophagy and cellular senescence. These processes reinforce one another and progressively reduce cellular resilience throughout the body, including within the ovary (López-Otín et al., 2023).

Most discussions about reproductive aging focus on chromosomes, but the nucleus occupies only a small proportion of the mature oocyte. The vast majority of the cell consists of cytoplasm containing mitochondria, messenger RNA, proteins, ribosomes, endoplasmic reticulum, calcium stores, lipids and numerous regulatory molecules that support fertilization and sustain the embryo until it activates its own genome. This is known as cytoplasmic competence. An oocyte may have a normal chromosome complement yet still fail to produce a viable embryo if its cytoplasm cannot meet the metabolic demands of fertilization and early embryonic development.

Among all of these cytoplasmic components, mitochondria deserve particular attention. The mature human oocyte contains more mitochondria than any other cell in the body, typically between 100,000 and 600,000. These mitochondria provide almost all of the energy required for chromosome segregation, fertilization and the first few days of embryo development. During this period the embryo relies almost entirely on the mitochondria inherited from the oocyte, as significant mitochondrial replication does not begin until the blastocyst stage. If mitochondrial function is already compromised within the mature oocyte, the embryo has very little capacity to compensate.

Healthy mitochondria continuously balance ATP production with the controlled generation of reactive oxygen species (ROS), which play important roles in normal cellular signaling. As mitochondria age, however, they typically become less efficient at producing ATP while generating increasing amounts of ROS. In other words, they produce less of what the oocyte needs and more of what contributes to cellular damage. At the same time, intracellular NAD⁺ levels decline, mitochondrial biogenesis slows, damaged mitochondria accumulate because mitophagy becomes less efficient, and chronic inflammatory pathways become increasingly activated. Together, these changes progressively reduce oocyte competence.

For many years, nutritional support in reproductive medicine focused almost exclusively on antioxidants. While reducing oxidative stress remains important, we now recognize that healthy mitochondrial function depends on much more than simply neutralizing free radicals. Adequate intracellular NAD⁺ availability, mitochondrial biogenesis, efficient mitophagy, preservation of mitochondrial membrane integrity and activation of endogenous cellular defense systems all contribute to normal mitochondrial function.

Rather than relying on a single antioxidant, we combine several interventions that target different aspects of mitochondrial biology. Some primarily improve ATP production, while others restore declining NAD⁺ levels, stimulate mitochondrial biogenesis, enhance mitophagy or activate endogenous antioxidant pathways. No single intervention addresses every aspect of mitochondrial function, but together they aim to improve the metabolic environment in which the oocyte completes its final stages of maturation. None of these interventions can reverse ovarian aging or guarantee a healthy embryo, but they may help optimize oocyte competence before IVF.

The timing of these interventions is equally important. The final stages of follicular development occur during the three months preceding ovulation. Beginning supplementation only a few days before ovarian stimulation is therefore unlikely to meaningfully influence oocyte biology. Whenever possible, we recommend starting mitochondrial support at least 6–8 weeks before stimulation, allowing these interventions to act throughout the final stages of oocyte maturation.

The Oocyte Mitochondrial Optimization Protocol

This protocol is primarily intended for women with advanced maternal age, diminished ovarian reserve, previous IVF failure associated with poor embryo development, recurrent embryo arrest, or repeated production of aneuploid embryos. It is also used in conjunction with several of our advanced treatment programs, including ovarian PRP, cytoplasmic transfer and mitochondrial replacement therapy, where optimizing the metabolic state of the recipient oocyte before stimulation is considered an important component of treatment.

Ideally, supplementation should begin approximately 8 weeks before ovarian stimulation. This corresponds to the final stages of follicular development, during which the future mature oocyte undergoes extensive metabolic and structural remodeling. While the primordial follicle pool was established before birth, the months immediately preceding ovulation represents a period during which the oocyte remains metabolically active and responsive to changes within its surrounding follicular environment. Supporting mitochondrial function during this period provides the greatest opportunity to influence cytoplasmic competence before egg retrieval.

Supplement	Recommended Dose	Timing	Biological Rationale
Tirzepatide (or Semaglutide)	Tirzepatide 1.25 mg once weekly (or Semaglutide 0.25 mg once weekly)	Any time of the day, once a week.	Beyond their metabolic effects, GLP-1 receptor agonists have been shown to improve mitochondrial biogenesis, enhance mitochondrial function, reduce oxidative stress and stimulate mitophagy in multiple tissues.
TruNiagen® (Nicotinamide Riboside)	300 mg twice daily	Morning and evening	Increases intracellular NAD⁺ concentrations, supporting oxidative phosphorylation, DNA repair, mitochondrial metabolism and activation of sirtuin pathways.
Coenzyme Q10 (Ubiquinol)	300 mg daily	With first meal of the day	Improves electron transport within the mitochondrial respiratory chain, increasing ATP production. The ubiquinol form has superior bioavailability compared with ubiquinone.
Pyrroloquinoline Quinone (PQQ)	20 mg daily	With first meal of the day	Supports mitochondrial biogenesis through activation of PGC-1α signalling, increasing the formation of healthy mitochondria.
Urolithin A	500–1,000 mg daily	With first meal of the day	Promotes mitophagy, allowing dysfunctional mitochondria to be removed and replaced by healthier mitochondrial populations.
Sulforaphane (Avmacol®, BROQ® or Prostaphane®)	Equivalent to 20–40 mg bioavailable sulforaphane daily	With food	Activates the Nrf2 pathway, increasing endogenous antioxidant enzyme production while improving resistance to oxidative and inflammatory stress.
Alpha-Lipoic Acid	600 mg daily	Split into two doses taken 2 hours before main meals.	Acts as a cofactor for mitochondrial enzyme complexes involved in oxidative metabolism while reducing oxidative injury within the oocyte.
Omega-3 Fatty Acids (Triglyceride Form)	2,000 mg combined EPA and DHA daily	1000 mg after lunch and 1000 mg after dinner.	Supports mitochondrial membrane integrity, improves membrane fluidity and reduces chronic inflammatory signaling within the follicular environment.

Low-dose GLP-1 Receptor Agonists (Tirzepatide or Semaglutide)

For many years, GLP-1 receptor agonists have been viewed almost exclusively as medications for type 2 diabetes and obesity. More recently, however, it has become apparent that many of their biological effects extend well beyond glucose regulation and appetite suppression. A growing body of experimental work suggests that GLP-1 receptor agonists influence several of the fundamental pathways responsible for maintaining healthy mitochondrial function.

Mitochondria are dynamic organelles that constantly undergo renewal, repair and removal. Healthy mitochondrial populations depend on a balance between mitochondrial biogenesis, ATP production, antioxidant defense and mitophagy. With advancing age, chronic inflammation and conditions such as endometriosis, this balance gradually shifts towards accumulation of dysfunctional mitochondria, reduced ATP production and increased oxidative stress. Since the mature oocyte contains the highest concentration of mitochondria of any cell in the human body, preservation of mitochondrial quality is likely to be particularly important during the final stages of oocyte maturation.

Experimental studies have shown that GLP-1 receptor agonists increase expression of PGC-1α, the principal regulator of mitochondrial biogenesis, while simultaneously improving mitochondrial membrane potential, reducing mitochondrial reactive oxygen species (ROS) production and enhancing mitochondrial quality control through pathways involving PINK1 and Parkin. In parallel, they suppress several inflammatory signaling pathways, including NF-κB, TNF-α and IL-6, all of which have been implicated in ovarian ageing and the inflammatory environment associated with endometriosis (Wang et al., 2024; Papakonstantinou et al., 2024). 

Although much of this evidence has been generated in animal models and cell culture rather than human reproductive tissues, the biological rationale is compelling. Recent systematic reviews conclude that GLP-1 receptor agonists consistently improve mitochondrial morphology, increase mitochondrial number and support mitochondrial quality, although direct human evidence remains limited (Old et al., 2025). With the safety data being very good, incorporating a low dose GLP-1 receptor agonist is one of the off-label adjuncts in fertility treatments aimed at mitochondrial optimization.

At our clinic, we occasionally incorporate micro-dose GLP-1 receptor agonists as part of a broader mitochondrial optimization strategy before egg retrieval. The objective is not weight loss in most patients, unless that is also a separate goal before establishing pregnancy. Instead, the aim is to reduce chronic inflammation while supporting the cellular pathways involved in mitochondrial renewal and function. We typically use either tirzepatide 1.25 mg once weekly or semaglutide 0.25 mg once weekly, beginning approximately 8 weeks before ovarian stimulation. At these doses, appetite suppression and weight loss are minimal, if any, making this approach suitable even for women with a normal body mass index.

It should be emphasized that this remains an off-label intervention. At present, there are no clinical trials demonstrating improved embryo development or pregnancy rates following pre-treatment with GLP-1 receptor agonists before IVF beyond anecdotal data. Nevertheless, given our current understanding of mitochondrial biology, together with the expanding literature describing the effects of GLP-1 receptor agonists on mitochondrial homeostasis, the years it would take before any such clinical design would yield results, and the favorable safety profile of GLP-1 receptor agonists, we believe this represents a biologically very plausible strategy.

Nicotinamide Riboside (Tru Niagen®)

Nicotinamide adenine dinucleotide (NAD⁺) is present in every living cell and participates in hundreds of metabolic reactions. Within mitochondria, it functions as an essential coenzyme during oxidative phosphorylation, allowing electrons generated through carbohydrate and fatty acid metabolism to be transferred efficiently through the respiratory chain. ATP production depends directly upon adequate NAD⁺ availability.

Beyond energy production, NAD⁺ also regulates several enzymes involved in DNA repair, cellular stress responses and mitochondrial maintenance. Of particular interest are the sirtuins, a family of NAD⁺-dependent deacetylase enzymes that influence mitochondrial biogenesis, oxidative metabolism, chromosomal stability and cellular ageing. Sirtuins cannot function efficiently when intracellular NAD⁺ concentrations decline.

Several compounds increase NAD⁺ levels, including nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Both are effective precursors, but we currently recommend nicotinamide riboside because it has been studied extensively in humans, has an excellent safety profile and is supported by multiple clinical studies demonstrating reliable increases in circulating NAD⁺ concentrations as well as improved fertility potential (Conze et al., 2019; Martens et al., 2018). Human clinical studies have consistently shown that oral nicotinamide riboside supplementation significantly increases whole-blood NAD⁺ concentrations, with increases of approximately 40–60% at doses of 300 mg/day and up to 90% at higher doses, while maintaining an excellent safety profile (Martens et al., 2018; Conze et al., 2019). Interest in reproductive medicine followed the landmark work of Bertoldo and colleagues, who demonstrated that age-related NAD⁺ depletion contributes directly to declining oocyte quality and that restoration of NAD⁺ levels improved mitochondrial function, spindle organization, ovulation, embryo development and live birth rates in aged animal models (Bertoldo et al., 2020). Subsequent experimental studies have confirmed that NAD⁺ restoration reduces oxidative stress, DNA damage and apoptosis within aging oocytes while improving embryonic developmental competence (Wei et al., 2020; Pollard et al., 2022). Although large, randomized IVF studies in humans are still awaited, the biological rationale is strong and the available evidence continues to support NAD⁺ restoration as one of the most promising strategies for improving mitochondrial function during oocyte maturation. Tru Niagen® contains a patented form of nicotinamide riboside chloride that has undergone extensive pharmacokinetic and toxicological evaluation (Conze et al., 2019).

Coenzyme Q10 (Ubiquinol) and Pyrroloquinoline Quinone (PQQ)

If NAD⁺ provides the substrate required for mitochondrial metabolism, Coenzyme Q10 (CoQ10) helps convert that energy into ATP. It is an essential component of the mitochondrial electron transport chain, where it transfers electrons between respiratory chain complexes during oxidative phosphorylation. The ATP generated by this process supplies the energy required for oocyte maturation, fertilization and early embryo development.

The mature oocyte has exceptionally high energy requirements. Completion of meiosis, chromosome segregation, spindle function and the first few cell divisions after fertilization all depend on adequate ATP production. We already know that as women get older, mitochondrial function gradually declines. Electron transport becomes less efficient, ATP production falls and reactive oxygen species increase. These changes are thought to contribute to many of the abnormalities seen in aging oocytes.

Among the supplements used in reproductive medicine, CoQ10 has probably accumulated the strongest evidence. Several randomized clinical trials in women with diminished ovarian reserve have reported improvements in ovarian response, the number of mature oocytes retrieved and embryo quality following supplementation (Xu et al., 2018; Lin et al., 2024). For this reason, CoQ10 has become part of routine clinical practice in many IVF centers.

CoQ10 is available as either ubiquinone or ubiquinol. Ubiquinol is the reduced, biologically active form and has superior bioavailability, particularly in older individuals whose ability to convert ubiquinone appears to decline with age. We therefore recommend 300 mg of ubiquinol daily, beginning approximately 8 weeks or more before ovarian stimulation. CoQ10 improves the performance of existing mitochondria, but it does not stimulate the formation of new ones. This is where Pyrroloquinoline Quinone (PQQ) can have a complementary role.

Experimental studies suggest that PQQ activates pathways involved in mitochondrial biogenesis, particularly through PGC-1α, while also improving mitochondrial respiration and reducing oxidative stress. Human reproductive data remain limited, and there are currently no clinical trials demonstrating improved IVF outcomes. Nevertheless, the available experimental evidence and its favorable safety profile make PQQ a reasonable addition to a broader mitochondrial support protocol (Harris et al., 2013; Jonscher et al., 2021).

The aim is not simply to increase the number of mitochondria. A mature oocyte already contains several hundred thousand mitochondria. What matters is how well they function. Mitochondria that produce ATP efficiently are far more valuable than a larger number of damaged or metabolically inefficient organelles. Combining CoQ10 with PQQ allows us to support both mitochondrial function and mitochondrial renewal, which is why we routinely include both as part of our own-oocyte optimization protocol.

Urolithin A

Mitochondria do not remain healthy simply because the cell keeps producing new ones. Older and damaged mitochondria also need to be identified and removed. This process is called mitophagy. When mitophagy becomes less efficient, dysfunctional mitochondria begin to accumulate. They produce less ATP and often release more reactive oxygen species, which can further damage the cell.

Urolithin A is a metabolite formed by intestinal bacteria from ellagitannins found in foods such as pomegranate, walnuts and some berries. However, the ability to produce it varies considerably between individuals. In one human study, only about 40% of participants produced meaningful amounts after consuming pomegranate juice, whereas direct supplementation produced a more consistent systemic exposure (Singh et al., 2022a). 

Urolithin A has attracted attention because it stimulates mitochondrial quality control, particularly mitophagy. Human trials have mainly examined skeletal muscle rather than reproductive tissue as these studies were more interested in longevity and health span rather than reproductive function. Nevertheless, they do provide with an excellent resource for our understanding of how urolithin A can help the mitochondria.

In middle-aged adults, supplementation improved measures of muscle strength and exercise performance and altered biomarkers associated with mitochondrial health (Singh et al., 2022b). A second randomized trial in adults aged 65–90 years found improvements in muscle endurance together with changes in biomarkers related to mitochondrial function (Liu et al., 2022). 

The reproductive evidence is currently experimental. Studies in bovine and porcine oocytes have reported significantly improved mitochondrial membrane potential, lower oxidative stress and improved subsequent embryo development after exposure to urolithin A (Fonseca et al., 2021; Shi et al., 2025). A recent mouse ovarian study also found reduced follicular injury in models of chemotherapy-related ovarian damage, although this is not the same as age-related infertility (Wang et al., 2025). 

The reason we consider urolithin A before egg retrieval is therefore quite specific. CoQ10 mainly supports the performance of mitochondria already present within the oocyte. Urolithin A addresses another part of the problem by helping the cell remove mitochondria that are no longer functioning properly. This is relevant because an older oocyte can still contain a very large number of mitochondria, but a greater proportion of them may be inefficient or damaged. These defective mitochondria do not simply contribute less ATP. They can also produce more reactive oxygen species, release other stress signals, and activate inflammatory pathways within the cell. As this damage accumulates, the metabolic environment of the oocyte becomes less stable and other cellular processes, including spindle function, chromosome segregation and early embryo development, can also be affected. By identifying and clearing mitochondria that are no longer functioning properly, the cell can reduce unnecessary oxidative and inflammatory stress and preserve a healthier mitochondrial population.

The objective is therefore not simply to increase mitochondrial number. An oocyte may already contain hundreds of thousands of mitochondria, but that number is of limited value if many of them are metabolically inefficient. What matters is maintaining a population that can produce ATP effectively without generating excessive cellular stress. This is the rationale for including interventions such as urolithin A, which support mitophagy and mitochondrial renewal, alongside compounds such as CoQ10 that primarily improve the function of the mitochondria already present.

In our practice, we generally use 500 mg daily, beginning at least 6 to 8 weeks before ovarian stimulation. Higher doses have been used in human mitochondrial studies, but there is no evidence that a higher dose produces better reproductive outcomes. Urolithin A remains an off-label component of the protocol, supported by human mitochondrial data and early reproductive studies.

Sulforaphane

Sulforaphane is a naturally occurring compound found in broccoli sprouts and other cruciferous vegetables. Its role is different from that of a conventional antioxidant. Rather than simply neutralizing reactive oxygen species directly, sulforaphane activates the cell’s own protective systems.

Its main action is through the Nrf2 pathway. Under normal conditions, Nrf2 remains relatively inactive. When the cell is exposed to oxidative or metabolic stress, Nrf2 moves into the nucleus and increases the expression of enzymes involved in glutathione production, detoxification and antioxidant defense. Sulforaphane is one of the better-studied nutritional activators of this pathway. It also interacts with inflammatory signaling, including NF-κB and the NLRP3 inflammasome (Baralić et al., 2024; Alves et al., 2025). 

This distinction matters in fertility treatment. Some degree of reactive oxygen signaling is normal and necessary within the follicle. The objective is therefore not to suppress all oxidative activity with very high doses of direct antioxidants. It is to improve the oocyte’s ability to regulate oxidative stress through its own cellular defense mechanisms.

Human studies have shown that sulforaphane is biologically active after oral administration, but absorption varies considerably according to the preparation. Products that contain active sulforaphane, or glucoraphanin combined with the enzyme myrosinase, tend to provide more reliable exposure than glucoraphanin alone (Yagishita et al., 2019). This is why we recommend the three specific brands mentioned on the table.

At present, there are no human studies showing that sulforaphane improves ovarian response, oocyte competence or IVF pregnancy rates. The rationale comes mainly from its established effect on Nrf2 signaling and from experimental studies showing improved mitochondrial defense, lower inflammation and greater resistance to oxidative injury. This makes it a reasonable supportive intervention, particularly in women with endometriosis, metabolic inflammation or other conditions in which the follicular environment is exposed to chronic oxidative stress. It should not, however, be presented as a proven fertility treatment.

In our protocol, we usually use a standardized broccoli-sprout preparation providing approximately 20–40 mg of active sulforaphane daily, or an equivalent glucoraphanin product that includes active myrosinase. The actual sulforaphane yield is more important than the total milligrams of broccoli extract stated on the label. We normally begin treatment around at least 6 to 8 weeks before ovarian stimulation.

Alpha-Lipoic Acid

Alpha-lipoic acid is a naturally occurring compound that functions as a cofactor for several mitochondrial enzyme complexes involved in energy production. It is active in both water- and fat-soluble environments and can also help regenerate other antioxidants, including glutathione, vitamin C and vitamin E.

Its relevance to oocyte support is not limited to antioxidant activity. Alpha-lipoic acid participates directly in mitochondrial glucose metabolism and can improve insulin signaling. This is particularly relevant in women with PCOS, insulin resistance or metabolic inflammation, but mitochondrial support is also useful in women without these conditions.

The human reproductive evidence is limited but more direct than it is for urolithin A or sulforaphane. In a small prospective randomized IVF study, overweight or obese women without PCOS received a combination of 800 mg alpha-lipoic acid, 2 g myo-inositol and folic acid daily for three months before stimulation. The number of retrieved and mature oocytes did not increase, but the treatment group had a higher proportion of top-quality embryos and differences in several oocyte and embryo morphokinetic parameters (Canosa et al., 2020). Because alpha-lipoic acid was administered as part of a combination, the study cannot tell us how much of the effect was due to alpha-lipoic acid alone. 

The current clinical evidence therefore supports a possible effect on the metabolic environment and embryo morphology, but it is not strong enough to claim that alpha-lipoic acid independently improves IVF success.

Alpha-lipoic acid has also been studied in experimental endometriosis models because oxidative stress, inflammation and abnormal autophagy are part of the disease process. Animal data suggest that it can modify inflammatory and implantation-related pathways, but this should not be confused with proof of improved implantation in women with endometriosis (Kirmizi et al., 2022). 

In practice, we normally use 300 mg twice daily, preferably away from food because absorption is reduced when it is taken with a meal. Some patients develop nausea or reflux when taking it fasting; in that situation, it can be taken with a light meal. We generally start it approximately three months before stimulation. Because alpha-lipoic acid can lower blood glucose, additional care is needed in women using insulin or other glucose-lowering medication.

Omega-3 Fatty Acids (EPA and DHA)

Omega-3 fatty acids have traditionally been recommended because of their cardiovascular benefits. More recently, however, they have attracted attention in reproductive medicine because of their effects on inflammation, cell membrane function and mitochondrial health. Unlike many nutritional interventions used in IVF, omega-3 fatty acids have been investigated in both experimental models and human fertility studies.

The two biologically important marine-derived omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Although they are usually combined in supplements, they perform slightly different functions. EPA primarily serves as a precursor for anti-inflammatory and pro-resolving lipid mediators, whereas DHA is incorporated directly into cellular membranes, where it helps maintain membrane fluidity and normal membrane function.

This distinction is particularly relevant in the ovary. Every oocyte is surrounded by a plasma membrane, but it also contains hundreds of thousands of mitochondria, each enclosed by an outer and inner mitochondrial membrane. These membranes are not simply structural barriers. They regulate calcium homeostasis, metabolite transport, maintenance of the mitochondrial membrane potential and many of the signaling pathways required for normal cellular function. The electron transport chain itself is embedded within the inner mitochondrial membrane, meaning that efficient ATP production depends not only on the activity of the respiratory complexes but also on the integrity and physical properties of the surrounding membrane.

As women age, these membranes become increasingly susceptible to oxidative damage and lipid peroxidation. The phospholipids that make up the membrane gradually become damaged, reducing membrane fluidity and altering the function of membrane-bound proteins, including components of the electron transport chain. The result is less efficient ATP production together with greater leakage of reactive oxygen species. DHA is incorporated into membrane phospholipids throughout the body, helping to preserve membrane integrity and maintain the environment in which these mitochondrial proteins function. While omega-3 supplementation cannot reverse all aspects of mitochondrial aging, maintaining healthy membrane structure is one of the ways it can help support mitochondrial efficiency.

EPA contributes through a different mechanism. Rather than becoming a major structural component of the membrane, it acts as the precursor for specialized pro-resolving mediators, including resolvins, protectins and maresins. These molecules do not simply suppress inflammation. Instead, they help bring inflammation to an appropriate conclusion and promote the return to normal tissue homeostasis (Calder, 2020). This is an important aspect. Ovulation itself is a physiological inflammatory process, and some inflammatory signaling is essential for normal follicular development. The problem arises when inflammation becomes chronic or excessive, as is often seen with endometriosis, obesity and reproductive aging. In these situations, persistent inflammatory signaling can contribute to oxidative stress, mitochondrial dysfunction and impaired oocyte competence.

Experimental studies have also shown that EPA and DHA influence mitochondrial biology more directly. In several tissues they reduce excessive mitochondrial reactive oxygen species production, improve mitochondrial membrane potential, support oxidative phosphorylation and activate signaling pathways involved in mitochondrial biogenesis, including AMPK and PGC-1α (Khan et al., 2024).

Human evidence has also become increasingly encouraging. Higher dietary intake or circulating concentrations of omega-3 fatty acids have been associated with improved embryo morphology, higher clinical pregnancy rates and, in some studies, improved live birth rates following IVF (Chiu et al., 2018). More recent systematic reviews have concluded that omega-3 supplementation appears to improve several reproductive outcomes, although differences in study design and supplementation protocols mean that further high-quality randomized trials are still needed (Trop et al., 2024).

It is unlikely that omega-3 fatty acids exert their effects through a single mechanism. Instead, they appear to create a healthier intracellular environment by preserving membrane integrity, reducing oxidative stress, promoting resolution of inflammation and supporting mitochondrial function. None of these effects alone is likely to transform oocyte quality. Together, however, they improve the metabolic environment in which the oocyte completes its final stages of maturation.

For this reason, omega-3 fatty acids have become a routine part of our own-oocyte optimization protocol. We generally recommend 2,000 mg daily of combined EPA and DHA, beginning approximately at least 6 to 8 weeks before ovarian stimulation. A good quality, clinical grade triglyceride form is always our recommendation. Pure encapsulations, Thorne, Nordic naturals and Life extension are among the supplements we usually recommend due to their purity and efficacy.

Magnesium

Magnesium rarely receives the same attention as CoQ10 or NAD⁺ when mitochondrial health is discussed, yet it is involved in hundreds of biochemical reactions throughout the body, many of which are directly related to energy production. In fact, magnesium is required for virtually every stage of ATP metabolism.

When people think about ATP, they often imagine it as the molecule that provides energy to the cell. What is less well known is that ATP normally does not exist on its own. Inside the cell it is almost always bound to magnesium, forming what is known as the Mg-ATP complex. This is the form recognized by most ATP-dependent enzymes. In other words, producing ATP is only part of the process. The cell also needs sufficient magnesium to use that ATP efficiently. This is particularly relevant in the mature oocyte. Few cells in the human body have greater energy requirements. Completion of meiosis, chromosome segregation, spindle assembly, calcium signaling during fertilization and the first few embryonic cell divisions all require a continuous supply of ATP. If magnesium availability is inadequate, ATP-dependent reactions become less efficient, even when ATP production itself remains relatively normal.

Magnesium also plays an important role in maintaining healthy mitochondria. It helps stabilize the mitochondrial membrane, supports oxidative phosphorylation and regulates calcium transport between the cytoplasm and the mitochondria. Calcium is essential for normal mitochondrial function, but excessive calcium accumulation within the mitochondria can trigger opening of the mitochondrial permeability transition pore, leading to mitochondrial swelling, loss of membrane potential and impaired ATP production. Magnesium helps maintain this balance and protects against mitochondrial dysfunction (de Baaij et al., 2015; Gröber et al., 2024).

Another aspect that often receives less attention is inflammation. Magnesium deficiency has been associated with chronic low-grade inflammation, increased oxidative stress and activation of inflammatory pathways including NF-κB, TNF-αand IL-6 (Nielsen, 2018). These same pathways have been implicated in ovarian ageing and endometriosis. Correcting magnesium deficiency is therefore likely to support mitochondrial function both directly and indirectly by reducing the inflammatory environment in which the oocyte develops.

Magnesium is available in many different forms. Some, such as magnesium oxide, are poorly absorbed and are used mainly as laxatives. We generally recommend magnesium glycinate, not because it has been shown to improve fertility more than other forms, but because it is well absorbed, well tolerated and less likely to cause gastrointestinal side effects. Magnesium citrate and magnesium malate are also reasonable alternatives. Malate is of theoretical interest because malic acid participates in the Krebs cycle, although there is currently no evidence that it improves reproductive outcomes compared with other well-absorbed magnesium salts.

One of the reasons we include magnesium alongside supplements such as nicotinamide riboside, CoQ10 and PQQ is that each supports a different part of mitochondrial biology. NAD⁺ helps shuttle electrons into the respiratory chain, CoQ10 transfers those electrons, the electron transport chain generates ATP, and magnesium allows the cell to use that ATP efficiently. None of these steps occurs in isolation, which is why we prefer to support several aspects of mitochondrial function rather than relying on a single supplement.

In our practice, we generally recommend 300-400 mg of elemental magnesium daily, usually as magnesium glycinate, beginning at least 6 to 8 weeks before ovarian stimulation. Patients with impaired kidney function should discuss magnesium supplementation with their physician before starting treatment.

Concluding Remarks

One thing you may have noticed is that none of these supplements does exactly the same job. Mitochondria are remarkably complex structures and there isn’t a single intervention that can correct every aspect of mitochondrial ageing. Some supplements improve ATP production, others help restore declining NAD⁺ levels, some encourage the formation of new mitochondria, while others help the cell identify and remove mitochondria that are no longer functioning properly. Others reduce inflammation or strengthen the cell’s own antioxidant defense systems. None of these interventions is likely to make a dramatic difference on its own, but together they aim to improve the metabolic environment in which the oocyte completes its final stages of maturation.

Of course, supplements are only one part of the picture. Sleep, regular exercise, a balanced diet, avoiding smoking, maintaining a healthy body weight and correcting nutritional deficiencies probably have a greater overall impact on mitochondrial health than any individual supplement. The products described here are intended to complement those lifestyle measures rather than replace them.

It is also important to keep expectations realistic. These supplements cannot reverse ovarian ageing, repair severe chromosomal abnormalities or guarantee a successful IVF cycle. What they can do is support the biology of the oocyte during the final few months before egg collection. Since this is one of the few aspects of oocyte quality that we may be able to influence before treatment begins, I believe it is worthwhile to optimize it as much as reasonably possible.

Finally, I would like to make one thing clear. I have no financial relationship with any of the companies or brands mentioned in this guide. I do not receive commissions, sponsorship, consulting fees or any other financial benefit from recommending their products. The brands I mention are simply those that, in my opinion, have consistently demonstrated good manufacturing standards and quality control.

When choosing supplements, I generally look for manufacturers that follow current Good Manufacturing Practice (cGMP) standards, use independent third-party testing to confirm that the ingredients and dosages on the label are actually present in the product, and routinely test for contaminants such as heavy metals, pesticides and microbial contamination. I also prefer companies that publish Certificates of Analysis (CoAs) or make them available on request, use ingredients that have been studied in clinical research whenever possible, and avoid unnecessary fillers or proprietary blends that do not clearly state the dose of each ingredient. In my view, the quality of the supplement is just as important as the ingredient itself.

References

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Baralić, K., Živančević, K., Javorac, D., Buha Đorđević, A. and Antonijević Miljaković, E. (2024) ‘Sulforaphane—A compound with potential health benefits for disease prevention and treatment: insights from pharmacological and toxicological experimental studies’, Molecules, 29(3), 602. https://doi.org/10.3390/molecules29030602.

Bertoldo, M.J., Listijono, D.R., Ho, W.H.J., et al. (2020) ‘NAD⁺ repletion rescues female fertility during reproductive ageing’, Cell Reports, 30(6), pp. 1670–1681.e7. https://doi.org/10.1016/j.celrep.2020.01.058.

Calder, P.C. (2017) ‘Omega-3 fatty acids and inflammatory processes: from molecules to man’, Biochemical Society Transactions, 45(5), pp. 1105–1115. https://doi.org/10.1042/BST20160474.

Canosa, S., Paschero, C., Carosso, A., Leoncini, S., Mercaldo, N., Gennarelli, G., Benedetto, C. and Revelli, A. (2020) ‘Effect of a combination of myo-inositol, alpha-lipoic acid, and folic acid on oocyte morphology and embryo morphokinetics in non-PCOS overweight/obese patients undergoing IVF: a pilot, prospective, randomized study’, Journal of Clinical Medicine, 9(9), 2949. https://doi.org/10.3390/jcm9092949.

Chiu, Y.-H., Karmon, A.E., Gaskins, A.J., et al. (2018) ‘Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction’, Human Reproduction, 33(1), pp. 156–165. https://doi.org/10.1093/humrep/dex335.
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