Research progress on multi-mechanism analysis and protection strategies of ovarian aging and fertility decline.

Although considerable progress has been made in the field of reproductive aging and fertility preservation, there are still many problems that need to be solved. Addressing these gaps will be essential for shifting the field from largely supportive interventions toward mechanism-informed, durable fertility protection. Future progress will depend on high-resolution characterization of ovarian aging across spatial, temporal, and cellular dimensions. Advanced platforms such as single-cell and spatial multi-omics, integrated with epigenomic, metabolomic, and proteomic profiling [ 14 , 97 , 134 – 138 ], will be critical for elucidating how genomic instability, telomere attrition, mitochondrial dysfunction, chronic low-grade inflammation, and oxidative stress converge within specific ovarian cell populations [ 6 , 14 , 139 ]. Such approaches may uncover early molecular inflection points that precede irreversible follicle loss, thereby identifying actionable targets for timely intervention [ 14 , 15 ]. Fertility decline is highly heterogeneous, shaped by the interplay of genetic background, reproductive endocrine dynamics, metabolic health, immune status, and environmental exposures [ 10 , 18 , 44 , 47 , 88 ]. Future fertility preservation paradigms should therefore move beyond age-based risk assessment toward biomarker-driven stratification [ 24 , 136 , 140 – 143 ]. Integrating genomic variants, telomere metrics, hormonal profiles, metabolic indicators, and inflammatory signatures may enable individualized prediction models and tailored intervention programs [ 1 , 47 , 141 , 144 , 145 ]. These programs could combine precision hormone modulation, pathway-specific pharmacologic agents, and targeted anti-inflammatory or antioxidant strategies to optimize both efficacy and safety. The emergence of next-generation anti-aging interventions, including senolytics, senomorphics, telomere-stabilizing agents, mitochondrial modulators, and stress-response regulators, offers new opportunities for ovarian protection [ 6 , 35 ]. However, their translation will require careful evaluation of timing, dosage, long-term safety, and combinatorial effects with hormonal and lifestyle interventions. Bridging the gap between experimental models and clinical application remains a major challenge, underscoring the need for well-designed longitudinal studies and controlled clinical trials [ 16 , 95 , 132 ]. As fertility preservation technologies become increasingly proactive and intervention-oriented, ethical questions regarding medicalization of aging, equitable access, and long-term outcomes for offspring must be addressed [ 119 , 125 , 146 , 147 ]. Establishing robust regulatory frameworks, standardized outcome measures, and long-term follow-up cohorts will be essential to ensure responsible clinical implementation [ 20 , 115 , 118 ]. In summary, the future of fertility preservation lies in integrating mechanistic insights with precision medicine, translational rigor, and ethical foresight [ 1 , 82 , 95 ]. Only through coordinated efforts spanning basic science, clinical research, and public health policy can clinically responsible and evidence-based strategies may be developed to better support reproductive health across the reproductive lifespan.

With the acceleration of population aging and the increasing postponement of childbearing, age-related fertility decline has become an important challenge in reproductive medicine and public health [ 1 , 2 ]. Aging affects multiple physiological systems and has profound effects on reproductive function, particularly ovarian function and oocyte competence [ 3 ]. Female fertility declines progressively with age, with a marked acceleration after the age of 30 years [ 3 , 4 ]. This decline is characterized not only by reduced natural conception rates, but also by progressive decreases in ovarian reserve and oocyte quality [ 5 ]. Over the past decades, extensive research has identified numerous molecular, cellular, and environmental factors contributing to reproductive aging, including genetic instability, oxidative stress, mitochondrial dysfunction, hormonal imbalance, metabolic disturbances, and chronic inflammation [ 2 , 6 – 12 ]. Despite these advances, existing literature often addresses these mechanisms in isolation, providing fragmented insights that do not fully explain how diverse insults are integrated within the ovary to drive progressive functional decline [ 2 , 6 ]. In particular, it remains difficult to clearly distinguish primary drivers of ovarian aging from secondary adaptive or downstream changes, as many pathways are highly interconnected and supported predominantly by experimental or preclinical evidence. In this review, we focus specifically on ovarian aging and summarize current evidence within an ovary-centered, multi-mechanistic framework. Rather than proposing a definitive causal hierarchy, we aim to integrate genetic, metabolic, cellular stress, signaling, and microenvironmental alterations into a conceptual model that may help explain how diverse age-associated insults collectively contribute to disrupted follicular homeostasis, accelerated follicle loss, and declining oocyte competence. By synthesizing these interconnected mechanisms alongside current and emerging fertility preservation strategies, this review seeks to provide a more integrative perspective on ovarian aging and to highlight potential directions for mechanism-oriented intervention and future translational research.

This narrative review is based on a comprehensive literature search of the PubMed database up to 2025, focusing on studies related to ovarian aging, fertility decline, and fertility preservation. Relevant original research articles, clinical studies, and authoritative reviews published in English were included, with emphasis on studies directly related to ovarian mechanisms and age-associated reproductive decline. Ovarian aging is a complex and multifactorial process involving interconnected molecular, cellular, and tissue-level alterations rather than a single dominant pathway [ 6 , 8 , 9 , 13 ]. Accumulating evidence has associated ovarian aging with genomic instability, telomere attrition, mitochondrial dysfunction, oxidative stress, chronic inflammation, altered signaling activity, and progressive remodeling of the ovarian microenvironment [ 2 , 6 , 8 , 13 – 16 ]. However, the temporal and causal relationships among these processes remain incompletely understood, and many mechanisms are highly interdependent and context dependent. In particular, several pathways implicated in follicular activation, stress adaptation, and tissue remodeling have been demonstrated primarily in experimental or preclinical models, whereas their precise contribution to physiological human ovarian aging remains under active investigation. Rather than proposing a definitive mechanistic hierarchy, this section synthesizes current evidence within an integrative conceptual framework that organizes these processes across molecular, cellular, signaling, and tissue levels (Fig.  1 ). As illustrated in Fig.  1 , genomic instability and mitochondrial dysfunction are discussed as major early-associated alterations that may contribute to cellular stress responses, signaling dysregulation, and progressive deterioration of the ovarian microenvironment. These interconnected changes are ultimately associated with impaired follicular homeostasis, accelerated follicle loss, and declining oocyte competence. Importantly, the relationships among these processes are likely bidirectional and mutually reinforcing rather than strictly linear, and the proposed framework is intended primarily as an organizational model for integrating current evidence on ovarian aging. Fig. 1 Conceptual framework of interconnected mechanisms underlying ovarian aging. This schematic summarizes major molecular, cellular, and tissue-level processes implicated in ovarian aging and age-related fertility decline. Aging-associated alterations, including genomic instability, telomere attrition, mitochondrial dysfunction, and impaired cellular homeostasis, are linked to oxidative stress, cellular senescence, apoptotic signaling, and altered stress responses in oocytes and ovarian somatic cells. Concurrently, dysregulation of signaling pathways involved in follicle activation and metabolic adaptation (including PI3K-AKT-mTOR, FOXO, AMPK-Sirtuin, and Hippo signaling) may contribute to disturbances in follicle dormancy, survival, and ovarian homeostasis. At the tissue level, chronic inflammation, endocrine alterations, stromal remodeling, and disrupted intercellular communication further influence the ovarian microenvironment. Collectively, these interconnected processes are associated with accelerated follicle depletion and declining oocyte quality, the two major functional features of ovarian aging. The figure is intended as an integrative conceptual framework to organize current evidence rather than as a definitive linear mechanistic sequence Conceptual framework of interconnected mechanisms underlying ovarian aging. This schematic summarizes major molecular, cellular, and tissue-level processes implicated in ovarian aging and age-related fertility decline. Aging-associated alterations, including genomic instability, telomere attrition, mitochondrial dysfunction, and impaired cellular homeostasis, are linked to oxidative stress, cellular senescence, apoptotic signaling, and altered stress responses in oocytes and ovarian somatic cells. Concurrently, dysregulation of signaling pathways involved in follicle activation and metabolic adaptation (including PI3K-AKT-mTOR, FOXO, AMPK-Sirtuin, and Hippo signaling) may contribute to disturbances in follicle dormancy, survival, and ovarian homeostasis. At the tissue level, chronic inflammation, endocrine alterations, stromal remodeling, and disrupted intercellular communication further influence the ovarian microenvironment. Collectively, these interconnected processes are associated with accelerated follicle depletion and declining oocyte quality, the two major functional features of ovarian aging. The figure is intended as an integrative conceptual framework to organize current evidence rather than as a definitive linear mechanistic sequence Accumulating evidence suggests that loss of genomic integrity is closely associated with ovarian aging and age-related fertility decline. Both inherited genetic variation and progressive accumulation of DNA damage may contribute to impaired ovarian reserve and reduced oocyte competence. Congenital genetic defects that impair DNA repair capacity or chromosomal stability, such as BRCA1/2 mutations, Turner syndrome (X chromosome monosomy), and fragile X chromosome premutation (FMR1), directly compromise ovarian reserve and oocyte quality by accelerating follicular atresia or disrupting follicle development [ 17 – 19 ]. In the general population, aging is accompanied by progressive accumulation of nuclear and mitochondrial DNA damage, increasing chromosomal aneuploidy, and declining DNA repair efficiency in oocytes, which remain arrested in prophase I for prolonged periods [ 6 , 8 , 9 ]. Accordingly, strategies aimed at enhancing DNA repair capacity or delaying the accumulation of genomic damage have emerged as important research priorities, while early genetic counseling and fertility preservation approaches, such as oocyte cryopreservation, are particularly relevant for individuals harboring high-risk genetic variants [ 20 , 21 ]. Telomere attrition is another prominent feature associated with ovarian aging and has been proposed as a potential molecular indicator linking chronological aging to reproductive lifespan [ 22 – 24 ]. Oocyte telomere length is largely established during fetal development and progressively erodes during the prolonged postnatal quiescent phase due to limited telomerase activity and cumulative oxidative damage [ 24 ]. Shortened telomeres may impair meiotic fidelity by affecting chromosome end protection, homologous pairing, and spindle organization, thereby increasing the risk of chromosomal segregation errors and embryonic aneuploidy. Telomere shortening in ovarian cells is closely related to the exhaustion of the follicle pool, which further leads to abnormal oocyte development and decreased ovarian function [ 25 ]. In granulosa cells, telomere shortening has also been associated with reduced proliferative capacity and impaired metabolic support for developing oocytes [ 26 ]. In the context of fertility preservation, the impact of telomere shortening on germ cells is particularly important. Studies have found that telomere length in oocytes is closely related to the success rate of in vitro fertilization (IVF), and shorter telomeres may lead to lower fertilization rates and embryo development potential [ 24 , 27 ]. Consistently, shortened telomeres in oocytes or granulosa cells are strongly associated with diminished ovarian reserve, premature ovarian insufficiency, and adverse assisted reproductive outcomes [ 26 , 28 , 29 ]. Collectively, genomic instability and telomere attrition are widely considered important components of ovarian aging biology. Although their precise causal relationships with other aging-associated processes remain incompletely defined, current evidence suggests that they may interact closely with mitochondrial dysfunction, oxidative stress, and altered cellular homeostasis during reproductive aging. Mitochondrial dysfunction is widely recognized as an important feature of ovarian aging and is closely associated with oxidative stress, impaired energy metabolism, and disrupted cellular homeostasis [ 6 , 8 , 16 ]. In aging ovarian cells, particularly oocytes and granulosa cells, accumulated nuclear and mitochondrial DNA damage compromises mitochondrial biogenesis and respiratory efficiency, resulting in impaired adenosine triphosphate (ATP) production and disrupted energy homeostasis [ 8 , 9 , 30 ]. Concomitantly, dysfunctional mitochondria may contribute to excessive reactive oxygen species (ROS) production, reflecting a breakdown of redox balance and predisposing cells to oxidative injury [ 6 , 8 , 31 ]. Under physiological conditions, moderate levels of ROS serve essential roles in intracellular signaling and metabolic regulation; however, excessive ROS generation overwhelms antioxidant defenses, resulting in oxidative stress [ 32 ]. This imbalance leads to cumulative damage to mitochondrial membranes, proteins, and DNA, further impairing mitochondrial function and establishing a self-perpetuating cycle of energetic failure and redox dysregulation [ 33 , 34 ]. In this manner, mitochondrial dysfunction and oxidative stress appear to interact bidirectionally, reinforcing its central role as a mechanistic hub in the ovarian aging cascade. Beyond intrinsic molecular damage, metabolic dysregulation emerges as a downstream consequence of mitochondrial dysfunction and impaired cellular homeostasis, while simultaneously representing a modifiable node that influences the pace of ovarian aging [ 6 , 9 , 16 , 35 , 36 ]. Maintenance of a balanced diet, adequate nutrient intake, and healthy body weight is essential for sustaining ovarian metabolic competence, whereas unhealthy dietary patterns, obesity, insulin resistance, and metabolic disorders such as polycystic ovary syndrome (PCOS) further reinforce this vicious cycle by exacerbating oxidative stress, endocrine imbalance, and mitochondrial inefficiency [ 37 – 39 ]. These external factors further aggravate mitochondrial stress, oxidative damage, and hormonal dysregulation, thereby accelerating ovarian functional decline [ 8 , 16 , 31 ]. Accumulating evidence indicates that both the quality and quantity of carbohydrate intake are particularly relevant to female fertility, especially in individuals with impaired lipid or glucose metabolism, and appropriate carbohydrate management may improve reproductive outcomes [ 40 ]. Dietary patterns rich in antioxidants, including vitamins C and E and glutathione, can partially counteract excessive ROS and mitigate oxidative stress-mediated damage to germ cells [ 37 ], while plant-based and Mediterranean dietary patterns have been consistently associated with improved fertility parameters [ 41 , 42 ], reflecting a more favorable metabolic and inflammatory profile. Metabolic disorders such as metabolic syndrome and PCOS, along with micronutrient deficiencies, reinforce this pathological cascade by exacerbating inflammation, oxidative stress, endocrine imbalance, and mitochondrial inefficiency [ 37 , 43 , 44 ]. Notably, insulin resistance has been shown to reduce the metabolic efficiency of oocytes, impairing their developmental competence and fertilization potential [ 11 , 12 , 40 , 44 , 45 ]. Overall, metabolic dysregulation interacts closely with mitochondrial dysfunction, oxidative stress, and endocrine imbalance during ovarian aging, and may influence the progression of ovarian functional decline through multiple interconnected pathways. Oxidative stress is widely recognized as an important component of ovarian aging and has been closely associated with impaired oocyte quality, granulosa cell dysfunction, and altered follicular homeostasis [ 16 ]. Excessive ROS not only directly damages oocytes and granulosa cells but also activates stress-responsive pathways that promote cellular senescence, apoptotic cell loss, and impaired embryonic developmental potential, leading to embryo implantation failure, miscarriage, and placental abnormalities [ 32 , 46 – 48 ]. Free radicals, especially ROS, are byproducts produced during cell metabolism. The generation of free radicals and excessive ROS leads to oxidative stress, which damages the membrane structure, DNA, and mitochondrial function of germ cells, thereby causing a series of problems in male and female reproduction [ 49 , 50 ]. Excessive ROS directly impairs oocyte quality and disrupts granulosa cell function, leading to defective follicular development and reproductive endocrine dysregulation [ 13 , 46 ]. Oxidative stress can trigger both intrinsic (mitochondrial-mediated) and extrinsic (death receptor-mediated) apoptotic pathways in ovarian cells, accelerating oocyte and granulosa cell loss and contributing to premature depletion of the follicle reserve [ 7 , 51 ]. Collectively, oxidative stress-mediated damage to germ cells represents a shared biological mechanism underlying age-related fertility decline across sexes [ 32 , 52 ]. Beyond direct cytotoxic effects, persistent oxidative stress has been implicated in the induction of cellular senescence, a stable state of irreversible cell-cycle arrest that represents a key execution outcome of aging-related stress [ 13 , 25 ]. Cellular senescence can be triggered by multiple insults, including persistent oxidative damage, DNA lesions, telomere attrition, and metabolic dysfunction [ 13 , 53 ]. The mechanism of cellular senescence is very complex, involving multiple aspects such as cell cycle arrest, senescence-associated secretory phenotype (SASP), telomere shortening, stress-induced premature senescence, macromolecular damage, and metabolic disorders [ 25 , 54 , 55 ]. These mechanisms may lead to decreased ovarian function and thus affect women’s fertility [ 56 ]. Senescent ovarian cells exhibit profound functional alterations, including impaired metabolic activity, reduced endocrine responsiveness, and disrupted cell-cell communication [ 13 , 56 ]. Although senescent cells lose proliferative capacity, they remain metabolically active and secrete a complex array of pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes, collectively referred to as the SASP [ 57 ]. In the ovary, sustained SASP may aggravate the deterioration of the tissue microenvironment and further damage follicle function [ 56 ]. In parallel with senescence, dysregulation of apoptotic pathways represents another critical fate decision driven by chronic oxidative stress. Persistent activation of stress-responsive signaling cascades promotes inappropriate apoptosis of oocytes and granulosa cells, thereby reducing the number of functional ovarian cells available to support follicular growth and maturation [ 7 , 13 , 51 ]. Together, oxidative stress-associated senescence and apoptosis are increasingly recognized as important cellular responses during ovarian aging. These processes may contribute to impaired follicular homeostasis, reduced ovarian reserve, and declining oocyte competence, while also interacting closely with mitochondrial dysfunction, inflammatory signaling, and alterations in the ovarian microenvironment. However, the precise temporal and causal relationships among these mechanisms remain incompletely understood. In addition to molecular damage and cellular stress responses, multiple signaling pathways participate in the regulation of follicle dormancy, activation, survival, and metabolic adaptation within the ovary [ 6 , 25 , 58 ]. Among these, the PI3K/AKT/mTOR, FOXO3, Hippo, AMH, and AMPK-Sirtuin pathways have been extensively studied for their roles in primordial follicle homeostasis and ovarian physiology [ 15 , 58 – 61 ]. Experimental studies have demonstrated that disruption of these pathways can alter follicle activation dynamics and ovarian reserve maintenance [ 58 , 61 ]. Although these signaling networks are strongly implicated in ovarian aging, the extent to which their dysregulation directly drives physiological ovarian aging in humans remains incompletely understood. Therefore, these pathways are best viewed as candidate regulatory hubs that may contribute to age-associated ovarian dysfunction through complex interactions with metabolic stress, oxidative damage, and microenvironmental alterations. The phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway is a central regulator of primordial follicle activation and dormancy [ 61 ]. Under physiological conditions, suppression of PI3K activity by PTEN and inhibition of mTORC1 by the TSC1/TSC2 complex preserve FOXO3 in its non-phosphorylated, nuclear state, thereby actively maintaining primordial follicle dormancy [ 61 ]. Disruption of these regulatory mechanisms, including PTEN or TSC deficiency, can induce widespread primordial follicle activation and accelerated depletion of the follicle reserve in animal models [ 58 ]. Similar signaling alterations have also been proposed to contribute to age-associated ovarian dysfunction, although direct evidence linking physiological ovarian aging to sustained PI3K/AKT/mTOR overactivation in humans remains limited. FOXO3 functions as an important downstream effector of PI3K/AKT signaling and plays a key role in maintaining primordial follicle dormancy [ 15 , 59 , 60 ]. Age-associated reductions in nuclear FOXO3 localization, driven by sustained PI3K/AKT signaling or impaired energy sensing, therefore compromise both the preservation of the follicle pool and oocyte quality [ 58 ]. FOXO3 also participates in oxidative stress resistance and DNA repair pathways, suggesting a broader role in oocyte homeostasis [ 60 ]. This loss of FOXO3 function is further exacerbated by declining levels of anti-Müllerian hormone (AMH), a granulosa cell-derived paracrine signal that physiologically restrains primordial follicle recruitment [ 58 ]. Declining AMH levels during reproductive aging may reduce this inhibitory restraint and thereby influence follicle activation dynamics, although the precise contribution of AMH signaling alterations to physiological ovarian aging remains under investigation [ 3 , 58 , 62 ]. Mechanical and microenvironmental cues also critically shape follicle behavior through the Hippo signaling pathway [ 63 ]. In the intact ovarian cortex, high tissue density and cell-cell contact maintain Hippo pathway activity, leading to phosphorylation and cytoplasmic sequestration of YAP/TAZ and suppression of pro-growth transcriptional programs [ 64 , 65 ]. Age-related stromal remodeling, inflammation, or fibrosis, as well as physical disruption during ovarian surgery or in vitro culture, attenuate Hippo signaling, permitting nuclear translocation of YAP/TAZ and induction of growth-promoting factors such as CTGF and CYR61 [ 17 , 66 ]. These observations suggest that mechanical signaling and tissue remodeling may influence follicle activation behavior, particularly under conditions of tissue injury or altered ovarian architecture [ 63 , 67 , 68 ]. However, the specific role of Hippo pathway dysregulation in natural ovarian aging remains incompletely defined. Counterbalancing these pro-activation pathways, the AMP-activated protein kinase (AMPK)-Sirtuin axis serves as a key energy-stress-responsive protective network [ 58 , 69 ]. AMPK senses cellular energy deficits through changes in the AMP/ATP ratio and suppresses mTORC1 activity while directly supporting FOXO3 activation [ 6 , 15 ]. In parallel, NAD⁺-dependent sirtuins, particularly NAD-dependent deacetylase sirtuin-1 (SIRT1) and NAD-dependent deacetylase sirtuin-3 (SIRT3), stabilize FOXO3 through deacetylation and mitigate oxidative stress by enhancing mitochondrial resilience [ 36 , 69 , 70 ]. During ovarian aging, mitochondrial dysfunction, reduced NAD⁺ availability, and chronic inflammation collectively blunt AMPK and sirtuin signaling [ 35 , 36 , 58 ]. The collapse of this adaptive network diminishes cellular stress tolerance, weakens maintenance of follicle dormancy, and increases susceptibility to oxidative and metabolic injury, thereby accelerating follicle loss and oocyte deterioration [ 6 , 58 ]. Nevertheless, the extent to which these alterations directly determine ovarian aging trajectories in humans requires further investigation. Importantly, these signaling alterations converge on downstream cell-cycle control mechanisms. Although primordial oocytes are arrested in prophase I, granulosa cells and activated follicles rely on tightly regulated cyclin-dependent kinase (CDK) activity to coordinate proliferation, differentiation, and DNA damage checkpoints [ 66 , 71 ]. Dysregulated PI3K/AKT/mTOR signaling, mitochondrial ATP insufficiency, and hormonal fluctuations can disrupt CDK-cyclin balance and checkpoint fidelity, promoting genomic instability, aberrant follicle activation, or premature atresia [ 25 , 30 , 72 , 73 ]. Thus, cell-cycle dysregulation in the aging ovary is best viewed not as an isolated defect, but as a downstream manifestation of signaling network reprogramming under chronic stress [ 13 , 66 ]. Collectively, PI3K/AKT/mTOR, FOXO3, AMH, Hippo, and AMPK-Sirtuin pathways form an interconnected regulatory network involved in follicle homeostasis, stress adaptation, and ovarian metabolic regulation [ 6 , 15 , 58 , 59 , 63 ]. Studies have demonstrated that perturbation of these pathways can profoundly alter follicle dynamics and ovarian reserve maintenance, particularly in animal and in vitro models [ 58 , 69 ]. Although the precise contribution of each pathway to physiological ovarian aging in humans remains incompletely defined, accumulating evidence suggests that dysregulation of these signaling networks may participate in age-associated ovarian dysfunction through interactions with oxidative stress, mitochondrial impairment, and altered tissue homeostasis [ 11 , 14 , 15 , 36 , 66 ]. Consequently, modulation of these pathways, including mTOR inhibition, metabolic regulation, and restoration of energy-sensing mechanisms, has emerged as a promising strategy for preserving ovarian function and delaying reproductive aging [ 35 , 59 , 70 , 74 ]. In addition to intracellular molecular and signaling alterations, ovarian aging is accompanied by progressive changes in the local ovarian microenvironment, including chronic low-grade inflammation, stromal remodeling, vascular alterations, and endocrine dysregulation [ 2 , 14 – 16 ]. These changes may influence follicular development, oocyte maturation, and ovarian tissue homeostasis through complex interactions among immune, stromal, vascular, and endocrine components. Although many of these alterations are closely associated with reproductive aging, their relative contributions to physiological ovarian aging versus secondary reproductive dysfunction remain incompletely understood. Chronic low-grade inflammation (inflammaging) is a state that commonly occurs with aging, characterized by the continuous release of inflammatory mediators (such as IL-1, NF-κB) and the activation of SASP (senescence-associated secretory phenotype), which is increasingly recognized as an important feature of the aging ovarian microenvironment [ 75 ]. Senescent ovarian cells may contribute to this inflammatory milieu through sustained secretion of SASP-associated cytokines, chemokines, and matrix-remodeling factors, thereby altering local tissue homeostasis [ 55 , 56 ]. Persistent inflammatory signaling has been associated with oxidative stress, impaired granulosa cell function, stromal remodeling, and altered follicular communication within the ovary [ 10 , 75 ]. Inflammatory mediators such as IL-1 and NF-κB have also been implicated in follicular dysfunction and age-associated decline in ovarian reserve [ 76 , 77 ]. In addition, chronic inflammatory gynecologic conditions such as endometriosis may further exacerbate ovarian dysfunction through local inflammatory and fibrotic changes, although these conditions should be distinguished from intrinsic physiological ovarian aging [ 78 – 80 ]. Overall, chronic inflammation is thought to contribute to deterioration of the ovarian niche, but the causal relationships between inflammaging and follicle depletion remain incompletely defined. In parallel, age-related hormonal imbalance represents a key component of microenvironmental deterioration, and the dynamic changes in their levels directly affect an individual’s fertility. Altered levels and rhythmicity of estrogen, progesterone, and AMH reflect declining ovarian function and, in turn, feed back to impair follicular development, endocrine responsiveness, and reproductive homeostasis. With age, women’s ovarian function gradually declines, resulting in a significant decrease in estrogen and progesterone levels, ultimately leading to menopause and the end of fertility [ 58 , 81 , 82 ]. Changes in the levels of other key hormones, such as follicle-stimulating hormone (FSH) and AMH, also reflect the reduction of ovarian reserve [ 83 , 84 ]. With age, FSH levels increase, while estrogen (E2) levels decrease, leading to a continuous decrease in ovarian reserve and accelerated oocyte quality degradation, and also heralding the process of ovarian aging [ 3 , 85 ]. Additionally, hormone-related diseases such as PCOS may lead to a decline in oocyte quality and affect the success rate of frozen oocytes [ 82 ]. Hormone imbalance can cause ovulation disorders, menstrual disorders, and affect the receptivity of the endometrium, which in turn hurts the success rate of pregnancy [ 86 ]. These endocrine disturbances interact closely with inflammatory and metabolic stress signals, further destabilizing the ovarian niche. Importantly, hormone imbalance not only affects female fertility but may also cause a variety of systemic problems related to aging, such as osteoporosis and cardiovascular disease [ 58 ]. Therefore, how to restore or maintain hormone balance through hormone replacement therapy, ovulation induction therapy, etc., is one of the current research focuses. Environmental and lifestyle-related exposures may further modulate the ovarian microenvironment during aging [ 4 , 86 , 87 ]. Chronic psychological stress, obesity, environmental pollutants, endocrine-disrupting chemicals, heavy metals, and airborne particulate matter have all been associated with increased oxidative stress, inflammatory activation, and endocrine imbalance within the ovary [ 88 – 90 ]. Collectively, these microenvironmental alterations serve as a downstream amplification layer within the ovarian aging cascade, linking cellular-level damage to progressive loss of reproductive capacity. Nevertheless, the relative contribution of environmental versus intrinsic aging-related mechanisms to ovarian functional decline remains difficult to disentangle. Ovarian aging is clinically characterized by two major reproductive manifestations: progressive depletion of the follicle pool and decline in oocyte quality. These processes occur in parallel with multilevel molecular, cellular, and microenvironmental alterations and together contribute to reduced reproductive capacity with advancing age. Although follicle depletion and impaired oocyte competence frequently coexist, the relative contribution and mechanistic relationships between these processes remain incompletely understood. The primordial follicle pool is finite and non-renewable, and its preservation is central to female reproductive lifespan [ 2 , 58 , 60 ]. Multiple signaling pathways, including PI3K/AKT/mTOR, FOXO3, AMH, and Hippo signaling, are established regulators of primordial follicle dormancy and activation [ 15 , 17 , 59 , 91 ]. Experimental studies suggest that alterations in these regulatory networks may contribute to abnormal follicle recruitment and accelerated follicle consumption under certain aging-related or stress conditions [ 58 , 92 , 93 ]. However, the extent to which these signaling alterations directly drive physiological ovarian aging in humans remains incompletely defined. Concurrently, increased oxidative stress, mitochondrial dysfunction, and accumulated DNA damage enhance follicular atresia by promoting granulosa cell apoptosis and impairing metabolic and trophic support for developing follicles [ 6 , 35 , 36 , 66 ]. Telomere attrition and cellular senescence further limit the proliferative and supportive capacity of granulosa cells, compromising follicle survival and accelerating follicular dropout [ 13 , 25 ]. Together, uncontrolled follicle activation and heightened atresia act synergistically to drive the rapid and irreversible depletion of the ovarian follicle pool, a hallmark of ovarian aging and diminished ovarian reserve [ 91 , 94 ]. In parallel with quantitative follicle loss, ovarian aging is characterized by a progressive deterioration in oocyte quality, which critically impacts reproductive outcomes even before complete follicle exhaustion occurs [ 86 , 95 ]. At the genomic level, accumulated DNA damage, impaired repair capacity, and telomere dysfunction compromise chromosomal integrity during meiosis, leading to spindle abnormalities, chromosome missegregation, and a markedly increased risk of aneuploidy [ 6 , 24 , 66 , 96 ]. These defects constitute a primary mechanistic basis for age-related declines in fertilization rates, embryonic developmental potential, and increased miscarriage risk [ 51 , 95 ]. At the cellular level, mitochondrial dysfunction leads to reduced ATP production, excessive ROS generation, and impaired redox and calcium homeostasis, thereby compromising energy-dependent processes essential for oocyte maturation, fertilization, and early embryonic development [ 8 , 9 , 31 ]. Additionally, age-related alterations in the ovarian microenvironment, including chronic low-grade inflammation, hormonal imbalance, and disrupted paracrine signaling, further exacerbate intrinsic oocyte defects [ 35 , 95 , 97 ]. Senescent somatic cells and inflammatory mediators impair follicle-oocyte communication, amplifying functional decline [ 25 ]. Reduced follicle number and declining oocyte competence are two closely associated features of reproductive aging, although their mechanistic relationship remains complex and incompletely understood. In many clinical and experimental contexts, diminished ovarian reserve coexists with impaired oocyte developmental potential [ 4 , 91 , 94 ]. However, whether these processes are directly causally linked, or instead arise in parallel from shared aging-associated stressors such as genomic instability, mitochondrial dysfunction, oxidative stress, and altered ovarian signaling, remains under investigation [ 13 , 16 , 98 ]. This distinction has important clinical implications, as preservation of follicle quantity does not necessarily guarantee maintenance of oocyte quality. Together, these reproductive phenotypes reflect the integrated impact of aging-associated molecular and cellular alterations on ovarian function.

Ovarian aging is a complex and multifactorial process involving coordinated alterations across molecular, cellular, signaling, and tissue levels, ultimately contributing to follicle depletion and declining oocyte quality. Rather than reflecting a single causative mechanism, reproductive aging is associated with the interaction of genomic instability, telomere attrition, mitochondrial dysfunction, oxidative stress, chronic stress responses, and alterations in ovarian signaling and microenvironmental homeostasis. In this review, we propose an ovary-centered, multi-mechanistic framework to organize these interconnected processes and to facilitate a more integrated understanding of ovarian aging. Importantly, this integrative perspective suggests that multiple biological processes associated with ovarian aging may represent potential targets for intervention. While established fertility preservation technologies, including oocyte, embryo, and ovarian tissue cryopreservation, remain clinically important, their effectiveness is influenced by biological age and underlying ovarian reserve at the time of intervention. Mechanism-oriented strategies targeting cellular stress, metabolic regulation, signaling pathways, and the ovarian microenvironment may therefore provide complementary approaches for preserving reproductive potential. Continued integration of mechanistic insight, biomarker-guided stratification, and rigorously validated interventions will be essential for advancing evidence-based fertility preservation in the context of aging.

Given the multifactorial nature of ovarian aging, intervention strategies are increasingly being explored across multiple biological levels. Rather than focusing on single targets, mechanism-informed approaches aim to integrate cellular damage control, signaling modulation, microenvironment optimization, and preservation of reproductive function (Fig.  2 ). Fig. 2 This schematic summarizes the major intervention strategies discussed in Mechanism-oriented, multi-target intervention strategies . These approaches aim to preserve reproductive potential by targeting multiple biological processes associated with ovarian aging. At the cellular level, interventions focus on mitigating oxidative stress and damage accumulation, including antioxidant-based approaches, modulation of redox balance, and senescence-targeted strategies (e.g., senolytics). At the signaling and metabolic level, pharmacological and metabolic interventions such as mTOR inhibition (e.g., rapamycin), AMPK-Sirtuin activation (e.g., metformin), and caloric restriction mimetics are intended to modulate pathways involved in follicle activation and adaptive stress responses. At the tissue level, microenvironment-oriented approaches, including endocrine modulation (e.g., hormone replacement therapy), anti-inflammatory strategies, and lifestyle-based metabolic optimization, aim to stabilize the ovarian microenvironment and support reproductive function. Established fertility preservation technologies provide clinically available options for preserving reproductive potential without directly reversing biological aging. Emerging and exploratory technologies, including stem cell-based gametogenesis, mitochondrial replacement therapy, gene/RNA-based interventions, and mitochondria-targeted pharmacological agents, represent next-generation approaches being explored to modulate or partially restore specific aspects of reproductive function. Collectively, these multi-layered strategies illustrate the transition toward increasingly mechanism-informed intervention paradigms in reproductive aging This schematic summarizes the major intervention strategies discussed in Mechanism-oriented, multi-target intervention strategies . These approaches aim to preserve reproductive potential by targeting multiple biological processes associated with ovarian aging. At the cellular level, interventions focus on mitigating oxidative stress and damage accumulation, including antioxidant-based approaches, modulation of redox balance, and senescence-targeted strategies (e.g., senolytics). At the signaling and metabolic level, pharmacological and metabolic interventions such as mTOR inhibition (e.g., rapamycin), AMPK-Sirtuin activation (e.g., metformin), and caloric restriction mimetics are intended to modulate pathways involved in follicle activation and adaptive stress responses. At the tissue level, microenvironment-oriented approaches, including endocrine modulation (e.g., hormone replacement therapy), anti-inflammatory strategies, and lifestyle-based metabolic optimization, aim to stabilize the ovarian microenvironment and support reproductive function. Established fertility preservation technologies provide clinically available options for preserving reproductive potential without directly reversing biological aging. Emerging and exploratory technologies, including stem cell-based gametogenesis, mitochondrial replacement therapy, gene/RNA-based interventions, and mitochondria-targeted pharmacological agents, represent next-generation approaches being explored to modulate or partially restore specific aspects of reproductive function. Collectively, these multi-layered strategies illustrate the transition toward increasingly mechanism-informed intervention paradigms in reproductive aging Cellular damage and chronic stress responses are widely implicated in ovarian aging and therefore represent potential targets for therapeutic intervention. Accordingly, intervention strategies aimed at mitigating oxidative injury, buffering stress responses, and limiting senescence-associated damage have been widely explored as potential approaches to preserve fertility and delay ovarian aging. Oxidative stress is a central driver of germ cell dysfunction and reproductive aging, rendering antioxidant-based interventions one of the most extensively investigated strategies [ 95 , 99 ]. The ovarian antioxidant defense system comprises enzymatic components, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as non-enzymatic antioxidants such as vitamins C and E, melatonin, and glutathione [ 52 , 95 , 100 , 101 ]. With advancing age, endogenous antioxidant capacity-particularly within oocytes-declines, increasing susceptibility to ROS-mediated damage [ 7 , 14 , 31 ]. Exogenous antioxidant supplementation has therefore been proposed to counteract age-associated oxidative stress [ 33 ]. In women, antioxidants such as melatonin have been reported to improve oocyte quality by enhancing mitochondrial function and reducing oxidative damage [ 48 , 95 ], while in men, antioxidant therapy can preserve sperm DNA integrity and improve fertilization outcomes [ 52 , 102 ]. In assisted reproductive technologies, antioxidant supplementation has also been explored to improve embryo quality during IVF [ 46 ]. In parallel, lifestyle modifications-including smoking cessation, reduced alcohol intake, and minimizing exposure to environmental pollutants- represent essential non-pharmacological strategies to lower oxidative burden and complement pharmacological approaches [ 46 ]. Beyond redox modulation, interventions targeting cellular senescence have emerged as promising avenues for fertility preservation [ 13 , 25 ]. Senescent cells accumulate in the aging ovary and contribute to tissue dysfunction through the SASP [ 25 ]. Preclinical studies suggest that senolytic agents or SASP-modulating strategies may partially restore ovarian function by eliminating senescent cells or attenuating their deleterious paracrine effects [ 13 , 25 ]. In addition, pharmacological modulation of stress-responsive pathways, including nutrient- and energy-sensing networks, has been explored to enhance ovarian resilience under aging and cytotoxic stress, providing a mechanistic bridge to signaling-oriented interventions discussed below [ 12 , 36 ]. Collectively, these strategies illustrate how targeting cellular damage and stress responses can influence the pace of ovarian aging. However, most interventions demonstrate partial efficacy and context dependence, underscoring the limitations of single-target approaches. The repurposing of FDA-approved drugs, combined with improved mechanistic stratification and personalized intervention frameworks, offers a promising avenue for translating these strategies into clinically meaningful fertility preservation and anti-aging applications. Alterations in ovarian signaling pathways and metabolic regulation are increasingly recognized as important contributors to follicle homeostasis, stress adaptation, and reproductive aging. Accordingly, pathways involved in follicle activation, energy sensing, and metabolic regulation have emerged as potential targets for interventions aimed at preserving ovarian function. The PI3K/AKT/mTOR pathway functions as a master regulator of primordial follicle activation, integrating nutrient availability, growth factor signaling, and intracellular stress cues. Under physiological conditions, tight suppression of this pathway, mediated by factors such as PTEN, TSC1/TSC2, and FOXO3, maintains primordial follicles in a dormant state, thereby safeguarding the finite ovarian reserve. However, dysregulated PI3K/AKT/mTOR signaling may contribute to excessive primordial follicle activation under certain aging-associated or stress-related conditions. Pharmacological inhibition of mTOR has therefore been explored as a mechanism-driven strategy to delay ovarian aging [ 71 , 103 ]. Rapamycin, a well-characterized mTOR inhibitor, has shown protective effects in several preclinical models by suppressing aberrant primordial follicle activation and preserving ovarian reserve [ 59 , 61 , 104 ]. In aging mice, rapamycin treatment delayed follicle depletion and extended reproductive lifespan, while in chemotherapy-exposed models, rapamycin attenuated mTOR activation and mitigated gonadotoxic damage [ 93 ]. These findings highlight the potential of mTOR inhibition to decelerate follicle pool exhaustion by restoring the balance between follicle dormancy and activation. However, whether physiological ovarian aging in humans is driven by comparable pathway alterations remains incompletely understood. Cellular energy-sensing pathways play a critical role in coordinating metabolic status with follicle fate decisions [ 12 , 41 ]. AMPK and sirtuins (notably SIRT1 and SIRT3) function as key sensors of cellular energy and redox states, promoting adaptive stress responses under conditions of nutrient limitation or metabolic stress [ 36 , 69 , 105 ]. Activation of AMPK suppresses mTOR signaling while supporting FOXO3 activity, thereby reinforcing follicle dormancy and enhancing cellular resilience [ 58 , 69 ]. Similarly, sirtuins modulate mitochondrial function, oxidative stress resistance, and DNA repair through NAD⁺-dependent deacetylation mechanisms [ 36 , 69 ]. Age-associated mitochondrial dysfunction and metabolic imbalance impair AMPK and sirtuin activity, weakening adaptive stress responses and rendering ovarian cells more susceptible to damage [ 8 , 12 ]. Pharmacological or nutritional activation of these pathways has therefore been proposed as a potential strategy to delay ovarian aging [ 15 , 35 , 70 ]. Metformin, an AMPK-activating agent widely used in metabolic disorders, has been reported to delay ovarian aging by suppressing mTOR signaling, enhancing SIRT1 expression, reducing oxidative stress, and modulating ovarian stromal remodeling [ 70 ]. Experimental studies further suggest that metformin may attenuate age-related ovarian fibrosis by altering the balance among fibroblasts, myofibroblasts, and immune cells [ 106 ], underscoring its multi-level regulatory potential. Beyond individual signaling pathways, systemic metabolic regulation exerts profound influence on ovarian aging. Caloric restriction and caloric restriction mimetics have been shown to extend lifespan and delay age-related functional decline across multiple tissues, including the ovary [ 11 , 58 , 59 , 87 ]. By reducing nutrient-driven mTOR activation and enhancing AMPK-sirtuin signaling, these interventions promote stress resistance, preserve follicle dormancy, and support mitochondrial function [ 15 , 58 , 105 ]. Although direct clinical evidence in humans remains limited, these findings provide a compelling mechanistic rationale for metabolic modulation as a strategy to preserve reproductive function [ 11 ]. Collectively, targeting ovarian signaling and metabolic pathways provides a biologically informed rationale for interventions aimed at preserving ovarian function and delaying reproductive decline [ 6 ]. However, the efficacy and safety of long-term pathway modulation-particularly with agents such as rapamycin-require careful evaluation, given their pleiotropic effects and potential systemic consequences [ 87 , 107 ]. These considerations highlight the need for refined dosing strategies, tissue-specific targeting, and patient stratification to maximize reproductive benefits while minimizing adverse effects. The ovarian microenvironment functions as a dynamic integrator of endocrine signals, metabolic status, inflammatory cues, and paracrine communication, thereby exerting a profound influence on follicle survival, oocyte competence, and the pace of ovarian aging. While upstream molecular damage and signaling dysregulation initiate the aging process, deterioration of the ovarian microenvironment acts as a downstream amplifier that accelerates functional decline. Accordingly, interventions aimed at stabilizing or optimizing this microenvironment represent an important adjunct strategy for preserving reproductive function. Hormonal imbalance is a hallmark of ovarian aging and contributes to disrupted follicle-somatic cell communication, altered inflammatory tone, and impaired metabolic support [ 13 , 25 , 95 ]. Hormone-based interventions, including hormone replacement therapy (HRT) and endocrine adjustment strategies, have therefore been employed to stabilize the endocrine milieu and alleviate symptoms associated with ovarian aging [ 108 ]. By supplementing exogenous estrogen, progesterone, or using gonadotropin-releasing hormone (GnRH) analogs, HRT can partially restore hormonal homeostasis, improve granulosa cell function, and create a more supportive environment for follicular development [ 108 , 109 ]. In individuals with ovulatory dysfunction or endocrine disorders, ovulation-inducing agents and hormonal modulators may improve endometrial receptivity and follicle maturation, thereby enhancing short-term reproductive outcomes [ 108 ]. However, hormone-based therapies primarily provide symptomatic and microenvironmental support rather than reversing intrinsic ovarian aging. Their efficacy is highly context-dependent and constrained by potential adverse effects, including thrombotic risk, vasomotor symptoms, and contraindications in hormone-sensitive conditions [ 63 , 110 ]. These limitations underscore the need for biomarker-guided, individualized endocrine interventions and careful evaluation of long-term risk-benefit profiles [ 63 ]. Beyond endocrine regulation, systemic metabolic and inflammatory states exert substantial influence on the ovarian microenvironment [ 10 , 47 ]. Lifestyle interventions-including maintenance of a healthy body weight, regular moderate exercise, smoking cessation, alcohol restriction, and stress management-have been shown to improve reproductive endocrine function and reduce chronic low-grade inflammation [ 10 , 111 ]. Obesity and insulin resistance, in particular, are associated with increased oxidative stress, inflammatory cytokine production, and hormonal dysregulation, all of which exacerbate ovarian aging and impair fertility [ 41 , 95 ]. Weight reduction and improved metabolic control can partially normalize these microenvironmental stressors and enhance reproductive potential [ 111 ]. Dietary composition further shapes the ovarian inflammatory and redox landscape [ 111 , 112 ]. Nutritional patterns rich in antioxidants, essential micronutrients, and healthy fats, such as Mediterranean and plant-based diets, have been associated with more favorable reproductive and metabolic profiles in some observational and interventional studies [ 42 , 111 ]. Antioxidant-rich nutrients, including vitamins C and E, trace elements, and polyphenols, contribute to neutralizing excessive reactive oxygen species and mitigating oxidative damage within the ovarian niche [ 39 , 112 – 114 ]. Nutritional supplements such as coenzyme Q10, melatonin, resveratrol, and inositol have been investigated for their potential roles in supporting mitochondrial and metabolic function, redox balance, and endocrine regulation, particularly in the context of age-related fertility decline [ 58 ]. While their efficacy varies among individuals, these interventions highlight the modifiable nature of the ovarian microenvironment. Importantly, interventions targeting the ovarian microenvironment are unlikely to reverse ovarian aging when applied in isolation [ 87 , 110 ]. Instead, their primary value lies in reducing the burden of chronic stress, enhancing tissue resilience, and improving responsiveness to mechanism-driven therapies targeting cellular damage and signaling dysregulation [ 10 , 13 , 106 ]. By lowering inflammatory tone, stabilizing endocrine support, and optimizing metabolic conditions, microenvironment-focused strategies may slow functional deterioration and extend the window during which more targeted interventions remain effective [ 2 , 47 , 95 ]. Collectively, modulation of the ovarian microenvironment represents a complementary and clinically accessible approach within a broader, mechanism-oriented framework for fertility preservation and reproductive aging management. Integrating microenvironment optimization with cellular- and signaling-level interventions may may provide complementary benefits for preserving ovarian function across the reproductive lifespan. To cope with the increasingly severe challenge of declining fertility, fertility preservation technology has received widespread attention and application [ 115 ]. Cryopreservation is a technology that preserves cells, tissues, or other biological structures at extremely low temperatures. It is widely used in the field of fertility preservation, especially in coping with age-related fertility decline [ 116 ]. The key to this process is to control the cooling rate and use cryoprotectants to prevent ice crystal formation and damage to cells. Advances in oocyte cryopreservation technology, especially vitrification technology, have significantly improved the survival rate of oocytes and the success rate of clinical applications [ 4 , 87 , 117 ]. Through ovarian stimulation and oocyte collection, mature oocytes are frozen and preserved for future use when needed [ 3 , 118 ]. This technology is not only used for medical indications (such as before cancer treatment or other disease treatment), but is also increasingly used for planned family planning to cope with age-related fertility decline [ 119 , 120 ]. Embryo cryopreservation is a well-established component of assisted reproductive technology (ART). Fertilized embryos generated through IVF are frozen and stored for later uterine transfer, improving cumulative pregnancy rates and allowing flexible embryo transfer strategies [ 121 ]. In general, embryo cryopreservation yields higher implantation and live birth rates than oocyte cryopreservation, largely due to prior confirmation of fertilization and early developmental competence [ 117 ]. However, its use requires sperm at the time of preservation and may raise ethical or legal considerations. Importantly, for both oocyte and embryo cryopreservation, clinical outcomes are strongly dependent on the age at freezing. Oocytes or embryos cryopreserved at younger ages are associated with higher post-thaw pregnancy and live birth rates, whereas advanced maternal age at freezing is linked to reduced success and increased miscarriage risk [ 19 ]. Thus, timing remains a critical determinant of efficacy. Ovarian tissue cryopreservation is an emerging fertility preservation technology that is particularly suitable for cancer patients or other people who need to undergo treatment that may impair ovarian function. By freezing and preserving ovarian tissue, it can be transplanted back into the body after treatment to restore fertility [ 82 ]. For girls who have not yet menarched and women who are unable to undergo oocyte/embryo freezing for some reason, ovarian tissue cryopreservation currently represents the primary fertility preservation option [ 17 , 122 ]. Although still considered experimental, there are case reports of successful pregnancies and births after transplantation of frozen ovarian tissue [ 119 , 123 ], indicating the potential of ovarian tissue transplantation to recover endocrine function and, in selected cases, achieve pregnancy after treatment [ 124 ]. Cryopreservation provides a fertility preservation strategy that allows women to bank oocytes or embryos at a younger age for potential use in realizing their reproductive plans later in life [ 118 ]. Sperm cryopreservation remains the most established and effective method for preserving male fertility and serves as a useful comparator for female fertility preservation technologies [ 125 ]. It is widely used prior to gonadotoxic therapies and is increasingly accessible through sperm banking services. For prepubertal boys who are unable to produce mature sperm, testicular tissue cryopreservation is currently the only available option [ 126 , 127 ]. Experimental strategies, including testicular tissue transplantation and in vitro spermatogenesis, are under active investigation but are not yet clinically available [ 127 , 128 ]. IVM has emerged as an alternative strategy aimed at reducing the risks associated with ovarian stimulation, particularly ovarian hyperstimulation syndrome (OHSS) [ 63 ]. Immature oocytes are retrieved without or with minimal hormonal stimulation and matured in vitro prior to fertilization or cryopreservation [ 20 ]. IVM is especially relevant for women with PCOS and for patients requiring urgent fertility preservation before cancer treatment [ 63 ]. While clinical outcomes remain inferior to conventional IVF, continued optimization may further improve the clinical utility of IVM in selected settings. Collectively, these current fertility preservation techniques provide clinically relevant options for preserving reproductive potential in the context of age-related fertility decline or anticipated gonadotoxic exposure (Table  1 ). However, each technique differs substantially in indications, maturity, success rates, and associated risks, highlighting the need for individualized counseling and informed clinical decision-making. Table 1 Comparison of current fertility preservation technologies Technique Indications Suitable Age / Population Technical Maturity Expected Benefits Key Limitations / Risks Oocyte cryopreservation Elective fertility preservation; pre-gonadotoxic therapy Post-pubertal women (optimal < 35 yrs) Established Preserves fertility without a partner; flexible future use Age-dependent success; requires ovarian stimulation Embryo cryopreservation ART cycles; fertility preservation with partner Reproductive-age women Established Higher implantation and live birth rates Requires sperm; ethical/legal considerations Ovarian tissue cryopreservation Cancer patients; prepubertal girls All ages Experimental–translational Only option for prepubertal girls; restores endocrine function Follicle loss post-transplant; malignancy risk Sperm cryopreservation Male fertility preservation Post-pubertal males Established High success; simple and cost-effective Requires mature sperm Testicular tissue cryopreservation Prepubertal boys Prepubertal males Experimental The only option before spermatogenesis No routine clinical application yet In vitro oocyte maturation (IVM) PCOS; urgent fertility preservation Reproductive-age women Emerging Avoids OHSS; minimal stimulation Lower success than conventional IVF Comparison of current fertility preservation technologies A new generation of emerging biotechnologies is expanding the conceptual boundaries of fertility preservation by targeting biological processes associated with reproductive aging at cellular and molecular levels. These approaches aim not only to mitigate functional decline, but also to explore whether key aspects of ovarian function can be partially restored or supported. While highly promising, most remain experimental and face substantial translational barriers. Stem cell-based strategies, particularly in vitro gametogenesis (IVG), offer the theoretical possibility of generating functional oocytes from induced pluripotent stem cells, potentially providing an expandable source of patient-specific germ cell-like cells for individuals with diminished ovarian reserve or gonadotoxic injury [ 64 ]. Although proof-of-concept studies in animal models are compelling, faithful recapitulation of human oogenesis, including meiotic fidelity and epigenetic reprogramming, remains unresolved, precluding near-term clinical application [ 129 ]. Mitochondrial replacement therapy (MRT), originally developed to prevent mitochondrial DNA disease transmission, is being explored as a means of oocyte “rejuvenation” in age-related infertility [ 67 , 130 , 131 ]. By restoring cytoplasmic mitochondrial function, MRT has been investigated for its potential to improve developmental competence in selected experimental or clinical contexts [ 12 , 132 ]. However, concerns regarding mitochondrial heteroplasmy, long-term offspring safety, limited impact on age-related aneuploidy, and ethical constraints currently restrict its clinical use [ 31 , 132 ]. Precision molecular interventions, including gene editing and RNA-based therapies, enable targeted modulation of pathways involved in inflammation, metabolism, and stress responses [ 8 , 31 ]. These tools hold promise for mechanistically precise interventions but are limited by delivery challenges, off-target risks, and profound ethical considerations associated with germline modification [ 31 ]. Finally, mitochondria-targeted pharmacological agents- such as Coenzyme Q10, NAD⁺ precursors, and mitochondria-specific antioxidants- represent a comparatively more clinically accessible area of investigation [ 6 , 9 , 133 ]. These compounds aim to enhance residual mitochondrial function and reduce oxidative damage in aging oocytes, but robust clinical evidence for sustained reproductive benefit remains limited [ 8 , 9 ]. Overall, these exploratory technologies reflect a shift toward increasingly mechanism-informed and potentially disease-modifying approaches to reproductive aging. Nonetheless, their clinical translation will require rigorous safety validation, long-term outcome data, and careful ethical and regulatory oversight [ 31 , 132 ].