Aging conundrum: A perspective for ovarian aging

Wu, Jinglan; Liu, Yang; Song, Yinhua; Wang, Lingjuan; Ai, Jihui; Li, Kezhen

doi:10.3389/fendo.2022.952471

Cited by 28 publications

(29 citation statements)

References 208 publications

(121 reference statements)

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“…The conversion of a pluripotent VSEL with open chromatin into OSCs involves extensive epigenetic changes, and this process is affected by aging. Ovarian aging can be reversed by transplanting MSCs directly into the ovaries ( Tian et al, 2021 ; Wu et al, 2022 ) and by providing a younger niche. Aged ovaries possess rare premeiotic germ cells that can generate oocytes, following transplantation into a young host environment ( Niikura et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Bhartiya¹,

Jha²,

Tripathi³

et al. 2023

Front. Cell Dev. Biol.

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The concept of dedifferentiation and reprogramming of mature somatic cells holds much promise for the three-front “war” against tissue damage, cancer, and aging. It was hoped that reprogramming human somatic cells into the induced pluripotent state, along with the use of embryonic stem cells, would transform regenerative medicine. However, despite global efforts, clinical applications remain a distant dream, due to associated factors such as genomic instability, tumorigenicity, immunogenicity, and heterogeneity. Meanwhile, the expression of embryonic (pluripotent) markers in multiple cancers has baffled the scientific community, and it has been suggested that somatic cells dedifferentiate and “reprogram” into the pluripotent state in vivo to initiate cancer. It has also been suggested that aging can be reversed by partial reprogramming in vivo. However, better methods are needed; using vectors or Yamanaka factors in vivo, for example, is dangerous, and many potential anti-aging therapies carry the same risks as those using induced pluripotent cells, as described above. The present perspective examines the potential of endogenous, pluripotent very small embryonic-like stem cells (VSELs). These cells are naturally present in multiple tissues; they routinely replace diseased tissue and ensure regeneration to maintain life-long homeostasis, and they have the ability to differentiate into adult counterparts. Recent evidence suggests that cancers initiate due to the selective expansion of epigenetically altered VSELs and their blocked differentiation. Furthermore, VSEL numbers have been directly linked to lifespan in studies of long- and short-lived transgenic mice, and VSEL dysfunction has been found in the ovaries of aged mice. To conclude, a greater interest in VSELs, with their potential to address all three fronts of this war, could be the “light at the end of the tunnel.”

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Section: Introductionmentioning

confidence: 99%

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Bhartiya¹,

Jha²,

Tripathi³

et al. 2023

Front. Cell Dev. Biol.

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“…Ovarian aging is a complex process resulting in senescence in mice and menopause in women and a topic of intense debate and several possible underlying mechanisms are discussed [26,27]. It eventually results in the aging of multiple organs and menopausal women suffer from a number of diseases like osteoporosis, cardiovascular disease, obesity, tumors, Alzheimer's disease and diabetes.…”

Section: Main Textmentioning

confidence: 99%

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Bhartiya

Sharma

2023

J Ovarian Res

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Multiple studies using single-cell RNA sequencing (scRNAseq) have failed to detect stem cells in adult ovaries. We have maintained that two populations of ovarian stem cells including pluripotent, very small embryonic-like stem cells (VSELs) and tissue-committed ‘progenitors’ termed ovarian stem cells (OSCs) can easily be detected in Hematoxylin and Eosin-stained ovary surface epithelial (OSE) cells smears prepared from both mice and human ovaries. Most likely the stem cells never get subjected to scRNAseq since they pellet down only by centrifuging cells suspension at 1000 g while cells for scRNAseq were invariably prepared by centrifuging at 200-400 g. A recent article provided further explanation for the failure of scRNAseq to detect ovarian stem cells. Extensive reanalysis of data (generated by scRNAseq) using an advanced software successfully detected OSCs and meiotic markers supporting neo-oogenesis in adult human ovaries. But this article remained critical on the biological relevance of VSELs and their relationship with OSCs. By carefully studying the OSE cells smears (which hold VSELs, OSCs and germ cell nests GCNs), prepared by partial trypsin digestion of intact mice ovaries during different stages of estrus cycle, we have successfully delineated novel functions of VSELs/OSCs in vivo under physiological conditions. VSELs undergo asymmetrical divisions to self-renew and give rise to slightly bigger OSCs which in turn undergo symmetrical divisions and clonal expansion to form GCNs, regular neo-oogenesis and follicle assembly. GCNs have been earlier described in fetal ovaries and during OSE cells culture (from adult ovaries) in response to FSH treatment. Dysfunction of VSELs/OSCs (which express ERα, ERβ, FSHR) due to neonatal exposure to endocrine disruption results in ovarian insufficiency and polycystic ovaries. VSELs have also been implicated in ovarian cancer. Age-related ovarian senescence/menopause is also due to dysfunction and blocked differentiation of VSELs/OSCs. These novel findings in vivo along with abundant in vitro and lineage tracing studies data in published literature provides huge scope for further research, offers novel avenues to manage ovarian pathologies and calls for re-writing of textbooks.

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“…Thus, mitochondrial dysfunction is a common feature of both oocytes and stem cells in aging. Defective mitochondria in aged oocytes increase ROS levels ( Wu et al, 2022 ). HSCs also exhibit increased ROS production during aging ( Nakamura-Ishizu et al, 2020 ).…”

Section: Oocyte Agingmentioning

confidence: 99%

“…Furthermore, before menopause, decline in oocyte function accompanies the decrease in their numbers with aging. In aged oocytes, chromosome aneuploidy increases and mitochondrial function declines (Wu et al, 2022). Meanwhile, the number of tissue stem cells also decreases with aging, and it could be hypothesized that oocytes and stem cells share common aging phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Oocyte aging in comparison to stem cells in mice

Nagamatsu

2023

Front. Aging

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To maintain homeostasis, many tissues contain stem cells that can self-renew and differentiate. Based on these functions, stem cells can reconstitute the tissue even after injury. In reproductive organs, testes have spermatogonial stem cells that generate sperm in men throughout their lifetime. However, in the ovary, oocytes enter meiosis at the embryonic stage and maintain sustainable oogenesis in the absence of stem cells. After birth, oocytes are maintained in a dormant state in the primordial follicle, which is the most premature follicle in the ovary, and some are activated to form mature oocytes. Thus, regulation of dormancy and activation of primordial follicles is critical for a sustainable ovulatory cycle and is directly related to the female reproductive cycle. However, oocyte storage is insufficient to maintain a lifelong ovulation cycle. Therefore, the ovary is one of the earliest organs to be involved in aging. Although stem cells are capable of proliferation, they typically exhibit slow cycling or dormancy. Therefore, there are some supposed similarities with oocytes in primordial follicles, not only in their steady state but also during aging. This review aims to summarise the sustainability of oogenesis and aging phenotypes compared to tissue stem cells. Finally, it focuses on the recent breakthroughs in vitro culture and discusses future prospects.

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Aging conundrum: A perspective for ovarian aging

Cited by 28 publications

References 208 publications

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Oocyte aging in comparison to stem cells in mice

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