Oocyte aging in focus: Environmental and endogenous stressors driving reproductive potential decline

Oocyte quality, a critical determinant of female reproductive potential, experiences a progressive decline with age, largely driven by the cumulative effects of oxidative stress and mitochondrial dysfunction. This review thoroughly synthesizes the latest evidence concerning the molecular, cellular, and environmental factors that disrupt redox homeostasis within oocytes. It particularly highlights the pivotal roles of reactive oxygen species, impaired mitochondrial metabolism, epigenetic dysregulation, and alterations in the ovarian microenvironment. We further elucidate how aging, environmental toxicants, lifestyle choices, and pathological conditions such as cystic ovaries and endometriosis exacerbate oxidative damage, thereby severely compromising meiotic competence and embryonic development. Compelling evidence from both human and animal models has shed light on the intricate mechanisms underlying ROS-induced oocyte deterioration, which will be discussed herein. Moreover, we evaluate promising emerging interventions, including antioxidant, dietary, lifestyle, and mitochondria-targeted strategies, all aimed at preserving reproductive longevity. Collectively, these insights firmly establish oxidative stress as a central and undeniable driver of oocyte aging, underscoring the urgent need for integrated biomedical and environmental strategies to safeguard female fertility. Similar content being viewed by others

In many animals, including humans, female fertility declines markedly with age [1, 2]. Moreover, advanced maternal age has been associated with an increased risk of pregnancy loss, abnormal fetal development, and birth-related complications [3,4,5,6]. As women increasingly delay their first childbearing [7,8,9], there is a warranted need to better understand the mechanisms linking aging with the decline in fecundity and other reproductive challenges. Several studies have demonstrated that oocyte quality is essential for successful reproduction and proper embryo development [10]. The transfer of oocytes from younger donors to older recipients almost completely prevents the age-related decrease in fertility, indicating the central role of oocyte quality [11,12,13,14]. However, cellular senescence is a complex process that is influenced by many factors. Therefore, assessment of oocyte competence should reflect the true biological state of cells to provide prognostic value in reproductive medicine. This requires the development and broader application of methods that are more accurate than chronological measures and account for specific characteristics of germ cells. As many women suffer from fertility problems earlier in life [15], the influence of environmental conditions [16,17,18,19], diet [20], and other lifestyle choices [21] on female reproduction is widely discussed in the scientific community. There is a need for a multi-level approach that considers not only individual decisions but also environmental, economic, and cultural determinants of reproductive health [22, 23]. The evidence from literature suggests that chronic exposure to external stressors may exacerbate oocyte senescence by stimulating production of reactive oxygen species (ROS). Excess ROS generates oxidative stress, which leads to damage to cellular components and dysregulation of fundamental biochemical processes [24,25,26,27,28]. Furthermore, meiotic disorders and changes in gene expression have been reported in numerous studies [29,30,31,32,33]. Human oocytes, which stay for a long time in prophase I of meiosis, can accumulate oxidative damage [34,35,36], leading to a gradual decline in oocyte quality with advancing maternal age (Fig. 1). Therefore, anti-oxidative treatments and lifestyle modifications are being investigated as potential protective strategies to restore redox balance and maintain reproductive capacity (Fig. 1). To make these interventions more effective, a better understanding of the processes underlying them is required. The connection between oocyte senescence, environmental stressors, and redox imbalance underscores the need for an interdisciplinary approach to mitigate age-related fertility decline. In this review, we summarize current knowledge on the environment-related oxidative stress response in oocytes and discuss potential strategies to protect oocyte quality. Furthermore, this manuscript aims to situate oxidative stress within a broader geroscience framework by integrating it with the known hallmarks of aging, which collectively contribute to reproductive decline. Oxidative stress intersects with multiple age-associated mechanisms, including mitochondrial dysfunction, genomic instability, epigenetic alterations, dysregulated nutrient sensing, and chronic low-grade inflammation. Framing oocyte aging within the geroscience paradigm highlights that reproductive decline is not solely a localized ovarian phenomenon but also reflects systemic aging processes. Oocyte aging as a redox imbalance phenomenon Reactive oxygen species are oxygen-containing free radicals with an unstable structure, making them highly reactive. They are produced during cellular metabolism and in response to external stressors, such as hypoxia, heme, or heavy metals. The most common ROS include hydrogen peroxide (H2O2), superoxide anion radical (O2•−), and hydroxyl radical (HO•) [37, 38]. Cells manage ROS through antioxidant enzymes, such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD), and non-enzymatic molecules like melatonin, ascorbic acid, and tocopherol. The intracellular ROS level depends on the balance between production and antioxidant activity (Fig. 1) [38]. Under physiological conditions, ROS act as signaling molecules that regulate differentiation, proliferation, apoptosis, and the immune response. In oocytes, they are involved in folliculogenesis, meiosis, and early embryo development [39]. Moderate ROS levels stimulate growth and division, but excessive accumulation disrupts redox balance, creating stress [38] that contributes to age-related decline in both oocyte quality and quantity [34, 35]. Among organelles, mitochondria play a central role in ROS generation (Fig. 2). They regulate energy metabolism, calcium homeostasis, signal transduction, and meiotic spindle formation. ROS are generated within the inner mitochondrial membrane as byproducts of oxidative phosphorylation (OXPHOS), making mitochondria a major source of intracellular ROS [37, 38]. Mitochondrial DNA (mtDNA), which encodes 37 genes essential for protein synthesis and energy production, is particularly susceptible to oxidative damage. Limited repair capacity leads to the accumulation of defects with age. Damaged mtDNA impairs OXPHOS, reducing ATP production and increasing ROS. Age-related declines in mitochondrial quality are also linked to reduced mitophagy and autophagy, contributing to the maintenance of dysfunctional mitochondria. Early oocytes exhibit limited Complex I activity, which keeps ROS levels low [40], but as oocytes mature, antioxidant defenses decline, allowing ROS accumulation [37]. Aging affects the expression of genes involved in redox regulation. Key antioxidant enzymes, such as glutathione peroxidase (GPX1), glutathione reductase (GSR), superoxide dismutase (SOD1 and SOD2), and members of the thioredoxin family, exhibit reduced expression in oocytes from aged animals. Similarly, genes associated with mitochondrial activity, including components of the respiratory chain and TCA cycle, are downregulated, leading to decreased ATP production and impaired redox balance [41,42,43,44,45,46]. These transcriptional changes create a self-amplifying cycle of ROS accumulation and mitochondrial decline [47, 48]. While many specific genes are affected, the overall trend is a progressive weakening of the oocyte antioxidant defense system. Oxidative stress also impacts epigenetic regulation in oocytes. DNA methylation, histone modifications, and sirtuin activity are all sensitive to ROS. Oxidative DNA damage can lead to global hypomethylation or locus-specific changes [49,50,51,52,53], while histone modification, such as reduced H3K4 methylation and altered acetylation of H3 and H4 residues affect the expression of genes controlling antioxidant defense and mitochondrial function [54,55,56,57,58,59]. Sirtuins, particularly SIRT1 [60], SIRT2 [61], and SIRT3 [62], decline with age. This is associated with impaired mitochondrial function, dysregulated OXPHOS, and increased ROS. In contrast, SIRT4 overexpression can cause meiotic defects and further ROS accumulation [63]. Altogether, redox-sensitive epigenetic changes compromise both transcriptional regulation and metabolic competence in aging oocytes. In addition, oocytes are influenced by their surrounding ovarian microenvironment. Granulosa cells (GCs) provide metabolic support and contribute to antioxidant defense. Aging is associated with increased ROS in GCs and reduced expression of genes involved in peroxide detoxification, NADPH production, and mitochondrial electron transport (Fig. 3) [42]. Such changes compromise GC function, further limiting oocyte quality and developmental potential. Therefore, oocyte aging also reflects the aging of the ovarian microenvironment. To summarize, age-related changes in mitochondria, antioxidant gene expression, and epigenetic regulation progressively lead to redox imbalance in oocytes, compromising their metabolic competence and genomic integrity. Notably, we emphasize that oocyte aging is a multifactorial phenomenon [64] and cannot be attributed solely to oxidative stress. In addition to redox imbalance, aging oocytes exhibit progressive genomic instability, deterioration of chromosome cohesion, and reduced efficiency of the spindle assembly checkpoint, all of which increase the risk of meiotic errors and aneuploidy. Age-related changes also involve metabolic alterations and inflammatory signaling within the ovarian microenvironment [65,66,67]. Oxidative stress, therefore, interacts with these hallmarks of aging rather than acting as an isolated driver of reproductive aging. Oxidative stress as a driver of reduced fertility with age Social and economic changes are leading women to increasingly postpone motherhood, and as a result, the proportions of pregnancies at advanced maternal age (AMA), commonly defined as ≥ 35 years, continue to rise [7,8,9]. This demographic trend has significant biological implications, as female fertility begins to decline around 30 years of age and accelerates dramatically after 35 [1, 2]. While hormonal changes and a diminishing ovarian reserve of oocytes, contribute to this decline, evidence indicates that the major driver of reduced fecundity in AMA is the progressive deterioration of oocyte quality, largely mediated by oxidative stress [11,12,13,14]. Clinically, AMA is associated with reduced fertility, higher miscarriage rates, and a markedly increased risk of aneuploidy, including trisomy 21, 18, 13, and sex chromosome abnormalities [4, 5]. Nonchromosomal congenital anomalies (NCAs) are also more common in pregnancies of aged women [3]. Pregnancy at AMA also carries additional risks, including ectopic pregnancy, preeclampsia, and cesarean delivery. Such complications may have long-term consequences for maternal health, including higher rates of postpartum depression and possible development of cardiovascular and cognitive disorders later in life [6]. Clinical observations in assisted reproductive technologies (ARTs) emphasize the central role of oocyte quality. The age of the oocyte donor is one of the strongest predictors of in vitro fertilization (IVF) success [11,12,13,14]. However, the mechanisms underlying these changes remain not fully understood, and cellular senescence does not always align with chronological age. This underscores the need for more reliable biomarkers that accurately reflect the biological state of cells. A key mechanism linking maternal age with diminished oocyte competence is redox imbalance. Oocytes may spend decades in arrested meiotic prophase I, making them vulnerable to cumulative oxidative damage. Age-related cohesion loss around centromeres, a significant contributor to errors in chromosome segregation, is exacerbated by ROS-induced oxidation and carbonylation of proteins essential for spindle formation and stability, thereby increasing the risk of aneuploidy in offspring [4, 38]. Oxidative stress also affects ovarian cells supporting the oocyte. ROS accumulation in GCs disrupts mitochondrial apoptosis and reduces the expression of several transcription factors, such as GDF9 and BMP15, which are crucial for oocyte competence. With age, expression of antioxidant enzymes and NADPH production in GCs decreases, resulting in a lower capacity to neutralize ROS. These changes contribute to diminished oocyte developmental potential [68]. Telomeres are repetitive DNA sequences located at the ends of chromosomes that protect genetic material from degradation and prevent the fusion of chromosome ends. Telomere shortening is another important age-related process, accelerated by ROS. Mammalian oocytes have low telomerase activity and, consequently, their telomeres shorten earlier than in most cell types. Importantly, short telomeres correlate with chromosomal instability, impaired maturation, and reduced reproductive success [69, 70]. Redox imbalance plays a central role not only in physiological aging but also in conditions often associated with poor reproductive outcomes, such as PCOS and endometriosis. For instance, follicular fluid (FF) in endometriosis patients contains decreased levels of antioxidant enzymes, such as SOD, GPX, and CAT, and glutathione (GSH). Furthermore, FF from PCOS patients is characterized by an excess of ROS and NOX2, a subunit of NADPH oxidase that generates superoxide radicals, contributing to altered follicular signaling [71,72,73,74]. Traditional markers, such as anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and antral follicle count (AFC), are used to estimate oocyte quantity but do not reflect the redox balance, which directly affects oocyte developmental competence (Fig. 3). Therefore, research increasingly focuses on oxidative stress markers in FF and serum. Some stress markers of FF and serum, including malondialdehyde (MDA), 8-Oxo-2’-deoxyguanosine (8-OHdG), and thiol oxidation, are associated with lower embryo quality, whereas higher Total Antioxidant Capacity (TAC) correlates with better fertilization rates and higher pregnancy success [75,76,77,78]. Proposed non-invasive biomarkers also include Oxidative Stress Index (OSI) and peroxiredoxin (PRDX4) [79]. Although aging is the strongest predictor of ovarian redox decline, environmental and lifestyle factors can further accelerate oxidative stress. Chronic exposure to pollutants, heavy metals, and endocrine-disrupting chemicals, as well as lifestyle habits such as smoking, an ultra-processed diet, and chronic stress, leads to redox imbalance in both oocytes and the ovarian microenvironment. Importantly, oocyte aging does not occur in isolation but reflects broader biological processes associated with organismal aging. Several mechanisms implicated in reproductive decline overlap with systemic hallmarks of aging described in geroscience frameworks [64]. Emerging evidence suggests that age-related inflammatory signaling may influence ovarian aging. Chronic low-grade inflammation, often referred to as inflammaging, has been associated with alterations in the ovarian microenvironment, potentially affecting follicular development and oocyte maturation [67]. Proteostasis decline may also contribute to oocyte aging through impaired protein folding, aggregation, and reduced activity of the ubiquitin–proteasome and autophagy systems. Cellular senescence in ovarian somatic cells, including GCs and stromal cells, may further exacerbate oxidative stress and inflammatory signaling within the follicular niche [80, 81, 82] Together, these interconnected mechanisms and hallmarks of aging suggest that reproductive aging shares common biological pathways with systemic aging, supporting the view that oocyte aging should be considered within a broader geroscience context. Women with endometriosis or exposure to environmental toxicants frequently show FF with increased levels of ROS, heavy metals like cadmium (Cd) and lead (Pb), and nitric oxide (NO), accompanied by reduced enzymatic antioxidant activity (Fig. 1) [83]. Excess ROS activates inflammasome pathways, including NLRP3 inflammasome, promoting pyroptosis, an inflammatory form of cell death (Fig. 2), in GCs and disrupting follicular structure and oocyte maturation [84]. Lifestyle-related oxidative stress outcomes have also been reported. These findings underscore that oxidative stress is a central driver of declining oocyte quality. Environmental oxidative damage: insights from animal and human studies Experimental models, both in vitro and in vivo, have been crucial for understanding the damage to oocytes caused by ROS and the impact of external factors on the ovarian microenvironment. These studies provide insight into how ROS accumulation disrupts cellular structures, signaling pathways, and epigenetic regulation, compromising oocyte quality and fertility. Controlled addition of ROS, typically 10–50 μM H2O2, to in vitro oocyte cultures is a widely used method for modeling oxidative stress [83]. Exposure of immature mouse oocytes at the germinal vesicle stage (GV oocytes) to H2O2 increases levels of reactive aldehydes, including 4-hydroxynonenal (4-HNE), which modifies and damages α-, β-, and γ-tubulins, essential for spindle assembly. This leads to meiotic defects, particularly in oocytes from aged females, highlighting the age-dependent susceptibility to oxidative damage [84]. Animal studies provide further evidence for the harmful effects of environmental factors on oocyte quality through ROS generation. Heat stress accelerates oxidative damage in oocytes, as demonstrated in bovine studies where gradual exposure to elevated temperatures (38,5–40,5 °C) induced oxidative stress and reduced expression of interferon tau (IFNT), a cytokine essential for embryo-maternal communication [25]. Contemporary research has provided evidence that heat stress has detrimental effects on oocytes, mediated by heat-induced molecular alterations, including mitochondrial dysfunction, elevated oxidative stress, and impaired DNA integrity within both the oocyte and its surrounding follicular microenvironment [85]. These results underscore the sensitivity of reproductive cells to temperature fluctuations. Chemical contaminants increasingly present in the environment also impair oocyte competence. Microplastics (MPs), originating from tire wear, synthetic fibers, industrial particles, or degraded plastic waste, disrupt spindle formation, chromosome arrangement, and cytoskeletal assembly in bovine oocytes. Oxidative stress alters mitochondrial function by modulating the expression of fusion-fission proteins, including mitofusin-1/2 (MFN1/2), optic atrophy protein 1 (OPA1), and dynamin-related protein 1 (DRP1). These defects are associated with DNA damage, altered mitochondrial gene expression, and enhanced apoptosis. ROS also affect transcription factors (NF-κB, AP-1, Nrf2) and signaling pathways (cAMP-PKA, PI3K-MAPK). DNA oxidation, particularly the formation of 8-oxoG, activates base excision repair (BER) pathways; accumulation of lesions may induce double-strand breaks and interfere with meiotic progression. In many studies, ROS-induced apoptosis is linked to cytochrome C release and caspase-3/9 9 (CASP3/9) activation [86,87,88]. Porcine oocytes exposed to MPs exhibit impaired choline and creatine metabolism, reducing cellular energy supply, as well as decreased GSH levels [27]. Additionally, ROS-driven dysregulation of microRNAs (miRNAs), including miR-23a, miR-141, and miR-132, has been linked to inhibition of antioxidant enzymes, further compromising redox homeostasis [89, 90]. Decabromodiphenyl ether (BDE-209), an industrial organic compound, has been shown to induce significant meiotic defects and fragmentation in murine oocytes, along with a decreased polar body extrusion (PBE) rate [91]. Comparable effects have been observed in mouse oocytes exposed to antimony (Sb) [92], porcine oocytes exposed to cadmium (Cd) [93], and methylmercury chloride (MMC) [28], and in the presence of phenanthrene (PHE) [30], which additionally perturbs calcium homeostasis. Agricultural chemicals are another source of oxidative stress. 3-methyl-4-nitrophenol (PNMC), a byproduct of insecticides and fuel combustion, impair mitochondrial function and ATP production in oocytes, disrupts spindle assembly, increases ROS levels, and induces apoptosis [94]. Similarly, perfluorooctane (PFOS) [31], a surfactant used in agricultural practices, can interfere with meiotic progression in mouse oocytes and modify histone methylation patterns. Lifestyle-related exposures, including smoking, diet, and chronic stress, have been modeled in both humans and animals. In vitro nicotine exposure increases ovarian apoptosis, presumably as an effect of DNA damage induced by ROS. Clinically, women who smoke show poorer IVF outcomes, including fewer retrieved oocytes and reduced fertilization rates [95, 96]. Mouse studies demonstrate that passive smoking also affects female reproductive health. Exposure to cigarette smoke or cigarette smoke condensate (CSC) leads to fragmented eggs and embryos with elevated ROS, increased apoptosis, shortened telomeres, and altered expression of Oct4, a transcription factor crucial for early embryonic development [33]. High consumption of ultra-processed or contaminated foods also promotes oxidative damage. Exposure to mycotoxins from vegetables and fruits, such as 3-nitropropionic acid (3-NP), disrupts mitochondrial function, decreases ATP production, increases ROS, and results in spindle defects and elevated apoptosis [97]. Moreover, mouse studies provide valuable insights into the influence of mental well-being on female fertility. Chronic psychosocial stress in mice elevates ROS in GCs, impairing follicular development and promoting apoptosis [24, 98]. The rapid development of biomedical technologies introduces additional concerns. Nano-graphene oxide (nGO), a carbon-based nanomaterial used for drug delivery, disrupts meiotic division in GV porcine oocytes by reducing α-tubulin acetylation and impairing kinetochore-microtubule attachments, ultimately compromising embryo development, particularly under oxidative stress [32]. These findings underscore the need for a comprehensive assessment of reproductive safety in emerging nanomaterials. Pathological models demonstrate that ROS-driven mechanisms are involved in reproductive disorders. In DHEA-induced PCOS mice, oocytes show morphological abnormalities, reduced polar body extrusion, and excessive cytoplasmic ROS. Epigenetic alterations, including decreased DNA methylation and modified histone marks (H3K9, H4K12), further compromise oocyte quality and meiotic progression [99]. Similarly, endometriosis in both patients and animal models is associated with elevated ROS in follicular fluid, NLRP3 inflammasome activation, GC pyroptosis, and loss of follicular integrity, collectively impairing oocyte maturation and fertility [71]. Therefore, animal and human models illustrate how environmental, lifestyle, and pathological stressors accelerate oocyte aging through ROS accumulation, impairing many essential cellular processes. These findings provide critical insight for developing interventions aimed at preserving oocyte quality and reproductive longevity. It is worth noting that although experimental models provide valuable mechanistic insights into how environmental stressors induce oxidative damage in oocytes, the translational relevance of this evidence requires further investigation and comparison with the human oocyte, which is often an ethical issue. Therefore, these approaches may not fully reflect the chronic, low-level environmental exposures typically experienced by women [100]. Moreover, species differences in folliculogenesis, mitochondrial dynamics, and reproductive lifespan complicate the direct extrapolation of findings from rodents or livestock to human reproductive biology. In vitro systems also lack the complex endocrine, metabolic, and immune interactions that shape the ovarian microenvironment in vivo [101, 102]. Another important limitation is that most studies investigate the effects of individual toxicants in isolation, whereas real-world environmental exposure involves complex mixtures of pollutants [100]. The potential synergistic or additive interactions between these factors remain poorly understood, despite growing evidence that combined exposures may amplify oxidative stress and reproductive toxicity [103]. Consequently, although current evidence strongly supports oxidative stress as a mediator of environmentally induced oocyte damage, we advocate conducting longitudinal human studies, mixture-based exposure analyses, and standardized exposure assessments to clarify the clinical relevance of these findings. Interventions targeting environmental ros: antioxidants, diet, and lifestyle Oxidative stress induced by environmental ROS disrupts spindle assembly, impairs chromosome segregation, compromises mitochondrial integrity, and interferes with meiotic progression. Therefore, strategies that restore redox balance are essential for preserving oocyte quality during aging. These approaches include antioxidant supplementation, dietary patterns, and lifestyle interventions. Importantly, the level of evidence supporting antioxidant-based interventions varies substantially across compounds. While numerous antioxidants demonstrate protective effects in cellular and animal models, the number of well-controlled human clinical trials remains limited. Furthermore, many studies rely on surrogate endpoints, such as oocyte maturation, fertilization rate, or oxidative stress biomarkers, rather than on clinically meaningful reproductive outcomes, such as the live birth rate. Consequently, although antioxidant supplementation is a promising strategy to mitigate oxidative damage in oocytes, the translational strength of evidence varies considerably across compounds and warrants careful evaluation. Natural and synthetic antioxidants (Fig. 1) represent the primary strategy for limiting ROS accumulation and may be administered in vitro, through diet, or pharmacologically. The most consistently studied compounds include melatonin [83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106], coenzyme Q10 (CoQ10), [107, 108] and N-acetylcysteine (NAC) [109, 110]. Melatonin improves oocyte maturation and embryo development while reducing ROS and stabilizing mitochondrial and calcium homeostasis, particularly in IVF patients with DOR or advanced age. Combination with vitamin E [83] or delivery in nanocomplexes with bilirubin [106] may further enhance its efficacy. CoQ10 supports mitochondrial function, delays ovarian reserve decline, and improves ovulation and embryo development in aged models[107, 108]. Its mitochondria-targeted analog, MitoQ, provides stronger protection by reducing ROS, increasing GSH, and limiting apoptosis, thereby preserving mitochondrial integrity [111,112,113]. NAC acts as both a ROS scavenger and metabolic modulator, improving ovarian function, restoring mitochondrial membrane potential, enhancing telomere maintenance, and improving IVF outcomes in experimental and clinical studies [109, 110]. Several additional antioxidants exhibit protective effects, mainly by reducing ROS and stabilizing mitochondria. Resveratrol (3,5,4-trihydroxy-trans-stilbene) attenuates post-ovulatory aging by increasing GSH levels and activating mitochondrial biogenesis regulators, such as SIRT1 and PGC-1α [114, 115]. Taurine restores mitochondrial function under microplastic-induced oxidative stress [116], while ergothioneine (EGT) enhances antioxidant defense through Nrf2-related pathways [117]. Metabolic precursors of NAD +, such as nicotinamide mononucleotide (NMN) and nicotinamide (NR), increase intracellular NAD + availability, thereby reducing meiotic defects, supporting telomere maintenance, and improving follicle development [118, 119]. Similarly, GSH supplementation restores redox homeostasis and DNA integrity following oxidative damage [93]. Other compounds primarily act by limiting ROS accumulation and preserving mitochondrial activity. Salidroside (Sal) increases ATP production and antioxidant capacity [120], diosmetin reduces oxidative stress and apoptosis [121], and L-carnitine enhances antioxidant enzyme activity and mitochondrial metabolism [122]. Overall, antioxidants that target mitochondrial function and redox homeostasis represent a promising approach to improving oocyte competence. However, the robustness of available evidence differs markedly between compounds. Melatonin and NAC have been evaluated in several human studies, particularly in patients undergoing ART, and demonstrate moderate clinical support for improving oocyte quality and fertilization outcomes. In contrast, many other compounds are supported primarily by preclinical data (Table 1). Despite providing important mechanistic insights, require further validation in randomized clinical trials (RCTs). Future research should prioritize standardized clinical endpoints, including live birth rate, cumulative pregnancy rate, and long-term offspring health, to better assess the true reproductive benefits of antioxidant interventions. In addition to small molecules, proteins that regulate the mitochondrial stress response also contribute to redox homeostasis. NCOA7 protects granulosa cells from senescence [123], whereas rapamycin promotes the removal of dysfunctional mitochondria through mTOR-dependent pathways [124]. Elamipredite improves mitochondrial structure and ATP production [125], while SIRT3 limits oxidative damage by regulating mitochondrial antioxidant enzymes [62]. Polyphenols and other bioactive compounds provide complementary protection against ROS-induced meiotic defects. Astaxanthin reduces oxidative stress and apoptosis and improves organelle function, thereby improving ART outcomes [126,127,128]. Epigallocatechin-3-gallate (EGCG) stabilizes mitochondrial activity and reduces ROS [129], whereas imperatorin (IMP) enhances antioxidant enzyme activity and supports embryo development [130]. Resolvin E1 (RvE1) improves cumulus-oocyte communication and activates antioxidant defenses [131], while growth-arrest-specific 6 (GAS6) reduces ROS and alleviates age-related meiotic abnormalities [132]. Dietary patterns also significantly influence oxidative balance. Diets rich in polyphenols, carotenoids, vitamins C and E, selenium, and zinc help reduce systemic oxidative stress and support oocyte quality [133, 134]. The Mediterranean diet, characterized by high intake of antioxidants and omega-3 fatty acids, improves metabolic homeostasis and reduces inflammation, thereby supporting reproductive competence [135]. Specific dietary bioactives further strengthen antioxidant defenses [136]. Compounds such as lycopene [137], fisetin [138], β-carotene [139], and sulforaphane (SFN) protect mitochondria and activate cytoprotective antioxidant pathways [97]. Diet also influences the gut microbiome, which modulates systemic oxidative stress. Microbial dysbiosis is associated with increased ROS and inflammatory signaling, whereas diets rich in fiber and polyphenols help restore microbial balance and indirectly support oocyte redox homeostasis [140]. Lifestyle factors further shape oxidative balance. The Oxidative Balance Score (OBS) integrates diet, physical activity, Body Mass Index (BMI), smoking, alcohol consumption, stress, and sleep, and correlates with reproductive antioxidant status. These observations highlight the importance of a holistic strategy combining molecular interventions with diet and lifestyle optimization [21, 134, 141] Despite extensive research, key aspects of oocyte aging remain elusive. Oocytes accumulate molecular damage over decades, making them particularly susceptible to oxidative stress, mitochondrial dysfunction, and epigenetic alterations [34,35,36]. With increasing environmental pollution and delayed childbearing [7,8,9], understanding the interaction between environmental exposures and redox imbalance has become critical for preserving reproductive potential. Emerging reproductive technologies, including mitochondrial replacement techniques, cytoplasmic transfer, and CRISPR-based approaches, offer potential strategies for restoring oocyte competence [47, 142,143,144]. Advanced experimental systems, such as ovarian organoids, may further improve mechanistic studies. However, current models have important limitations, including species differences, incomplete representation of the ovarian microenvironment in vitro, and limited availability of human oocytes. In addition, male factors such as paternal age and environmental exposure contribute to ROS-related reproductive outcomes, highlighting the need for integrated studies; however, this goes beyond the major focus of this review and will not be discussed in detail here. Finally, although antioxidant supplementation is a promising strategy to mitigate oxidative damage in oocytes, the translational strength of evidence varies considerably across compounds, and this review advocates for a careful evaluation. A summarizing overview of preclinical and clinical evidence for selected antioxidants which influence oocyte aging are listed in Table 1.

and future research directions In conclusion, there is no doubt that systemic physiological health in females is significantly modulated by ovarian function, which extends beyond reproductive capacity to influence metabolic stability and survival [145]. The transition into a post-reproductive state, such as menopause or estropause, is associated with the development of a systemic pro-oxidant environment characterized by increased reactive oxygen species and diminished antioxidant defenses [146]. This physiological shift often results in pronounced metabolic dysregulation, including increased adiposity, insulin resistance, and impaired glucose tolerance [146]. Besides, calorie restriction (CR) has been shown to be an effective strategy for mitigating the aforementioned age-related declines, preserving ovarian reserve, enhancing antioxidant capacity, and improving biochemical profiles by reducing visceral fat and increasing insulin sensitivity [146]. Furthermore, the maintenance of health in post-reproductive environments is partially mediated by ovarian somatic tissues, which appear to function independently of germ-cell or follicle-driven hormonal output [145, 147]. Recent evidence suggests that these somatic components can rejuvenate circulating apolipoproteins, such as ApoA-I and ApoE, thereby promoting cognitive health and reducing neuroinflammatory signaling in the brain [147]. Consequently, integrating dietary modifications, such as CR, alongside preservation of ovarian somatic function represents a critical pathway for enhancing female health span and resisting oxidative stress [145, 147]. Despite the growing interest in oxidative stress biomarkers, their clinical utility in reproductive medicine remains uncertain. Many markers, including MDA and 8-OHdG, reflect general oxidative damage rather than oocyte-specific processes. In addition, substantial variability exists across studies in sample type, measurement techniques, and patient populations. Importantly, relatively few studies have directly linked these biomarkers to clinically meaningful outcomes such as live birth rates, which remain the most relevant endpoint in assisted reproduction. In summary, maintaining oocyte quality and delaying reproductive aging requires a strategy that connects advanced biomedical methods with environmental prevention and lifestyle optimization. As environmental challenges grow and demographic changes accelerate, this integrated approach becomes an essential priority for both modern medicine and public health. Future research should prioritize clinically relevant biomarkers of oocyte aging and adopt interdisciplinary approaches combining molecular biology, environmental toxicology, metabolomics, and bioinformatics. Preventive strategies, including environmental regulation and lifestyle interventions, remain essential for protecting reproductive health. We advocate conducting prospective clinical studies to validate proposed biomarkers, to provide improved mechanistic understanding of the interactions among oxidative stress, genomic stability, and metabolic regulation in oocyte aging, and to allow a rigorous evaluation of antioxidant and environmental interventions with clear clinical endpoints. Data Availability not applicable.

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During the preparation of this manuscript, the authors used Grammarly for the purposes of improving English style and writing. Figures have been created with Biorender. The authors have reviewed and edited the output and take full responsibility for the content of this publication. Funding Open Access funding enabled and organized by Projekt DEAL. This research was funded by the National Science Centre, grant number OPUS28/2024/55/B/NZ9/02063. This work was also supported by the Nicolaus Copernicus University IDUB programme through funding awarded to the FemLife_OMICS Research Team for Women's Health Across the Lifespan. Author information Authors and Affiliations Contributions K.R. and P.K.: writing, review, and editing; P.K.: visualization, P.K.: funding acquisition. All authors have read and agreed to the published version of the manuscript.” Corresponding author Ethics declarations Ethics statement Not applicable. Informed consent statement Not applicable. Conflicts of interest The authors declare no conflicts of interest. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. About this article Cite this article Ratajewska, K., Kordowitzki, P. Oocyte aging in focus: Environmental and endogenous stressors driving reproductive potential decline. GeroScience (2026). https://doi.org/10.1007/s11357-026-02243-6 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s11357-026-02243-6