Views and reviews
The development of a competent oocyte intimately depends on the maintenance of energetic homeostasis in the ovarian and follicular microenvironment. On this basis, it is very likely that the oocyte ages as the ovary ages. Starting from the molecular evidence for energy perturbations in the whole ovary, we review current knowledge on the involvement of endogenous highly reactive metabolites in follicle aging. The first part provides an update of recent findings that confirm the key role of oxidative stress in aged granulosa cells. The second part focuses on studies providing evidence for the implication of advanced glycation end product (AGE) in aging reproductive dysfunction. With their prolonged half-life and ability to act as signaling molecules AGEs may gradually accumulate in the ovary and potentiate the wide spatiotemporal spread of oxidative stress. Clinical evidence for this view supports the hypothesis that AGE is a good candidate as a predictive marker and therapeutic target in new strategies for improving reproductive counseling in aging women.
- Advanced glycation end products;
- carbonyl stress;
- follicle aging;
- oxidative stress
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The ovary is the main regulator of female fertility, and its biological clock is set to ensure reproductive success during a definite life stage. According to the evolutionary concept that organisms maximize fitness by promoting production of progeny, allocation of resources between reproductive and somatic functions is finely regulated during life (1). Thus, it has been speculated that the premature aging of the ovary when compared with somatic organs might result from increased energy demand for maintenance and repair processes in the soma compartment during aging (1). According to the human biologic clock, female fertility begins to decline significantly in the early 30s with a steep decrease beginning after age 35, culminating in the menopause at 50 to 51 years of age 2 ; 3. This would preserve women from the physical stress of pregnancy in advanced age and maximize the length of time they can bear children (4). The modern tendency to postpone childbearing to the fourth decade of life has made reproductive aging an age-related disease that entails careful consideration in our health care systems (5). Given the intrapopulation variability of the reproductive life span (6), it is generally accepted that coping with this issue requires a careful reproductive counseling based on accurate predictive markers.
It is well established that ovarian functional decline is related to the gradual loss of resting follicles and decreased biologic competence of those surviving age-related atresia 7; 8 ; 9. Although clear perturbations in dynamic of follicle growth do not seem to occur, the oocytes that reach ovulation during reproductive aging are likely to exhibit cellular and chromosomal defects that seriously hamper the reproductive process 10 ; 11. For decades, research on reproductive aging has been focusing on the so-called quantitative aspect of ovarian aging, which has led to mathematical models predicting follicle loss on the basis of chronologic age without taking into account biologic markers (12). When the concept of oocyte aging as the main determinant of fertility decline has become clear (13), researchers have begun to expand investigations into the whole ovarian microenvironment in search of age-related changes with potential effects on follicle and oocyte competence.
The molecular fingerprint obtained by the ovarian gene expression profile provides a clear picture of the aging female gonad. According to recent studies, changes occurring in the ovary with aging are mostly ovary specific (14). Germ line genes, oocyte-specific genes, and the intraovarian signaling pathway are down-regulated. Consistent with somatic organs, down-regulation of genes related to mitochondrial electron transport chain is observed and is considered a hallmark of dysregulation of energy homeostasis. It has been proposed that energy perturbations might be both the cause and the effect of increased production of toxic metabolic byproducts such as reactive oxygen species (ROS), which can seriously damage biomolecules and impair key regulatory mechanisms (15). On this basis, the process of ovarian aging can be viewed as the progressive and irreversible accumulation of damage to macromolecular integrity leading to loss of metabolic homeostasis and decrease of primary functions.
We review the current state of knowledge about factors that can impair ovarian functions with aging by taking into account the hypothesis that increased production of toxic metabolites might be relevant to age-related oxidative stress in granulosa cells (11), the oocyte’s companion cells through which a continuous cross-talk between the somatic and germ cell compartments occurs 16 ; 17. In this context, our purpose is to shed some light on the possible role of reactive carbonyl compounds such as ROS that are toxic byproducts of cellular metabolism.
Reactive oxygen species and oxidative stress in the aging follicle: a brief update
Unavoidable products of aerobic metabolism, the ROS include superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide (18). The main source of ROS is the leakage of electrons from the inner mitochondrial membrane during oxidative phosphorylation and ATP generation. In steroidogenic tissues such as the ovary, steroidogenic cytochrome P450 enzymes are also relevant sources of ROS (19).
Together, enzymatic and nonenzymatic defense systems permit cells to live in an oxidative environment, perform necessary biochemical processes, and even use ROS as signaling molecules 20 ; 21. Given their high reactivity and short half-life, measurement of ROS levels in the follicle microenvironment has led to conflicting results about their role in fertility (11). Nevertheless, increasing research in this field has confirmed that modulation of ROS levels through ROS scavenging systems may regulate follicular development and/or survival. In addition, ROS might be involved in the initiation of apoptosis in antral follicles and are a necessary signal for ovulation 22 ; 23.
More than half a century after the proposal of the free radical theory of aging (24), research on female reproductive aging has provided compelling evidence for the key role of oxidative stress in the age-related decline of ovarian function. In line with previous hypotheses (11), valuable results in this field have recently been achieved thanks to a multidisciplinary approach based on overall evaluation of the redox state. In this regard, relevant findings are those by Lim and Luderer (25), who revealed significant age-related increases in oxidatively damaged lipids, proteins, and DNA in different ovarian compartments, including granulosa cells and ovarian interstitial tissue, along with alterations of antioxidant enzyme expression. Further evidence of oxidative stress in the ovarian follicle was obtained by research on stress signaling pathways in older granulosa cells 26 ; 27.
Collectively, these studies have identified in older cells a stress-response signaling pathway leading to up-regulation of glutathione transferase type 1 (GSTT1), an antioxidant enzyme that covalently links reactive chemicals with glutathione (GSH) and aids in detoxification of toxic substances (28). Furthermore, previous hypotheses about reduced ROS scavenging efficiency in the follicular environment have been confirmed by observations in cumulus cells (29). Enzymatic activity and protein level of superoxide dismutase (SOD), the enzyme that reacts with superoxide anion radicals to form oxygen and H2O2, were found to decrease with age, and lower levels of SOD activity are associated with unsuccessful IVF outcomes.
Carbonyl reactive species and carbonyl stress in the aging follicle
Dicarbonyls: Highly Reactive Toxic Compounds from Cellular Metabolism
Seeking an alternative view to the free radical theory of aging, many researchers have begun to look for reactive endogenous metabolites other than ROS that have high reactivity with biomolecules. In this context, attention has been drawn to a heterogeneous group of low-molecular-weight carbonyls derived from metabolic processes and, in particular, from glycolysis (30). Reactive carbonyl species (RCS) share common features with ROS: they interact with proteins, DNA, and lipids to generate products that contribute to the pathogenesis of diseases across different organ systems. Unlike ROS, RCS are stable and attach to targets far from the site of their formation, thereby providing a more deleterious insult to the macromolecular integrity of the cell and extracellular microenvironment (30).
Methylglyoxal (MG) and glyoxal are highly reactive carbonyls generated from carbohydrate metabolism. They belong to a class of RCS known as the α-oxoaldehydes and referred to as dicarbonyls for the presence of two adjacent carbonyl groups (31). Methylglyoxal is formed from the spontaneous degradation of glycolytic intermediates and from other nonenzymatic and enzymatic pathways (32). Glyoxal is formed by lipid peroxidation and degradation of monosaccharides and glycated proteins. Concentrations of MG and glyoxal in human blood plasma are in the range of 100–120 nM, while cellular concentrations are in the range of 1–5 μM for MG, and 0.1–1.0 μM for glyoxal. Given its ability to inhibit mitochondrial respiration and proliferation, induce apoptosis and increase ROS production, MG is considered the most powerful glycating agent 32; 33 ; 34.
Glycation and AGEs
Reactive carbonyl species promote posttranslational modification of proteins by glycation, a nonenzymatic reaction with free amino groups residing on proteins, lipids, and nucleic acids. The early stage of this process involves a complex series of reactions, often referred to collectively as the Maillard reaction, leading to formation of intermediates that are initially reversible but ultimately form stable end-stage adducts called advanced glycation end-products (AGEs) 35 ; 36. These AGEs are heterogeneous substances—a prevalent AGE in vivo is carboxymethyl lysine (CML), a form of nonfluorescent AGE. Other AGEs such as pentosidine are characterized by their ability to form cross-links and to fluoresce (37). For example, MG is known to primarily react with arginin residues to form hydroimidazolones and argpyrimidine 38 ; 39, here referred to as MG-AGEs.
Glycation of proteins is potentially damaging to the proteome. Targeting mostly extracellular long-lived proteins, this posttransductional modification impairs protein functions and causes trapping and molecular cross-linking (40). These irreversible cross-linked proteins contribute to atherosclerosis as well as to kidney failure, conditions worsened in diabetes (41). Elevated circulating AGEs are associated with an increased risk of developing many chronic age-related diseases (42).
In addition to endogenous AGEs, humans are exposed to AGEs ingested in foods. Exogenously, preparation of food at high temperatures is reported to facilitate AGE formation (43). Thus, a relevant factor influencing AGE level in tissues and body fluids is the dietary intake of these glycotoxins. In experimental animal models, reduction of AGE levels either by pharmacologic intervention or reduced dietary intake of AGEs counteracts systemic and tissue oxidative stress, prevents aging-associated disease, and prolongs life span (44). These observations have given rise to the so-called Maillard theory or carbonyl stress theory, which proposes that accumulation of AGEs accelerates the multisystem functional decline that occurs with aging, thus contributing to the aging phenotype.
The Glyoxalase System: The Most Powerful Defense against Carbonyl Stress and AGE
To counteract the deleterious effects of dicarbonyl overload, a condition referred to as carbonyl stress, organisms have evolved a series of enzymatic and nonenzymatic defenses. In this regard, the extent of glycation is under control of the glyoxalase system (37). Detoxification of MG mainly occurs via glyoxalase-1 (GLO1) and glyoxalase-2 (GLO2): GLO1 catalyses the formation of S-d-lactoylglutathione from MG, with reduced GSH acting as a cofactor; GLO2 catalyses the hydrolysis of S-d-lactoylglutathione to d-lactate and regenerates GSH. There is mounting evidence for the key role of GLO1 activity in prevention of AGE formation. In the model organism Caenorhabditis elegans, overexpression of GLO1 increases life span by 40%, while RNA interference (RNAi)–mediated silencing GLO1 decreases life span by 40% (45). Moreover, poor glyoxalase defense has been observed in old age and might be one reason for AGE increase in the aged human brain (46).
The Interplay between AGE and Oxidative Stress: The Role of RAGE
The AGEs can be considered as both the trigger and the result of oxidative stress 47 ; 48. The latter, in fact, is a key factor in AGE production because it promotes the last step of advanced glycation (41). Additional mechanisms are involved in the interplay between AGE accumulation and increased ROS level. Proteins modified by AGEs exert their action through activation of cell responses by interacting with specific cell-surface receptors, such as the receptor for AGEs (RAGE) (49). RAGE is a multiligand member of the immunoglobulin superfamily of cell surface. Upon engagement by AGEs, RAGE triggers intracellular signaling pathways, culminating in the activation of the transcription factor nuclear factorκB (NF-κB), leading to proinflammatory gene expression and ROS generation 50 ; 51. The role of RAGE has been studied in a number of chronic inflammatory diseases such as diabetes, arteriosclerosis, rheumatoid arthritis, inflammatory kidney disease, and neurodegenerative disorders (51). Because the gene targets of NF-κB include RAGE genes, the accumulation of AGEs is associated with an overexpression of these receptors (52). Moreover, the increased production of ROS can result in the depletion of GSH and NADPH, which can in turn decrease the activity of GLO1 and thereby increase the concentration of MG and the formation of AGEs (53). This positive feedback loop makes AGE formation a valuable persistent marker of increased production of short half-life reactive metabolites.
Involvement of Carbonyl Stress in Follicle Aging
The present overview of mechanisms underlying accumulation of molecular damage with aging would provide a framework to properly approach the hypothesis of the involvement of carbonyl stress in ovarian aging. Based on the above observations, this theory is intriguing because the potential accumulation of AGEs in the human ovary may account for a number of age-related features of ovarian dysfunction, including impaired vascularization and consequent hypoxia and reduced intake of nutrients by follicle cells (11). With their prolonged half-life and ability to act as signaling molecules, AGEs may gradually accumulate in the ovary and potentiate the wide spatiotemporal spread of oxidative stress. Prolonged exposure to AGEs during reproductive life may cause subtle oxidative damage in primordial follicles (8) and ovarian stroma vessels (54), promoting a gradual increase of ROS in the ovarian microenvironment during folliculogenesis. These conditions, in turn, may jeopardize granulosa cell metabolism, assembly of antioxidant defense, and development of efficient perifollicular vascularization, and endanger maturation, chromosomal constitution, and developmental capacity of the oocytes. Decreased antioxidant and antiglycation defenses along with mitochondrial dysfunctions might be the driving force for the activation of a positive feedback loop involving oxidative stress, carbonyl stress, and gradual accumulation of AGEs, valuable persistent markers of age-related molecular damage in the ovary (Fig. 1).
Initially, this view of follicle aging arose from the finding of AGE in the human ovarian tissue of young women (55). By using a specific antibody, the investigators observed AGE-modified proteins in granulosa cells and theca layers, and found that RAGE was highly expressed in the ovary in granulosa cells, theca interna, and endothelial and stromal cells. The finding of increased levels of AGE in the serum and ovary of polycystic ovary syndrome (PCOS) patients was viewed as the first evidence of AGE involvement in ovarian dysfunctions 55 ; 56. Moreover, animal studies have identified dietary glycotoxins in the ovary (57). Finally, an interesting study searching for a causative link between AGE and cytogenesis in PCOS tissue has provided evidence for a potential role of AGE signaling in the control of the ovarian extracellular matrix during follicular development (58).
A possible correlation of AGE with follicle aging was first reported by an observational study that found increased levels of pentosidine in the primordial, primary, and atretic follicles of premenopausal women (59). However, the first evidence that the mammalian ovary experiences a condition of carbonyl stress associated with aging was obtained in the mouse model (60):  the activity and expression of GLO1 decreased in aged ovaries,  MG-AGE accumulated with aging in specific ovarian compartments, and  a preliminary analysis of proteome revealed increased glycation of specific polypeptides.
Further evidence for the role of AGEs in follicle aging was provided by measurements in follicular fluid and serum of soluble RAGE (s-RAGE), a circulating isoform of RAGE that can neutralize the ligand-mediated damage (61). Based on measurements in young and reproductive-aged women, the investigators suggested that changes in the interplay between RAGE and vascular endothelial growth factor (VEGF) may result in reproductive dysfunction in aging women. Indeed, VEGF signaling is deregulated in the follicular microenvironment of aged women and may account for alterations in follicular vasculature (62).
Notably, assay of MG cytotoxicity in mouse oocytes has recently revealed the effects of a possible RCS overload with aging 63 ; 64. In vivo and in vitro experiments have shown that MG induced a significant reduction in the rate of oocyte maturation, fertilization, and in vitro embryonic development probably via apoptotic process. Methylglyoxal was found to cause disturbances in redox regulation and distribution of mitochondria, aberrant and delayed spindle formation, and DNA damage. The importance of antiglycation defense in folliculogenesis has been revealed by the finding of Glo1 and Glo2 transcripts in mouse cumulus cells and oocytes. Consistent with their role within the ovarian follicle, glyoxalase transcripts were found to decrease in ovulated oocytes when compared with oocytes from antral follicles. Moreover, aged cumulus cells exhibited a decreased ability to protect the oocyte from MG toxicity (64). Together, these findings suggest that an increased MG level may contribute to a predisposition to aneuploidy and reduced oocyte developmental potential with aging 65 ; 66. Further evidence for the crucial role of glyoxalases in the ovary has been provided by the finding that dietary glycotoxins and hyperandrogenic states decrease GLO1 activity in rat ovaries, possibly contributing to increased AGE accumulation in granulosa cells (67).
A relevant study has shown that AGEs affect reproduction in a clinical setting. Jinno et al. (68) reported that accumulation of some AGEs—namely, pentosidine, carboxymethyl lysine (CML), and the so-called toxic AGE (TAGE) (69)—in follicular fluid and in serum correlated negatively with follicular growth, fertilization, and embryonic development. They established that serum levels of TAGE above 7.24 IU/mL indicated ovarian dysfunction and caused diminished fertility, and that they correlated positively with altered glucose metabolism, age, and factors related to obesity, dyslipidemia, hyperglycemia, and insulin resistance.
Targeting AGEs: A Potential Approach for Delaying Follicle Aging
Interventions against carbonyl stress and AGE formation may offer potential innovative strategies for saving or rescuing ovarian follicle health with aging. In this respect, attention must be paid to synthetic compounds with antiglycation activity as well as to dietary agents and lifestyle. Regarding the first issue, a wide range of molecules, including amino guanidine, metformin, benfotiamine, and pyridoxamine, are under study as drugs for preventing AGE-related dysfunctions. Inhibitors of AGE may act by various mechanisms at different steps of AGE formation and AGE-mediated damage such as trapping of reactive carbonyl compounds, AGE cross-link breaking, RAGE blocking, and RAGE-signaling blocking as well as glycemia reduction 70; 71 ; 72. Dietary agents have been found to be compounds that possess AGE-inhibitor activity, such as the numerous commonly used medicinal plants and plant constituents that possess antiglycation activity 73 ; 74. Prominent among them are green tea and its major bioactive constituents the polyphenol compounds, which are MG trapping agents more powerful than aminoguanidine (75). Encouraging studies in animal models have recently revealed that further strategies to be taken into account as anti-AGE measures are reduced intake of glycotoxins (76) and physical exercise. Experiments on murine brains have demonstrated that regular running lowers the chance of carbonyl stress during aging and reduces molecular damage profiles by enhancing activities of MG-scavenging systems 77 ; 78. The potential of synthetic molecules, dietary components, modification of diet AGE content, and exercise to prevent protein glycation prompts us to hypothesize that these may be exploited for controlling AGE accumulation during aging and ovarian dysfunction.
Final remarks and future challenge
In the past few years, the carbonyl stress theory of aging has gained a great deal of attention from researchers and clinicians who are involved in female reproductive aging. In the meantime, increased evidence for impaired regulation of energetic metabolism in the aging follicle has been provided by animal studies showing that caloric restriction or antioxidant supplementation can prevent loss of oocyte competence throughout reproductive life 22 ; 79. Based on these concepts, we encourage further investigation of the network involving mitochondrial dysfunction, ROS/RCS overload, and relative stress response pathways in the follicle. In this regard, human granulosa cells from IVF patients may provide a valuable model for studying age-related dysfunction in the ovarian microenvironment. Greater understanding of these issues could be helpful in creating innovative strategies for counteracting the effects exerted on fertility by age or aging-like insults (i.e., xenobiotics and anticancer drugs).
The authors thank Ursula Eichenlaub-Ritter, Riccardo Focarelli, and Giovanna Di Emidio for their valuable contribution to the issues discussed and reviewed in our article.
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