Mtor inhibition by INK128 extends functions of the ovary reconstituted from germline stem cells in aging and premature aging mice

Dai, Hongyue; Sheng, Xiaoyan; Tian, Chenglei; Li, Jie; Liu, Linlin; Gou, Mo

doi:10.1111/acel.13304

Cited by 8 publications

(5 citation statements)

References 101 publications

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“…On the other hand, an in vivo experiment in mice observed that permutation transcripts were closely associated with mitochondrial and ovarian abnormalities (86). mTOR is closely related to the metabolic process of mitochondria in ovarian cells (87), and inhibition of mTOR significantly improved follicular development and endocrine functions of the ovaries, thereby extending reproductive aging and premature aging of POF mice (88). These observations suggested that abnormal FMR1 transcription potentially causes…”

Section: Fragile X Messenger Ribonucleoprotein 1 (Fmr1)mentioning

confidence: 90%

Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management

Yang

2023

Front. Med.

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Premature ovarian failure (POF) is an insidious cause of female infertility and a devastating condition for women. POF also has a strong familial and heterogeneous genetic background. Management of POF is complicated by the variable etiology and presentation, which are generally characterized by abnormal hormone levels, gene instability and ovarian dysgenesis. To date, abnormal regulation associated with POF has been found in a small number of genes, including autosomal and sex chromosomal genes in folliculogenesis, granulosa cells, and oocytes. Due to the complex genomic contributions, ascertaining the exact causative mechanisms has been challenging in POF, and many pathogenic genomic characteristics have yet to be elucidated. However, emerging research has provided new insights into genomic variation in POF as well as novel etiological factors, pathogenic mechanisms and therapeutic intervention approaches. Meanwhile, scattered studies of transcriptional regulation revealed that ovarian cell function also depends on specific biomarker gene expression, which can influence protein activities, thus causing POF. In this review, we summarized the latest research and issues related to the genomic basis for POF and focused on insights gained from their biological effects and pathogenic mechanisms in POF. The present integrated studies of genomic variants, gene expression and related protein abnormalities were structured to establish the role of etiological genes associated with POF. In addition, we describe the design of some ongoing clinical trials that may suggest safe, feasible and effective approaches to improve the diagnosis and therapy of POF, such as Filgrastim, goserelin, resveratrol, natural plant antitoxin, Kuntai capsule et al. Understanding the candidate genomic characteristics in POF is beneficial for the early diagnosis of POF and provides appropriate methods for prevention and drug treatment. Additional efforts to clarify the POF genetic background are necessary and are beneficial for researchers and clinicians regarding genetic counseling and clinical practice. Taken together, recent genomic explorations have shown great potential to elucidate POF management in women and are stepping from the bench to the bedside.

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Section: Fragile X Messenger Ribonucleoprotein 1 (Fmr1)mentioning

confidence: 90%

Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management

Yang

2023

Front. Med.

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“…However, the majority of PGCs enter meiosis and undergo folliculogenesis soon after transplantation, and proliferative PGCs and meiocytes disappear about six weeks following transplantation [ 270 ]. Encouragingly, mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice [ 271 ].…”

Section: Ovarian Aging Intervention Strategymentioning

confidence: 99%

Ovarian aging: mechanisms and intervention strategies

Zhu

Liu

2022

Medical Review

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Ovarian reserve is essential for fertility and influences healthy aging in women. Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes. The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered. In this review, we highlight some of critical factors that impact oocyte quantity and quality during aging. Germ cell and follicle reserve at birth determines reproductive lifespan and timing the menopause in female mammals. Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency. Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes, telomere shortening, DNA damage and associated genetic mutations, oxidative stress, mitochondrial dysfunction and epigenetic alteration. We also discuss the intervention strategies to delay ovarian aging. Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed. Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells. We propose directions for future interventions. As couples increasingly begin delaying parenthood in life worldwide, understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.

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“…The ovary has two main roles: the female reproductive organ and a hormone secretion system. The ovaries function cyclically; in humans, their function declines with age from the mid-30s, and their menopause-disrupting endocrine function starts in the mid-50s [ 1 ]. Ovarian function declines early relative to other organs in the body and is implicated in predicting ovarian menopause [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study focused on preventing pathological changes in ovarian cells by mTOR inhibition, which postponed follicular activation and development and extended the follicle reserve and endocrine function of the ovaries [ 1 ]. Additionally, ovarian fibrosis in stromal interstitial tissues surrounding follicles is a key causal factor of obesity-induced ovarian dysfunction and the process is similar to that of reproductive aging [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved the fertility and ovarian function of perimenopausal mice undergoing natural aging

Shin,

Jeong,

Lee

et al. 2024

Stem Cell Res Ther

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Objectives Currently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence. Materials and methods In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function. Results The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow. Conclusions Multiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.

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Mtor inhibition by INK128 extends functions of the ovary reconstituted from germline stem cells in aging and premature aging mice

Cited by 8 publications

References 101 publications

Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management

Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management

Ovarian aging: mechanisms and intervention strategies

Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved the fertility and ovarian function of perimenopausal mice undergoing natural aging

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