Ovarian Aging: Causes, Age-Related Problems, and Possible Treatments

Telomeres, composed of repetitive noncoding DNA sequences and associated binding proteins, cap the ends of eukaryotic chromosomes, safeguarding genomic integrity and chromosomal stability [53, 54]. Telomere length is closely related to reproductive lifespan and life expectancy [55]. A study of leukocyte telomere length found that each 1‐kilobase (kb) increase in telomere length corresponded to a 10.2‐month delay in the onset of natural menopause [56]. Women with the longest telomeres experienced menopause approximately 3 years later than those with the shortest telomeres, suggesting that leukocyte telomere length may serve as a predictive biomarker for menopausal timing [56]. In addition, telomere length may be associated with human aneuploid development [57]. Telomere DNA testing of polar bodies obtained by in vitro fertilization (IVF) revealed that aneuploid polar bodies had lower quantities of telomere DNA compared with that in paired sibling euploid polar bodies [57]. Another IVF‐based study suggested that telomere shortening may contribute to embryo fragmentation and preimplantation apoptosis, further linking telomere integrity to reproductive potential [58].

The progressive shortening of telomeres is largely attributed to diminished telomerase activity. Telomerase, a ribonucleoprotein enzyme complex composed of telomerase reverse transcriptase (TERT) and telomerase RNA component, counteracts telomere erosion by adding hexametric repeats to chromosomal termini [59]. Telomere‐associated proteins, including telomeric repeat binding factors 1 (TRF1) and 2 (TRF2) and protection of telomeres 1a (POT1a), safeguard telomere structure and function [60]. In human ovarian GCs and oocytes, the expression of TERT, TRF1, TRF2, and POT1 progressively declines from fetal development to menopause, coinciding with a reduction in telomere signal intensity [61]. Studies in telomerase‐knockout mice demonstrate progressive telomere attrition across successive generations, accelerating both systemic and reproductive aging [62]. In humans, GCs from patients with biochemical premature ovarian insufficiency (POI) exhibit lower telomerase activity compared with healthy controls [63], with similar reductions observed in patients with both occult and overt POI [64, 65]. As occult POI is often asymptomatic apart from subfertility, its clinical diagnosis remains challenging. Telomere length and telomerase activity may serve as valuable early biomarkers for predicting POI risk. Conversely, estrogen has been shown to regulate telomerase activity. Estrogen‐deficient mice exhibit suppressed telomerase function, resulting in accelerated telomere attrition and exacerbated ovarian aging [66]. By and large, the studies indicate that telomere shortening and reduced telomerase activity may significantly contribute to ovarian aging, with estrogen deficiency also adversely affecting telomere length. Further research is needed to explore the relationship between telomere dynamics and ovarian aging.

The DNA damage response (DDR) plays a pivotal role in preserving genomic integrity during reproductive aging, activating repair pathways to mitigate DNA lesions [67]. With advancing age, DDR efficiency declines, leading to the accumulation of DNA damage, increased oocyte attrition, and a heightened risk of infertility and miscarriage [16].

BRCA1 and BRCA2 are key genes involved in homologous recombination repair. Mutations in these genes increase the risk of breast and ovarian cancer. They are also linked to an earlier onset of menopause [1, 68]. Studies in rhesus monkeys indicate that DSB accumulation in follicles escalates with age, while BRCA1 expression declines in GCs and oocytes, compromising DNA repair capacity [68]. Similarly, human oocytes from older individuals exhibit reduced BRCA1 expression compared with those from younger counterparts [69]. BRCA1 and BRCA2 function within the DDR by facilitating DSB repair via the ataxia telangiectasia mutated (ATM) pathway [70]. Knockdown of ATM in oocytes results in an increased burden of unrepaired DSBs, decreased oocyte survival, and premature apoptosis [71]. Furthermore, women carrying BRCA1 and BRCA2 loss‐of‐function mutations experience menopause approximately 2.63 and 1.54 years earlier, respectively, than noncarriers [67].

The checkpoint kinase 2 (CHEK2) gene, another critical DDR component, is instrumental in maintaining genomic stability. A loss‐of‐function variant in CHEK2 has been shown to delay natural menopause by 3.49 years and is associated with enhanced ovarian reserve [67, 72]. CHEK2 phosphorylates and activates tumor protein p53 (TP53), orchestrating DDR outcomes [73]. Additionally, TAp63, a TP53 isoform uniquely expressed in oocytes, triggers apoptosis in response to DNA damage upon activation by CHEK2 [74]. These findings underscore the essential roles of BRCA and CHEK2 in ovarian aging, highlighting their contributions to follicular depletion and variations in menopausal timing.

ROS, primarily generated by mitochondria, serve as both signaling molecules and markers of ovarian aging, with their levels increasing as ovarian aging progresses [67, 75, 76]. OS arises when ROS production exceeds the capacity of cellular antioxidant defenses, leading to molecular damage [77]. Under normal conditions, cells eliminate excess ROS; however, with advancing age, antioxidant capacity declines [78]. This imbalance contributes to mitochondrial dysfunction, telomere attrition, and structural deterioration of oocytes and surrounding somatic cells, ultimately compromising ovarian function [79]. Furthermore, aged oocytes exhibit a diminished ability to generate antioxidants, exacerbating their vulnerability to OS‐induced damage [16]. Notably, reduced expression of the antioxidant enzyme superoxide dismutase 1 in aged mouse oocytes has been linked to increased OS and ferroptotic cell death in primordial follicles [78]. In GCs, elevated OS is associated with reduced follicle‐stimulating hormone receptor (FSHR) expression and impaired FSHR‐mediated signaling, potentially explaining the diminished ovarian response to elevated follicle‐stimulating hormone (FSH) in aging women [80]. The mechanisms underlying ROS dysregulation in ovarian aging remain incompletely understood. Emerging evidence suggests that abnormal iron metabolism may be a contributing factor [81]. In aged mice, oocyte iron accumulation correlates with increased oxidative damage, while iron chelation improves ovarian redox balance and enhances oocyte quantity and quality [81].

In addition to ROS, advanced glycation end products (AGEs) are another key driver of OS in the ovary. AGEs, formed through nonenzymatic glycation reactions, accumulate endogenously over time and can also be obtained from dietary sources [82]. Their accumulation in follicular fluid and serum has been implicated in impaired folliculogenesis, fertilization, and embryonic development [83]. AGEs may compromise oocyte quality by triggering inflammatory responses within the follicular microenvironment [84]. Upon binding to AGEs receptors, AGEs activate nuclear factor kappa B (NF‐κB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, promoting ROS generation [85]. In turn, OS accelerates the final steps of advanced glycation, creating a deleterious feedback loop [86]. Given the intricate interplay between AGEs and ROS, their cumulative effects likely play a pivotal role in OS‐induced ovarian aging.

Mitochondria, essential for ATP production and cellular metabolism, undergo age‐related structural and functional deterioration in oocytes. In older women, mitochondrial density and number decline, while their morphology becomes increasingly aberrant [87]. During oocyte maturation, mtDNA copy number increases dramatically, supporting the energy demands of meiotic progression [88]. However, age‐related ROS accumulation directly damages mtDNA, leading to DSBs and impairments in ATP synthesis. To repair these breaks, poly ADP‐ribose polymerase 1 (PARP1) is activated, depleting cellular pools of nicotinamide adenine dinucleotide (NAD⁺) and ATP, thereby perpetuating a cycle of mitochondrial dysfunction [21]. Mitochondria continuously divide and replicate throughout life, but with age, replication errors accumulate, leading to a progressive increase in mtDNA mutations [21, 89]. Compounding this issue, the efficiency of mtDNA repair mechanisms declines over time, accelerating mitochondrial genomic instability. The interdependence of ROS generation and mtDNA damage exacerbates mitochondrial dysfunction, ultimately compromising both ovarian function and systemic health. Single‐cell transcriptomic analysis of ovarian cells from young and aged nonhuman primates highlights oxidative damage as a critical factor in the age‐related decline of ovarian function [90].

Apoptosis and autophagy are two forms of programmed cell death, that being fundamental to tissue homeostasis and organismal development [18]. Apoptosis occurs via two primary pathways: the intrinsic (mitochondrial) pathway, regulated by intracellular signals, and the extrinsic pathway, triggered by extracellular factors [91]. GCls play a pivotal role in oocyte survival by supplying essential nutrients and growth factors while also shielding oocytes from OS [92]. GC apoptosis is a key driver of follicular atresia [93]. Gene expression analysis in nonhuman primate GCs revealed that age‐related upregulation of 62 genes was predominantly associated with positive regulation of apoptotic pathways [90]. Apoptosis is also associated with a decrease in follicle number. It has been shown that deficiency of the proapoptotic factor BAX maintains primordial follicle numbers to some extent and prolongs fertility [18]. However, a study found that the overexpression of the antiapoptotic protein BXL‐2 increased follicle number in newborn mice but had no effect on the ovaries of adult mice [94]. It remains to be seen whether this positive effect in newborn mice extends ovarian lifespan.

Like apoptosis, autophagy is a highly regulated process of cellular degradation, characterized by the sequestration of cytoplasmic components into autophagic vacuoles for lysosomal degradation [92]. Under physiological conditions, autophagy maintains cellular homeostasis by removing damaged organelles and proteins. Ovarian aging may be related to excessive autophagy that can promote apoptosis and accelerate follicular depletion [95]. During in vitro maturation of porcine oocytes, aberrant autophagic activation disrupted mitochondrial and autophagosome distribution, leading to compromised oocyte viability, suggesting a role for autophagy in oocyte quality control [96]. However, other studies indicate that ovarian aging is associated with decreased autophagy. Reduced expression of genes associated with autophagy initiation and maintenance was found in aged rat models [97]. Another study found that the expression of nerve growth factor inducible gene B (Nur77) was reduced in the ovaries of aging mice. Overexpression of Nur77 activates mitochondrial autophagy, reduces apoptosis, and regulates follicular number and hormonal abnormalities caused by ovarian aging, ultimately improving ovarian function [98]. These apparently conflicting findings may reflect differences in species and experimental models (e.g., porcine in vitro systems versus rodent in vivo studies), the stage‐specific roles of autophagy (protective at basal levels but detrimental when hyperactivated), and methodological variation in measuring autophagic flux (gene expression versus functional assays). A synthesized perspective suggests that basal autophagy is vital for oocyte quality, whereas both insufficient and excessive activation can impair ovarian function depending on context, calling for more research to delineate thresholds and regulatory mechanisms across models.

In summary, the paradoxical role of autophagy in ovarian aging can be reconciled through the principle of homeostatic control. As a fundamental quality‐control mechanism, autophagy is neither inherently protective nor detrimental; its functional outcome depends on the precision of its regulation. An age‐related decline promotes the accumulation of cellular damage, while excessive activation can trigger cell death. Consequently, ovarian aging may stem primarily from a loss of autophagic balance rather than a simple deficit or surplus. Future therapeutic strategies should therefore aim to restore this homeostatic set‐point, not nonspecifically enhance or inhibit autophagy.

Protein homeostasis is essential for cellular function and is maintained through a finely tuned network of synthesis, folding, modification, and degradation. However, aging disrupts this balance, leading to the accumulation of misfolded or damaged proteins [92]. In aged mouse oocytes, dysregulated protein metabolism impairs oocyte quality and accelerates reproductive senescence. Comparative transcriptomic analyses have shown that genes involved in protein modification and metabolism are significantly enriched in young follicles, suggesting that younger oocytes possess a more robust protein quality control system [99]. Proper protein folding is a crucial step in proteostasis. Misfolded proteins activate the unfolded protein response (UPR) in both the endoplasmic reticulum and mitochondria [92]. Failure to restore proteostasis triggers excessive endoplasmic reticulum stress, ultimately inducing apoptosis [100]. The mitochondrial caseinolytic peptidase P (CLPP) is a key enzyme that degrades misfolded proteins. Knockout of CLPP in mice resulted in accelerated depletion of the ovarian reserve and a significant reduction in oocyte number, highlighting the essential role of proteostasis in ovarian lifespan [101]. Mitochondrial ATP‐dependent Lon protease 1 (LONP1) is another critical protease that safeguards mitochondrial proteostasis by degrading misfolded proteins, regulating mtDNA replication, and stabilizing the electron transport chain [102, 103, 104]. Age‐dependent alterations in LONP1 expression have been observed in animal models, implicating it in ovarian aging [105]. Conditional ablation of LONP1 in mouse oocytes impairs follicular progression from the secondary to antral stage, triggers persistent activation of the mitochondrial UPR, and culminates in infertility [106]. These findings establish LONP1 as a gatekeeper of mitochondrial function and oocyte survival. Beyond aging, proteostasis regulators intersect with disease states. Notably, the interaction between LONP1 and cytochrome P450 family 11 subfamily A member 1 has been implicated in polycystic ovary syndrome (PCOS), and pharmacological interventions such as artemisinin have been shown to alleviate PCOS phenotypes by enhancing this interaction [107]. These insights position proteostasis not only as a determinant of ovarian aging but also as a potential therapeutic target for reproductive disorders.

Fibrosis is not only a hallmark of tissue aging, but also a crucial factor leading to structural and functional deterioration. Among the canonical pathways implicated in fibrogenesis, the transforming growth factor β (TGF‐β)/Samd and IL‐6/Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascades occupy central roles. In the ovary, studies in PCOS patients have demonstrated that aberrant activation of the TGF‐β/Smad pathway promotes stromal fibrosis [108, 109]. Evidence further suggests that FSH/FSHR signaling enhances TGF‐β1/Smad activity, linking endocrine dysregulation to fibrotic remodeling. Inhibition of FSH, FSHR, or TGF‐β1 attenuates fibrosis and restores ovarian reserve [110]. Besides, the JAK–STAT signaling pathway is also observed in the fibrosis process of other organs such as the heart and ureter [111, 112]. However, the IL‐6/JAK–STAT axis remains underexplored in the context of ovarian aging. Picrosirius Red staining reveals a significant increase in stromal fibrosis in mice at 7 and 9 months of age compared with younger counterparts [113]. Moreover, the extent of fibrosis correlates with chronological age, becoming more pronounced with ovarian aging [113]. Within the extracellular matrix (ECM), age‐related collagen deposition contributes to increased ovarian stiffness [114]. In contrast, levels of hyaluronan (HA), a key ECM component, decline with age, potentially due to dysregulated expression of HA synthases and hyaluronidases [114]. This age‐related collagen deposition and HA reduction increases ovarian stiffness [114]. Follicle expansion requires a soft ECM. This age‐related ECM remodeling limits follicle expansion and disrupts mechanical signaling pathways (primarily mechanosensitive pathways such as Hippo and PI3K/AKT), which convert mechanical signals into biochemical responses ultimately linked to follicle fate [115, 116]. Additionally, ovarian hypoxia caused by defects in the construction of the ovarian vascular network due to age‐related ovarian fibrosis also affects follicle growth and development [117]. Studies have shown that ovarian fibrosis induced by premature ovarian failure (POF) is closely associated with a reduction in vascular distribution within ovarian stromal tissue [118]. The decrease in vascular density and collagen deposition may impede the diffusion of nutrients and oxygen. In summary, ovarian fibrosis disrupts the balance between follicular dormancy and activation, impairing ovarian function through multiple pathways. These alterations in stromal composition may impair follicular development and contribute to ovarian aging. The mechanisms by which fibrosis contributes to ovarian aging require further investigation.

Aging is associated with chronic low‐grade inflammation, a phenomenon often referred to as "inflammaging," which is linked to tissue fibrosis and functional decline [16]. The ovarian follicular microenvironment is no exception. In human follicular fluid, levels of specific proinflammatory cytokines—including IL‐3, IL‐7, IL‐15, TGF‐β1, and MIP‐1—increase with age and inversely correlate with AMH levels [119]. Notably, the age‐related elevation of TGF‐β3 appears to be unique to the ovarian stroma, implicating stromal inflammation as a key contributor to ovarian aging [119]. Inflammation has a profound impact on both oocyte quality and follicular depletion [113, 120]. Studies in knockout mouse models of proinflammatory cytokines have demonstrated that genetic ablation of specific inflammatory mediators extends reproductive lifespan and preserves ovarian reserve [121, 122].

Macrophages, the predominant immune cells in the ovary, play a dual role in ovarian physiology [123]. The balance between proinflammatory M1 and anti‐inflammatory M2 macrophages is critical for maintaining ovarian function [123]. With advancing age, expression of M1‐associated markers declines, whereas M2‐associated markers increase, indicating a shift in polarization from M1 toward M2 during ovarian aging [124]. Inhibition of M2 macrophage polarization in aging mice attenuated ovarian fibrosis and improved ovarian function and fertility [125]. This may be because anti‐inflammatory M2 macrophages stimulate fibroblasts to produce collagen, and appropriate collagen promotes tissue repair, while excessive collagen deposition promotes fibrosis [126]. In addition, compared with monocyte‐derived macrophages, the proportion of tissue‐resident macrophages was significantly reduced in aged ovaries, which seems to be the reason for the shift of macrophage polarization in ovaries [124, 127, 128]. Furthermore, suppression of proinflammatory signaling in aged ovaries reduced macrophage infiltration and restored ovarian function [129]. Chronic low‐grade inflammation from proinflammatory factors and macrophages may accelerate ovarian aging through fibrosis and dysfunction. Further research is needed to explore specific signaling pathways and target factors.

Ovarian vascular aging has recently emerged as a critical yet understudied contributor to ovarian decline. The maintenance of ovarian function in adult women depends on continuous vascular remodeling, which supports follicular growth and ovulation [130]. Temporarily inhibiting vascularization in the ovaries of young women using axitinib can reduce follicle depletion, maintain long‐term ovarian reserve, and ultimately delay ovarian aging [131]. Recent studies identify endothelial cell aging as a central driver of impaired ovarian vascularization. Age‐related reductions in vascular remodeling limit nutrient and oxygen delivery, thereby compromising follicle development. GC‐derived vascular endothelial growth factor A (VEGFA) is pivotal in sustaining ovarian angiogenesis. Declines in VEGFA expression with age correlate with diminished vascular formation and reduced ovarian perfusion. Transcriptomic comparisons between young and middle‐aged ovaries further implicate endothelial dysfunction in the deterioration of vascular support. Supplementing with salidroside can enhance ovarian vascular function and improve fertility in older women [132]. This provides new avenues for exploring vascular‐targeted therapies as a strategy to extend reproductive healthspan.

Estrogen exerts multiple cardioprotective effects, which decline with ovarian aging. In aging ovariectomized rats, estrogen has been shown to attenuate left ventricular remodeling, potentially by suppressing fibrotic responses and inhibiting myofibroblast differentiation via downregulation of the angiotensin‐II pathway [145, 146]. In postmenopausal women, estrogen deficiency exacerbates OS, contributing to left ventricular hypertrophy, which in turn increases the risk of diastolic dysfunction and heart failure with preserved ejection fraction [147]. Furthermore, reduced estrogen levels are associated with a decline in cardiomyocyte sarcoplasmic ATP‐sensitive K⁺ (K_ATP) channels, decreasing myocardial stress tolerance in older women [148]. Beyond its direct myocardial effects, estrogen modulates vascular homeostasis by regulating chemokine and cytokine expression following vascular injury and limiting leukocyte infiltration [149]. It downregulates neutrophil chemokines, reduces C‐reactive protein levels in damaged arteries, and suppresses ROS production, thereby mitigating vascular inflammation and oxidative damage [150, 151]. However, the loss of estrogen after menopause leads to a decline in these protective mechanisms, contributing to a significant rise in cardiovascular morbidity [152].

The link between ovarian aging and CVD has been substantiated by multiple clinical studies (Table 1). The European Prospective Investigation into Cancer and Nutrition‐CVD study, which included 15,402 European women aged 35–70 years at baseline, demonstrated a linear association between earlier menopause and increased coronary heart disease (CHD) risk, with an adjusted hazard ratio (HR) of 1.02 per year decrease in menopausal age (p = 0.001) [153]. Additionally, women who underwent surgical menopause experienced a higher risk of CHD compared with those with natural menopause (adjusted HR 1.25[95% confidence interval [CI], 1.10–1.42], p < 0.001) [153]. A 2016 pooled meta‐analysis of 32 observational studies involving 310,329 nonoverlapping women observed similar findings. The risks of overall (relative risk [RR], 1.50 [95% CI, 1.28–1.76]) and fatal CHD (RR, 1.11 [1.03–1.20]) escalated in women with early menopause (<45 years) compared with women with menopause at the age of 45 years or older [154]. Moreover, women with early menopause (<45 years) encountered a significantly greater risk of heart failure than those with later menopause, as shown by a meta‐analysis of three prospective studies involving 3,568 heart failure cases (HR, 1.33 [1.15–1.53]) [155]. A cross‐sectional study enrolled 2037 Korean women aged 44–56 years across various menopausal stages (premenopausal, early menopause transition [MT], late MT, and postmenopausal) found significantly higher blood pressure in late MT compared with early MT [156]. Longitudinal assessments of carotid artery morphology during the menopausal transition further demonstrated that carotid intima‐media thickness and adventitia diameter increased most prominently in the late perimenopausal stage, relative to premenopausal and early perimenopausal stages [157]. Over a mean follow‐up of 2.3 years, aortic pulse wave velocity was observed to increase more rapidly in middle‐aged women undergoing menopause than in premenopausal or postmenopausal women [158]. Overall, these findings underscore the critical impact of ovarian aging on cardiovascular health, with the menopausal transition representing a period of heightened CVD risk.

Alzheimer's disease (AD) is an age‐related neurodegenerative disorder characterized by progressive dementia, functional impairment, and a diminished quality of life. The hallmark pathological features of AD include extracellular amyloid‐β (Aβ) deposition and intracellular tau neurofibrillary tangles (NFTs) [159, 160]. New evidence indicates that ovarian aging and the resulting decrease in sex steroid hormones may influence AD pathogenesis by affecting Aβ and tau pathology, potentially enhancing their toxicity. In female triple transgenic AD (3xTgAD) mice, ovariectomy‐induced hormone depletion led to a substantial increase in Aβ accumulation and cognitive impairment [203]. Treatment with estradiol induced a decrease in Aβ levels and aggregation into plaques in female mice expressing the Swedish and Indiana mutations of human amyloid precursor protein (APP) compared with wild‐type mice [204]. Estrogen may influence Aβ levels by shifting APP processing toward the nonamyloidogenic (α‐secretase) pathway via the activation of extracellularly regulated kinases 1 and 2 (ERK1/2) and protein kinase C signaling [203]. Additionally, ERK1/2 activation inhibits γ‐secretase, thereby downregulating β‐site APP‐cleaving enzyme 1 (BACE1) and reducing Aβ production [203]. Given that OS enhances BACE1 activity, estradiol may further suppress Aβ accumulation by stimulating antioxidant defenses and reinforcing ERK1/2‐mediated inhibition of γ‐secretase and BACE1 [203]. NFTs, composed of hyperphosphorylated tau aggregates, represent another defining histopathological feature of AD. In vitro studies indicate that estradiol decreases protein kinase A activity, an enzyme involved in tau phosphorylation, and rescues abnormal tau proteins [203]. In 3xTgAD female mice, both continuous and cyclic administration of estradiol and progesterone mitigated tau hyperphosphorylation. This protective effect may stem from estradiol‐mediated inhibition of glycogen synthase kinase 3β (GSK‐3β), a key enzyme in tau hyperphosphorylation, and progesterone‐induced suppression of GSK‐3β expression and tau protein levels [203]. Taken together, these findings demonstrated that sex hormones, especially estrogen, are able to modulate AD‐related neuropathology and preserve cognitive function.

Mounting evidence coming from human studies also elucidated the impacts of ovarian aging on AD. The prevalence of AD is twice as high in women as in men at the age of 65 years [205]. The menopausal transition may contribute to this increased susceptibility in women, as the dysregulation of neuromodulatory hormones, such as estrogen, disrupts various brain systems, including bioenergetics, inflammation, and lipid profiles [161, 162, 163]. Changes in hormone profiles directly impact brain function and can be used as predictors of cognitive decline, with the estrogen to FSH ratio specifically indicating mild cognitive impairment (MCI) [164]. Furthermore, earlier menopause has been associated with an increased risk of AD and accelerated cognitive decline. One study reported that women experiencing early menopause had higher odds of verbal fluency, visual memory, and psychomotor speed decline (odds ratios [ORs] of 1.51, 1.43, and 1.36, respectively), with an overall HR of 1.35 for AD [165]. Xi et al. [166] observed similar findings. They noted that prolonged childbearing and delayed menopause were associated with a decreased risk of AD (OR = 0.96 and 0.949, respectively) [166]. Moreover, bilateral oophorectomy performed before natural menopause significantly elevates the risk of MCI, with an adjusted OR of 2.21 (p < 0.001) [167]. Surgical menopause at an earlier age correlated with a more rapid decline in cognitive function, particularly in domains such as episodic and semantic memory [206]. Ovarian aging and the associated decrease in estrogen may contribute to Aβ accumulation and tau protein hyperphosphorylation, resulting in cognitive decline. More high‐quality clinical data are necessary to strengthen the evidence linking ovarian aging to AD.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is marked by the progressive degeneration of dopamine‐producing neurons in the substantia nigra and the formation of Lewy bodies, which are intraneuronal protein aggregates primarily composed of α‐synuclein [207]. Accumulating evidence suggests that estrogen exerts neuroprotective effects on the nigrostriatal dopaminergic system, mitigating neuronal degeneration through multiple mechanisms. These include modulation of monoamine oxidase activity, inhibition of IL‐6 to suppress neuroinflammation, activation of ERK signaling to enhance autophagic maturation in dopaminergic brain regions, and downregulation of both the nigrostriatal renin–angiotensin system and NADPH oxidase activity [168, 169, 170]. In nonhuman primates, prolonged estrogen deprivation leads to irreversible dopaminergic neurodegeneration. Within 30 days of ovariectomy, over 30% of nigrostriatal dopaminergic neurons are permanently lost [208]. Notably, transient estrogen replacement restores tyrosine hydroxylase‐immunoreactive cell densities when initiated within 10 days of ovariectomy but fails to do so after 30 days, underscoring the critical temporal window for estrogen‐mediated neuroprotection [208].

Data from human studies observed similar findings on estrogen deprivation. Using a Mendelian randomization approach, Kusters et al. [171] identified an inverse association between age at menopause and risk of PD, reporting an OR of 0.84 (95% CI, 0.73–0.98; p = 0.03) per year increase in menopausal age. Other studies have confirmed this linear association. A cross‐sectional study recruited women with PD and age matched healthy women controls indicated a significant positive correlation between age at menopause and age at PD onset (r = 0.55, p = 0.001) [172]. Similarly, Frentzel et al. [173] analyzed age‐matched male and female PD patients, demonstrating a positive correlation between later menopause and delayed PD onset (p < 0.01). Moreover, a higher rate of early menopause was observed in female PD cohorts than in age‐matched female controls (24 vs. 16%) [174]. Surgical menopause further exacerbates PD risk. A recent study by Canonico et al. [175] revealed that bilateral oophorectomy, but not hysterectomy, was significantly associated with the increased risk of PD (OR = 3.55, 95% CI = 1.75–7.20). In summary, both earlier natural menopause and surgical menopause heighten the risk of PD, likely due to the abrupt or premature decline in estrogen levels.

Osteoporosis is the most prevalent age‐related bone disease, characterized by low bone mass and disrupted bone microarchitecture, resulting in increased fragility and fracture risk [178]. This condition arises from an imbalance between osteoblast‐mediated bone formation and osteoclast‐mediated bone resorption, disrupting skeletal homeostasis [176]. In postmenopausal osteoporosis, estrogen deficiency accelerates bone resorption while impairing bone formation, leading to progressive bone loss [177]. A key mechanism underlying estrogen‐mediated bone homeostasis involves the receptor activator of NF‐κB (RANK)–RANK ligand (RANKL)–osteoprotegerin (OPG) signaling pathway [209]. Estrogen deficiency dysregulates this pathway by increasing RANKL expression in stromal cells and lymphocytes, thereby enhancing osteoclast sensitivity to RANKL and promoting osteoclast differentiation and activation [177]. Concurrently, diminished estrogen levels reduce OPG secretion from osteoblasts, weakening OPG's inhibitory effect on RANKL‐induced osteoclast activation [177]. As a result, ovarian aging drives excessive bone resorption, culminating in net bone loss and skeletal fragility.

The detrimental effects of ovarian aging on bone metabolism are particularly evident during the MT, as confirmed by epidemiological data. Osteoporosis prevalence in women surpasses that in men, affecting 19.6% of women over 50 years and 27.1% of those over 65 years, compared with 4.4 and 5.7%, respectively, in age‐matched men [178]. Notably, women account for 71% of osteoporotic fractures [180]. Bone mass peaks around the age of 30 years, after which women lose approximately 30% of cortical bone and 50% of trabecular bone over their lifetime, with the most rapid loss occurring around menopause [179]. While premenopausal women maintain relatively stable bone mass, bone loss begins 1–3 years before menopause at an annual rate of about 2%, persisting for 5–10 years postmenopause [181]. Nearly half of lifetime bone loss occurs within the first 5 years following menopause, with the steepest decline beginning 2 years before the final menstrual period [210]. After this phase, bone density continues to decline at approximately 0.5% per year, resulting in an average 30% reduction in bone mass by the age of 80 years compared with its peak [181]. The clinical implications of postmenopausal osteoporosis are profound. Globally, one in three women over 50 years of age will experience an osteoporotic fracture [211]. Hip fractures, in particular, carry severe consequences, with a mortality rate exceeding that of breast, uterine, and ovarian cancers combined [212]. Hospitalization is often required, and up to 25% of hip fracture patients require long‐term care, while 50% suffer permanent mobility loss [181]. This highlights the significant threat of osteoporosis related to ovarian aging and the need for preventive and therapeutic measures.

CKD is a progressive condition characterized by deteriorating kidney function, persistent structural abnormalities, and other indicators of kidney impairment [213]. Estrogen is essential for maintaining kidney normal structure and function, exerting protective effects through multiple mechanisms. It prevents glomerular structural malformations by inhibiting mesangial cell proliferation, reducing collagen deposition and interstitial fibrosis, and mitigating podocyte loss and glomerular hypertrophy [182, 183]. Additionally, estrogen suppresses glomerulosclerosis by reducing the synthesis of type I and type IV collagen and preventing excessive ECM accumulation [214]. Estrogen also regulates kidney homeostasis through its influence on sodium and water balance. It downregulates the expression and activity of α‐, β‐, and γ‐subunits of the epithelial sodium channel and α‐sodium/potassium adenosine triphosphatase (α‐Na/K‐ATPase), while increasing the expression of angiotensin type 2 receptor and inhibiting aldosterone secretion, which regulate osmoregulation and water–electrolyte homeostasis [184]. Estrogen modulates blood pressure by influencing the renin–angiotensin–aldosterone system and regulates erythrocyte levels either directly by affecting erythropoietin (EPO) production or indirectly by altering the tissue‐specific response to EPO [184]. Notably, estrogen therapy in ovariectomized mice has been shown to attenuate renal fibrosis associated with kidney dysfunction [215]. Taken together, estrogen deficiency resulting from ovarian aging may exacerbate structural and functional renal decline.

Human studies show a linear increase in CKD prevalence with age, rising from 13.7% in the 30–40 years age group to 34.3% in the 70–80 years age group [216]. Women have a higher risk of CKD than men, with 15.3% of women affected compared with 12.4% of men [184]. The impact of ovarian aging on kidney function is further underscored by studies linking early menopause to an elevated CKD risk. A study involving 4945 postmenopausal women found that women experiencing early menopause before the age of 45 years had an increased risk of CKD compared with women experiencing natural menopause at the age of ≥45 years (OR = 1.26, 95% CI = 1.01–1.56) [185]. Similarly, a population‐based study of 1653 women demonstrated a higher risk of CKD in women with bilateral oophorectomy (HR = 1.42, 95% CI = 1.14–1.77) [6]. In addition, aging‐related decline in renal function is associated with renal fibrosis, a hallmark of progressive CKD. While glomerular loss and renal fibrosis due to hypertension and diabetes progress more slowly in women than in men, this sex‐based advantage diminishes following menopause. Premenopausal women with diabetes are at a lower risk of developing end‐stage renal disease than age‐matched men, but this protective effect is lost with ovarian aging [217]. These observations suggest that estrogen supplementation may hold potential as a therapeutic strategy for mitigating CKD progression in postmenopausal women.

Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease and liver transplants worldwide [218]. It progresses through four histological stages: nonalcoholic fatty liver, nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH‐associated hepatocellular carcinoma [219]. Sex differences in NAFLD pathophysiology highlight the protective role of estrogen. Female mice demonstrate greater insulin sensitivity, enhanced fatty acid oxidation, and higher expression of c‐Jun N‐terminal kinase and AMPK compared with males [220]. Additionally, females exhibit increased hepatic expression of CD36, promoting fatty acid uptake, while a more pronounced downregulation of aquaporin 9 lowers glycerol absorption, collectively reducing liver hypertrophy [220]. Estrogen exerts multifaceted metabolic effects that mitigate NAFLD risk. It suppresses hepatic gluconeogenesis while enhancing glycogen synthesis and storage, leading to lower blood glucose levels [186]. By upregulating glucose transporter 2 and activating key glycolytic enzymes, estrogen facilitates glucose utilization and glycogen deposition [221]. It also stimulates phosphofructokinase activity and promotes glycolysis, further reducing circulating glucose levels [221]. In lipid metabolism, estrogen enhances very‐low‐density lipoprotein secretion and mitochondrial β‐oxidation, while reducing fatty acid uptake and de novo lipogenesis [222]. Additionally, it inhibits lipolysis in adipose tissue, thereby limiting the release of free fatty acids into circulation and promoting their oxidation in skeletal muscle [223]. These mechanisms collectively prevent hepatic lipid accumulation and NAFLD progression. It also lowers low‐density lipoprotein cholesterol and increases high‐density lipoprotein (HDL) cholesterol levels [187]. In estrogen‐deficient animals, cholesterol synthesis does not increase, but the conversion of cholesterol to bile acids decreases due to reduced cholesterol 7α‐hydroxylase activity, resulting in lower HDL cholesterol excretion from the liver [187]. Evidence from aged ovariectomized rodent models indicates that ovarian insufficiency exacerbates OS and hepatic inflammation, accelerating liver damage [188]. The decline in estrogen during menopause, coupled with a relative rise in androgen levels, creates a metabolic profile that predisposes individuals to atherosclerosis and insulin resistance, potentially explaining the greater prevalence of NAFLD in postmenopausal women [224].

Clinical studies support the link between ovarian aging and NAFLD risk. Estrogen deficiency, particularly following oophorectomy or POF, is associated with a heightened likelihood of NAFLD, with the risk increasing with prolonged deficiency [225, 226]. NAFLD prevalence rises substantially from 42.9% in premenopausal obese women to 60.2% in postmenopausal counterparts [190]. Another study found a 60% prevalence of NAFLD in postmenopausal women compared with 32% in premenopausal women [189]. Women with premature menopause experience a higher risk of severe liver fibrosis, and those with NAFLD have an increased risk of fibrosis progression as they age [227]. Postmenopausal women also display greater fibrosis severity, particularly in cases of hepatocellular ballooning and portal vein inflammation [228]. Menopause‐associated fat redistribution exacerbates insulin resistance, dyslipidemia, hypertension, and diabetes, further compounding NAFLD risk [229]. Hormone replacement therapy in postmenopausal women may lower the risk of NAFLD and fibrosis progression.

Type 2 diabetes mellitus (T2DM) has reached pandemic proportions, affecting 10.5% of the global population, with prevalence driven largely by aging and escalating obesity rates [230]. Increased obesity rates and estrogen deficiency due to ovarian aging heighten women's susceptibility to T2DM [192]. Menopausal estrogen deficiency triggers metabolic changes that lead to adiposity accumulation and redistribution, particularly central adiposity [192]. This excess adipose tissue promotes a proinflammatory milieu characterized by the release of cytokines and adipokines, which contribute to peripheral insulin resistance and chronic low‐grade systemic inflammation [191]. Beyond its effects on adipose tissue, estrogen deficiency disrupts insulin homeostasis through multiple mechanisms. It modulates insulin secretion, signaling, and degradation, thereby influencing glucose metabolism [192]. The decline in estrogen leads to increased circulating free fatty acids, elevated triglyceride levels, and impaired insulin signaling, all of which contribute to reduced insulin sensitivity [192]. Concurrently, alterations in pancreatic β‐cell function, including increased apoptosis, diminished insulin secretion, and enhanced insulin degradation, result in progressive β‐cell failure. As a consequence, the availability of free insulin declines over time, ultimately impairing glucose regulation and predisposing women to T2DM [192].

Compelling evidence from human studies also demonstrated the association between ovarian aging and T2DM. An analysis of 1407 women aged 42–52 years from the Study of Women's Health Across the Nation showed that lower estradiol levels during premenopausal and early MT periods were related to increased risk of T2DM [231]. Similarly, an 11‐year prospective study demonstrated that women with POF faced a 32% higher risk of T2DM compared with those with normal ovarian function. Additionally, a shorter reproductive lifespan correlated with a higher T2DM risk (HR = 1.06, 95% CI = 1.01–1.12) [193]. Findings from the Women's Health Initiative, which included 124,379 postmenopausal women, further substantiated this association—those with a reproductive lifespan of less than 30 years exhibited a 37% greater risk of T2DM compared with women with a reproductive span of 36–40 years [194]. A systematic review confirmed these trends, demonstrating that each year of reproductive lifespan reduction was associated with a 6–15% increase in T2DM risk [195].

COPD is a progressive lung disease marked by age‐related decline in lung function, partially reversible airflow obstruction, reduced lung elasticity, and alveolar enlargement [232, 233]. Emerging evidence suggests that ovarian aging and associated hormonal fluctuations influence lung structure and function. Herring et al. [196] reported a significant reduction in alveolar number in ovariectomized animals, underscoring the detrimental impact of reproductive hormone loss on alveolar morphology [196]. Conversely, estrogen replacement therapy facilitated alveolar regeneration in ovariectomized mice, highlighting estrogen's critical role in maintaining alveolar integrity [234]. Given that small airway patency depends on the tethering effect of alveolar attachments, estrogen‐mediated preservation of alveolar architecture may mitigate lung function decline and enhance respiratory capacity [197]. OS is a key contributor to COPD [198]. In a murine COPD model, progesterone treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid, enhanced antioxidant enzyme activity, and lowered levels of malondialdehyde, a marker of lipid peroxidation, indicating its protective role against OS and inflammation in COPD [235].

Clinical studies further support the link between ovarian aging and pulmonary function decline. Postmenopausal women demonstrate poorer lung function than their premenopausal counterparts, evidenced by lower force expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) [236]. A 21‐year cohort study involving 2020 women found that postmenopausal women experienced reduced FVC, FEV₁, and 25–75% forced expiratory flow (FEF_25–75) [199]. Consistently, data from the UK Biobank, encompassing 141,076 women, revealed that naturally menopausal women had diminished FVC and FEV₁, along with an increased risk of pulmonary impairment (FVC < lower limit of normal), compared with menstruating women [200]. Notably, earlier onset of natural menopause correlated with greater declines in lung function [200]. A large prospective cohort study in the UK (2006–2010) involving 271,271 women identified an elevated risk of COPD‐related hospitalization or mortality among those who experienced menopause before the age of 47 years [201]. Similarly, an analysis of 11,258 Australian women found an inverse relationship between age at menopause and COPD risk [202]. More recent multinational research from Australia, the UK, and Sweden further reinforced the association between earlier menopause and increased COPD susceptibility [8].

Beyond its impact on the aforementioned conditions, ovarian aging influences a spectrum of other age‐related diseases. Estrogen deficiency contributes to muscle atrophy and the progressive decline in muscle mass, a hallmark of age‐related sarcopenia, through mechanisms involving altered protein turnover, increased apoptosis, and enhanced protein degradation [237]. Additionally, postmenopausal estrogen depletion doubles the prevalence of age‐related macular degeneration in older women compared with men, heightening the risk of severe visual impairment [238]. Estrogen supports the health of sensory cells by promoting neuronal survival and enhancing the secretion of VEGF in the cochlea, suggesting its role in age‐related hearing loss [239, 240, 241]. The influence of estrogen extends to skin and hair health, as ERs are widely expressed in cutaneous tissues, including the scalp. Menopause‐associated collagen depletion is particularly pronounced, with levels dropping by approximately 30% within the first 5 years and continuing to decline at a rate of 2% per year over the subsequent 15 years [242]. This decline contributes to common issues like skin aging and hair loss commonly observed during MT. Moreover, declining estrogen levels compromise immune function, predisposing postmenopausal women to a higher incidence of infections and autoimmune diseases. Estrogen serves as a key regulator of humoral immunity, and its absence impairs immune homeostasis [243, 244]. Consequently, menopausal women exhibit increased susceptibility to infections such as human papillomavirus and human immunodeficiency virus and often experience exacerbations of pre‐existing autoimmune conditions [245, 246, 247].

In conclusion, ovarian aging exerts far‐reaching systemic consequences, extending beyond reduced fertility and menopausal transition to contribute to the pathogenesis of various age‐related diseases including CVD, AD, PD, and COPD. A deeper understanding of the mechanisms driving ovarian aging is crucial for recognizing its multisystem implications, and interventions aimed at delaying ovarian aging may offer promising strategies for mitigating a spectrum of age‐related organ pathologies.

Ovarian ageing reflects a progressive decline in ovarian reserve, defined by the number of PGCs. As discussed earlier, both the quantity and quality of primordial follicles diminish with age, and once the follicle pool falls below a critical threshold, ovulation ceases and menopause ensues.

AFC measured by ultrasound is a widely used noninvasive marker of ovarian reserve [248]. Typically defined as follicles 2–10 mm in diameter, AFC correlates with the primordial follicle pool, providing a theoretical basis for its use as a surrogate biomarker [249]. However, follicle size‐specific dynamics complicate this relationship. In a cross‐sectional study of 366 women aged 21–41 years, the number of 2–4 and 5–7 mm follicles declined with age, whereas the number of 8–10 mm follicles paradoxically increased [250]. Although limited, evidence suggests that AFC is low at birth (2–5 follicles), peaks around the age of 15 years (10–25 follicles), and subsequently declines [251]. Overall, AFC exhibits a negative association with age, supporting its utility as a biomarker of ovarian ageing [252].

OV, also assessed by ultrasound, is another physiological marker. In a cohort of 100 infertile women, OV demonstrated a strong negative correlation with age (r = −0.876) [253] In addition to chronological ageing, factors such as contraceptive use, menopausal status, and obesity also modulate OV, with menopausal status exerting the greatest influence [254, 255]. On average, OV measures 4.9 mL in premenopausal women and 2.2 mL in postmenopausal women [256]. Combining OV with counts of nongrowing follicles has been proposed to refine estimates of ovarian reserve in healthy women [251].

AMH, secreted by GCs of pre‐antral and early antral follicles, is widely considered the most sensitive endocrine biomarker of ovarian reserve. AMH production ceases once follicle diameter exceeds 6–8 mm [252]. Unlike FSH or AFC, AMH levels remain relatively stable across the menstrual cycle, making it particularly useful for clinical assessment [252, 257]. Studies confirm that AMH outperforms age, AFC, OV, FSH, and inhibin B as a predictor of menopause [258, 259]. Even after adjusting for demographic factors, AMH is independently associated with menopausal timing and correlates with diverse reproductive outcomes, including infertility, irregular menstruation, and oligomenorrhea [260]. AMH also predicts live birth rates after IVF/intracytoplasmic sperm injection (ICSI) and the risk of diminished ovarian reserve (DOR) following chemotherapy [261, 262]. However, the lack of standardized assays remains a major limitation. While AMH can help identify women at risk of POI, it cannot precisely predict the age of onset [263].

FSH levels rise during perimenopause as declining estrogen reduces negative feedback to the hypothalamic–pituitary axis. However, FSH alone is an imperfect biomarker, as premature elevation can be masked by estradiol‐driven feedback [264]. Inhibin B, secreted by GCs in developing follicles, is also one of the factors that contribute to women of reproductive age maintain lower FSH levels [265]. As POI progresses, inhibin levels decrease significantly [266]. Studies suggest that a reduction in inhibin B levels can effectively reflect a decreased ovarian reserve in healthy reproductive‐age women, and when AFC is less than 5–7, inhibin B is more advantageous than FSH [265]. However, other studies indicate that, compared with AMH and FSH, inhibin B is less significant in terms of age‐related changes (p = 0.18, p < 0.001, and p = 0.12, respectively) [267].

Advances in ovarian biology continue to expand the repertoire of potential biomarkers. Mitochondrial dysfunction and energy metabolism are central to ovarian ageing, with metabolites such as coenzyme Q10 (CoQ10) and phosphatidic acid emerging as candidate biomarkers [268]. Reduced mtDNA copy number has been linked to earlier menopause, while animal studies suggest that circulating NUSN4 gene expression may predict ovarian ageing [269]. Proteostasis regulators such as cohesins SA1/SA2, deacetylase glycerol‐3‐phosphate dehydrogenase 1‐like, and plasminogen activator inhibitor 1, front fork transcription factor 3 (FOXO3) have also been implicated [270, 271, 272, 273]. Additionally, animal experiments have shown that bone morphogenetic protein 15, growth differentiation factor 9, C‐KIT, and a protein network composed of cytochrome P450 family members Fdx1, Cyp17a1, Cyp11a1, and Cyp2u1 may represent a novel biomarker for mouse with POF [274, 275].

Noncoding RNAs represent another frontier. Alterations in ovarian miRNA profiles accompany aging [276]. The miR‐200 family is elevated in murine serum exosomes [277], while miR‐146a upregulation has been observed in patients with POI [278]. In women with DOR, GC miR‐6881‐3p correlates positively with FSH and negatively with AMH and AFC [279]. circRNAs, interacting with miRNAs, modulate follicle development and hormone production, further expanding the potential biomarker landscape [275]. However, most candidates remain unvalidated in large clinical cohorts, and their translational feasibility requires further investigation.

Resveratrol (RES), a polyphenolic compound predominantly found in grapes and red wine, exerts potent anti‐inflammatory and antioxidant effects [344]. A key activator of the longevity‐associated gene SIRT1, RES has been shown to enhance telomerase activity, extend telomere length, and preserve the follicular reserve in aged mice, thereby mitigating age‐related infertility [294]. In a rat model of POI, RES attenuates OS and inhibits GC apoptosis via activation of the PI3K/Akt/mTOR signaling pathway [295]. Moreover, RES demonstrates protective effects against chemotherapy‐induced ovarian damage. Preclinical studies suggest that RES reduces follicular DNA damage and apoptosis, resulting in elevated AMH levels [296, 297, 345]. These protective effects may stem from the suppression of chemotherapy‐induced caspase‐3 and PARP1 activation [296, 297, 345]. It has also been found that RES alone does not prevent cisplatin‐induced DNA damage and apoptosis in the ovary. Rather, its coadministration with melatonin induces SIRT1 overexpression, effectively protecting against DNA damage [346].

RES treatment reduces apoptosis in infertility female GCs under OS conditions [347]. Interestingly, its effects appear concentration‐dependent: while low doses (1 µM) suppress apoptosis, higher doses (10–50 µM) enhance OS, inhibit DNA synthesis, and promote apoptosis in human umbilical vein endothelial cells [348]. In contrast, another study demonstrated that both 1 and 10 µM RES significantly reduced apoptosis [347]. Besides, RES increased ATP production and cellular activity in human GCs and promoted mitochondrial biogenesis [349]. These findings suggest that RES may serve as a promising therapeutic agent for ovarian aging. However, its clinical application remains complex, as RES has been associated with decidualization effects in the endometrium and adverse events such as headaches, dizziness, and hepatotoxicity [350]. Further studies are necessary to optimize dosing strategies and evaluate its long‐term safety and efficacy.

NAD⁺ is a critical coenzyme involved in energy metabolism, redox homeostasis, and DNA repair [351]. NAD⁺ levels decline with age, contributing to the pathogenesis of multiple age‐related disorders, including ovarian dysfunction [352]. As a precursor of NAD⁺, nicotinamide mononucleotide (NMN) supplementation restores NAD⁺ levels and enhances ovarian reserve in aged mice by improving mitochondrial function, autophagy, protease activity, and energy metabolism, while reducing ovarian inflammation [298, 299]. NMN administration also ameliorates age‐related oocyte deterioration, potentially via SIRT2 overexpression, which stabilizes meiotic spindle assembly and reduces aneuploidy incidence [300, 301]. Given that proper spindle formation is ATP‐dependent, timely NMN supplementation may ensure adequate NAD⁺ availability to sustain this process [300]. Beyond aging, NMN has demonstrated a protective role against chemotherapy‐induced ovarian toxicity and female infertility. Importantly, its cytoprotective effects do not appear to interfere with the efficacy of cancer treatments, suggesting its potential for fertility preservation in oncology patients [353]. Another NAD⁺ precursor, nicotinamide riboside (NR), has been shown to enhance ovarian mitochondrial function, increase ovarian reserve, and improve live birth rates in aged mice [354].

However, despite promising preclinical findings, NAD⁺ depletion in human oocytes has been observed at different meiotic stages, with variability in precursor abundance [76]. The precise effects of NAD⁺ and its precursors on human ovarian function remain an active area of investigation. Future research should focus on identifying the most effective precursor, optimizing dosing regimens, and translating these findings into clinical applications.

Melatonin, a potent free radical scavenger and antioxidant, is synthesized by the pineal gland and various peripheral tissues, including the ovaries, where it is present in follicular fluid [355, 356]. Aging‐associated depletion of follicular melatonin leads to excessive ROS accumulation, which compromises oocyte quality. By activating the Sirt1/Sod2 pathway, melatonin reduces OS and enhances oocyte viability [302]. Melatonin further alleviates OS through multiple signaling pathways, including melatonin membrane receptor 1 (MT1) /p53‐signaling pathway, MT1/AMPK pathway, and SIRT3 [303, 357, 358]. In addition to ROS neutralization, melatonin mitigates age‐ and chemotherapy‐induced follicular loss and ovarian dysfunction by suppressing inflammation, reducing apoptosis, and maintaining telomere integrity, with the PTEN/PI3K/Akt/mTOR/AMPK and SIRT pathways playing central roles [304, 305, 358, 359]. Moreover, melatonin preserves intercellular communication, a key factor in sustaining oocyte quality during aging [360].

Clinical studies further support melatonin's role in ovarian function. Women with DOR exhibit lower melatonin levels in follicular fluid and serum compared with those with normal ovarian function [361]. Serum and follicular melatonin levels negatively correlate with age and baseline FSH but positively correlate with AMH and AFC, suggesting a strong link between melatonin levels and ovarian reserve [361]. Another study found that melatonin supplementation improved in IVF outcomes in older women, with a significant increase in clinical pregnancy rates (from 20.3 to 46.0%), ongoing pregnancy rates (from 15.3 to 36.5%), and live birth rates (from 15.3 to 33.3%) [362]. Notably, animal studies indicate that the timing of melatonin intervention is critical. Initiating melatonin supplementation at 23 weeks of age in mice significantly enhances reproductive outcomes, whereas treatment beginning at 33 weeks yields no significant benefits compared with controls [363]. These findings suggest that melatonin therapy may be most effective when administered before the onset of ovarian aging. However, there are currently no corresponding population studies indicating the appropriate timing and dosage range for melatonin treatment of ovarian aging. Larger clinical studies are needed in the future.

CoQ10 is an important component involved in the electron transport chain and plays an essential role in protecting mitochondria from ROS‐induced oxidative damage [307, 364]. The CoQ10 content of oocytes progressively decreases with age, which is consistent with diminished oocyte quality and age‐related fertility decline [309]. As a potent antioxidant, CoQ10 enhances oocyte quality by reducing ROS and increasing Bcl2 and Sirt1 expression, indicating that it may alleviate ovarian aging by suppressing apoptosis [306, 307, 365]. A study applying cyclophosphamide (CTX)‐induced mouse POF model showed that CoQ10 acts on FSHR and proliferation cell nuclear antigen (PCNA), which are important genes related to folliculogenesis [307]. In addition, CoQ10 facilitates the differentiation of ovarian stem cells derived from the ovarian surface epithelium and improves ovarian function and oocyte quality in a mouse model of chemically induced ovarian failure [308]. Mitochondrial dysfunction is a hallmark of ovarian aging [87]. Supplementation of CoQ10 in aged mice delays ovarian reserve depletion, restores mitochondrial gene expression in oocytes, and improves mitochondrial activity [309]. Intriguingly, CoQ10 exerts no effect on ovarian reserve or oocyte quality in young females, indicating that its benefits are specific to age‐related mitochondrial dysfunction [309]. In patients undergoing IVF, decreased CoQ10 levels in granular cells have been associated with impaired mitochondrial function, while in vitro CoQ10 supplementation has been shown to enhance mitochondrial activity in these cells [366].

Clinical studies suggest a potential role for CoQ10 in improving reproductive outcomes. A randomized, double‐blind study in reproductively older women reported a reduction in oocyte aneuploidy rates with CoQ10 treatment (62.8 vs. 46.8%) and a modest increase in clinical pregnancy rates (26.7–33%), although the results did not reach statistical significance due to the limited sample size [367]. In younger women with DOR, CoQ10 supplementation significantly elevated serum estrogen levels, enhanced ovarian response to stimulation, and improved oocyte and embryo quality during IVF–ICSI cycles, leading to higher clinical pregnancy and live birth rates and a lower miscarriage rate [338]. A meta‐analysis identified an optimal regimen of 30 mg/day CoQ10 for 3 months before ovarian stimulation, particularly benefiting women with DOR under 35 years of age [368]. Although current evidence highlights CoQ10 as a promising therapeutic for ovarian aging, its impact on live birth rates remains uncertain. Further large‐scale animal and clinical studies are essential to validate the clinical efficacy and optimize the therapeutic protocol for CoQ10 in ovarian aging [368].

N‐acetyl‐L‐cysteine (NAC) has been widely used as a therapeutic agent for acetaminophen (paracetamol) overdose. As a precursor for glutathione synthesis, NAC possesses potent antioxidant properties and functions as both a direct and indirect free radical scavenger [369, 370, 371]. Studies suggest that NAC supplementation in the oocyte culture medium can counteract OS‐induced damage [371]. In addition to reducing OS by lowering NOX4 and p22 levels, NAC inhibits ovarian apoptosis by suppressing the p53/caspase‐3 cascade reaction to ameliorate radiation‐induced POF in rats [310]. Additionally, NAC has been shown to alleviate chemotherapy‐induced ovarian toxicity, improving ovarian function in treated mice [372]. Long‐term NAC administration in drinking water has been reported to delay oocyte aging and enhance oocyte quality in aged mice. Compared with controls, NAC‐treated mice exhibited increased ovarian telomerase activity and extended telomere length, both of which are indicative of improved ovarian health [311]. Despite these promising findings, studies on NAC in ovarian aging remain limited. Further investigations are necessary to determine its therapeutic efficacy and safety, particularly in clinical applications.

Metformin, a first‐line therapy for T2DM, is widely recognized for its favorable safety profile and high tolerability [373]. Beyond its antidiabetic properties, metformin has been implicated in reducing cancer risk, improving cancer prognosis, and delaying aging in nonhuman primates [374, 375, 376]. In aged mice, metformin treatment has been shown to mitigate ovarian aging by enhancing SIRT1 expression and reducing oxidative damage, thereby preserving ovarian reserve [312]. Studies of both murine and human ovaries suggest that metformin counteracts age‐related fibrosis by modulating the ovarian immune microenvironment and altering the balance of fibroblasts, myofibroblasts, and immune cells [315, 316]. Masson's trichrome staining revealed that while untreated postmenopausal ovaries exhibited collagen structures characteristic of age‐related fibrotic remodeling, those exposed to metformin retained a more youthful collagen organization similar to that of premenopausal ovaries [316]. Additionally, metformin has been shown to inhibit apoptosis via the PI3K–Akt–FOXO3a pathway, partially reversing d‐galactose‐induced ovarian dysfunction in mice [313].

Metformin also protects against chemotherapy‐induced ovarian damage in mice, primarily by reducing OS and inflammation, a process closely linked to its activation of the AMPK pathway [314]. In human ovaries, metformin has been shown to regulate multiple metabolic pathways associated with POI through AMPK upregulation [377]. Notably, AMPK expression negatively correlates with body mass index, FSH, and leptin levels, while positively correlating with estrogen levels in POI patients [377]. A 2‐month intervention with a therapeutic diabetic dose of metformin in nine women with POI resulted in increased AMPK activation and ATP levels, alongside decreased leptin and TNF‐α concentrations in blood mononuclear cells, with no reported adverse effects [377]. In the context of assisted reproduction, low‐dose metformin may enhance pregnancy outcomes in IVF patients without PCOS by improving insulin sensitivity [378]. However, despite its promising potential in ovarian aging, excessive metformin use can lead to lactic acidosis, particularly in patients with severe CKD, and is contraindicated in individuals with an estimated glomerular filtration rate (eGFR) below 30 mL/min [379]. Generally, metformin represents a compelling candidate for mitigating ovarian aging through both direct and indirect activation of AMPK [373]. Nevertheless, further clinical studies are essential to fully elucidate its therapeutic potential and establish its efficacy in preserving ovarian function and fertility.

Despite promising preclinical and clinical findings, several limitations hinder the therapeutic translation of antiaging drugs for ovarian aging. Melatonin and CoQ10, while improving oocyte quality and IVF outcomes, face challenges such as poor bioavailability, variability in patient response, and uncertainty regarding optimal timing and dosing, with limited evidence for long‐term safety. Similarly, NAC demonstrates antioxidative and telomere‐preserving benefits in animal models, but data remain scarce, and its clinical relevance is yet to be established. Metformin shows potential through AMPK activation and modulation of ovarian fibrosis; however, its application is constrained by risks of lactic acidosis in patients with renal impairment and limited clinical trials specific to ovarian aging. Importantly, most studies focus on monotherapies, failing to address the multifactorial mechanisms of ovarian decline. A lack of large‐scale randomized controlled trials (RCTs) and incomplete mechanistic insights further restricts their clinical adoption, emphasizing the need for multitargeted strategies and rigorous translational studies.

Tissue engineering offers a promising strategy to counter ovarian aging by reconstructing the follicular microenvironment through biomimetic scaffolds. Decellularized whole‐ovarian ECM scaffolds preserve the native ultrastructure and biochemical cues necessary for follicle survival and steroidogenesis, while recellularization with homologous fibroblasts restores endocrine functionality [394]. In rats, human ovary‐derived decellularized scaffolds seeded with ovarian cells maintained follicular structures and significantly increased estradiol and progesterone secretion [331]. Similarly, ovary decellularization in mice generated bioscaffolds that sustained cell viability and recapitulated ovarian architecture [396]. Synthetic hydrogels provide an alternative, with 3D‐printed microporous constructs supporting follicle development, angiogenesis, and even partial fertility restoration in mice [330]. Despite these advances, translation to human application remains limited to in vitro models, with major barriers including ischemic follicle loss, variable scaffold preparation, and incomplete understanding of long‐term safety. Nonetheless, by integrating biomaterial science with reproductive biology, tissue engineering holds potential as a next‐generation approach to extend ovarian health span.

Emerging drug delivery systems, stem‐cell‐derived EVs and nucleic acid therapeutics, platelet‐rich plasma (PRP), and nanocarriers, have emerged as promising targeted strategies to restore ovarian function. MSC‐derived exosomes and nanocarriers can concentrate bioactive molecules within the ovarian niche, modulating OS, apoptosis, and inflammatory pathways. Activation of Nrf2/GPX4 and PI3K/AKT cascades has been shown to restore GC survival and endocrine balance [320, 380]. In addition, miRNAs, which are key posttranscriptional regulators in folliculogenesis, oocyte maturation, and steroidogenesis [397], represent a novel frontier in therapeutics. In preclinical models, delivery of protective miRNAs, such as exosomal miR‐10a, via liposomal systems attenuates chemotherapy‐induced follicular atresia by targeting apoptotic pathways and improving follicle survival [333]. Follicular‐fluid‐derived exosomes carrying miR‐320a‐3p also rejuvenate ovarian aging through FOXQ1 inhibition [335]. PRP delivers angiogenic and mitogenic growth factors, promoting paracrine and vascular repair in situ [332, 398]. Follicle‐targeted nanocarriers encapsulating growth hormone alleviate aging‐associated dysfunction, restoring follicular activity and reducing ROS [334]. A recent study demonstrated that CeNPs, known for their catalytic antioxidant activity, significantly mitigate OS in ovarian tissues and promote regeneration in aged models, adding a novel functional nanomaterial to the ovarian rejuvenation armamentarium [336].

Rodent models of ovarian aging, induced by chemotherapy or natural senescence, demonstrate that MSC‐EVs restore follicle counts, normalize hormone profiles, and improve fertility outcomes [320, 322, 325]. Exosomal miR‐17‐5P delivery alleviated ROS accumulation and restored ovarian phenotype and function in CTX‐induced POI model mice by inhibiting SIRT7 expression [319]. Direct ovarian injection of PRP may enhance follicle development and oocyte retrieval. In a rat model of ovarian ischemia, PRP increased VEGF levels and protected against reperfusion‐related oxidative damage, likely due to its proangiogenic and proliferative properties [399]. Current clinical data remain preliminary. Meta‐analyses indicate that intraovarian PRP injections can improve ovarian reserve markers and reproductive parameters in women with DOR [400]. Stem cell therapies are in nascent trials, while miRNA‐based and nanocarrier approaches have yet to reach clinical application. CeNPs are so far confined to animal studies with no human data.

There are several limitations of the drug delivery. Translation is hindered by (i) scarcity of RCTs with live birth as primary endpoint, (ii) uncertain long‐term safety and intergenerational risks of nanoparticles and gene therapies, (iii) heterogeneity in PRP and EV preparation, and (iv) regulatory ambiguity regarding classification of biologics and nanomaterials. Standardization of biologic preparations, integration of miRNA delivery platforms with nanocarriers, and further exploration of redox‐active nanoparticles such as CeNPs are promising avenues. Long‐term safety validation, intergenerational toxicology, and rigorous multicenter trials remain critical to move from experimental promise to clinical translation.

In summary, emerging interventional strategies offer promising avenues for delay ovarian aging and extending reproductive potential. Future advances will require the integration of foundational research with translational applications, applications, ultimately bridging fertility preservation with broader goals of promoting healthy longevity.