Melatonin delays ovarian aging in mice by slowing down the exhaustion of ovarian reserve.
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ABSTRACT:
SUBMITTER: Yang C
PROVIDER: S-EPMC8102596 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ovarian aging is a natural process characterized by follicular depletion and a reduction in oocyte quality, resulting in loss of ovarian function, cycle irregularity and eventually infertility and menopause. The factors that contribute to ovarian aging have not been fully characterized. Activation of the NLRP3 inflammasome has been implicated in age-associated inflammation and diminished function in several organs. In this study, we used Asc -/- and Nlrp3 -/- mice to investigate the possibility that chronic low-grade systemic inflammation mediated by the inflammasome contributes to diminished ovarian reserves as females age. Pro-inflammatory cytokines, IL-6, IL-18, and TNF-α, were decreased in the serum of aging Asc -/- mice compared to WT. Within the ovary of reproductively aged Asc -/- mice, mRNA levels of major pro-inflammatory genes Tnfa, Il1a, and Il1b were decreased, and macrophage infiltration was reduced compared to age-matched WT controls. Notably, suppression of the inflammatory phenotype in Asc -/- mice was associated with retention of follicular reserves during reproductive aging. Similarly, the expression of intra-ovarian pro-inflammatory cytokines was reduced, and follicle numbers were significantly elevated, in aging Nlrp3 -/- mice compared to WT controls. These data suggest that inflammasome-dependent inflammation contributes to the age-associated depletion of follicles and raises the possibility that ovarian aging could be delayed, and fertile window prolonged, by suppressing inflammatory processes in the ovary.
| S-EPMC7905095 | biostudies-literature
Project description:RasGRF1 is a Ras-guanine nucleotide exchange factor implicated in a variety of physiological processes including learning and memory and glucose homeostasis. To determine the role of RASGRF1 in aging, lifespan and metabolic parameters were analyzed in aged RasGrf1(-/-) mice. We observed that mice deficient for RasGrf1(-/-) display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival was also enhanced in these animals. Aged RasGrf1(-/-) displayed better motor coordination than control mice. Protection against oxidative stress was similarly preserved in old RasGrf1(-/-). IGF-I levels were lower in RasGrf1(-/-) than in controls. Furthermore, SIRT1 expression was increased in RasGrf1(-/-) animals. Consistent with this, the blood metabolomic profiles of RasGrf1-deficient mice resembled those observed in calorie-restricted animals. In addition, cardiac glucose consumption as determined PET was not altered by aging in the mutant model, indicating that RasGrf1-deficient mice display delayed aging. Our observations link Ras signaling to lifespan and suggest that RasGrf1 is an evolutionary conserved gene which could be targeted for the development of therapies to delay age-related processes.
| S-EPMC3091520 | biostudies-literature
Project description:BackgroundDiminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. Recently, the role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. However, details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear.ObjectiveA systems pharmacology strategy was proposed to elucidate the potential therapeutic mechanism of melatonin on DOR at the molecular, pathway, and network levels.MethodsThe systems pharmacological approach consisted of target identification, data integration, network construction, bioinformatics analysis, and molecular docking.ResultsFrom the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to DOR development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others. Eight hub targets (MAPK1, AKT1, EGFR, HRAS, SRC, ESR1, AR, and ALB) were identified. From the pathway level, 17 significant pathways, including the PI3K-Akt signaling pathway and the estrogen signaling pathway, were identified. In addition, the 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules. From the network point of view, by regulating five target subnetworks (aging, cell growth and death, development and regeneration, endocrine and immune systems), melatonin could exhibit anti-aging, anti-apoptosis, endocrine, and immune system regulation effects. The molecular docking results showed that melatonin bound well to all hub targets.ConclusionThis study systematically and intuitively illustrated the possible pharmacological mechanisms of OR improvement by melatonin through anti-aging, anti-apoptosis, endocrine, and immune system regulation effects.
| S-EPMC8095380 | biostudies-literature
Project description:Melatonin is probably produced in all cells but is only secreted by the pineal gland. The pineal secretion of melatonin is determined by the light-dark cycle, and it is only released at night. Melatonin regulates biological rhythms via its receptors located in the suprachiasmatic nuclei of the hypothalamus. Melatonin also has strong antioxidant activities to scavenge free radicals such as reactive oxygen species (ROS). The direct free radical scavenging actions are receptor independent. ROS play an important role in reproductive function including in the ovulatory process. However, excessive ROS can also have an adverse effect on oocytes because of oxidative stress, thereby causing infertility. It is becoming clear that melatonin is located in the ovarian follicular fluid and in the oocytes themselves, which protects these cells from oxidative damage as well as having other beneficial actions in oocyte maturation, fertilization, and embryo development. Trials on humans have investigated the improvement of outcomes of assisted reproductive technology (ART), such as in vitro fertilization and embryo transfer (IVF-ET), by way of administering melatonin to patients suffering from infertility. In addition, clinical research has examined melatonin as an anti-aging molecule via its antioxidative actions, and its relationship with the aging diseases, e.g., Alzheimer's and Parkinson's disease, is also underway. Melatonin may also reduce ovarian aging, which is a major issue in assisted reproductive technology. This review explains the relationship between melatonin and human reproductive function, as well as the clinical applications expected to improve the outcomes of assisted reproductive technology such as IVF, while also discussing possibilities for melatonin in preventing ovarian aging.
| S-EPMC7036809 | biostudies-literature
Project description:Chronic fetal hypoxia is a common complication observed in human pregnancy, impacting pregnancies across global contexts. Exposure to chronic intrauterine hypoxia has major short- and long-term consequences for offspring health. However, the impact of chronic gestational hypoxia on female reproductive system development is unknown. We aimed to understand the impact of exposure to chronic fetal hypoxia on the developing female reproductive system. Wistar rat dams underwent normoxia (21%) or hypoxia (13%) during pregnancy. Postnatally, all female offspring were maintained in normoxic conditions into early adulthood. Female rats exposed to chronic gestational hypoxia (13%) during their intrauterine development had decreased ovarian primordial follicular reserve compared to controls (P < 0.05). Adult females who had been exposed to chronic fetal hypoxia had significantly reduced somatic ovarian telomere length (P < 0.05) and reduced ovarian protein expression of KU70, a critical component of the DNA-activated protein kinase repair complex (P < 0.01). Gene expression of NADPH oxidase 2-mediated oxidative stress markers was increased (P < 0.05). Exposure to chronic hypoxia during fetal development leads to accelerated aging of the somatic ovary and decreased ovarian reserve in adulthood. Ovarian aging is highly sensitive to gestational hypoxia, with implications for future fertility in next-generation offspring of high-risk pregnancies.-Aiken, C. E., Tarry-Adkins, J. L., Spiroski, A.-M., Nuzzo, A. M., Ashmore, T. J., Rolfo, A., Sutherland, M. J., Camm, E. J., Giussani, D. A., Ozanne, S. E. Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next-generation adult rats.
| S-EPMC6529349 | biostudies-literature
Project description:Ovarian reserve is a key factor in the reproductive function of the ovaries. Ovarian aging is characterized by a gradual decline in the quantity and quality of follicles. The underlying mechanism of ovarian aging is complex and age-related oxidative stress is considered one of the most likely factors. Secoisolariciresinol diglucoside (SDG) has been shown to have good scavenging ability against reactive oxygen species (ROS) which slowly accumulates in ovarian tissues. However, it is unknown whether SDG had beneficial effects on aging ovaries. In this study, we used 37-week-old female C57BL/6J mouse as a natural reproductive aging model to evaluate the role of SDG in ovarian aging. SDG (7 and 70 mg/kg) intragastric administration was performed in the mice daily. After 8 weeks, the effects of SDG on aging ovaries were evaluated by counting the number of follicles and the expression of follicle-stimulating hormone receptors (FSHR) in the ovary. The mechanism of SDG on the aging ovaries was further explored through ovarian metabolomics. It was found that SDG can effectively increase the number of growing follicles and increase the expression of the FSHR protein. The metabolomics results showed that the ovaries in the SDG intervention group achieved better uptake and transport of nutrients, including amino acids and glucose that are necessary for the development of oocytes. At the same time, the ovaries of the SDG intervention group showed that the drug reduced ROS generation. Additionally, we found that ovarian telomere length and ovarian mitochondrial DNA copy number that are highly susceptible to ROS damage and are also related to aging. The results showed that SDG can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. These data indicate that SDG improves ovarian reserve by inhibiting oxidative stress.
| S-EPMC8764264 | biostudies-literature
Project description:Interval timing is a fundamental component of action and is susceptible to motor-related temporal distortions. Previous studies have shown that concurrent movement biases temporal estimates, but have primarily considered self-modulated movement only. However, real-world encounters often include situations in which movement is restricted or perturbed by environmental factors. In the following experiments, we introduced viscous movement environments to externally modulate movement and investigated the resulting effects on temporal perception. In two separate tasks, participants timed auditory intervals while moving a robotic arm that randomly applied four levels of viscosity. Results demonstrated that higher viscosity led to shorter perceived durations. Using a drift-diffusion model and a Bayesian observer model, we confirmed these biasing effects arose from perceptual mechanisms, instead of biases in decision making. These findings suggest that environmental perturbations are an important factor in movement-related temporal distortions, and enhance the current understanding of the interactions of motor activity and cognitive processes.
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Project description:Fluids cooled to the liquid-vapor critical point develop system-spanning fluctuations in density that transform their visual appearance. Despite a rich phenomenology, however, there is not currently an explanation of the mechanical instability in the molecular motion at this critical point. Here, we couple techniques from nonlinear dynamics and statistical physics to analyze the emergence of this singular state. Numerical simulations and analytical models show how the ordering mechanisms of critical dynamics are measurable through the hierarchy of spatiotemporal Lyapunov vectors. A subset of unstable vectors soften near the critical point, with a marked suppression in their characteristic exponents that reflects a weakened sensitivity to initial conditions. Finite-time fluctuations in these exponents exhibit sharply peaked dynamical timescales and power law signatures of the critical dynamics. Collectively, these results are symptomatic of a critical slowing down of chaos that sits at the root of our statistical understanding of the liquid-vapor critical point.
| S-EPMC6517405 | biostudies-literature
Project description:During female reproductive life, ovarian follicle reserve is reduced by maturation and atresia until menopause ensues. Foxo3 is required to maintain the ovarian reserve in mice. Here we show that overexpression of constitutively active FOXO3 can increase ovarian reproductive capacity in mice. We find increased follicle numbers and decreased gonadotropin levels in aging FOXO3-transgenic mice compared with wild-type littermates, suggesting maintenance of a greater ovarian reserve. Based on cumulative progeny in aging animals, we find 31-49% increased fertility in transgenic females. The gene expression profile of Foxo3-/- knockout ovaries appears older than that of wild-type littermates, and the transgene induces a younger-looking profile, restoring much of the wild-type transcriptome. This is the first gain-of-function model of augmented reproductive reserve in mice, thus emphasizing the role of Foxo3 as a guardian of the ovarian follicle pool in mammals and a potential determinant of the onset of menopause.
| S-EPMC4504230 | biostudies-literature
Project description:BackgroundTanshinone IIA (TSA), a major lipophilic component extracted from the roots of Salvia miltiorrhiza Bunge, has been widely used in China for its various biological activities. However, its effect on ovarian reserve in aged mice was not studied elsewhere.ObjectivesThis study aimed to explore the effect of TSA on the ovarian reserve of aged mice as well as young mice. Forty weeks old mice (N = 40) were considered as aged group compared to 4 weeks old mice (N = 40), and these groups were subdivided into four subgroups (N = 10) to receive different doses of TSA (0, 10, 20, and 40 μg/g/day).MethodsThe effect of TSA was evaluated by counting follicular number by histological examination. Basal serum levels of FSH, LH, E2, and anti-Mullerian hormone (AMH) were measured by ELISA. Moreover, the expression levels of antioxidant genes (CAT, Nrf2, GPX1), gap junction (Cx37), ERK1/2, and Smad5 family gene were examined at both mRNA (qPCR) and protein levels (western blot).ResultsFollicular number, level of AMH and E2, and the expression of CAT, Nrf2, and GPX1 genes increased significantly (p < 0.05) in aged mice administrated with medium (20 μg/g/day) and high (40 μg/g/day) doses of TSA, whereas FSH and LH levels were significantly low compared to low dose (10 μg/g/day) and control (0 μg/g/day) aged subgroups. However, we did not observe any effect of all doses of TSA on young mice.ConclusionsAdministration of TSA with medium and high doses up-regulates the expression of antioxidative genes, reduces the oxidative injury, increases levels of AMH, and E2 levels that are relatively comparable to those in young mice, and consequently results in a healthy oocyte development.
| S-EPMC9297741 | biostudies-literature