Skip to main content

Advertisement

Log in

Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Our previous studies found that deletion of nuclear receptor interacting protein 1 (Nrip1) extended longevity in female mice and delayed cell senescence. The current study investigates the role of NRIP1 in regulating functions of adipose-derived mesenchymal stem cells (ADMSCs) and explores the mechanisms of NRIP1 in skin aging. We first verified the skin aging phenotypes in young (6 months) and old (20 months) C57BL/6J (B6) mice and found deletion of Nrip1 can delay skin aging phenotypes, including reduced thickness of dermis and subcutaneous white adipose tissue (sWAT), as well as the accumulation of senescent cells in sWAT. In ADMSCs isolated from sWAT, we found that deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis. Interestingly, deletion of Nrip1 also reduced cell senescence and maintain cell quiescence of ADMSCs. Moreover, the expressions of genes associated with senescence (p21, and p53), inflammation (p65, IL6, and IL1a), and growth factor (mTOR, Igf1) were reduced in Nrip1 knockout ADMSCs, as well as in siNrip1-treated ADMSCs. Suppression of Nrip1 by siNrip1 also decreased the expressions of mTOR, p-mTOR, p65, and p-p65 in ADMSCs. Reduced expressions of p65 and p-p65 were also confirmed in the skin of Nrip1 knockout mice. These findings suggest that NRIP1 plays an important role in delaying skin aging by reducing ADMSCs senescence and maintaining ADMSCs quiescence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Al-Mohanna MA, Manogaran PS, Al-Mukhalafi Z, Al-Hussein KA, Aboussekhra A. The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Oncogene. 2004;23:201–12. https://doi.org/10.1038/sj.onc.1206927.

    Article  CAS  PubMed  Google Scholar 

  2. Augereau P, Badia E, Carascossa S, Castet A, Fritsch S, Harmand PO, et al. The nuclear receptor transcriptional coregulator RIP140. Nucl Recept Signal. 2006;4:e024. https://doi.org/10.1621/nrs.04024.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Aziz MH, Chen X, Zhang Q, DeFrain C, Osland J, Luo Y, et al. Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo. Oncotarget. 2015;6:39714–24. https://doi.org/10.18632/oncotarget.5356.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Biggar KK, Storey KB. Perspectives in cell cycle regulation: lessons from an anoxic vertebrate. Curr Genomics. 2009;10:573–84. https://doi.org/10.2174/138920209789503905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cho IJ, Lui PP, Obajdin J, Riccio F, Stroukov W, Willis TL, et al. Mechanisms, Hallmarks, and Implications of Stem Cell Quiescence. Stem Cell Rep. 2019;12:1190–200. https://doi.org/10.1016/j.stemcr.2019.05.012.

    Article  CAS  Google Scholar 

  6. Fafian-Labora JA, Morente-Lopez M, Arufe MC. Effect of aging on behaviour of mesenchymal stem cells. World J Stem Cells. 2019;11:337–46. https://doi.org/10.4252/wjsc.v11.i6.337.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Flurkey K, Yuan R. How the evolutionary theory of aging can guide us in the search for aging genes. Aging (Albany NY). 2012;4:318–9. https://doi.org/10.18632/aging.100460.

    Article  Google Scholar 

  8. Gan B, DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle. 2009;8:1003–6. https://doi.org/10.4161/cc.8.7.8045.

    Article  CAS  PubMed  Google Scholar 

  9. Gaur M, Dobke M, Lunyak VV. Mesenchymal Stem Cells from Adipose Tissue in Clinical Applications for Dermatological Indications and Skin Aging. Int J Mol Sci. 2017;18. https://doi.org/10.3390/ijms18010208.

  10. Ghosh S, Thakur MK. Tissue-specific expression of receptor-interacting protein in aging mouse. Age (Dordr). 2008;30:237–43. https://doi.org/10.1007/s11357-008-9062-3.

    Article  CAS  Google Scholar 

  11. Haller S, Kapuria S, Riley RR, O’Leary MN, Schreiber KH, Andersen JK, et al. mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance. Cell Stem Cell. 2017;21:806–18 e805. https://doi.org/10.1016/j.stem.2017.11.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Harkema L, Youssef SA, de Bruin A. Pathology of Mouse Models of Accelerated Aging. Vet Pathol. 2016;53:366–89. https://doi.org/10.1177/0300985815625169.

    Article  CAS  PubMed  Google Scholar 

  13. Haustead DJ, Stevenson A, Saxena V, Marriage F, Firth M, Silla R, et al. Transcriptome analysis of human ageing in male skin shows mid-life period of variability and central role of NF-kappaB. Sci Rep. 2016;6:26846. https://doi.org/10.1038/srep26846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018;128:1238–46. https://doi.org/10.1172/JCI95148.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hu Y, Zhu Y, Lian N, Chen M, Bartke A, Yuan R. Metabolic Syndrome and Skin Diseases. Front Endocrinol (Lausanne). 2019;10. https://doi.org/10.3389/fendo.2019.00788.

  16. Izzard TD, Taylor C, Birkett SD, Jackson CL, Newby AC. Mechanisms underlying maintenance of smooth muscle cell quiescence in rat aorta: role of the cyclin dependent kinases and their inhibitors. Cardiovasc Res. 2002;53:242–52. https://doi.org/10.1016/S0008-6363(01)00444-8.

    Article  CAS  PubMed  Google Scholar 

  17. Jain AK, Allton K, Iacovino M, Mahen E, Milczarek RJ, Zwaka TP, et al. p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells. PLoS Biol. 2012;10:e1001268. https://doi.org/10.1371/journal.pbio.1001268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khavkin J, Ellis DA. Aging skin: histology, physiology, and pathology. Facial Plast Surg Clin North Am. 2011;19:229–34. https://doi.org/10.1016/j.fsc.2011.04.003.

    Article  PubMed  Google Scholar 

  19. Kim J-H, Jung M, Kim H-S, Kim Y-M, Choi E-H. Adipose-derived stem cells as a new therapeutic modality for ageing skin. 2011;20:383–7. https://doi.org/10.1111/j.1600-0625.2010.01221.x.

  20. Kohl E, Steinbauer J, Landthaler M, Szeimies RM. Skin ageing. J Eur Acad Dermatol Venereol. 2011;25:873–84. https://doi.org/10.1111/j.1468-3083.2010.03963.x.

    Article  CAS  PubMed  Google Scholar 

  21. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24:2463–79. https://doi.org/10.1101/gad.1971610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li L, Bhatia R. Stem cell quiescence. Clin Cancer Res. 2011;17:4936–41. https://doi.org/10.1158/1078-0432.CCR-10-1499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu JY, Souroullas GP, Diekman BO, Krishnamurthy J, Hall BM, Sorrentino JA, et al. Cells exhibiting strong p16 (INK4a) promoter activation in vivo display features of senescence. Proc Natl Acad Sci U S A. 2019;116:2603–11. https://doi.org/10.1073/pnas.1818313116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017;2. https://doi.org/10.1038/sigtrans.2017.23.

  25. Lopez-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008;43:813–9. https://doi.org/10.1016/j.exger.2008.06.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luan C, Chen X, Hu Y, Hao Z, Osland JM, Chen X, et al. Overexpression and potential roles of NRIP1 in psoriasis. Oncotarget. 2016;7:74236–46. https://doi.org/10.18632/oncotarget.12371.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Maimets T, Neganova I, Armstrong L, Lako M. Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells. Oncogene. 2008;27:5277–87. https://doi.org/10.1038/onc.2008.166.

    Article  CAS  PubMed  Google Scholar 

  28. Micheli L, D’Andrea G, Ceccarelli M, Ferri A, Scardigli R, Tirone F. p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise. Front Cell Neurosci. 2019;13:10. https://doi.org/10.3389/fncel.2019.00010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pavlidou T, Marinkovic M, Rosina M, Fuoco C, Vumbaca S, Gargioli C, et al. Metformin Delays Satellite Cell Activation and Maintains Quiescence. Stem Cells Int. 2019;2019:5980465–19. https://doi.org/10.1155/2019/5980465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130:1715–25. https://doi.org/10.1002/ijc.27316.

    Article  CAS  PubMed  Google Scholar 

  31. Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature. 2014;510:393–6. https://doi.org/10.1038/nature13255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013;32:5129–43. https://doi.org/10.1038/onc.2012.640.

    Article  CAS  PubMed  Google Scholar 

  33. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014;28:99–114. https://doi.org/10.1101/gad.235184.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Salminen A, Kaarniranta K. Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal. 2010;22:573–7. https://doi.org/10.1016/j.cellsig.2009.10.006.

    Article  CAS  PubMed  Google Scholar 

  35. Schosserer M, Grillari J, Wolfrum C, Scheideler M. Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review. Gerontology. 2018;64:229–36. https://doi.org/10.1159/000485183.

    Article  CAS  PubMed  Google Scholar 

  36. Starr ME, Saito M, Evers BM, Saito H. Age-Associated Increase in Cytokine Production During Systemic Inflammation-II: The Role of IL-1beta in Age-Dependent IL-6 Upregulation in Adipose Tissue. J Gerontol A Biol Sci Med Sci. 2015;70:1508–15. https://doi.org/10.1093/gerona/glu197.

    Article  CAS  PubMed  Google Scholar 

  37. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-kappaB in Aging and Disease. Aging Dis. 2011;2:449–65.

    PubMed  PubMed Central  Google Scholar 

  38. van Velthoven CTJ, Rando TA. Stem Cell Quiescence: Dynamism, Restraint, and Cellular Idling. Cell Stem Cell. 2019;24:213–25. https://doi.org/10.1016/j.stem.2019.01.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang AS, Dreesen O. Biomarkers of Cellular Senescence and Skin Aging. Front Genet. 2018;9:247. https://doi.org/10.3389/fgene.2018.00247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang J, Chen X, Osland J, Gerber SJ, Luan C, Delfino K, et al. Deletion of Nrip1 Extends Female Mice Longevity, Increases Autophagy, and Delays Cell Senescence. J Gerontol A Biol Sci Med Sci. 2018;73:882–92. https://doi.org/10.1093/gerona/glx257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wollina U, Wetzker R, Abdel-Naser MB, Kruglikov IL. Role of adipose tissue in facial aging. Clin Interv Aging. 2017;12:2069–76. https://doi.org/10.2147/CIA.S151599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yao G. Modelling mammalian cellular quiescence. Interface Focus. 2014;4:20130074. https://doi.org/10.1098/rsfs.2013.0074.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zouboulis CC, Makrantonaki E. Clinical aspects and molecular diagnostics of skin aging. Clin Dermatol. 2011;29:3–14. https://doi.org/10.1016/j.clindermatol.2010.07.001.

    Article  PubMed  Google Scholar 

  44. Zschiedrich I, Hardeland U, Krones-Herzig A, Berriel Diaz M, Vegiopoulos A, Muggenburg J, et al. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood. 2008;112:264–76. https://doi.org/10.1182/blood-2007-11-121699.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Lisa Hensley kindly edited the manuscript. Division of Laboratory Animal Medicine of Southern Illinois University School of Medicine provides excellent environment for animal research.

Funding

The work is funded by U.S. NIH grant AG046432, internal research seed grants of Southern Illinois University School of Medicine, team science grant of simmons cancer institute at Southern Illinois University School of Medicine, CAMS Innovation Fund for Medical Sciences (CIFMS-2017-I2M-1-017), and China Scholarship Council (No. 201806210434).

Author information

Authors and Affiliations

Authors

Contributions

RY conceived and designed the project; YH, YZ, SDG, and JMO performed the experiments; RY, YH, YZ, and SDG analyzed experimental results; YH and RY wrote the manuscript with approval from all authors; RY, HG, and MC revised the manuscript.

Corresponding authors

Correspondence to Heng Gu or Rong Yuan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Y., Zhu, Y., Gerber, S.D. et al. Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence. GeroScience 43, 1815–1833 (2021). https://doi.org/10.1007/s11357-021-00344-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-021-00344-y

Keywords

Navigation