Role and mechanisms of plant polyphenols in ovarian aging

Abstract

The ovary is a vital organ in female animals, playing a crucial role in regulating reproductive and endocrine functions. Ovarian aging is characterized by declining oocyte quality and ovarian reserve quantity, ultimately leading to infertility and increased risk of age-related diseases. Oxidative stress, inflammation, endocrine disorders, and ovarian microenvironmental disruption are central mechanisms contributing to ovarian aging. Despite the growing incidence of delayed childbearing, there are limited effective interventions to preserve ovarian function. Plant polyphenols, a diverse group of naturally occurring compounds with potent biological activities, have emerged as promising candidates for improving ovarian function and reproductive health. However, a comprehensive synthesis of their classification, mechanisms of action, translational potential, and clinical application prospects remain lacking. In this review, we describe the mechanisms of ovarian aging, systematically classify plant polyphenols and summarize their specific bioactivities related to ovarian function. Furthermore, we highlight that these natural compounds have the potential to delay ovarian aging by alleviating oxidative stress, reducing inflammation, modulating hormone balance, and regulating gut microbiota. Consequently, they hold promise as a novel intervention strategy to mitigate the adverse outcomes of ovarian aging. While plant polyphenols hold considerable promise, several critical challenges remain unresolved, specifically inconsistent dosing regimens, poor bioavailability, and a lack of robust clinical validation. Overall, this review aims to provide a comprehensive overview of the protective roles and underlaying biological mechanisms of plant polyphenols in ovarian aging and propose future research directions for developing safe and effective plant polyphenol-based interventions for female reproductive longevity.

Introduction

Aging is an inevitable, progressive process in humans and animals, characterized by structural degeneration, functional decline, and diminished adaptability to environmental and physiological stressors [1]. In females, the ovary is one of the most important organs that functions as a natural biological clock, controlling the aging process [2]. Ovarian aging is a complex biological process characterized by the progressive decline in oocyte quality and the depletion of follicular reserve, and it represents a key factor in age-related infertility [3]. Notably, given that ovarian reserve is non-renewable and reproduction function is time-limited, ovarian aging occurs earlier than aging in most other organs. It is closely associated with conditions such as osteoporosis, cardiovascular disease, and neurodegenerative disorders, thereby serving as a key signal of female biological aging [4]. Although the underlying mechanisms ovarian aging are not yet fully understood, growing evidence suggests that it is closely linked to oxidative stress, mitochondrial dysfunction, chronic inflammation, epigenetics alterations, disturbances in the ovarian microenvironmental, especially disruptions in the hypothalamic-pituitary-ovary (HPO) axis [5]. While hormone replacement therapy and assisted reproductive technologies improve the reproductive rate, they do not prevent the underlying decline in ovarian function. Therefore, there is growing interest in natural, safe, and effective compounds that can intervene earlier in the aging process. Among these, plant polyphenols have received increasing attention for their multi-targeted protective effects.

Plant polyphenols are naturally occurring secondary metabolites, with over 8000 identified types distributed across a wide range of botanical sources such as fruits, vegetables, nuts, seeds, herbs, spices, and medicinal plants [6]. These compounds are broadly categorized into flavonoids, stilbenes, tannins, phenolic acids, and others [7]. Due to their unique chemical structures, plant polyphenols possess strong biological activities, including antioxidant, anti-inflammatory, antibacterial, and antiviral properties, all of which are considered beneficial to health [8–11]. Of note, a growing number of studies suggest that plant polyphenols can reduce the risk of age-related diseases such as cardiovascular disease, diabetes, and neurodegenerative disorders [12, 13]. These benefical effects making them attractive candidates for delaying ovarian aging. In this review, we discuss the mechanisms underlying ovarian aging, categorize plant polyphenols along with their bioactive properties, and summarize recent research progress on their effects in the context of ovarian aging. Furthermore, we highlight the molecular pathways through which plant polyphenols may exert protective effects on ovarian function and delay ovarian aging. These insights are intended to inform future research and support the development of novel strategies for promoting female reproductive health.

The mechanisms of ovarian aging

Folliculogenesis and ovarian aging

Fulliculogenesis is a fundamental determinant of ovarian function and reproductive longevity. As the functional unit of the ovary, the quality and dynamics of follicle are tightly regulated throughout a female’s reproductive lifespan. As shown in Fig. 1, folliculogenesis commences with the recruitment of primordial follicles, proceeds through the selection of dominant follicles, and culminates in either ovulation of mature follicles or atretic degeneration [14]. Despite the abundance of primordial follicles, their ultimate fate is different. For instance, Humans possess 6–7 million primordial follicles at the embryonic stage, forming the ovarian reserve [5]. With aging, the follicle reserve continuously depletes, leaving only approximately 1,000 follicles available for ovulation, ultimately leading to reproductive decline [15]. In fact, primordial follicle activation, development and atresia are the key factors in ovarian aging, whereas follicle reserve depletion is its primary cause [16]. However, follicle reserve varies widely among animal species and is influenced by genetic and environmental factors [17]. Follicular atresia and dysfunction are largely influenced by oxidative stress, which is hallmark of ovarian aging and will be further discussed.

Fig. 1.

Schematic overview of folliculogenesis: key stages of follicle development and their physiological fates

Oxidative stress and ovarian aging

Among various theories, the free radical theory, proposed in the 1950 s, is considered a classical theoretical basis for ovarian aging [18]. Free radicals are highly reactive oxidative products, including reactive oxygen species (ROS) and reactive nitrogen (RNS). As signaling molecules, ROS participate in intercellular signal transduction and maintain normal ovarian physiological functions. They also play a crucial role in follicle development [19]. However, excessive ROS disrupt the redox balance, leading to mitochondrial function damage, telomere shortening, apoptosis, and inflammation (Fig. 2). As the primary energy producers, mitochondria serve as both the source and the target of ROS. Oxidative stress leads to mitochondrial DNA (mtDNA) mutations, impairing oxidative phosphorylation and ATP synthesis, ultimately compromising ovarian function [20]. Telomere shortening is considered to be a biomarker of cellular aging, highly sensitive to ROS-induced damage and difficult to repair. Telomere shortening due to oxidative stress is a contributor to ovarian aging [21]. Oxidative stress also induces ovarian cell apoptosis through the mitochondrial pathway, death receptor pathway, and endoplasmic reticulum stress pathway, resulting in ovarian aging due to massive follicular atresia [22]. Additionally, oxidative stress triggers inflammation by activating the NOD-like receptor protein 3 (NLRP3) inflammasome and nuclear factor kappa-B (NFκB) signaling, promoting pro-inflammatory cytokine production that exacerbates ovarian aging [23]. Understanding the mechanisms of oxidative stress-induced ovarian aging is essential for developing targeted interventions.

Fig. 2.

Mechanisms by which oxidative stress contributes to ovarian aging: telomere shorten, granulosa cell apoptosis, mitochondrial dysfunction, inflammation, cell membrane damage

Epigenetics and ovarian aging

Epigenetic modifications can alter chromatin structure without changing the DNA sequence and then regulate gene expression and biological character, which plays a crucial role in cell differentiation, development, and the maintenance of cellular functions [24]. Female germ cells exhibit abnormal epigenetic modifications during aging, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) regulation [25]. DNA methylation can lead to gene silencing, reduced transcription levels, and chromatin remodeling. Methylation abnormalities in females, resulting from ovarian aging, increase ovarian cell apoptosis, accelerate follicle depletion, and significant hormonal fluctuations [26]. Moreover, a study shown that differential gene methylation also results in changes in cellular transcription in aged oocytes [27]. Histone modifications regulate chromatin architecture and can either activate or suppress target gene expression. This epigenetic mechanism may impair oocyte maturation and accelerate ovarian aging in females [28]. ncRNAs regulate gene expression epigenetically through molecular interactions with DNA, RNA, or protein complexes, and their dysregulation contributes to oocyte deterioration and ovarian aging [29]. These epigenetic changes often interact with are influenced by the ovarian microenvironment, which involves the niche of granulosa cells, stromal signaling, and inflammatory cytokines.

Ovarian microenvironment and ovarian aging

The ovarian microenvironment refers to the structural and signaling milieu that supports follicle development and hormone production [30]. Communication between oocytes and the ovarian microenvironment is facilitated through direct interaction with adjacent cells, the extracellular matrix, as well as signaling molecules such as hormones, growth factors, and metabolites [31]. The ovarian stromal microenvironment supports follicular development by providing a biochemical scaffold while supplying nutrients through paracrine signaling. However, the accumulation of age-related metabolites or external negative stimuli leads to the remodeling of the ovarian microenvironment and disrupts ovarian physiological homeostasis [32]. The study on in situ transplantation of ovarian tissues in young and aged mice has demonstrated that healthy microenvironment plays a crucial role in folliculogenesis [33]. The disruption of the equilibrium between the synthesis and degradation of ovarian extracellular matrix components leads to tissue fibrosis. It is reported that ovarian tissue fibrosis within the mouse ovarian stroma increases with aging is considered an early signal of ovarian aging [34]. Ovarian microenvironment alterations in metabolic processes, redox balance, and hormone secretion are found in aging ovaries [35]. Additionally, gut microbiota and their metabolites may shape ovarian microenvironment via gut-ovary axis.

Gut microbiota and ovarian aging

The gut microbiota is a complex symbiotic ecosystem that plays a crucial role in female health and pathogenesis. More importantly, significant alterations in the composition of dominant microorganisms, bacterial diversity, and functions have been observed in aging and age-related diseases [36]. A study has shown that transplanting microbiota from aged mice accelerates age-related neurodegeneration, whereas transplantation from young mice can reverse this effect, indicating that gut microbiota is linked to specific organs aging [37]. Moreover, findings from fecal microbiota transplantation study provide a novel perspective on alleviating ovarian aging, suggesting that maintain a youthful gut microbiota may help preserve ovarian function and reproductive health [38]. There is an interaction between gut microbiota and ovarian function. The ovary influences the gut microbial homeostasis by secreting hormones, while the gut microbiota can regulate ovarian function through metabolic signaling molecules such as short chain fatty acid, neurotransmitters, and bile acids. Additionally, a recent review described the association between ovarian aging and gut microbiota, highlighting that changes in the composition, structure, and functional characteristics of the gut microbiota profoundly impact ovarian aging [39]. Therefore, the gut microbiota-ovary axis may play a role in ovarian function and ovarian aging. These diverse but interconnected mechanism underscore the complexity of ovarian aging and critical need for early intervention.

Plant polyphenols

Classification of plant polyphenols

Plant polyphenols are a class of secondary metabolites that plants produce to adapt to environmental changes. They exist extensively in plants or plant-based foods such as grapes, mangoes, blueberries, tea, onions, soybeans, and red wine. Their structure is characterized by at least two benzene rings and one or more hydroxyl substituents [40]. Plant polyphenols are among the most abundant natural compounds, ranking fourth in nature after cellulose, hemicellulose, and Lignin. To date, over 8,000 types of plant polyphenols have been identified, exhibiting diverse sources and structural variations [7]. Based on the chemical structure, plant polyphenols are classified into six categories (Fig. 3): phenolic acids (including hydroxybenzoic and hydroxycinnamic acids), stilbenes, lignans, flavonoids (including flavones, isoflavones, anthocyanins, flavanols, and flavanones), tannins, and curcuminoids [41].

Fig. 3.

The classification of plant polyphenols

Digestion, absorption, and metabolism of plant polyphenols

The digestion, absorption, and metabolism of plant polyphenols are complex processes. Plant polyphenols first undergo initial digestion in the oral cavity and stomach, where they are exposed to saliva and gastric acid, respectively. In the small intestine, they may be converted into aglycones. Complex polymeric plant polyphenols are broken down by hindgut microbiota into aglycones and phenolic acids, which are then absorbed or excreted [42]. Most plant polyphenols in plants exist as glycosylated, esterified and polymeric forms and must undergo hydrolysis by intestinal enzymes or microbiota to be absorbed [43]. In the small intestine, plant polyphenols are primarily absorbed through active transport and passive diffusion. After absorption, they undergo Phase I and Phase Ⅱ metabolism in the liver, where they are methylated, sulfated, or glucuronidated before entering the bloodstream. Complex plant polyphenols that are not absorbed in the small intestine reach the hindgut, where they are metabolized by microbiota. The resulting metabolites can be absorbed in the hindgut and further transformation in the liver, while unutilized compounds are excreted in the feces [44].

Bioactive properties of plant polyphenols

Plant polyphenols exhibit a variety of bioactive properties that contribute to improving overall health. As a powerful natural antioxidant, which alleviate oxidative stress damage by directly scavenging ROS and indirectly activating antioxidant enzyme systems [45]. Importantly, they can prevent diseases associated with oxidative stress, such as cardiovascular disease, type 2 diabetes, and neurodegenerative diseases. Plant polyphenols also have anti-inflammatory and immune-modulating activities. Studies have shown that plant polyphenols can reduce inflammation by limiting the production and secretion of inflammatory factors [46], as well as exert immune regulation by enhancing cellular and humoral immunity [47]. Furthermore, plant polyphenols exhibit broad-spectrum antimicrobial activity, which inhibits the proliferation of pathogenic bacteria by reducing bacterial adhesion and altering or disrupting cell membrane permeability, thus preventing bacterial invasion [48]. In terms of antiviral properties, research has demonstrated that plant polyphenols can hinder viral infection by suppressing viral attachment, internalization, and release [49]. Moreover, the bioactive properties of plant polyphenols are not limited to the above-mentioned effects, studies have shown that they also play a positive role in gut microbiota regulation, metabolic function, and ovarian function [50, 51].

Plant polyphenols and aging

Aging is a complex physiological process characterized by the decline in cellular, tissue, and organ functions, ultimately leading to an increased risk of mortality. It is closely associated with pathophysiological process including oxidative stress, inflammation, cellular damage, and metabolic disorders. Plant polyphenols possess a variety of bioactive properties that may contribute to alleviating aging and reducing the risk of aging-related diseases [52]. Data from the Aging Intervention Testing Program, supported by the National Institute on Aging (USA), showed that certain plant polyphenols, including resveratrol, green tea extract, and curcumin, are effective and popular natural anti-aging agents [53]. The recent study investigated the effects of polyphenol-rich natural extract in aged mice through daily oral administration, and the results demonstrated that the extract significantly extended the lifespan of mice and improved several aging-related phenotypes across multiple tissues, including fur quality, hair follicle diameter, bone structure, bone mineral, grip strength, muscle fibrosis, and glomerular diameter [54]. Furthermore, a growing number of studies indicate that plant polyphenols can alter aging-related biomarkers and slow the aging process through various mechanisms, such as regulating mitochondrial function, modulating telomere dynamics, maintaining genomic stability, altering epigenetic modifications, and delaying cellular senescence [55, 56]. These findings highlight the critical role of plant polyphenols in anti-aging interventions and disease prevention.

Effects of plant polyphenols on ovarian aging

Despite aging is considered an inevitable and irreversible process, it is possible to delay its progression. Given the multiple bioactive activities of plant polyphenols and the close association with aging, an increasing number of studies have explored their effects on ovarian aging in humans and animals, aiming to improve female ovarian health and reproductive performance. In this section, we summarize the role of common plant polyphenols (derived from various sources) in alleviating ovarian aging (Table 1).

Table 1.

Effects of plant polyphenols on ovarian aging

Plant polyphenol	Classification	Chemical structures	Experimental model	Does (route)	Major results	Reference
Resveratrol	Stilbenes		Human granulosa cells	0.001–20 μM	Low doses of resveratrol have a protective effect against induced-oxidative stress on COV434 and primary granulosa cells	Moreira-Pinto et al., 2021 [57]
			Malathion-induced estrus cycle disorder mice	30 mg/kg (IP)	Improved the disorders of estrus cycle and steroid hormone synthesis, reduced ROS accumulation, inhibited ovarian cells apoptosis and autophagy	Yong et al., 2021 [58]
			Poor ovarian reserve women	150 mg/d (PO)	Acted on mitochondrial microRNAs to improve follicular microenvironment by transcriptomic and proteomic modifications in granulosa cells	Battaglia et al., 2022 [59]
			Aging mice	400 mg/kg (PO)	Increased mitochondrial membrane potential and ATP content, restored oocyte quality, and promoted embryonic development	Okamoto et al., 2022 [60]
			Aging mice	30 mg/L (WD)	Reversed transcriptome and shifted the methylome to a younger profile of aging ovary	Gou et al., 2022 [61]
			Aging rats	20 mg/kg (IP)	Increased the numbers of primordial and primary follicles, reduced oxidative damage, and delayed ovarian aging	Wu et al., 2022 [35, 62, 63]
			Human ovarian granulosa cells	1, 10, and 100 μM	Rescued the granulosa cells apoptosis caused by oxidative stress, and protected ovarian health	Liang et al., 2023 [64]
			Premature ovarian failure mice	7 and 15 mg/kg (IP)	Preserved the number of primordial follicles, increased the growing follicles and the AMH level, decreased the atretic follicles, inhibited DNA damage and apoptosis, and maintained antioxidant defense	Herrero et al., 2023 [65]
			6-, 9,—and 12-month fish	200 mg/kg (DA)	Increased oocyte proportions, decreased atretic follicles, relieved ovarian inflammation and endoplasmic reticulum stress	Zhu et al., 2023 [15, 66]
			Oxidative stress laying hens	600 mg/kg (DA)	Improved egg laying rate, reduced follicle atresia, alleviated ovarian damage induced oxidative stress	Wang et al., 2022 [67]
Tea polyphenol	Flavonoids		Gestating sows	0, 100, 200, 300, and 400 mg/kg (catechins, DA)	Enhanced antioxidative capacity and improved reproductive performance	Fan et al., 2015 [68]
			Laying hens exposed to Vanadium	165 mg/kg (EGCG, DA)	Decreased ovarian cells apoptosis, increased the Haugh unit of eggs, upregulated the levels of immune response proteins	Wang et al., 2017 [69]
			Bovine oocytes	0, 25, 50, 100, 200 μM (EGCG)	Increased cumulus cell expansion, decreased ROS level and oocytes early apoptosis and improved oocyte maturation	Huang et al., 2018 [70]
			Doxorubicin induced human ovarian tissue	10 mg/mL (EGCG)	Reduced inflammatory responses, improved the preservation of follicles and protected reproductive potential	Fabbri et al., 2019 [71]
			Cisplatin-exposed porcine oocytes	50 μM	Eliminated excessive ROS, inhibited the accumulation of DNA damage and oocytes apoptosis	Zhou et al., 2019 [72]
			Tri-ortho-cresyl phosphate induced ovarian damage mice	100 mg/mL	Rescued ovarian cells autophagy and damage by inhibiting oxidative stress	Yang et al., 2020 [73]
			Cyclophosphamide induced ovarian damage mice	100 and 400 mg/kg (EGCG, IG), 15 and 60 mg/kg (Theaflavins, IG)	Alleviated ovarian DNA damage, reduced the overactivation of primordial follicles and improved ovarian endocrine and reproductivity	Chen et al., 2021 [74–76]
			Old layers	100 mg/kg (Theabrownins, DA)	Improved egg production and egg quality, enhanced ovarian antioxidant capacity	Xu et al., 2023 [77]
			Aged mice	In vitro: 1, 10, and 100 μM (EGCG); In vivo: 0.1, 1, 5, and 10 mg/kg (EGCG, IP)	Enhanced the quality of aged oocytes both in vitro and in vivo, reduced oxidative stress, and improved fertility	Zhang et al., 2024a [78]
			Laying hens	100 mg/kg (Theabrownins, DA)	Increased egg weight, decreased ovarian cell apoptosis, and improved ovarian function	Zhang et al., 2024b [79]
Quercetin	Flavonoids		H2O2-induced rat granulosa cells	5, 20, and 50 μM	Rescued the decrease in cell viability, ameliorated the H2O2-induced downregulation of oxidative stress-related proteins including superoxide dismutase-1, catalase, and glutathione synthetase	Wang et al., 2018 [80]
			Aged mice and human oocytes	Mice oocytes:5, 20, and 50 μM; Human oocytes: 10μM	Promotes in vitro maturation and early embryonic development of oocytes, improves oocytes quality	Cao et al., 2020 [81, 82]
			Dehydroepiandrosterone-induced PCOS rat	100 mg/kg (IG)	Relieved inflammation and ovarian cells apoptosis, regulated hormone secretion and alleviated ovulatory aberrations	Zheng et al., 2022 [83]
			Aged porcine oocytes	5, 10, and 20 μM	Improved oocyte maturation, reduced oxidative stress, reduced apoptosis and autophagy	Jiao et al., 2022 [84]
			Porcine ovarian granulosa cells	1, 10, and 100 μg/mL	Inhibited cell apoptosis, stimulated progesterone secretion, improved reproductive functions and prevented reproductive disorders	Tarko et al., 2023 [85]
			Letrozole-induced PCOS mice	125 mg/kg (PO)	Regenerated the corpus luteum, prevented the degradation of ovarian follicle, reversed ration of LH/FSH, and protected ovary tissue structure and components	Shah et al., 2023 [86]
			Human ovarian cells and middle- aged mice	In vitro: 10 μM; In vivo: 50 mg/kg (OG)	Delayed human ovarian cells aging, improved the estrous cycle, follicle count, pregnancy rate, and ovary reserve of middle-aged mice	Wu et al., 2024 [87]
			H2O2-induced rat granulosa cells	20 μM	Increased cell viability, decreased cell apoptosis, stimulated estradiol secretion, upregulated autophagy-related proteins expression, resisted ovarian injury and aging	Cai et al., 2024 [88]
			Old chicken	200, 400, and 600 mg/kg (DA)	Improved egg production performance and mitigated ovarian ferroptosis in aging chickens	Wei et al., 2024 [89]
			Chicken granulosa cells	1 μg/mL	Enhanced cell vitality and proliferation, reduced cell apoptosis, promoted the expression of steroid hormone synthesis-related genes and proteins	Li et al., 2024 [90]
Proanthocyanidin	Tannins		Human granulosa cells	0.01, 0.1, 1, 10, and 50 μg/mL	Reduced oxidative stress, improved progesterone and estradiol secretion, had no effects on cell proliferation and viability	Barbe et al., 2019 [91]
			Oocytes of diabetic mice	5 μg/mL	Regulated mitochondrial function, reduced the generation of ROS, promoted oocytes viability, improved the oocyte quality of diabetic mice	Luo et al., 2020 [92]
			Porcine oocytes	100 μM	Reduce oxidative stress, inhibit apoptosis of oocytes and cumulus, improve the quality of oocytes, and promote the embryo development	Gao et al., 2021 [93]
			Fumonisin B1-induced porcine oocytes	200 μM	Restored cell cycle progression, protected mitochondrial function, reduced oxidative stress, improved oocytes quality	Li et al., 2021 [94, 95]
			Letrozole-induced PCOS rats	50 mg/kg (OG)	Decrease the ratio of LH/FSH, increase antioxidant enzymes protein expression, inhibit oxidative stress and improve ovarian fibrosis	Zhou et al., 2021b [96]
			H2O2-exposed hens granulosa cells	10 μM	Restore cell autophagy, increase cell viability, reduce oxidative stress damage, retard ovarian aging	Zhou et al., 2022 [97]
			3-nitropropionic acid-induced mice ovary	200 mg/kg (IG)	Increased ovarian index, follicle count, estradiol and progesterone levels, decreased ovaria cells apoptosis, and reduced oxidative stress	Huang et al., 2024b [98]
Curcumin	Curcuminoids		Aged mice	100 mg/kg (IP)	Increased ovarian volume and number of follicles, increased AMH and estrogen levels, enhanced oocyte maturation and embryo development	Azami et al., 2020 [99]
			Aged mice	100 mg/kg (IP)	Maintained ovarian reserve, improved hormone levels, protected primordial follicles from overactivation	Lv et al., 2021 [100]
Magnolol	Lignans		Late-phase laying hens	100, 200, and 300 mg/kg (DA)	Enhanced antioxidant capacity, improved egg production and egg quality	Chen et al., 2021 [75]
			Laying hens	300 and 500 mg/kg (DA)	Alleviated ovarian oxidative stress, improved laying rate	Chu et al., 2025 [101]
Ferulic acid	Phenolic acids		Aged bovine oocyte	5 μM	Improved antioxidant capacity, reduced DNA damage, improved oocyte quality, prevented oocyte aging	Yin et al., 2023 [102]
Pterostilbene	Stilbenes		Aging chicken	100, 200, and 400 mg/kg (DA)	Enhanced antioxidant capacity, decreased ovarian cells apoptosis, improved laying performance	Wang et al., 2024 [103]
Chlorogenic acid	Phenolic acids		Chronic unpredictable stress mice	100 mg/kg (PO)	Reduced oxidative stress, improved ovarian function, decreased ovarian cells apoptosis, alleviated diminished ovarian reserve	Qian et al., 2025 [104]

Administration route IP Intraperitoneal injection, PO Oral administration, IG Intragastrical administration, OG Oral gavage, DA Dietary administration, WD Water adnimistration

Resveratrol

Resveratrol is a widely studied plant polyphenol belonging to the stilbene, found in more than 70 plant and fruit species, including grapes, peanuts, mulberries, etc. Its anti-aging effects on female reproductive function are correlated with the antioxidant and anti-apoptotic properties [105]. In vitro studies have demonstrated that resveratrol significantly enhanced the antioxidant capacity of aging ovarian cells, inhibited ovarian cell apoptosis, and promote follicular growth and development [57, 64]. Similarly, in vivo experiments have shown that dietary supplementation or oral administration with resveratrol alleviated ovarian oxidative stress damage, restored hormone levels, reduced ovarian cell apoptosis, and improved reproductive performance in animals [58, 60, 62, 65–67]. Most studies focused on establishing ovarian damage or ovarian aging models through drugs or age restriction, and resveratrol was increasingly recognized as an effective intervention for improving ovarian function and alleviating ovarian aging of humans and animals. Furthermore, resveratrol also affected the epigenetic of aging ovary. There is a study reveals that resveratrol ameliorated ovarian aging transcriptome of oocytes and granulosa cells, including decline in oxidoreductase activity, metabolism and mitochondria function, as well as elevated DNA damage and apoptosis, these alterations of transcriptome are associated with specific changes in methylome. Interestingly, this study also suggests that aberrantly increased DNA methylation by ten-eleven translocation (Tet2) enzyme deficiency promotes further ovarian aging in epigenome, which cannot be effectively restored to younger state of aging ovaries by resveratrol [61]. The other study proposes that resveratrol, by inducing modifications in the granulosa cell miRNome acting specifically on the miRNAs involved in mitochondrial pathways, improves oocytes quality and pregnancy outcomes [59]. These studies suggest that resveratrol may have potential in the prevention and intervention for ovarian aging. However, high concentrations of resveratrol (> 5 μM) have been shown to impair the viability and steroidogenic function of ovarian cells [57], while excessively high does (100 μM) may exert toxic effects, potentially threatening ovarian health [64].

Tea polyphenols

Tea leaves, as a traditional therapeutic herb in Chinese medicine, have a potential role in preventing and treating various diseases [106]. Tea polyphenols are extracted from tea leaves and belong to the flavonoids group. Tea polyphenols are rich in catechins, which account for approximately 65–80%. Catechins contain four main active compounds: epicatechin (EC, 6.4%), epigallocatechin (EGC, 19%), epicatechin gallate (ECG, 16.5%), and epigallocatechin gallate (EGCG, 59%) [107]. In the doxorubicin (DOX)-induced human ovarian damage model, EGCG significantly reduced inflammatory responses, improved the ovarian reserve, and protected ovarian function [71]. Similarly, in the cyclophosphamide (CTX)-induced mouse ovarian damage model, EGCG and theaflavins alleviated oxidative stress, reduced primordial follicles overactivation and growing follicles apoptosis, and improved ovarian endocrine function and reproductivity of mice [74]. For ovarian cells, a study found that tea polyphenols can rescue tri-ortho-cresyl phosphate (TOCP)-induced autophagy and oxidative stress of mouse ovarian granulosa cells [73]. EGCG is reported to exhibit the capacity to enhance the quality of aged oocytes both in vivo and vitro, and improve fertility in aged mice [78]. In addition to humans and mice, researches in other mammals, such as gestating sows and bovines, have found that tea polyphenols play a positive role in alleviating ovarian aging and improving reproductive performance by enhancing oocytes quality and reducing oxidative stress [68, 70, 72]. In our previous studies, the results have shown that tea polyphenols (including EGCG and theabrownins) significantly improve laying performance and egg quality by reducing oxidative stress, decreasing ovarian cell apoptosis, and protecting ovarian function in laying hens [69, 79, 108]. Additionally, we found that the beneficial effects of tea polyphenols become more pronounced with the increasing age of laying hens [77]. It is important to note that excessively high concentration of tea polyphenols may inhibit oocyte maturation and even exert toxic effects, potentially leading to adverse outcomes [70].

Quercetin

Quercetin, a flavonoid (flavanols) plant polyphenol found abundantly in fruits, vegetables, grains, and traditional Chinese herbs, has garnered significant attention due to its high bioactivity and low toxicity recently. Quercetin contains three benzene rings and five phenolic hydroxyl groups, which allow it to donate a substantial number of electrons and scavenge free radicals, exhibiting strong antioxidant capabilities [109]. In H₂O₂-induced aging and injury studies, quercetin significantly increased granulosa cell viability, stimulated estradiol (E2) secretion, inhibited granulosa cell apoptosis, and reduced oxidative stress damage, suggesting it has the potential effect of delaying ovarian aging [80, 88]. In polycystic ovary syndrome (PCOS) models induced using pharmacological agent, mice had irregular ovulation, estrous cycles, and hormone secretion, along with increased ovarian cells apoptosis and inflammation, all these changes are reversed after the administration of quercetin [83, 86]. Notably, a study found that quercetin promotes in vitro maturation and embryonic development of oocytes from aged mice and humans, providing direct evidence that quercetin can alleviate ovarian aging [81]. Furthermore, a study exploring drugs for ovarian aging found that quercetin can slow down the human ovarian cells aging, and administrated orally to middle-aged mice, improves the estrous cycle, follicle count, pregnancy rate, and ovary reserve [87]. In addition, a growing number of studies have shown that quercetin can enhance granulosa cells viability and proliferation, reduce ovarian cells apoptosis, alleviate oxidative stress and improve oocytes quality, thereby protecting ovarian health and improving reproductive performance of livestock and poultry animals [84, 85, 89, 90]. From above studies, it would be indicated that quercetin plays a positive role in delaying ovarian aging and improving reproductivity in both humans and animals, but the underlaying mechanisms remain unclear.

Proanthocyanidins

Proanthocyanidins, also known as condensed tannins, are a common type of plant polyphenol belonging to the tannin group. They are widely found in fruits, seeds, and flowers, and are particularly rich in grape seeds. Proanthocyanidins contain multiple hydroxyl groups and are considered to be among the most powerful natural antioxidants [110]. Moreover, numbers studies have demonstrated that proanthocyanidins possess anti-inflammatory, protecting vision, and delaying aging properties [111]. Indeed, the role of proanthocyanidins in ovarian health has been widely reported. The study found that grape seeds proanthocyanidin B2 significantly increased steroidogenesis and decrease oxidative stress without affecting cell proliferation and viability in human granulosa cells [91]. In 3-nitropropionic acid (3-NPA)-induced mice premature ovarian failure (POF) model, proanthocyanidins significantly reduced oxidative stress, increased E2 and progesterone levels, and inhibited ovarian cells apoptosis [98]. Proanthocyanidins have been reported to alleviate PCOS by modulating hormone levels, reducing oxidative stress and improving ovarian fibrosis in rats [96]. Analogously, in a diabetic mouse model, proanthocyanidins reduce ROS generation and improve oocytes viability and quality [92]. These finds suggest that proanthocyanidins have potential as innovative therapeutic agents for preventing and treating ovarian damage or ovarian aging. Furthermore, proanthocyanidins have been shown to significantly improved porcine oocytes quality by ameliorating oxidative stress [93, 94]. In addition, another study found increased ovarian cells autophagy in old laying hens, it was worth noting that proanthocyanidins increase survival of granulosa cells by preventing autophagy caused by oxidative stress [97]. Overall, these studies indicate that proanthocyanidins contribute to alleviate ovarian aging, and provide a possible strategy to improve reproductive performance of livestock and poultry. In addition, excessive concentrations of proanthocyanidins (> 50 μg/mL) might cause ovarian damage by inhibiting granulosa cell proliferation and viability, increasing ROS levels [91], and more than 200 μM would impair oocyte maturation [93].

Others

In addition to the above widely studied plant polyphenols such as resveratrol, tea polyphenols, quercetin, and proanthocyanidins, which have demonstrated positive effects in alleviating ovarian aging, there are also reports on other plant polyphenols-related studies in ovarian aging. Curcumin is a natural plant polyphenolic compound extracted from the root of turmeric of Curcuma Longa Linn. (Zingiberaceae) and belongs to curcuminoids group [112]. It has been found to delay the ovarian aging process by increasing follicular number, modulating hormone secretion, reducing oxidative stress, enhancing oocyte maturation and embryo development in an aged mouse model [99]. Another study shown long-term treatment with curcumin improved ovarian reserve and protect primordial follicles overactivation, indicating curcumin is a potential drug for premature ovarian insufficiency (POI) patients [100]. Chlorogenic acid, belongs to phenolic acids, has been reported to alleviate stress-induced diminished ovarian reserve by mitigating oxidative stress and ovarian cells apoptosis [104]. Ferulic acid, also classified as phenolic acids, was beneficial for enhancing antioxidant capacity, reducing DNA damage, and maintaining quality and maturation in aged bovine oocyte [102]. Magnolol is a lignan plant polyphenol, which have been shown significantly improved egg production performance and egg quality by alleviating oxidative stress in laying hens [75, 101]. Additionally, pterostilbene, a member of the stilbene groups, has been reported to improve ovarian function and laying performance in aging chickens by ameliorating oxidative stress [103]. Collectively, these studies indicate that plant polyphenols can effectively improve ovarian health and play an important role in delaying ovarian aging, providing new insights for further exploration of the underlying mechanisms.

Mechanisms of plant polyphenols in alleviating ovarian aging

Plant polyphenols have been demonstrated to possess a variety of bioactive properties, such as antioxidant, anti-inflammatory, antibacterial, and immunomodulatory activities. These health-promoting properties contribute to improving ovarian health and have been identified as playing a beneficial role in alleviating ovarian aging in various in vivo and in vitro models of humans and animals. Ovarian aging refers to the gradual decline and loss in ovarian function due to age, stress, and disease [15]. It is considered to be the pacemaker of female aging and drives the aging of multiple organs. As life expectancy has increases, delaying ovarian aging has become an essential goal for promoting extend reproductive health in both humans and animals. Of note, the deterioration of ovarian reserve quantity and quality directly influences ovarian health and lifespan [5]. An increasing number of evidences show that alleviating oxidative stress, reducing inflammation, modulating hormone secretion and altering gut microbiota are potential mechanisms by which plant polyphenols delay ovarian aging (Fig. 4). In this section, we summarize and discuss the underlying mechanisms of plant polyphenols in delaying ovarian aging.

Fig. 4.

The mechanisms of plant polyphenols in delaying ovarian aging, involve modulation of oxidative stress, inflammation response, hormone regulation, and gut microbiota. 1) Oxidative stress: plant polyphenols active the PI3K-AKT-mTOR, Nrf2/Keap1-HO-1/NQO1, Sirt1-FoxO1/P53, and Wnt-β-catenin to reduce ovarian oxidative damage. 2) Inflammation response: plant polyphenols inhibit inflammatory signaling through the TLRs-NF-κB and NLRP3 inflammasome pathways to regulate expression of inflammation cytokines. 3) Hormone regulation: plant polyphenols modulate reproductive-related hormone by the HPO axis or acting as estrogen-like compounds. 4) Gut microbiota: plant polyphenols alter the composition and structure of the gut microbiota, promoting beneficial bacteria and reducing harmful species, which may indirectly alleviate ovarian aging. PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; mTOR: mechanistic target of rapamycin; Nrf2: nuclear factor erythroid 2-related factor 2; ARE: antioxidant response element; HO-1: heme oxygenase-1; NQO1: NAD(P)H quinone oxidoreductase 1; Sirt1: silent information regulator 1; FoxO1: forkhead box O1; TLRs: toll-like receptors; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α: tumor necrosis factor-α; IL: interleukin; NLRP3: NOD-like receptor family pyrin domain-containing 3; ASC: apoptosis-associated speck-like protein containing a CARD; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; ER: estrogen receptor; ERE: estrogen response element; AMH: anti-müllerian hormone

Alleviating ovarian oxidative stress

ROS are important signaling molecules involved in the regulation ovarian function. At appropriate levels, ROS promote follicular development and hormone secretion. However, prolonged exposure to excessive ROS can induce oxidative stress, exacerbate follicular atresia and ovarian cells apoptosis, ultimately accelerate ovarian aging [19]. Therefore, the reduction in ovarian reserve quantity and quality cause by oxidative stress is one of the critical triggers of ovarian aging. Plant polyphenols are considered as natural antioxidants with significant potential to delay ovarian aging by governing a diversity of signaling pathway related to oxidative stress.

Serine/threonine kinase (AKT), a downstream activating protein of phosphoinositide 3-kinase (PI3K), plays an important role in regulating several kinds of physiological process. Importantly, the PI3K-AKT pathway regulates various downstream proteins, including mammalian target of rapamycin (mTOR) and B-cell lymphoma-2 (Bcl-2), and is involved in cell signaling transmission (apoptosis, autophagy, and proliferation) correlated with oxidative stress [113]. The study has found that oral administration of resveratrol to POI mic significantly increased superoxide dismutase (SOD) level and decreased malondialdehyde (MDA) content, activated the PI3K-AKT-mTOR signaling pathway, and down-regulated the expression levels of apoptosis-related genes (Bcl-2 and Caspase-3) [114]. In the D-galactose-induced POF mice model, quercetin-treated was found to significantly improve ovarian antioxidant capacity and change the expressions of apoptosis-related genes by activating PI3K-AKT signaling pathway [115]. Moreover, EGCG has been reported to maintain the follicular survival and reduce ovarian cells apoptosis through the PI3K-AKT pathway in sheep ovarian tissue [116]. These studies suggest that plant polyphenols can effectively inhibit ovarian aging by alleviating oxidative stress and cell apoptosis via PI3K-AKT signaling pathway.

Nuclear factor-E2-related factor (Nrf2) is a critical regulator involved in antioxidant responses and maintaining cellular normal activity. Under oxidative stress, Kelch-like ECH-associated protein 1 (Keap1) undergoes a conformational change, leading to Nrf2 ubiquitination and degradation. Nrf2 is then translocated to the nucleus, where it binds to antioxidant response elements (ARE) and activates a series of target genes such as hemeoxygenase-1 (HO-1), quinone-oxidoreductase (NQO1), and SOD [117]. Therefore, the Keap1-Nrf2-ARE signaling pathway has been widely studied and is considered a key mechanism in aging due to its role in regulating the transcription of multiple antioxidant enzymes. In the CTX-induced mouse ovarian damage model, both EGCG (green tea polyphenol) and theaflavins (black tea polyphenol) improved the ovarian endocrine function and reproductive performance, and alleviated oxidative stress-induced ovarian damage by activating Nrf2-HO1/SOD2 signaling pathways, as well as reduced primordial follicles overactivation by inhibiting the AKT-mTOR signaling pathway [74]. Curcumin has been reported that have a potential protective role in resisting POF, and the underlaying mechanism involves inhibiting oxidative stress and ovarian cells apoptosis via Nrf2-HO1 signaling pathway [115]. Another study in H₂O₂-challenged human granulosa cells has demonstrated that quercetin supplementation decreased ROS production and apoptosis, which was positively correlated with the Keap1-Nrf2-ARE signaling pathway [118]. Furthermore, resveratrol intervention to H₂O₂-induced rat ovarian granulosa-lutein cell has been shown to enhance antioxidant enzymes activities, reduce cellular total ROS levels, and attenuate apoptosis via Nrf2-ARE signaling pathway [119]. These studies provide an important molecular mechanism for improving ovarian aging by alleviating oxidative stress.

Silent mating type information regulation 2 homolog-1 (SIRT1) is a nicotinamide adenine dinucleotide + (NAD +) dependent deacetylases that participates in the aging process by deacetylating transcription factors such as Forkhead box O (FoxO) [63]. Knockdown or knockoff of SIRT1 in ovarian cells leads to hormone disorders, exacerbates oxidative stress, and reduces cell quality, ultimately impairing ovarian function and reproductive performance [120, 121]. Previous research has reported that SIRT1-FoxO1 signaling pathway was involved in oxidative stress-induced granulosa cell apoptosis and oocyte quality decreased [122]. Importantly, the role of SIRT1-FoxO1 signaling pathway in improving ovarian function and reproductive performance by alleviating oxidative stress have been demonstrated in recent studies. The study found that dietary supplementation with proanthocyanidin significantly alleviated oxidative stress and improved laying performance in aging hens. Additionally, in vitro experiment further revealed that proanthocyanidin could protect granulosa cells from oxidative stress-induced autophagy by inhibiting FoxO1 acetylation and activating SIRT1 signaling pathway [97]. Likewise, oral resveratrol supplementation ameliorated tert-butyl hydroperoxide-induced ovarian oxidative stress damage and egg-laying rate reduction by regulating SIRT1-FoxO1/P53 signaling pathway in laying hens [67]. These findings reveal the possible mechanism for plant polyphenols to delay ovarian aging by alleviating oxidative stress via the SIRT1-FoxO1 signaling pathway.

The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway that play an essential role in embryonic development and physiological homeostasis by regulating cell proliferation, differentiation, apoptosis and autophagy [123]. A growing number of evidence suggests that Wnt/β-catenin signaling pathway has broad functional significance in various diseases. It was confirmed that patients with PCOS exhibit higher expression levels of Wn1, Wn3, and Wn4, which is correlated with granulosa cell apoptosis [124]. Furthermore, the Wnt/β-catenin signaling pathway is proved to be involved in plant polyphenols improving ovarian health. Proanthocyanidin has been shown to inhibit the self-renewal capacity of ovarian cancer stem cells by suppressing the expression of β-catenin and activating the Wnt/β-catenin signaling pathway, suggesting its great potential as an anti-ovarian cancer agent [125]. Additionally, in a mouse model of POF, puerarin significantly increase primordial follicle number and decrease follicular atresia ratio, the expression levels of Wnt1, β-catenin, and SOD2 showed obvious recovery, further in vitro experiment demonstrated that puerarin may enhance the survival of female reproductive stem cells by relieving oxidative stress via the Wnt/β-catenin signaling pathway [76]. Accordingly, plant polyphenols probably act on targets within the Wnt/β-catenin signaling pathway to delay ovarian aging.

In recent years, clinical evidence has also suggested that plant polyphenols may alleviate ovarian aging by reducing oxidative stress. A randomized controlled trial involving 72 women with PCOS reported that supplementation with 1500 mg/kg curcumin three times daily for three months significantly increased the activity of glutathione (GSH) enzyme and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), while no significant differences were observed in SOD activity and SIRT1 expression [126]. Another randomized, triple-blind, placebo-controlled clinical trial involving 56 women with PCOS, 60-day supplementation with 800 mg/kg resveratrol significantly reduced total oxidant status and oxidative stress index in follicular fluid, increased SIRT1 and PGC-1α protein levels, and exhibited higher rates of oocyte maturity and higher rate of high-quality embryos [127]. These clinical trials highlight that plant polyphenols hold considerable potential as adjunctive therapies in the clinical management of ovarian aging and dysfunction related to oxidative stress.

Reducing inflammatory response

Inflammation is a complex biological response of tissues and cells to harmful stimuli, driving immune system activation and the release of signaling molecules to initiate repair process. Acute inflammation is a protective response, while chronic inflammation contributes to the development of various diseases. Recently, most of the evidence indicates that inflammatory response is one of the critical mechanisms for aging process. Indeed, the inflammatory response is aggravated with the advancement of aging process, senescent cells secrete more pro-inflammatory cytokines, accelerating the senescence of normal immune cells, ultimately breaking down the immune system and creating a vicious cycle [128]. Therefore, elevated pro-inflammatory cytokines including Interleukin-6 (IL-6), IL-10, and IL-1β serve as the predictive biomarkers for overall fertility in aging female [129]. An increasing number of studies have shown that inflammation adversely affect ovarian reserve quality and quantity [130, 131], and “inflammaging” is considered as a potential mechanism of ovarian aging.

NF-κB is a well-known dominant signal in the regulation of inflammation that expressed in nearly all cells of humans and animals. The primary function of NF-κB is represented by regulating both innate and adaptive immune responses of the immune system [132]. Moreover, NF-κB has been reported to be involved in regulating follicle development and ovarian function by controlling downstream transcription factor, including inflammasome NLRP3 and ASC, related-enzyme COX-2 and iNOS, and inflammatory cytokine IL-6, IL-1β and TNF-α [23]. The study showed that the NLRP3-ASC-Caspase1 inflammasome signaling pathway was activated, and the expression levels of pro-inflammatory cytokine was increased in the ovaries of aged mice [133]. In POF mice, the NF-κB family proteins expression (including p65 and p50) were obviously altered, and NF-κB-deficient mice exhibited fewer follicles and litters [134]. These studies suggest that inflammation may be one of the underlying mechanisms responsible for ovarian aging.

Plant polyphenols possess the anti-inflammatory bioactive property, numbers studies have explored the mechanism by which they delay ovarian aging by reducing inflammatory response. Following quercetin treatment in rats with ovarian damage, notable reductions were observed in NF-κB and COX-2 expression levels and IL-6 content, indicating its potential role in protecting ovarian health by reducing inflammatory response [135]. In a rat POF model, exogenous chrysin supplementation effectively preserved the normal ovarian histoarchitecture and inhibited the follicular loss, and significantly down-regulated the levels of the inflammatory markers NF-κB, iNOS, and COX-2 in ovary [136]. Another study found that resveratrol significantly reversed the inflammatory response by suppressing NF-κB expression and decreasing pro-inflammatory cytokine levels, thereby alleviating ovarian failure in a rat model [137]. Additionally, in the human ovarian damage model, EGCG has been shown to improve ovarian follicle preservation by reducing inflammatory response, including the decline of COX-2 and IL-6 expression [71].

Clinical research has shown that curcumin supplementation (500 mg every 12 h for 10 days) significantly alleviates premenstrual syndrome, potentially via inhibiting NF-κB signaling and reducing pro-inflammatory cytokine production [138]. Women with PCOS received a daily dosage of 500 mg of quercetin for 40 days exhibited a significant reduction in IL-6 and TNF-α levels, along with improved oocyte and embryo quality [139]. Accumulating evidence from clinical studies indicates that regular consumption of plant polyphenols can effectively reduce inflammation response, conferring potential benefits in mitigating ovarian aging and managing related diseases [140].

Collectively, these findings provide evidence for the potential protective role of plant polyphenols in relieving ovarian damage or aging by reducing inflammatory response through the activation of the NF-κB signaling pathway. However, these significant effects of plant polyphenols on inflammatory response are observed in ovarian damage models and patients, the improvement of ovarian function and reproductive performance by anti-inflammatory strategies in naturally aging humans or animals remains to be further investigation.

Regulating reproductive hormone levels

The endocrine system plays a crucial role in regulating various physiological processes through a series of hormone secretion, and forming an interlocking regulatory network. Aging is associated with the dysfunction of the endocrine system and alterations in hormone secretion, contributing to changes in physiological homeostasis, such as metabolic disturbances, muscle wasting and osteoporosis, and increased susceptibility to age-related diseases, particularly ovarian aging in females [141]. Ovarian reproductive function is controlled by the HPO axis, a tightly controlled and reciprocally regulated endocrine pathway. The HPO axis involves the hypothalamus secreting gonadotropin-releasing hormone (GnRH), further stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), ultimately influencing ovarian hormone production and follicular development. Indeed, ovarian aging is characterized by a dysregulated HPO axis and a progressive depletion of the ovarian reserve, resulting in a decline in both the quality and quantity of ovarian cells [142]. The ovarian aging process involves alterations in the pulse frequency and amplitude of GnRH secretion from the hypothalamus, which weakens the pituitary response and negatively affects the synthesis and secretion of gonadotropins. Ovary is considered a target organ of HPO axis, and ovarian aging leads to lower sensitivity to pituitary-derived FSH and LH, inhibiting follicle development and ovulation. Conversely, follicular dysfunction reduces estrogen secretion and weakens the negative feedback regulation on the hypothalamus and pituitary, thereby producing more GnRH and FSH, further disrupting ovarian function and accelerate ovarian aging [143].

Notably, it is a crucial mechanism to regulate follicle development and ovarian reserve through synergistic action of reproductive-related hormones derived from HPO axis. The decreased Anti-Müllerian Hormone (AMH) and increased FSH are considered biological markers of diminished ovarian reserve and ovarian aging [144]. In patients with PCOS and diminished ovarian reserve (DOR), found the levels of FSH and LH significantly elevated, while AMH and E2 levels markedly decreased [145]. Accumulating evidence has demonstrated the potential of plant polyphenols in mitigating ovarian aging through regulating the sensitivity and secretion of key reproductive hormones. The aged mouse ovarian tissues cultured in vitro were long-term treated with curcumin, which significantly improved the ovarian reserve indicators of AMH, FSH, and E2 levels [100]. Quercetin has been shown to significantly increased primordial follicles number and AMH level in POF mice, indicating its protective effect against ovarian damage [146]. In a PCOS mice model, addition to quercetin or proanthocyanidin effectively restored the LH/FSH ratio to normal and increased AMH level [86, 96]. Moreover, lower levels of serum progesterone, FSH and E2 were observed in late-phase laying hens, and dietary supplementation with theabrownins significantly restored reproductive hormone levels and improved egg production performance [77]. In addition, the chemical structures of certain plant polyphenols (isoflavones: genistein, biochanin and daidzein) resemble estrogen, allowing them to exert phytoestrogenic effects by binding to and activating estrogen receptors (ER). In radiation-induced POF mice, exogenous genistein supplementation protected primordial follicles and growing follicles, reversed ovarian apoptosis by activating ERβ expression and restoring the circulating estradiol and AMH levels [147].

Clinical trials are most important in validating the health benefits of plant polyphenols, providing controlled evidence of their efficacy, safety, and mechanisms to prevent ovarian aging by regulating hormone levels. A randomized, double-blind, and placebo-controlled trial, phytoestrogens driven form plant polyphenols (37.5 mg genistein, 10 mg daidzein, and 2.5 mg glycitein) were administrated to patients with PCOS for 12 weeks, and this intervention resulted in a significant increase in LH level alongside reductions in free androgen index, triglyceride and monoaldehyde levels, suggesting a beneficial role of phytoestrogens in the management of PCOS [148]. Resveratrol intakes have been reported to reduce LH, testosterone, and dehydroepiandrosterone levels in patients with PCOS, potentially alleviating ovarian dysfunction [149]. In addition, a growing number of preclinical and clinical studies have highlighted the therapeutic potential of plant polyphenols in various ovarian aging-related disorders, including PCOS, POF, and age-associated decline in fertility, these compounds exert beneficial effects of ovarian health through regulating hormone secretion [150, 151]. Therefore, plant polyphenols can regulate reproductive hormone levels through the HPO axis and phytoestrogenic effects, offering a promising strategy for prevention and management of ovarian aging and ovarian health.

Altering gut microbiome

The gut microbiota refers to a complex and dynamic ecosystem comprising bacteria, archaea, viruses, and fungi. Regarded as the “second genome” of the host, it plays a crucial role in maintaining physiological homeostasis and influencing disease pathogenesis in humans and animals. Species of animals, physiological stages, lifestyle, and health status contribute to dynamic changing in gut microbiota. In healthy adults, Bacteroidetes and Firmicutes constitute the core of the gut microbial community, and maintain relative balance [152]. However, stability does not imply immutability. A review reports that numerous studies have described alterations in structure, diversity, richness, and composition of gut microbiota occurred across aging and age-related diseases [153]. Furthermore, a growing number of evidence suggests that gut microbiota is closely correlated with ovarian aging. The study found that both alpha and beta diversity of the gut microbiota were significantly altered, with Barnesiella, Bacteroides, and Mucispirillum being the primary dominant microbiota in 4-Vinylcyclohexene diepoxide-induced ovarian aging mice [82]. Interestingly, another study on mice found that transplantation of young donor gut microbiota to aged recipient improved ovarian aging signal markers, including reduced primordial follicle loss, atretic follicle, and cell apoptosis [38]. Moreover, the gut microbiota composition and functional characteristics of the fecal microbiota transplantation (FMT)-treated aged mic resembled those of young mice [38]. These results highlight the critical role of gut microbiota in ovarian aging. Of particular is maintaining a younger gut microbiota may delay ovarian aging.

The credible mechanism underlying the interaction between gut microbiota and ovarian aging is based on the gut-microbiota-ovary axis theory, which contributed to follicular development and hormone secretion [39]. Emerging evidence suggests that plant polyphenols may delay ovarian aging by regulating gut microbiota-ovary axis. In a high-fat and high-sugar diet-induced ovarian aging mice model, oral administration of cranberry-derived exosomes rich in various plant polyphenols significantly reduced atretic follicles number and cell apoptosis, and improved E2, AMH, and FSH levels. Further analysis revealed that mice treated with cranberry-derived exosomes significantly altered gut microbial diversity and richness, with an increased abundance of beneficial bacteria (Akkermansia and Allobaculum) and a deceased harmful bacteria [154]. Notably, our group has conducted extensive research using laying hens as a model. We found that dietary supplementation with theabrownin significantly improved egg production performance and ovarian function, as well as altered the gut microbial diversity and composition [79]. In a H₂O₂-induced hens ovarian damage model, addition to resveratrol significantly improved laying performance and altered gut microbiota, further FMT experiment demonstrated that resveratrol could improve ovarian function by modulating the gut microbiota [67]. Overall, plant polyphenols delaying ovarian aging by altering gut microbiota represent a novel and intriguing mechanism, and may provide new strategies for enhancing female reproductive health and fertility.

Comparative insights into different classes of plant polyphenols and their molecular targets

Different classes of plant polyphenols possess unique chemical backbones that govern their absorption, cellular distribution, and bioactivity profiles. While many share overlapping antioxidant and anti-inflammatory properties, their specific molecular targets and signaling pathways in the context of ovarian aging differ significantly. Stilbenes, represented by resveratrol and pterostilbene, alleviating ovarian aging by reducing oxidative stress via activating SIRT1 signaling pathway, and improving mitochondrial function and DNA methylation [62, 67, 103]. Flavonoids, such as quercetin and EGCG, exhibit strong Nrf2-Keap1 activation, offering robust antioxidant protection and inhibition of inflammatory cytokines via NF-κB signaling [80, 95, 108, 135]. Some flavonoids that exert estrogen-like effects can also improve ovarian function by regulating hormone levels, which is different from other plant polyphenols [147]. Tannins, particularly proanthocyanidins, inhibit oxidative stress by targeting Wnt/β-catenin pathways, protecting ovarian granulosa cells and enhancing follicular development [91, 125]. Curcuminoids are more often manifested in regulating hormone levels and promoting oocytes and follicles growth [99, 115]. Other types of plant polyphenols exhibit broader multi-pathway actions. For instance, phenolic acids, due to their carboxyl groups, have a more prominent effect on improving ovarian function by regulating intestinal pH and enhancing the gut microbiota [46, 104, 154]. Future studies should further explore class-specific polyphenol combinations or delivery systems to maximize their therapeutic potential in ovarian aging and female reproductive health.

Conclusions and perspectives

Ovarian aging is a complex, multifactorial process characterized by the decline of oocyte quality and follicular reserve, contributing to infertility and endocrine disorders in women. Plant polyphenols have gained attention as natural compounds with diverse bioactive properties, such as antioxidant, anti-inflammatory, antibacterial, and antiviral activities. This review summarized current studies evidence showing that plant polyphenols may delay ovarian aging by 1) alleviating oxidative stress via PI3K-AKT, Nrf2/Keap1, Sirt1-FoxO1, and Wnt/β-catenin; 2) suppressing inflammation via NF-κB and NLRP3; 3) modulating reproductive hormone levels through the HPO axis and estrogen receptor signaling; 4) shaping gut microbiota to support gut-ovary axis.

However, despite significant progress in understanding the role of plant polyphenols in delaying ovarian aging, the elucidation of their specific underlying biological mechanisms remains challenging. Firstly, plant polyphenols display substantial variability in origin and chemical structure, while their bioavailability, tissue-specific distribution, and molecular targets remain poorly characterized. The low bioavailability and poor stability of plant polyphenols result in insufficient concentration reaching the ovaries. To address these limitations, nano-based drug delivery systems for plant polyphenols (nanocurcumin, resveratrol-ZnO nanohybrid, liposome-quercetin) have been recently developed for improvement ovarian health and treatment ovarian diseases [155]. These technologies can enhance the stability and targeted delivery of plant polyphenols, thereby improving their therapeutic efficacy. Although limited studies have investigated these approaches specifically in the context of ovarian aging, such strategies hold great promise and warrant further investigation. Secondly, in addition to the signaling pathways involved in oxidative stress mentioned earlier, there are various other signaling molecules and pathways that may play a critical role, whether plant polyphenols can target these specific pathways requires further investigation to comprehensively enrich the regulatory network of plant polyphenols delay ovarian aging by alleviating oxidative stress. Thirdly, the bidirectional interplay between ovarian aging and gut microbiota remains underexplored, and the mechanisms by which plant polyphenols delay ovarian aging through altering gut microbiota are still unclear. Although previous scientific literature suggests that microbial metabolites play a critical role in this process, the specific molecular mechanisms involved remain uncertain. Plant polyphenols can reshape gut microbiota, further regulating metabolites produced by specific microbiota is of particular importance. Understanding this symbiotic relationship may help identify a new strategy combining plant polyphenols and probiotics to delay ovarian aging. Lastly, although plant polyphenols are generally considered safe, emerging evidence suggests that high concentrations may exert pro-oxidant or cytotoxic effects and may interact with estrogen pathways or drug-metabolizing enzymes, posing potential risks. Regulatory agencies such as the European Food Safety Authority have set a tolerable upper intake limit of some plant polyphenols [156]. Therefore, future applications should carefully consider dose-dependent effects and safety profiles to ensure clinical relevance.

In conclusion, plant polyphenols hold significant promise for preserving ovarian function and alleviating ovarian aging. Integrating molecular insights with clinical validation will be essential for advancing their application in preventive and therapeutic settings.

Author’s contributions

Haojie Gong and Hongye Zhang conceived the article and were major contributors. Jianping Wang, Yan Liu and Xiangbing Maohelped revise this manuscript. All authors read and approved the final manuscript.

Funding

The National Key Research and Development Program of China (NO. 2022YFD1301200).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

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Not applicable.

Competing interests

The authors declare no competing interests.