Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

  • Huifen Lu 1,3 ,
  • Ying Jing 1,3 ,
  • Chen Zhang 10 ,
  • Shuai Ma 4,6,8,17,18 ,
  • Weiqi Zhang 5,7,8,9,11,12,18 ,
  • Daoyuan Huang 1,3 ,
  • Bin Zhang 4,5,17 ,
  • Yuesheng Zuo 5,7,9 ,
  • Yingying Qin 15,16 ,
  • Guang-Hui Liu , 1,3,4,5,6,8,17,18 ,
  • Yang Yu , 13,14 ,
  • Jing Qu , 2,5,6,8,17,18 ,
  • Si Wang , 1,3,10,18
Expand
  • 1. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
  • 2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 3. Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
  • 4. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 5. University of Chinese Academy of Sciences, Beijing 100049, China
  • 6. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
  • 7. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
  • 8. Institute for Stem cell and Regeneration, CAS, Beijing 100101, China
  • 9. China National Center for Bioinformation, Beijing 100101, China
  • 10. The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
  • 11. Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China
  • 12. Sino-Danish Center for Education and Research, Beijing 101408, China
  • 13. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University, Third Hospital, Beijing 100191, China
  • 14. Clinical Stem Cell Research Center, Peking University, Third Hospital, Beijing 100191, China
  • 15. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
  • 16. Key Laboratory of Reproductive Endocrinology of Ministry of Education, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, China
  • 17. Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 18. Aging Biomarker Consortium, Beijing 100101, China
ghliu@ioz.ac.cn
yuyang5012@hotmail.com
qujing@ioz.ac.cn
wangsi@xwh.ccmu.edu.cn

Received date: 04 Oct 2023

Accepted date: 29 Oct 2023

Published date: 15 May 2024

Copyright

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent-associated secretory phenotype, senescence, and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

Cite this article

Huifen Lu , Ying Jing , Chen Zhang , Shuai Ma , Weiqi Zhang , Daoyuan Huang , Bin Zhang , Yuesheng Zuo , Yingying Qin , Guang-Hui Liu , Yang Yu , Jing Qu , Si Wang . Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics[J]. Protein & Cell, 2024 , 15(5) : 364 -384 . DOI: 10.1093/procel/pwad063

1
Adashi EY. Endocrinology of the ovary. Hum Reprod 1994; 9:815–27.

DOI

2
Aging Atlas C. Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 2021; 49:D825–30.

DOI

3
Aging Biomarker C, Bao H, Cao J et al. Biomarkers of aging. Sci China Life Sci 2023; 66:893–1066.

DOI

4
Ahmed TA, Ahmed SM, El-Gammal Z et al. Oocyte aging: the role of cellular and environmental factors and impact on female fertility. Adv Exp Med Biol 2020; 1247:109–23.

DOI

5
Amargant F, Manuel SL, Tu Q et al. Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Aging Cell 2020; 19:e13259.

DOI

6
Ata B, Seyhan A, Seli E. Diminished ovarian reserve versus ovarian aging: overlaps and differences. Curr Opin Obstet Gynecol 2019; 31:139–47.

DOI

7
Auersperg N, Wong AS, Choi KC et al. Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 2001; 22:255–88.

DOI

8
Bai H, Mu L, Qiu L et al. Complement C3 regulates inflammatory response and monocyte/macrophage phagocytosis of Streptococcus agalactiae in a teleost fish. Int J Mol Sci 2022; 23:15586.

DOI

9
Ben Yaakov T, Wasserman T, Aknin E et al. Single-cell analysis of the aged ovarian immune system reveals a shift towards adaptive immunity and attenuated cell function. Elife 2023; 12:e74915.

DOI

10
Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev 2020; 34:1565–76.

DOI

11
Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009; 30:465–93.

DOI

12
Brown HM, Russell DL. Blood and lymphatic vasculature in the ovary: development, function and disease. Hum Reprod Update 2014; 20:29–39.

DOI

13
Burris-Hiday SD, Scott EE. Steroidogenic cytochrome P450 17A1 structure and function. Mol Cell Endocrinol 2021; 528:111261.

DOI

14
Cai Y, Song W, Li J et al. The landscape of aging. Sci China Life Sci 2022; 65:2354–454.

DOI

15
Castrillon DH, Quade BJ, Wang TY et al. The human VASA gene is specifically expressed in the germ cell lineage. Proc Natl Acad Sci U S A 2000; 97:9585–90.

DOI

16
Cheng C, Liu ZG. Autophagy and the metabolism of misfolding protein. Adv Exp Med Biol 2019; 1206:375–420.

DOI

17
Cheng S, Li Z, Gao R et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 2021; 184:792–809e23.

DOI

18
Debacq-Chainiaux F, Erusalimsky JD, Campisi J et al. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 2009; 4:1798–806.

DOI

19
Dries R, Zhu Q, Dong R et al. Giotto: a toolbox for integrative analysis and visualization of spatial expression data. Genome Biol 2021; 22:78.

DOI

20
Duffy DM, Ko C, Jo M et al. Ovulation: parallels with inflammatory processes. Endocr Rev 2019; 40:369–416.

DOI

21
Efremova M, Vento-Tormo M, Teichmann SA et al. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc 2020; 15:1484–506.

DOI

22
Fan X, Chuva de Sousa Lopes SM. Molecular makeup of the human adult ovary. Curr Opin Endocr Metab Res 2021; 18:187–93.

DOI

23
He S, Wang LH, Liu Y et al. Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs. Genome Biol 2020a; 21:294.

DOI

24
He X, Memczak S, Qu J et al. Single-cell omics in ageing: a young and growing field. Nat Metab 2020b; 2:293–302.

DOI

25
Huang D, Zuo Y, Zhang C et al. A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis. Protein Cell 2022; 14:887-907.

DOI

26
Husain MA, Laurent B, Plourde M. APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics. Front Neurosci 2021; 15:630502.

DOI

27
Isola JVV, Ocañas SR, Hubbart CR et al. A single-cell atlas of the aging murine ovary. bioRxiv 2023.

DOI

28
Jia L, Wang W, Liang J et al. Analyzing the cellular and molecular atlas of ovarian mesenchymal cells provides a strategy against female reproductive aging. Sci China Life Sci 2023; 66:2818–2836.

DOI

29
Jing Y, Zuo Y, Yu Y et al. Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging. Protein Cell 2023; 14:497–512.

DOI

30
Kanehisa M, Furumichi M, Sato Y et al. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res 2021; 49:D545–51.

DOI

31
Komatsu K, Masubuchi S. Observation of the dynamics of follicular development in the ovary. Reprod Med Biol 2017; 16:21–7.

DOI

32
Lehallier B, Gate D, Schaum N et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med 2019; 25:1843–50.

DOI

33
Leng SX, Pawelec G. Single-cell immune atlas for human aging and frailty. Life Med 2022; 1:67–70.

DOI

34
Lengyel E, Li Y, Weigert M et al. A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing. Cell Rep 2022; 41:111838.

DOI

35
Li J, Zheng Y, Yan P et al. A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev 2021; 8:nwaa127.

DOI

36
Liberzon A, Birger C, Thorvaldsdóttir H et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015; 1:417–25.

DOI

37
Lin SN, Musso A, Wang J et al. Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells—a novel mechanism for maintenance of intestinal inflammation. Matrix Biol 2022; 113:1–21.

DOI

38
Liu J, Sun D, Liu J et al. FibroAtlas: a database for the exploration of fibrotic diseases and their genes. Cardiol Res Pract 2019; 2019:4237285.

DOI

39
López-Otín C, Blasco MA, Partridge L et al. Hallmarks of aging: an expanding universe. Cell 2023; 186:243–78.

DOI

40
Lovell TM, Gladwell RT, Groome NP et al. Ovarian follicle development in the laying hen is accompanied by divergent changes in inhibin A, inhibin B, activin A and follistatin production in granulosa and theca layers. J Endocrinol 2003; 177:45–55.

DOI

41
Ma S, Sun S, Geng L et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus Norvegicus aging. Cell 2020; 180:984–1001.e22.

DOI

42
Ma S, Sun S, Li J et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 2021; 31:415–32.

DOI

43
Ma S, Chi X, Cai Y et al. Decoding aging hallmarks at the single- cell level. Annu Rev Biomed Data Sci 2023; 6:129–52.

DOI

44
Machlin JH, Shikanov A. Single-cell RNA-sequencing of retrieved human oocytes and eggs in clinical practice and for human ovarian cell atlasing. Mol Reprod Dev 2022; 89:597–607.

DOI

45
Mara JN, Zhou LT, Larmore M et al. Ovulation and ovarian wound healing are impaired with advanced reproductive age. Aging (Albany NY) 2020; 12:9686–713.

DOI

46
Mishina T, Tabata N, Hayashi T et al. Single-oocyte transcriptome analysis reveals aging-associated effects influenced by life stage and calorie restriction. Aging Cell 2021; 20:e13428.

DOI

47
Pal L, Santoro N. Premature ovarian failure (POF): discordance between somatic and reproductive aging. Ageing Res Rev 2002; 1:413–23.

DOI

48
Perry JR, Murray A, Day FR et al. Molecular insights into the aetiology of female reproductive ageing. Nat Rev Endocrinol 2015; 11:725–34.

DOI

49
Petrosino JM, Disilvestro D, Ziouzenkova O. Aldehyde dehydrogenase 1A1: friend or foe to female metabolism? Nutrients 2014; 6:950–73.

DOI

50
Read A, Schröder M. The unfolded protein response: an overview. Biology (Basel) 2021; 10:384.

DOI

51
Rouillard AD, Gundersen GW, Fernandez NF et al. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford) 2016; 2016:baw100.

DOI

52
Sasano H, Suzuki T. Localization of steroidogenesis and steroid receptors in human corpus luteum classification of human corpus luteum (CL) into estrogen-producing degenerating CL, and nonsteroid-producing degenerating CL. Semin Reprod Endocrinol 1997; 15:345–51.

DOI

53
Shi Y, Guo Y, Zhou J et al. A spatiotemporal gene expression and cell atlases of the developing rat ovary. Cell Prolif 2023; 56:e13516.

DOI

54
Sun Y, Li Q, Kirkland JL. Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging. Life Med 2022; 1:103–19.

DOI

55
Sun G, Zheng Y, Fu X et al. Single-cell transcriptomic atlas of mouse cochlear aging. Protein Cell 2023; 14:180–201.

DOI

56
Tang F, Barbacioru C, Wang Y et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 2009; 6:377–82.

DOI

57
Tew WP. Ovarian cancer in the older woman. J Geriatr Oncol 2016; 7:354–61.

DOI

58
Trapnell C, Cacchiarelli D, Grimsby J et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 2014; 32:381–6.

DOI

59
Vollenhoven B, Hunt S. Ovarian ageing and the impact on female fertility. F1000Res 2018; 7:F1000 Faculty Rev-1835.

DOI

60
Wagner M, Yoshihara M, Douagi I et al. Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nat Commun 2020; 11:1147.

DOI

61
Wang S, Hu B, Ding Z et al. ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discov 2018; 4:2.

DOI

62
Wang S, Zheng Y, Li J et al. Single-cell transcriptomic atlas of primate ovarian aging. Cell 2020; 180:585–600 e519.

DOI

63
Wang S, Cheng F, Ji Q et al. Hyperthermia differentially affects specific human stem cells and their differentiated derivatives. Protein Cell 2022; 13:615–22.

DOI

64
Wei Y, Yu R, Cheng S et al. Single-cell profiling of mouse and primate ovaries identifies high levels of EGFR for stromal cells in ovarian aging. Mol Ther Nucleic Acids 2023; 31:1–12.

DOI

65
Woad KJ, Robinson RS. Luteal angiogenesis and its control. Theriogenology 2016; 86:221–8.

DOI

66
Wu T, Hu E, Xu S et al. clusterProfiler 40: a universal enrichment tool for interpreting omics data. Innovation (Camb) 2021; 2:100141.

DOI

67
Wu J, Liu Y, Song Y et al. Aging conundrum: a perspective for ovarian aging. Front Endocrinol (Lausanne) 2022; 13:952471.

DOI

68
Yuan L, Yin P, Yan H et al. Single-cell transcriptome analysis of human oocyte ageing. J Cell Mol Med 2021; 25:6289–303.

DOI

69
Zhang W, Zhang S, Yan P et al. A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 2020; 11:2202.

DOI

70
Zhang B, Yan H, Liu X et al. SenoIndex: S100A8/S100A9 as a novel aging biomarker. Life Med 2023; 2:lnad022.

DOI

71
Zhao H, Ji Q, Wu Z et al. Destabilizing heterochromatin by APOE mediates senescence. Nat Aging 2022; 2:303–16.

DOI

72
Zhou Y, Zhou B, Pache L et al. Metascape provides a biologist- oriented resource for the analysis of systemslevel datasets. Nat Commun 2019; 10:1523.

DOI

73
Zhou T, Kiran M, Lui KO et al. Decoding liver fibrogenesis with single-cell technologies. Life Med 2022; 1:333–44.

DOI

74
Zhu Z, Xu W, Liu L. Ovarian aging: mechanisms and intervention strategies. Med Rev (Berlin, Germany) 2022; 2:590–610.

DOI

Outlines

/