Effects of Hyperglycemia and Doxorubicin on Aging Induction Optimization: Focus on the Role of p53 and mTOR in Human Dermal Fibroblast Cells

  • Dimas Adhi Pradita Universitas Padjadjaran, Bandung, Indonesia
  • Achadiyani Universitas Padjadjaran, Bandung, Indonesia
  • Muhammad Hasan Bashari Universitas Padjadjaran, Bandung, Indonesia
Keywords: Hyperglycemia, Doxorubicin, Aging Induction, Optimization, p53, mTOR, Human Dermal Fibroblast Cells.

Abstract

Aging, a kind of physiological process, is influenced by a number of different biological and genetic factors, the driver for all age-related diseases. Aging of the skin can use samples of human fibroblasts (preputium) which are induced with high glucose media and doxorubicin using cell culture methods. Aging is measured using markers at the genetic level, namely p53 and mTOR. The p53 protein is one of the most important markers of apoptosis and the mTOR protein plays an important role in the proliferation, growth, motility, survival, autophagy of cell, including the synthesis of protein. Therefore, the optimization strategy of cell aging is well suited to physiological aging conditions In this review, we explore the optimization of aging in fibroblast cell cultures induced by high-glucose media and doxorubicin and review signs of aging, namely the biomarkers p53 and mTOR. The hope to be able to know aging is close to the original condition so that it becomes an opportunity as well as a challenge for the transition of basic research into developing interventions. Several major electronic databases, including Embase, PubMed, Cochrane, and CINAHL were used to select articles from the period between February 2013 and February 2023. From 5 available literatures, we demonstrated the activity of high-glucose media and doxorubicin as induction of fibroblast senescence. High-glucose media and doxorubicin showed an aging effect by increasing p53 and mTOR markers in fibroblast cell cultures. It is hoped that, with this article on aging optimization, insights into future research directions can be achieved.

References

Abdul Malik, N., Mohamed, M., Mustafa, M. Z., & Zainuddin, A. (2020). In vitro modulation of extracellular matrix genes by stingless bee honey in cellular aging of human dermal fibroblast cells. Journal of Food Biochemistry, 44(1), 1–8. https://doi.org/10.1111/jfbc.13098

Alikhani, M., MacLellan, C. M., Raptis, M., Vora, S., Trackman, P. C., & Graves, D. T. (2007). Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. American Journal of Physiology. Cell Physiology, 292(2). https://doi.org/10.1152/AJPCELL.00356.2006

Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., Yurova, M. N., Antoch, M. P., & Blagosklonny, M. V. (2010). Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice. The American Journal of Pathology, 176(5), 2092. https://doi.org/10.2353/AJPATH.2010.091050

Bartke, A. (2008). Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings. Aging Cell, 7(3), 285–290. https://doi.org/10.1111/J.1474-9726.2008.00387.X

Bergfelt, D. R. (2009). Anatomy and Physiology of the Mare. Equine Breeding Management and Artificial Insemination, 113–131. https://doi.org/10.1016/B978-1-4160-5234-0.00011-8

Berlanga-Acosta, J. A., Guillén-Nieto, G. E., Rodríguez-Rodríguez, N., Mendoza-Mari, Y., Bringas-Vega, M. L., Berlanga-Saez, J. O., García del Barco Herrera, D., Martinez-Jimenez, I., Hernandez-Gutierrez, S., & Valdés-Sosa, P. A. (2020). Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity. Frontiers in Endocrinology, 11(September), 1–18. https://doi.org/10.3389/fendo.2020.573032

Blüher, M., Kahn, B. B., & Kahn, C. R. (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science (New York, N.Y.), 299(5606), 572–574. https://doi.org/10.1126/SCIENCE.1078223

Buranasin, P., Mizutani, K., Iwasaki, K., Na, C. P., Kido, D., Takeda, K., & Izumi, Y. (2018). High Glucose-Induced Oxidative Stress Impairs Proliferation and Migration of Human Gingival Fibroblasts. 25862043, 1–19.

Calautti, E., Li, J., Saoncella, S., Brissette, J. L., & Goetinck, P. F. (2005). Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. The Journal of Biological Chemistry, 280(38), 32856–32865. https://doi.org/10.1074/JBC.M506119200

Conn, C. S., & Qian, S. B. (2011). mTOR Signaling in Protein Homeostasis: Less is more? Cell Cycle, 10(12), 1940. https://doi.org/10.4161/CC.10.12.15858

Cristofalo, V. J., Beck, J., & Allen, R. G. (2003). Commentary and Author ’ s Response to Commentary. America, 58(9), 776–779.

Damasceno, A. (2016). Noncommunicable Disease. In Heart of Africa: Clinical Profile of an Evolving Burden of Heart Disease in Africa. https://doi.org/10.1002/9781119097136.part5

De Boer, J., Andressoo, J. O., De Wit, J., Huijmans, J., Beems, R. B., Van Steeg, H., Weeda, G., Van der Horst, G. T. J., Van Leeuwen, W., Themmen, A. P. N., Meradji, M., & Hoeijmakers, J. H. J. (2002). Premature Aging in Mice Deficient in DNA Repair and Transcription. Science (New York, N.Y.), 296(5571), 1276–1279. https://doi.org/10.1126/SCIENCE.1070174

Dekker, P., Maier, A. B., van Heemst, D., de Koning-Treurniet, C., Blom, J., Dirks, R. W., Tanke, H. J., & Westendorp, R. G. J. (2009). Stress-Induced Responses of Human Skin Fibroblasts in Vitro Reflect Human Longevity. Aging Cell, 8(5), 595–603. https://doi.org/10.1111/J.1474-9726.2009.00506.X

Dick, M. K., Miao, J. H., & Limaiem, F. (2021). Histology, Fibroblast. StatPearls Publishing, Treasure Island (FL).

Ding, X., Bloch, W., Iden, S., Rüegg, M. A., Hall, M. N., Leptin, M., Partridge, L., & Eming, S. A. (2016). mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation. Nature Communications, 7. https://doi.org/10.1038/ncomms13226

Dysfunction, E. C. (2017). HHS Public Access. 118(4), 620–636. https://doi.org/10.1161/CIRCRESAHA.115.306301.Endothelial

Ewald, J. A., Desotelle, J. A., Wilding, G., & Jarrard, D. F. (2010). Therapy-induced senescence in cancer. Journal of the National Cancer Institute, 102(20), 1536–1546. https://doi.org/10.1093/jnci/djq364

Fang, E. F., Scheibye-knudsen, M., Chua, K. F., Mattson, M. P., Croteau, D. L., Bohr, V. A., & Alto, P. (2016). HHS Public Access. 17(5), 308–321. https://doi.org/10.1038/nrm.2016.14.Nuclear

Fernandes, I. R., Russo, F. B., Pignatari, G. C., Evangelinellis, M. M., Tavolari, S., Muotri, A. R., & Beltrão-Braga, P. C. B. (2016). Fibroblast sources: Where can we get them? Cytotechnology, 68(2), 223–228. https://doi.org/10.1007/s10616-014-9771-7

Gritsenko, D. A., Orlova, O. A., Linkova, N. S., & Khavinson, V. K. (2017). Transcription factor p53 and skin aging. Advances in Gerontology, 7(2). https://doi.org/10.1134/S2079057017020072

Guarente, L., & Kenyon, C. (2000). Genetic pathways that regulate ageing in model organisms. Nature, 408(6809), 255–262. https://doi.org/10.1038/35041700

Gunn, D. A., Rexbye, H., Griffiths, C. E. M., Murray, P. G., Fereday, A., Catt, S. D., Tomlin, C. C., Strongitharm, B. H., Perrett, D. I., Catt, M., Mayes, A. E., Messenger, A. G., Green, M. R., van der Ouderaa, F., Vaupel, J. W., & Christensen, K. (2009). Why Some Women Look Young for Their Age. PLoS ONE, 4(12). https://doi.org/10.1371/JOURNAL.PONE.0008021

Hartono, B. (2017). Jual Beli Tanah Wakaf Pemakaman dalam Pandangan Hukum Islam (Studi di Pekon Pajajaran Kecamatan Kotaagung Barat KabupatenTanggamus). UIN Raden Intan Lampung.

Huang, S. (2020). mTOR Signaling in Metabolism and Cancer. Cells, 9(10). https://doi.org/10.3390/CELLS9102278

Hudu, S. A., Alshrari, A. S., Syahida, A., & Sekawi, Z. (2016). Cell culture, technology: Enhancing the culture of diagnosing human diseases. Journal of Clinical and Diagnostic Research, 10(3), DE01–DE05. https://doi.org/10.7860/JCDR/2016/15837.7460

Jäger, K., Mensch, J., Grimmig, M. E., Neuner, B., Gorzelniak, K., Türkmen, S., Demuth, I., Hartmann, A., Hartmann, C., & Wittig, F. (2022). A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts.

Jain, S., Patel, N., Shah, M. K., Khatri, P., & Vora, N. (2017). Recent Advances in Lipid-Based Vesicles and Particulate Carriers for Topical and Transdermal Application. Journal of Pharmaceutical Sciences, 106(2), 423–445. https://doi.org/10.1016/j.xphs.2016.10.001

Kim, S. J., Chun, M., Wan, J., Lee, C., Yen, K., & Cohen, P. (2019). GRSF1 is an age-related regulator of senescence. Scientific Reports, 9(1), 1–9. https://doi.org/10.1038/s41598-019-42064-6

Kurniawati, Y., Adi, S., Achadiyani, A., Suwarsa, O., Erlangga, D., & Putri, T. (2015). Kultur Primer Fibroblas: Penelitian Pendahuluan. Majalah Kedokteran Andalas, 38(1), 33. https://doi.org/10.22338/mka.v38.i1.p33-40.2015

Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274. https://doi.org/10.1016/J.CELL.2012.03.017

Lee, K. H., Ng, Y. P., Cheah, P. S., Lim, C. K., & Toh, M. S. (2017). Molecular characterization of glycation-associated skin ageing: an alternative skin model to study in vitro antiglycation activity of topical cosmeceutical and pharmaceutical formulations. The British Journal of Dermatology, 176(1), 159–167. https://doi.org/10.1111/BJD.14832

Lephart, E. D. (2018). A review of the role of estrogen in dermal aging and facial attractiveness in women. Journal of Cosmetic Dermatology, 17(3), 282–288. https://doi.org/10.1111/JOCD.12508

Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A., Thorner, M., & Scrable, H. (2004). Modulation of mammalian life span by the short isoform of p53. Genes & Development, 18(3), 306. https://doi.org/10.1101/GAD.1162404

McAuley, M. T., Guimera, A. M., Hodgson, D., McDonald, N., Mooney, K. M., Morgan, A. E., & Proctor, C. J. (2017). Modelling the molecular mechanisms of aging. Bioscience Reports, 37(1), 1–20. https://doi.org/10.1042/BSR20160177

Mice, C., Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V, Tyndyk, M. L., Yurova, M. N., & Antoch, M. P. (2010). Short Communication. 176(5), 2092–2097. https://doi.org/10.2353/ajpath.2010.091050

Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., & Giordano, A. (2020). Role of p53 in the regulation of cellular senescence. Biomolecules, 10(3), 1–16. https://doi.org/10.3390/biom10030420

Muntafiah, L., Shabrina, B. A., Sulistyowati, D., Novi, M. R., & Jenie, R. I. (2016). Anti-Aging Activity of Cucurbita moschata Ethanolic Extract Towards NIH3T3 Fibroblast Cells Induced by Doxorubicin. June, 49–53.

Noordam, R., Gunn, D. A., Tomlin, C. C., Maier, A. B., Mooijaart, S. P., Slagboom, P. E., Westendorp, R. G. J., De Craen, A. J. M., & Van Heemst, D. (2013). High serum glucose levels are associated with a higher perceived age. Age, 35(1). https://doi.org/10.1007/s11357-011-9339-9

Nosrati, F., Grillari, J., Azarnia, M., & Nabiuni, M. (2023). The expression of fibrosis ‑ related genes is elevated in doxorubicin ‑ induced senescent human dermal fibroblasts , but their secretome does not trigger a paracrine fibrotic response in non ‑ senescent cells. Biogerontology, 24(2), 293–301. https://doi.org/10.1007/s10522-022-10013-y

Otero, M., Favero, M., Dragomir, C., Hachem, K. El, Hashimoto, K., Plumb, D. A., & Goldring, M. B. (2012). Human Cell Culture Protocols. 806, 301–336. https://doi.org/10.1007/978-1-61779-367-7

Pageon, H., Zucchi, H., Rousset, F., Monnier, V. M., & Asselineau, D. (2014). Skin aging by glycation: lessons from the reconstructed skin model. Clinical Chemistry and Laboratory Medicine, 52(1), 169–174. https://doi.org/10.1515/CCLM-2013-0091

Pérard-viret, J., Quteishat, L., & Alsalim, R. (2020). Cell Culutre: Growing Cells as Model Systems In Vitro. January, 94–95.

Sadowska-Bartosz, I., & Bartosz, G. (2020). Effect of Antioxidants on the Fibroblast Replicative Lifespan in Vitro. Oxidative Medicine and Cellular Longevity, 2020(Phase III). https://doi.org/10.1155/2020/6423783

Soydas, T., Sayitoglu, M., Sarac, E. Y., Cınar, S., Solakoglu, S., Tiryaki, T., & Sultuybek, G. K. (2021). Metformin reverses the effects of high glucose on human dermal fibroblasts of aged skin via downregulating RELA/p65 expression. Journal of Physiology and Biochemistry, 77(3), 443–450. https://doi.org/10.1007/s13105-021-00823-y

Tobin, D. J. (2017). Introduction to skin aging. Journal of Tissue Viability. https://doi.org/10.1016/j.jtv.2016.03.002

Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., Sang, H. P., Thompson, T., Karsenty, G., Bradley, A., & Donehower, L. A. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature, 415(6867), 45–53. https://doi.org/10.1038/415045A

Weinmüllner, R., Zbiral, B., Becirovic, A., Stelzer, E. M., Nagelreiter, F., Schosserer, M., Lämmermann, I., Liendl, L., Lang, M., Terlecki-Zaniewicz, L., Andriotis, O., Mildner, M., Golabi, B., Waidhofer-Söllner, P., Schedle, K., Emsenhuber, G., Thurner, P. J., Tschachler, E., Gruber, F., & Grillari, J. (2020). Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging. Npj Aging and Mechanisms of Disease, 6(1). https://doi.org/10.1038/s41514-020-0042-x

Xu, S., Cai, Y., & Wei, Y. (2014). mTOR signaling from cellular senescence to organismal aging. Aging and Disease, 5(4), 263–273. https://doi.org/10.14336/AD.2014.0500263

Xu, X., Zheng, Y., Huang, Y., Chen, J., Gong, Z., Li, Y., Lu, C., Lai, W., & Xu, Q. (2018). Cathepsin D contributes to the accumulation of advanced glycation end products during photoaging. Journal of Dermatological Science, 90(3), 263–275. https://doi.org/10.1016/J.JDERMSCI.2018.02.009

Yokota, M., Masaki, H., Okano, Y., & Tokudome, Y. (2017). Effect of glycation focusing on the process of epidermal lipid synthesis in a reconstructed skin model and membrane fluidity of stratum corneum lipids. Dermato-Endocrinology, 9(1). https://doi.org/10.1080/19381980.2017.1338992

Zhao, D., Yang, J., & Yang, L. (2017). Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes. Oxidative Medicine and Cellular Longevity, 2017. https://doi.org/10.1155/2017/6437467

Published
2023-10-04
How to Cite
Pradita, D. A., Achadiyani, & Bashari, M. H. (2023). Effects of Hyperglycemia and Doxorubicin on Aging Induction Optimization: Focus on the Role of p53 and mTOR in Human Dermal Fibroblast Cells. International Journal of Science and Society, 5(4), 665-681. https://doi.org/10.54783/ijsoc.v5i4.834