Introduction

Ovarian aging is a significant cause of female infertility [1]. As a woman ages, the quantity and quality of the follicle or oocyte degenerates, resulting in a decrease in ovarian reserve function (DOR). During this process, fewer oocytes are produced in the ovaries and their quality or ability is diminished. Menopause is the last stage of the ovarian aging process, with most women entering menopause between the ages of 49 and 52. [2]. In modern society, women often postpone childbirth due to a variety of factors, including economics, careers, and lifestyles [3]. However, as humans age, fertility rates begin to decline around 30 years of age and become clinically relevant between the ages of 35 and 40, after which they continue to decline significantly. [4]. The decline in fertility associated with women’s age has become an important issue that troubles modern women.

Changes in the energy metabolism of oocytes due to age can affect the cellular levels of intermediates and byproducts, consequently impacting oocyte quality. However, the mechanisms underlying the effects of changes in the intermediary steps of energy metabolism on adenosine 5'-triphosphate (ATP) generation in oocytes, as well as the influence of related products and proteins on oocyte quality and subsequent ovarian aging, remain unclear.

The metabolism of energy is important in the development and maturation of oocytes. Energy metabolism processes influence nutrient absorption, macromolecular biosynthesis, energy production, and cellular redox status. The mitochondria-nucleus communication plays a critical role in cellular adaptability, organismal health, and longevity, as well as energy metabolism. [5, 6]. The metabolic pathways of oocytes are complex (Fig. 1). Although cumulus cells produce ATP and provide it to oocytes [7], a decrease in ATP, a decrease in energy production capacity, and a decline in mitochondrial function are all part of the aging of the oocytes [8,9,10,11,12,13,14,15]. Reduced ATP production leads to a decline in oocyte quality, specifically resulting in decreased metabolic activity, which may affect cell cycle regulation, spindle formation during mitosis, chromosome segregation, fertilization, embryo development, and implantation, as discussed in other literature [16,17,18]. Age-related changes in oocyte energy metabolism can affect the expression of intermediates and byproducts within the cell, thereby influencing oocyte quality. However, it remains unclear how changes in intermediary steps of energy metabolism in oocytes affect ATP generation and how related products and proteins influence oocyte quality, consequently affecting ovarian aging.

Fig.1
figure 1

Energy metabolism of oocytes. Oocyte metabolism relies on glucose metabolites provided by cumulus cells. The majority of glucose is metabolized in cumulus cells through anaerobic glycolysis, resulting in lactate production. Cumulus cells can convert glucose into pyruvate, lactate, or nicotinamide adenine dinucleotide phosphate (NADPH) through anaerobic glycolysis and the pentose phosphate pathway. These metabolites are then transferred to oocytes through paracrine signaling and gap junctions, providing energy substrates for oocyte metabolism. Oocytes generate ATP through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Additionally, some glucose can be directly transported to oocytes and metabolized through the pentose phosphate pathway and hexosamine synthesis pathway. Oocytes acquire free fatty acids from the follicular fluid and gap junctions with cumulus cells, and they can also synthesize fatty acids endogenously. After entering the cells, free fatty acids can be converted and stored in lipid droplets or enter mitochondria for β-oxidation. Fatty acids in lipid droplets are esterified and stored as neutral triglycerides (TAGs). Fatty acyl-CoA is synthesized by acyl-CoA synthetases, which catalyze triglycerides into fatty acyl-CoA. Carnitine transports fatty acyl-CoA to mitochondria. The TCA cycle and OXPHOS in mitochondria process fatty acids into acetyl-CoA that is then oxidized, producing ATP once they enter the mitochondrial matrix. Glutamine enters oocytes through the follicular fluid and gap junctions, and oocytes can also synthesize glutamine. Glutamine is metabolized in the mitochondrial matrix as a fuel source for the cycle. Oocytes may possess the ability to convert Adenosine monophosphate (AMP) to ATP through the adenosine salvage pathway. Cumulus cells can also produce ATP through the adenosine salvage pathway and directly supply ATP and AMP to oocytes through gap junctions

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Therefore, this review focuses on the oocyte metabolism in age-related ovarian aging and its impact on oocyte quality. This study investigates the relationship between age-related changes in oocyte energy metabolism, decline in oocyte quality, and subsequent decrease in fertility rates. In addition, it helps identify biomarkers and treatment methods.

Ovarian aging and oocyte energy metabolism

Alterations in several facets of oocyte energy metabolism in individuals suffering from ovarian senescence, such as the Tricarboxylic Acid (TCA) Cycle, Oxidative Phosphorylation, Lipid Metabolism, Glutamine Metabolism, and the Adenosine Remedial Pathway, critically impact the quality of oocytes (Fig. 2).

Fig. 2
figure 2

Changes in energy metabolism and potential effects on oocyte

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TCA cycle

The TCA cycle completely oxidizes the acetyl coenzyme A in cells to produce CO2, ATP, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH2), and subsequently OXPHOS for the production of ATP. The TCA cycle is a crucial component in signaling pathways and metabolic disorders associated with aging, making it an important target for anti-aging treatment strategies [19, 20]. The TCA cycle takes place in oocytes, and its activity is inhibited with age [7, 11, 21]. Specifically, as age increases, the cross-regional transport of substances such as pyruvate and lactate salts from granulosa cells to oocytes decreases, but metabolites such as pyruvate, lactate salts, and glutamine gradually accumulate in the oocytes [7, 22]. Glucose [7], glucose-6-phosphate [7], sorbitol [13], mannitol [13], urea cycle intermediates such as aspartate [7], ornithine [7], and arginine [7] increase in oocytes of older mothers, indicating that energy substrates are diverted to the pentose phosphate pathway, hexosamine synthesis pathway, and urea cycle; the TCA cycle cannot process available substrates. Furthermore, the TCA cycle intermediates succinate [7], fumarate [7], citrate [11], isocitrate [11], and malate [11] decrease in an age-dependent manner in oocytes. The reduced levels of NAD + and FAD in oocytes are also observed [7, 11, 23,24,25,26]. The age-related changes in TCA cycle activity differ between species. For example, in the oocytes of horses, although the glucose abundance in the cumulus cells of older horses is higher, the level of pyruvate in the oocytes of older mares is consistently lower than that of young mares during the GV, MI, and MII stages. This suggests impaired transport or production of pyruvate, possibly due to reduced transzonal transport [13, 22]. These differences may be attributed to variations in samples and species.

The activity of TCA cycle metabolism decreases with age, leading to reduced levels of NAD + restoration [7, 23,24,25]. NAD + plays a central role in controlling hundreds of pathways in both energy metabolism and cell survival. Both NAD + and its reduced form are involved in various biological processes [20, 27,28,29,30]. Increased NAD + production or decreased degradation appears to be profitable, as reduced NAD + levels can lead to metabolic and age-related diseases [31]. In terms of aging, NAD + is essential in antioxidation, mitochondrial function, central carbon metabolism, cellular aging, protein deacetylation, and DNA damage [20, 29, 30]. Some enzymes consume NAD + , such as the sirtuin enzyme family (SIRTs) and poly(ADP-ribose) polymerase (PARP) [20]. These enzymes have become critical factors in aging [20]. In mouse ovaries with a knockout of NAD + synthesis genes, NAD + levels decrease in mid-aged mice, resulting in the impairment of oocyte quality, characterized by increased abnormal spindle and reactive oxygen species (ROS) formation [32]. Supplementation of NAD + precursor nicotinamide riboside (NR) can increase ovarian reserve and improve oocyte quality [32, 33].

The alterations in the TCA cycle intermediates can impact oocyte quality. The levels of TCA cycle intermediates, including succinic acid [7], jasmonic acid [7], citrate [11], malate [11], and fumarate [11], decrease with age in oocytes and can influence epigenetic changes. Decreased levels of succinic acid and fumarate can influence the levels of DNA and histone methylation, while decreased levels of citrate can weaken its ability to enhance histone acetylation. These effects can further contribute to the aging process [34, 35]. In addition, the TCA cycle is also related to metabolite production and biosynthesis. Intermediates of the TCA cycle can serve as precursors for amino acid synthesis, nucleotide synthesis, and fatty acid and cholesterol synthesis. In oocytes, oral administration of dimethyl fumarate can alleviate oxidative stress and delay age-related infertility in mice ovaries [36]. Moreover, the decrease in citrate levels within the follicular fluid has the potential to impact the process of oocyte maturation [37].

Phosphorylation of oxidation

The decline in oxidative phosphorylation caused by mitochondrial dysfunction is an important marker of human aging [38]. In oocytes, the energy released from glycolysis and the TCA cycle is mostly stored in reduced coenzymes and needs to be synthesized into ATP through the oxidative phosphorylation process in the mitochondria [21]. The respiratory chain consists of more than 15 components, mainly including NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), cytochrome c oxidoreductase (complex III), cytochrome c oxidase (complex IV), coenzyme Q (CoQ), and cytochrome C. The electron transport chain (ETC) facilitates the translocation of protons (H +) from the matrix to the intermembrane space, consequently establishing a proton-motive force (PMF). The energy produced by PMF is used by ATP synthase to phosphorylate adenosine diphosphate (ADP) into ATP. There are two non-exclusive mechanisms for regulating oxidative phosphorylation. It can be dynamically regulated, enabling an adjustment in ATP synthesis rate to meet ATP demand [10]. Oxidative phosphorylation can also be regulated by altering the number of mitochondria [10]. OXPHOS is highly active in oocytes [39]. With age, ATP generation through oxidative phosphorylation in oocytes decreases, and the function of ETC is impaired [12,13,14]. The expression of the majority of genes encoding subunits of respiratory chain complexes I to V is downregulated [11, 23, 334,335,336,337,338].

Others

In recent years, many therapies have been proven to improve the processes related to oocyte energy metabolism. For example, brown adipose tissue-derived exosomes can prevent the deterioration of mitochondrial function caused by oocyte aging in mice and increase the ATP content in oocytes [339]. Salidroside can promote lipid metabolism, improve mitochondrial function, and enhance the maturation of pig oocytes [340]. Dehydroepiandrosterone activates energy metabolism in the theca and granulosa cells, thereby transferring energy to oocytes and promoting oocyte regeneration [341]. Growth hormone has a repairing effect on mitochondrial function in oocytes and can directly or indirectly promote oxidative stress balance and cellular antioxidant defense, as well as facilitate oxidative phosphorylation pathways [342]. FoxO3a is an important factor in regulating oocyte metabolism, and curcumin can regulate the PTEN/AKT/FoxO3a pathway to protect ovarian reserve [198]. However, further clinical and basic experiments are needed to determine the relevant mechanisms and clinical effects of these therapies.

Conclusions

The decline in fertility associated with women’s increasing age has become a significant issue for modern women [1,2,3,4]. As age increases, there is a decrease in ATP within the oocytes, leading to a decline in energy production capacity and mitochondrial function [8,9,10,11,12,13,14,15]. The changes in energy metabolism of oocytes with age have an impact on oocyte quality and are an important mechanism of reproductive aging [16,17,18]. However, it is still unclear how the changes in the intermediate steps of energy metabolism in oocytes affect ATP generation and how the related products and proteins influence oocyte quality, thus affecting ovarian aging. Therefore, this review summarizes the characteristics of oocyte energy metabolism, the changes in the TCA cycle, oxidative phosphorylation, lipid metabolism, glutamine metabolism, and the Adenosine remedial pathway in oocytes during age-related ovarian aging, as well as how these changes affect oocyte quality. This review also introduces the important proteins SIRTs and FoxO3a that regulate oocyte metabolism. Finally, this review discusses some treatment strategies for delaying ovarian aging, which may partially act by influencing oocyte energy metabolism. In conclusion, understanding the changes in oocyte metabolism and their influence on oocyte quality in age-related ovarian aging helps us comprehend the relationship between oocyte quality decline and the subsequent decline in fertility, and aids in identifying biomarkers and treatment methods.