Aging and the environment affect gamete and embryo potential: can we intervene?
Open accessAbstract
Optimal maturation of the oocyte depends on its environment and determines embryo competence, because the embryonic genome is not active until the cleavage stage and new mitochondria are not produced until blastulation. Adverse environmental factors include aging, andropause, oxidative stress, obesity, smoking, alcohol, and psychologic stress, whereas androgen supplementation, a prudent diet, exercise, nutritional supplements, and psychologic interventions have beneficial effects. Mitochondrial function and energy production deteriorate with age, adversely affecting ovarian reserve, chromosome segregation, and embryo competence. In aging mice, the mitochondrial cofactor coenzyme Q10 reverses most of these changes. Early human experience has been encouraging, although only a small study using a shorter duration of intervention compared with the murine model has been carried out. Mitochondrial metabolic stress can result in an abnormal compensatory increase in mitochondrial DNA, which can be assessed in biopsied blastomeres of trophectoderm as a predictive biomarker of implantation failure. Psychologic stress may reduce oocyte competence by shifting blood flow away from the ovary as part of the classic "fight or flight" physiologic response, and methods to reduce stress or the body's reaction to stress improve pregnancy success. Enhancing oocyte competence is a key intervention that promises to reduce the number of euploid embryos failing to produce viable deliveries.
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It is well-established that obesity is related to menstrual disorders, infertility, miscarriage, obstetric complications, live birth rate and can affect the success of assisted reproductive technology.
“It is well-established that obesity is related to menstrual disorders, infertility, miscarriage, obstetric complications, live birth rate and can affect the success of assisted reproductive technology.29–32”
From Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles (2019) · cites this paper as [30]
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Effects of Granulosa Cell Mitochondria Transfer on the Early Development of Bovine Embryos In Vitro
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Ovarian ageing: the role of mitochondria in oocytes and follicles
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Role of oxidative stress, infection and inflammation in male infertility
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Advanced Maternal Age in IVF: Still a Challenge? The Present and the Future of Its Treatment
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“The oocyte microenvironment is altered with reproductive aging, which has been shown to promote ovulatory dysfunction (Meldrum et al., 2016).”
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Therapeutic options for premature ovarian insufficiency: an updated review
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“Furthermore, mtDNA is prone to mutations due to the absence of histone protection and DNA repair enzymes [39].”
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Effect of aging on the female reproductive function
Shirasuna, K., & Iwata, H. (2017) · Contraception and Reproductive Medicine · doi:10.1186/s40834-017-0050-9 · Cited by 91 · see citing works
Ovarian aging: mechanisms and intervention strategies
Zhu, Z., Xu, W., & Liu, L. (2022) · Medical Review · doi:10.1515/mr-2022-0031 · Cited by 87 · see citing works
Ovarian aging: energy metabolism of oocytes
Bao, S., Yin, T., & Liu, S. (2024) · Journal of Ovarian Research · doi:10.1186/s13048-024-01427-y · Cited by 89 · see citing works
Khan, R., Jiang, X., Hameed, U., & Shi, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.639704 · Cited by 79 · see citing works
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Novel reproductive technologies to prevent mitochondrial disease
Craven, L., Tang, M., Gorman, G. S., Sutter, P. D., & Heindryckx, B. (2017) · Human Reproduction Update · doi:10.1093/humupd/dmx018 · Cited by 71 · see citing works
“There is substantial proof that meiotic and embryonic aneuploidies are related to both female age and mitochondrial activity (Schatten et al., 2014), and so oocyte competence, including cytoplasmic quality and particularly the mitochondria, may be affected by ageing (Meldrum et al., 2016).”
BackgroundEffects of Supplementation with Natural Antioxidants on Oocytes and Preimplantation Embryos
Budani, M. C., & Tiboni, G. M. (2020) · Antioxidants · doi:10.3390/antiox9070612 · Cited by 68 · see citing works
Dietary patterns and semen quality: a systematic review and meta‐analysis of observational studies
Arab, A., Rafie, N., Mansourian, M., Miraghajani, M. S., & Hajianfar, H. (2017) · Andrology · doi:10.1111/andr.12430 · Cited by 68 · see citing works
“Semen quality, as one of important factors leading to the fertilization of female gamete (Meldrum et al., 2016), can contribute to impairment of male infertility.”
BackgroundIn vitro fertilisation/intracytoplasmic sperm injection beyond 2020
Crawford, G., & Ledger, W. J. (2018) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.15526 · Cited by 66 · see citing works
The Influence of Smoking and Cessation on the Human Reproductive Hormonal Balance
Jandíková, H., Dušková, M., & Stárka, L. (2017) · Physiological Research · doi:10.33549/physiolres.933724 · Cited by 62 · see citing works
“Some studies have shown that female smoking is associated with fewer oocytes (Barbieri et al. 2005), decreased rates of fertilization (Neal et al. 2005), fewer pregnancies (Pineles et al. 2014) and increased miscarriage rates (Meldrum et al. 2016).”
BackgroundAbdulhasan, M. A., Li, Q., Dai, J., Abu‐Soud, H. M., Puscheck, E. E., & Rappolee, D. A. (2017) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-017-1027-y · Cited by 56 · see citing works
“CoQ10 appears to increase efficacy of IVF/ART both in vitro and in vivo, and can improve aged oocytes and decrease miscarriage, thus affecting gametes and embryos [7, 66, 67].”
BackgroundBoucret, L., Bris, C., Seegers, V., Goudenège, D., Desquiret‐Dumas, V., Domin‐Bernhard, M., Ferré-L’Hôtellier, V., Bouet, P., Descamps, P., Reynier, P., et al. (2017) · Human Reproduction · doi:10.1093/humrep/dex268 · Cited by 54 · see citing works
“Ovarian ageing may affect oocyte competence by targeting cytoplasmic components, including mitochondria, thereby entailing serious cellular consequences including nuclear chromosomal abnormalities (Meldrum et al., 2016).”
BackgroundAli, I., Padhiar, A. A., Wang, T., He, L., Chen, M., Wu, S., Zhou, Y., & Zhou, G. (2022) · Cells · doi:10.3390/cells11233713 · Cited by 52 · see citing works
Control of Mammalian Oocyte Development by Interactions with the Maternal Follicular Environment
Clarke, H. J. (2017) · Results and problems in cell differentiation · doi:10.1007/978-3-319-60855-6_2 · Cited by 52 · see citing works
Applications of Melatonin in Female Reproduction in the Context of Oxidative Stress
Jiang, Y., Shi, H., Liu, Y., Zhao, S., & Zhao, H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6668365 · Cited by 52 · see citing works
“Mitochondrial function degrades with age, adversely affecting ovarian reserves, and triggers ovarian aging [24].”
BackgroundMitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes
Kobayashi, H., & Imanaka, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313144 · Cited by 51 · see citing works
“The most critical consequence of age-related mitochondrial dysfunction is impaired ATP synthesis and mtDNA damage, which negatively influences chromosome segregation [46,47] and compromises embryonic development [48–50] (Figure 1).”
Cigarette smoking and hormones
Haham, L. M., & Shulman, A. (2016) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0000000000000283 · Cited by 51 · see citing works
Kunitomi, C., Harada, M., Takahashi, N., Azhary, J. M. K., Kusamoto, A., Nose, E., Oi, N., Takeuchi, A., Wada‐Hiraike, O., Hirata, T., et al. (2019) · Molecular Human Reproduction · doi:10.1093/molehr/gaz066 · Cited by 50 · see citing works
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“In general, oxidative stress on embryos developed in vivo is caused by aging and other environmental factors [27].”
BackgroundImproving oocyte quality by transfer of autologous mitochondria from fully grown oocytes
Kristensen, S. G., Pors, S. E., & Andersen, C. Y. (2017) · Human Reproduction · doi:10.1093/humrep/dex043 · Cited by 48 · see citing works
“As a result of this procedure, more than a dozen healthy live births or ongoing pregnancies have been reported (Fakih et al., 2015; Meldrum et al., 2016).”
Pharmacology of medications used for ovarian stimulation
Quaas, A. M., & Legro, R. S. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.10.002 · Cited by 48 · see citing works
“In-vitro, animal and clinical studies have been conducted to investigate the relationship between ovarian aging and function of the mitochondria, which are strictly maternally inherited [69].”
BackgroundTransient Sperm Starvation Improves the Outcome of Assisted Reproductive Technologies
Navarrete, F., Águila, L., Martín‐Hidalgo, D., Tourzani, D. A., Luque, G. M., Ardestani, G., García‐Vázquez, F. A., Levin, L. R., Buck, J., Darszon, A., et al. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00262 · Cited by 47 · see citing works
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“Altogether, these findings are beginning to support the use of mtDNA copy number as a marker of oocyte and embryo quality, which may enable its future use in clinics of assisted reproduction (Fragouli and Wells, 2015; Meldrum et al., 2016).”
BackgroundPrenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes
Chappell, N. R., Zhou, B., Schutt, A. K., Gibbons, W. E., & Blesson, C. S. (2020) · Endocrine Connections · doi:10.1530/ec-19-0553 · Cited by 40 · see citing works
Melatonin as Potential Targets for Delaying Ovarian Aging
Yang, Y., Cheung, H., Zhang, C., Wu, J., & Chan, W. (2018) · Current Drug Targets · doi:10.2174/1389450119666180828144843 · Cited by 39 · see citing works
Maternal age affects oocyte developmental potential at both ends of the age spectrum
Krisher, R. L. (2018) · Reproduction Fertility and Development · doi:10.1071/rd18340 · Cited by 38 · see citing works
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Air pollution and semen parameters in men seeking fertility treatment for the first time
Wdowiak, A., Wdowiak, E., Bień, A., Bojar, I., Iwanowicz-Palus, G., & Raczkiewicz, D. (2019) · International Journal of Occupational Medicine and Environmental Health · doi:10.13075/ijomeh.1896.01355 · Cited by 28 · see citing works
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Ovarian Aging: Mechanisms, Age‐Related Disorders, and Therapeutic Interventions
Liu, X., Zhao, Y., Feng, Y., Wang, S., & Zhang, J. (2025) · MedComm · doi:10.1002/mco2.70481 · Cited by 33 · see citing works
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“plasmic changes in aged oocytes and causes decreased cytoplasmic competence.(6) For oocytes, mitochondria are the multifunctional powerhouses”
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Enhanced branched-chain amino acid metabolism improves age-related reproduction in C. elegans
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“The number of mitochondria increases from 6000 at the primordial follicle stage to 400,000 or more prior to fertilization (MII oocyte); this increase prepares the oocyte for the increased energy demand during fertilization and early embryo development [3].”
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Can peri-ovulatory putrescine supplementation improve egg quality in older infertile women?
Tao, Y. G., Tartia, A. P., Lawson, M. S., Zelinski, M. B., Wu, W., Liu, J., Smitz, J. E. J., Léveillé, M.-C., Leader, A., Wang, H., et al. (2018) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-018-1327-x · Cited by 24 · see citing works
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Aging-related mitochondrial alterations in bovine oocytes
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“Due to these characteristics, OS induces cellular senescence, diminishes ovarian reserves and oocyte quality, and ultimately causes follicular atresia [3].”
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Intrauterine CRH‐treated PBMC in repeated implantation failure
Makrigiannakis, A., Vrekoussis, T., Makrygiannakis, F., Ruso, H., Kalantaridou, S., & Gürgan, T. (2019) · European Journal of Clinical Investigation · doi:10.1111/eci.13084 · Cited by 20 · see citing works
“The study design presents major strengths including the use of the same patients as controls, as well as the fact that it involved young participants (age <30 years), ensuring an overall good quality of embryos.(18,19) This is important especially in case of studying cases with RIF, since RIF is mainly associated with…”
MethodMaternal ageing impairs mitochondrial DNA kinetics during early embryogenesis in mice
May‐Panloup, P., Brochard, V., Hamel, J. F., Desquiret‐Dumas, V., Chupin, S., Reynier, P., & Duranthon, V. (2019) · Human Reproduction · doi:10.1093/humrep/dez054 · Cited by 19 · see citing works
Algal and Fungal Antioxidants Alleviate Oxidative Stress‐Induced Reproductive Defects
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“At the same time, the ovarian microenvironment is altered during aging and characterized by a ROS overload [2,35,36].”
BackgroundPourjafari, F., Haghpanah, T., Nematollahi‐Mahani, S. N., Pourjafari, F., & Ezzatabadipour, M. (2020) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-020-03083-3 · Cited by 16 · see citing works
Age-related changes in gene expression patterns of immature and aged rat primordial follicles
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“© 2017 Taylor & Francis abnormalities (chromosomal breakages and mutations) leading to cell death [Collins and Jones 2016; Meldrum et al. 2016].”
BackgroundAge‐related changes in the bovine corpus luteum function and progesterone secretion
Hori, K., Matsuyama, S., Nakamura, S., Iwata, H., Kuwayama, T., Miyamoto, A., & Shirasuna, K. (2018) · Reproduction in Domestic Animals · doi:10.1111/rda.13303 · Cited by 16 · see citing works
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NADPH oxidase-4 and MATER expressions in granulosa cells: Relationships with ovarian aging
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Role of glucose metabolism and signaling pathways at different stages of ovarian folliculogenesis
Mo, D., Zeng, Z., Sui, X. Y., Li, R., & Yang, Y. (2023) · Reproductive and Developmental Medicine · doi:10.1097/rd9.0000000000000079 · Cited by 15 · see citing works
“Moreover, disruption of mitochondrial OXPHOS in aged oocytes can contribute to meiotic spindle abnormalities, chromosomal misalignment, and reduced embryonic development [70] .”
BackgroundMitochondria Research in Human Reproduction
Lee, Y.-X., Lin, P.-H., Rahmawati, E., Ma, Y.-Y., Chan, C., & Tzeng, C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813209-8.00020-0 · Cited by 15 · see citing works
Melatonin Signaling Pathways Implicated in Metabolic Processes in Human Granulosa Cells (KGN)
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“This microenvironment depends on the maternal metabolic environment, which can affect the oocyte epigenetic and metabolic programming throughout follicular growth [5].”
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“In older women, oocytes may exhibit decreased mitochondrial quality, which is characterized by decreased number of mitochondria, the accumulation of mitochondrial DNA mutations, decreased ATP production, and increased oxidative stress, leading to poor fertility or premature ovarian aging [93].”
BackgroundBeneficial antioxidant effects of Coenzyme Q10 on reproduction
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The Effects of Adjuvant Therapies on Embryo Transfer Success.
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Mitochondria and reproduction: possibilities for testing and treatment
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Exploring the protective effects of coenzyme Q10 on female fertility
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Delayed parenthood and its influence on offspring health: what have we learned from the mouse model
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Potential role of tea extract in oocyte development
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Transcriptome analysis of PCOS arrested 2-cell embryos
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“Mitochondrial structural abnormalities in the oocyte have adverse effects on embryo competence because metabolic activity and ATP production are decreased [9].”
BackgroundWhat Changed on the Folliculogenesis in the Process of Mouse Ovarian Aging?
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“Studies have shown that accumulation of reactive oxygen species (ROS) and free radicals and the action of environmental factors such as radiation and chemotherapeutic drugs used in cancer patients can cause DNA damage in the oocytes during long periods of dictyate arrest and without repairing, the extent of DNA damage…”
BackgroundFisch, J., de Oliveira, I. V., Gomes, J. F., Paim, L. M. G., Zandoná, M. R., Lopes, E. F., de Mello, F. B., & de Oliveira, A. T. D. (2017) · Theriogenology · doi:10.1016/j.theriogenology.2017.02.014 · Cited by 9 · see citing works
The role of mitochondria in premature ovarian failure: A review
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Oocyte Morphology and Reproductive Outcomes - Case Report and Literature Review
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“Suspension of alcohol consumption during treatment is beneficial in reproductive outcomes (Prasad et al., 2016; Meldrum et al., 2016).”
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“Nutritional components or supplements with antioxidant functions have been examined in attempts to rescue aging-dependent infertility [16].”
BackgroundAdverse reproductive effects of S100A9 on bovine sperm and early embryonic development in vitro
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Lightening the burden of care in assisted reproductive technology
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Self-citationThe most appropriate indicators of successful ovarian stimulation
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“The beneficial effects of a healthy diet on ovarian function are thought to be due to the high levels of antioxidants in fruits and vegetables, which can help to protect the ovaries from oxidative stress and damage [11].”
Lifestyle Related Fertility Disorders in North Jordan: Potential for Improvement
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Paxillin knockout in mouse granulosa cells increases fecundity
Vann, K., Weidner, A. E., Walczyk, A. C., & Astapova, O. (2023) · Biology of Reproduction · doi:10.1093/biolre/ioad093 · Cited by 7 · see citing works
“Both germ cell factors, mainly oocyte aneuploidy [2, 3] and mitochondrial dysfunction [4, 5], and somatic ovarian cell factors have been implicated in subfertility with ovarian aging.”
BackgroundEffects of Calorie Restriction on Preserving Male Fertility Particularly in a State of Obesity
Zafar, M. I., & Chen, X. (2024) · Current Obesity Reports · doi:10.1007/s13679-024-00557-0 · Cited by 7 · see citing works
“While direct research connecting IF with male fertility is limited, it stresses the importance of lifestyle factors—including diets—on male fertility, indicating an open window to new strategies for reproductive outcomes [108].”
Khurana, P., Smyth, N. R., Sheth, B., Velazquez, M. A., Eckert, J. J., & Fleming, T. P. (2021) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174421000325 · Cited by 7 · see citing works
- Authors
- Meldrum, D. R., Casper, R. F., Diez-Juan, A., Simon, C., Domar, A. D., & Frydman, R.
- Affiliations
- University of California San Diego (US)
- Mount Sinai Hospital (CA)
- Beth Israel Deaconess Medical Center (US)
- Hôpital Foch (FR)
- Corresponding author
- Meldrum, David R.
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 105
- Issue
- 3
- Pages
- 548-559
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W2271112859
- Cited by
- 159
- References
- 138
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 11 · 2022: 17 · 2021: 21 · 2020: 19 · 2019: 16 · 2018: 19 · 2017: 20 · 2016: 6
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- oocyte aging, oocyte developmental competence, embryo developmental competence, mitochondrial function, oxidative stress, andropause, obesity, smoking, psychological stress, coenzyme Q10, mitochondrial DNA copy number, implantation failure, ovarian reserve, androgen supplementation, diet and exercise, dietary supplements, stress reduction intervention
- MeSH terms
- Maternal Health, Age Factors, Aging, Animals, Blastocyst, DNA, Mitochondrial, Embryo Transfer, Energy Metabolism, Environment, Female, Fertility, Fertilization in Vitro, Infertility, Life Style, Male, Mitochondria, Oocytes, Pregnancy, Risk Factors, Spermatozoa, Stress, Physiological, Stress, Psychological, Treatment Outcome, Reproductive Techniques, Assisted, Risk Reduction Behavior, Oocyte Retrieval
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