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The process of ovarian aging: it is not just about oocytes and granulosa cells

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Abstract

Ovarian age is classically considered the main cause of female reproductive infertility. In women, the process proceeds as an ongoing decline in the primordial follicle stockpile and it is associated with reduced fertility in the mid-thirties, irregular menstruation from the mid-forties, cessation of fertility, and, eventually, menopause in the early fifties. Reproductive aging is historically associated with changes in oocyte quantity and quality. However, besides the oocyte, other cellular as well as environmental factors have been the focus of more recent investigations suggesting that ovarian decay is a complex and multifaceted process. Among these factors, we will consider mitochondria and oxidative stress as related to nutrition, changes in extracellular matrix molecules, and the associated ovarian stromal compartment where immune cells of both the native and adaptive systems seem to play an important role. Understanding such processes is crucial to design treatment strategies to  slow down ovarian aging and consequently prolong reproductive lifespan and, more to this, alleviaingt side effects of menopause on the musculoskeletal, cardiovascular, and nervous systems.

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References

  1. Touati SA, Wassmann K. How oocytes try to get it right: spindle checkpoint control in meiosis. Chromosoma. 2016;125:321–35.

    Article  PubMed  Google Scholar 

  2. Zuckerman S, Zuckerman S, Zuckerman SLZ, Zuckerman LM. The number of oocytes in the mature ovary. Recent Prog Horm Res. 1951. p. 63–109.

  3. De Felici M. The formation and migration of primordial germ cells in mouse and man. Results Probl Cell Differ. 2016;58:23–46.

    Article  PubMed  CAS  Google Scholar 

  4. Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod. 2008;23:699–708.

    Article  PubMed  Google Scholar 

  5. Micevych P, Sinchak K, Mills RH, Tao L, LaPolt P, Lu JKH. The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology. 2003;78:29–35.

    Article  CAS  PubMed  Google Scholar 

  6. Mills RH, Romeo HE, Lu JKH, Micevych PE. Site-specific decrease of progesterone receptor mRNA expression in the hypothalamus of middle-aged persistently estrus rats. Brain Res. 2002;955:200–6.

    Article  CAS  PubMed  Google Scholar 

  7. Santoro N, Banwell T, Tortoriello D, Lieman H, Adel T, Skurnick J. Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women. Am J Obstet Gynecol. 1998;178:732–41.

    Article  CAS  PubMed  Google Scholar 

  8. Yonker JA, Chang V, Roetker NS, Hauser TS, Hauser RM, Atwood CS. Hypothalamic–pituitary–gonadal axis homeostasis predicts longevity. Age. 2013;35:129–38.

    Article  CAS  PubMed  Google Scholar 

  9. Park M-R, Choi Y-J, Kwon D-N, Park C, Bui H-T, Gurunathan S, et al. Intraovarian transplantation of primordial follicles fails to rescue chemotherapy injured ovaries. Sci Rep. 2013;3:1384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Donnez J, Dolmans M-M. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet. 2015;32:1167–70.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Marcozzi S, Rossi V, Salustri A, De Felici M, Klinger FG. Programmed cell death in the human ovary. Minerva Ginecol. 2018;70:549–60.

    Article  PubMed  Google Scholar 

  12. Gebel J, Tuppi M, Chaikuad A, Hötte K, Schröder M, Schulz L, et al. p63 uses a switch-like mechanism to set the threshold for induction of apoptosis. Nat Chem Biol. 2020;16:1078–86.

    Article  CAS  PubMed  Google Scholar 

  13. Kerr JB, Hutt KJ, Michalak EM, Cook M, Vandenberg CJ, Liew SH, et al. DNA damage-induced primordial follicle oocyte apoptosis and loss of fertility require TAp63-mediated induction of Puma and Noxa. Mol Cell. 2012;48:343–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McLaughlin EA, McIver SC. Awakening the oocyte: controlling primordial follicle development. Reproduction. 2009;137:1–11.

    Article  CAS  PubMed  Google Scholar 

  15. Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev. 2009;30:438–64.

    Article  CAS  PubMed  Google Scholar 

  16. Reddy P, Zheng W, Liu K. Mechanisms maintaining the dormancy and survival of mammalian primordial follicles. Trends Endocrinol Metab. 2010;21:96–103.

    Article  CAS  PubMed  Google Scholar 

  17. Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11:162–78.

    Article  PubMed  CAS  Google Scholar 

  18. Masciangelo R, Hossay C, Chiti MC, Manavella DD, Amorim CA, Donnez J, et al. Role of the PI3K and Hippo pathways in follicle activation after grafting of human ovarian tissue. J Assist Reprod Genet. 2020;37:101–8.

    Article  PubMed  Google Scholar 

  19. Kawamura K, Ishizuka B, Hsueh AJW. Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve. Reprod Biomed Online. 2020;40:245–53.

    Article  CAS  PubMed  Google Scholar 

  20. Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science. 2003;301:215–8.

    Article  CAS  PubMed  Google Scholar 

  21. Pelosi E, Omari S, Michel M, Ding J, Amano T, Forabosco A, et al. Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice. Nat Commun. 2013;4:1843.

    Article  PubMed  CAS  Google Scholar 

  22. Maidarti M, Clarkson YL, McLaughlin M, Anderson RA, Telfer EE. Inhibition of PTEN activates bovine non-growing follicles in vitro but increases DNA damage and reduces DNA repair response. Hum Reprod. 2019;34:297–307.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang H, Risal S, Gorre N, Busayavalasa K, Li X, Shen Y, et al. Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice. Curr Biol. 2014;24:2501–8.

    Article  CAS  PubMed  Google Scholar 

  24. Kingery HM. Oogenesis in the white mouse. J Morphol. 1917;30:261–315.

    Article  Google Scholar 

  25. Simkins CS. Development of the human ovary from birth to sexual maturity. Am J Anat. 1932;51:465–505.

    Article  Google Scholar 

  26. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–50.

    Article  CAS  PubMed  Google Scholar 

  27. Bukovsky A, Gupta SK, Virant-Klun I, Upadhyaya NB, Copas P, Van Meter SE, et al. Study origin of germ cells and formation of new primary follicles in adult human and rat ovaries. In: Hou SX, Singh SR, editors. Germline Stem Cells. Totowa: Humana Press; 2008. p. 233–65.

    Chapter  Google Scholar 

  28. Zou K, Hou L, Sun K, Xie W, Wu J. Improved efficiency of female germline stem cell purification using fragilis-based magnetic bead sorting. Stem Cells Dev. 2011;20:2197–204.

    Article  CAS  PubMed  Google Scholar 

  29. Park E-S, Tilly JL. Use of DEAD-box polypeptide-4 (Ddx4) gene promoter-driven fluorescent reporter mice to identify mitotically active germ cells in post-natal mouse ovaries. Mol Hum Reprod. 2015;21:58–65.

    Article  CAS  PubMed  Google Scholar 

  30. Ding X, Liu G, Xu B, Wu C, Hui N, Ni X, et al. Human GV oocytes generated by mitotically active germ cells obtained from follicular aspirates. Sci Rep. 2016;6:28218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Satirapod C, Wang N, MacDonald JA, Sun M, Woods DC, Tilly JL. Estrogen regulation of germline stem cell differentiation as a mechanism contributing to female reproductive aging. Aging (Albany NY). 2020;12:7313–33.

    Article  CAS  Google Scholar 

  32. Nobuhiro S, Stephanie AP, Aleksandar R. Candidate genes for premature ovarian failure. Curr Med Chem. 2007;14:353–7.

    Article  Google Scholar 

  33. Tesarik J, Galán-Lázaro M, Mendoza-Tesarik R. Ovarian aging: molecular mechanisms and medical management. Int J Mol Sci. 2021;22:1371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Steuerwald NM, Bermúdez MG, Wells D, Munné S, Cohen J. Maternal age-related differential global expression profiles observed in human oocytes. Reprod Biomed Online. 2007;14:700–8.

    Article  CAS  PubMed  Google Scholar 

  35. Ratnam S, Mertineit C, Ding F, Howell CY, Clarke HJ, Bestor TH, et al. Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development. Dev Biol. 2002;245:304–14.

    Article  CAS  PubMed  Google Scholar 

  36. Md BY, Russanova VR, Gravina S, Hartley S, Mullikin JC, Ignezweski A, et al. DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3′-end GC density. Oncotarget. 2015;6:3627–43.

    Article  Google Scholar 

  37. Kawai K, Harada T, Ishikawa T, Sugiyama R, Kawamura T, Yoshida A, et al. Parental age and gene expression profiles in individual human blastocysts. Sci Rep. 2018;8:2380.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. van den Berg IM, Eleveld C, van der Hoeven M, Birnie E, Steegers EAP, Galjaard R-J, et al. Defective deacetylation of histone 4 K12 in human oocytes is associated with advanced maternal age and chromosome misalignment. Hum Reprod. 2011;26:1181–90.

    Article  PubMed  CAS  Google Scholar 

  39. Coccia ME, Rizzello F. Ovarian reserve. Ann N Y Acad Sci. 2008;1127:27–30.

    Article  CAS  PubMed  Google Scholar 

  40. Tarin JJ. Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. Mol Hum Reprod. 1996;2:717–24.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang C, Tao L, Yue Y, Ren L, Zhang Z, Wang X, et al. Mitochondrial transfer from induced pluripotent stem cells rescues developmental potential of in vitro fertilized embryos from aging females. Biol Reprod. 2021;104:1114–25.

    Article  PubMed  Google Scholar 

  42. Truman AM, Tilly JL, Woods DC. Ovarian regeneration: The potential for stem cell contribution in the postnatal ovary to sustained endocrine function. Mol Cell Endocrinol. 2017;445:74–84.

    Article  CAS  PubMed  Google Scholar 

  43. Lim J, Luderer U. Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary1. Biol Reprod. 2011;84:775–82.

    Article  CAS  PubMed  Google Scholar 

  44. Yang L, Chen Y, Liu Y, Xing Y, Miao C, Zhao Y, et al. The role of oxidative stress and natural antioxidants in ovarian aging. Front Pharmacol. 2021;11:2364.

    Article  Google Scholar 

  45. Keefe DL, Franco S, Liu L, Trimarchi J, Cao B, Weitzen S, et al. Telomere length predicts embryo fragmentation after in vitro fertilization in women—toward a telomere theory of reproductive aging in women. Am J Obstet Gynecol. 2005;192:1256–60.

    Article  CAS  PubMed  Google Scholar 

  46. Pollack AZ, Rivers K, Ahrens KA. Parity associated with telomere length among US reproductive age women. Hum Reprod. 2018;33:736–44.

    Article  CAS  PubMed  Google Scholar 

  47. Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, et al. Age-associated telomere shortening in mouse oocytes. Reprod Biol Endocrinol. 2013;11:108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Liu L, Franco S, Spyropoulos B, Moens PB, Blasco MA, Keefe DL. Irregular telomeres impair meiotic synapsis and recombination in mice. PNAS. 2004;101:6496–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu L, Blasco MA, Keefe DL. Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles. EMBO Rep. 2002;3:230–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cajas YN, Cañón-Beltrán K, Ladrón de Guevara M, Millán de la Blanca MG, Ramos-Ibeas P, Gutiérrez-Adán A, et al. Antioxidant nobiletin enhances oocyte maturation and subsequent embryo development and quality. Int J Mol Sci. 2020;21:5340.

    Article  CAS  PubMed Central  Google Scholar 

  51. Kawamura Y, Uchijima Y, Horike N, Tonami K, Nishiyama K, Amano T, et al. Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J Clin Invest. 2010;120:2817–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu J, Liu M, Ye X, Liu K, Huang J, Wang L, et al. Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum Reprod. 2012;27:1411–20.

    Article  CAS  PubMed  Google Scholar 

  53. Yang Q, Dai S, Luo X, Zhu J, Li F, Liu J, et al. Melatonin attenuates postovulatory oocyte dysfunction by regulating SIRT1 expression. Reproduction. 2018;156:81–92.

    Article  CAS  PubMed  Google Scholar 

  54. Tatone C, Di Emidio G, Vitti M, Di Carlo M, Santini S, D’Alessandro AM, et al. Sirtuin functions in female fertility: possible role in oxidative stress and aging. Oxid Med Cell Longev. 2015;2015:e659687.

    Article  Google Scholar 

  55. Miao Y, Cui Z, Gao Q, Rui R, Xiong B. Nicotinamide mononucleotide supplementation reverses the declining quality of maternally aged oocytes. Cell Rep. 2020;32(5):107987. https://doi.org/10.1016/j.celrep.2020.107987.

  56. Zhang H, Li C, Wen D, Li R, Lu S, Xu R, et al. Melatonin improves the quality of maternally aged oocytes by maintaining intercellular communication and antioxidant metabolite supply. Redox Biol. 2022;49:102215.

    Article  CAS  PubMed  Google Scholar 

  57. Azami SH, Nazarian H, Abdollahifar MA, Eini F, Farsani MA, Novin MG, et al. The antioxidant curcumin postpones ovarian aging in young and middle-aged mice. Reprod Fertil Dev. 2020;32:292–303.

    Article  CAS  PubMed  Google Scholar 

  58. Cao Y, Zhao H, Wang Z, Zhang C, Bian Y, Liu X, et al. Quercetin promotes in vitro maturation of oocytes from humans and aged mice. Cell Death Dis. 2020;11:1–15.

    Article  CAS  Google Scholar 

  59. Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M, et al. Single-cell transcriptomic atlas of primate ovarian aging. Cell. 2020;180:585-600.e19.

    Article  CAS  PubMed  Google Scholar 

  60. Tatone C, Carbone MC, Falone S, Aimola P, Giardinelli A, Caserta D, et al. Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells. Mol Hum Reprod. 2006;12:655–60.

    Article  CAS  PubMed  Google Scholar 

  61. Seifer DB, DeJesus V, Hubbard K. Mitochondrial deletions in luteinized granulosa cells as a function of age in women undergoing in vitro fertilization. Fertil Steril. 2002;78:1046–8.

    Article  PubMed  Google Scholar 

  62. Ito M, Muraki M, Takahashi Y, Imai M, Tsukui T, Yamakawa N, et al. Glutathione S-transferase theta 1 expressed in granulosa cells as a biomarker for oocyte quality in age-related infertility. Fertil Steril. 2008;90:1026–35.

    Article  CAS  PubMed  Google Scholar 

  63. Yu Y-Y, Sun C-X, Liu Y-K, Li Y, Wang L, Zhang W. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertil Steril. 2015;104:145-153.e6.

    Article  CAS  PubMed  Google Scholar 

  64. Selesniemi K, Lee H-J, Muhlhauser A, Tilly JL. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. PNAS. 2011;108:12319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nelson JF, Gosden RG, Felicio LS. Effect of dietary restriction on estrous cyclicity and follicular reserves in aging C57BL/6J mice1. Biol Reprod. 1985;32:515–22.

    Article  CAS  PubMed  Google Scholar 

  66. Jacobs L, Gerards M, Chinnery P, Dumoulin J, de Coo I, Geraedts J, et al. mtDNA point mutations are present at various levels of heteroplasmy in human oocytes. Mol Hum Reprod. 2007;13:149-154*.

    Article  CAS  PubMed  Google Scholar 

  67. May-Panloup P, Boucret L, Chao de la Barca J-M, Desquiret-Dumas V, Ferré-L’Hotellier V, Morinière C, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum Reprod Update. 2016;22:725–43.

    Article  CAS  PubMed  Google Scholar 

  68. Perez GI, Trbovich AM, Gosden RG, Tilly JL. Mitochondria and the death of oocytes. Nature. 2000;403:500–1.

    Article  CAS  PubMed  Google Scholar 

  69. Ewald CY. The matrisome during aging and longevity: a systems-level approach toward defining matreotypes promoting healthy aging. Gerontology. 2020;66:266–74.

    Article  CAS  PubMed  Google Scholar 

  70. Woodruff TK, Shea LD. A new hypothesis regarding ovarian follicle development: ovarian rigidity as a regulator of selection and health. J Assist Reprod Genet. 2011;28:3–6.

    Article  PubMed  Google Scholar 

  71. Tingen CM, Kiesewetter SE, Jozefik J, Thomas C, Tagler D, Shea L, et al. A macrophage and theca cell-enriched stromal cell population influences growth and survival of immature murine follicles in vitro. Reproduction. 2011;141:809–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Briley SM, Jasti S, McCracken JM, Hornick JE, Fegley B, Pritchard MT, et al. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction. 2016;152:245–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mara JN, Zhou LT, Larmore M, Johnson B, Ayiku R, Amargant F, et al. Ovulation and ovarian wound healing are impaired with advanced reproductive age. Aging (Albany NY). 2020;12:9686–713.

    Article  CAS  Google Scholar 

  74. Curry TE, Osteen KG. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol Reprod. 2001;64:1285–96.

    Article  CAS  PubMed  Google Scholar 

  75. Amargant F, Manuel SL, Tu Q, Parkes WS, Rivas F, Zhou LT, et al. Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Aging Cell. 2020;19:e13259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ouni E, Bouzin C, Dolmans MM, Marbaix E, Pyrdit Ruys S, Vertommen D, et al. Spatiotemporal changes in mechanical matrisome components of the human ovary from prepuberty to menopause. Hum Reprod. 2020;35:1391–410.

    Article  CAS  PubMed  Google Scholar 

  77. Ouni E, Peaucelle A, Haas KT, Van Kerk O, Dolmans M-M, Tuuri T, et al. A blueprint of the topology and mechanics of the human ovary for next-generation bioengineering and diagnosis. Nat Commun. 2021;12:5603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pennarossa G, De Iorio T, Gandolfi F, Brevini TAL. Impact of aging on the ovarian extracellular matrix and derived 3D scaffolds. Nanomaterials. 2022;12:345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang Z, Schlamp F, Huang L, Clark H, Brayboy L. Inflammaging is associated with shifted macrophage ontogeny and polarization in the aging mouse ovary. Reproduction. 2020;159:325–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Best CL, Pudney J, Welch WR, Burger N, Hill JA. Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause. Hum Reprod. 1996;11:790–7.

    Article  CAS  PubMed  Google Scholar 

  81. Wu R, Van der Hoek KH, Ryan NK, Norman RJ, Robker RL. Macrophage contributions to ovarian function. Hum Reprod Update. 2004;10:119–33.

    Article  PubMed  Google Scholar 

  82. Goh SYP, Henderson NC, Heredia JE, Eagle AR, Odegaard JI, Lehwald N, et al. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc Natl Acad Sci U S A. 2013;110(24):9914–9. https://doi.org/10.1073/pnas.1304046110.

  83. Martínez de Toda I, Ceprián N, Díaz-Del Cerro E, De la Fuente M. The role of immune cells in oxi-inflamm-aging. Cells. 2021;10:2974.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Rowley JE, Amargant F, Zhou LT, Galligos A, Simon LE, Pritchard MT, et al. Low molecular weight hyaluronan induces an inflammatory response in ovarian stromal cells and impairs gamete development in vitro. Int J Mol Sci. 2020;21:1036.

    Article  CAS  PubMed Central  Google Scholar 

  85. McNally AK, Anderson JM. Macrophage fusion and multinucleated giant cells of inflammation. In: Dittmar T, Zänker KS, editors. Cell Fusion in Health and Disease. Dordrecht: Springer, Netherlands; 2011. p. 97–111.

    Chapter  Google Scholar 

  86. Foley KG, Pritchard MT, Duncan FE. Macrophage-derived multinucleated giant cells: hallmarks of the aging ovary. Reproduction. 2021;161:V5-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Uri-Belapolsky S, Shaish A, Eliyahu E, Grossman H, Levi M, Chuderland D, et al. Interleukin-1 deficiency prolongs ovarian lifespan in mice. PNAS. 2014;111:12492–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lliberos C, Liew SH, Zareie P, La Gruta NL, Mansell A, Hutt K. Evaluation of inflammation and follicle depletion during ovarian ageing in mice. Sci Rep. 2021;11:278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Youm Y-H, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 2013;18:519–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Song F, Ma Y, Bai X-Y, Chen X. The expression changes of inflammasomes in the aging rat kidneys. J Gerontol A Biol Sci Med. 2016;71:747–56.

    Article  CAS  Google Scholar 

  91. Liao Z, Liu C, Wang L, Sui C, Zhang H. Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in female reproductive diseases. Front Endocrinol. 2021;12:711.

    Article  Google Scholar 

  92. Igboeli P, El Andaloussi A, Sheikh U, Takala H, ElSharoud A, McHugh A, et al. Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure: two case reports and a review of the literature. J Med Case Rep. 2020;14:108.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Chang Z, Zhu H, Zhou X, Zhang Y, Jiang B, Li S, et al. Mesenchymal stem cells in preclinical infertility cytotherapy: a retrospective review. Stem Cells Int. 2021;2021:e8882368.

    Article  Google Scholar 

  94. Zhao Y, Chen S, Su P, Huang F, Shi Y, Shi Q, et al. Using mesenchymal stem cells to treat female infertility: an update on female reproductive diseases. Stem Cells Int. 2019;2019:e9071720.

    Article  Google Scholar 

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Camaioni, A., Ucci, M.A., Campagnolo, L. et al. The process of ovarian aging: it is not just about oocytes and granulosa cells. J Assist Reprod Genet 39, 783–792 (2022). https://doi.org/10.1007/s10815-022-02478-0

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