Effect and mechanism of Chinese medicine on inhibiting the senescence of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are pluripotent stem cells isolated from human tissues. Due to their strong self-renewal capacity, pluripotency, and immunomodulatory properties, MSCs have garnered significant attention in cell therapy and tissue regeneration. However, cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation, making it crucial to develop interventions that delay or reverse the senescence process. From a traditional Chinese medicine perspective, senescence stems from spleen and stomach deficiency, kidney deficiency, and related factors; thus, medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy. Chinese medicine, characterized by low toxicity and multi-target, multi-functional properties, has become prominent in anti-senescence research. This paper examines the MSC senescence process by discussing its causes, characteristics, and mechanisms, then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence, facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.

Keywords

Mesenchymal stem cells / Inhibiting / Senescence / Chinese medicine / Natural compounds

References

[1] Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the Crypt. Development. 1990; 110(4):1001-1020. https://doi.org/10.1242/dev.110.4.1001.

[2] Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991; 9(5):641-650. https://doi.org/10.1002/jor.1100090504.

[3] Short B, Brouard N, Occhiodoro-Scott T, et al. Mesenchymal stem cells. Arch Med Res. 2003; 34(6):565-571. https://doi.org/10.1016/j.arcmed.2003.09.007.

[4] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy Position Statement. Cytotherapy. 2006; 8(4):315-317. https://doi.org/10.1080/14653240600855905.

[5] Prager P, Kunz M, Ebert R, et al. Mesenchymal stem cells isolated from the anterior cruciate ligament: characterization and comparison of cells from young and old donors. Knee Surg Relat Res. 2018; 30(3):193-205. https://doi.org/10.5792/ksrr.17.067.

[6] Beane OS, Fonseca VC, Cooper LL, et al. Impact of aging on the regenerative properties of bone marrow, muscle, and adipose-derived mesenchymal stem/stromal cells. PLoS One. 2014; 9(12):e115963. https://doi.org/10.1371/journal.pone.0115963.

[7] Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006; 7(1):14. https://doi.org/10.1186/1471-2121-7-14.

[8] Fossett E, Khan WS. Optimising human mesenchymal stem cell numbers for clinical application: a literature review. Stem Cells Int. 2012;2012:465259. https://doi.org/10.1155/2012/465259.

[9] Wang Y, Han ZB, Song YP, et al. Safety of mesenchymal stem cells for clinical application. Stem Cells Int. 2012;2012:652034. https://doi.org/10.1155/2012/652034.

[10] Zhou T, Yuan Z, Weng J, et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021; 14(1):24. https://doi.org/10.1186/s13045-021-01037-x.

[11] Li SH, Guo PD, Wang WJ. Research progress of bone marrow mesenchymal stem cells differentiation into nerve-like cells induced by traditional Chinese medicine. Chin J Orthop Traumatol. 2010; 23(3):233-235. https://doi.org/10.3969/j.issn.1003-0034.2010.03.029.

[12] Chen M, Feng W, Cao H, et al. A traditional Chinese medicine formula extracts stimulate proliferation and inhibit mineralization of human mesenchymal stem cells in vitro. J Ethnopharmacol. 2009; 125(1):75-82. https://doi.org/10.1016/j.jep.2009.06.013.

[13] Dong S, Su SB. Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis. J Integr Med. 2014; 12(3):147-155. https://doi.org/10.1016/S2095-4964(14)60022-4.

[14] Sun S, Liu F, Fan F, et al. Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets. Heliyon. 2023; 9(11):e22005. https://doi.org/10.1016/j.heliyon.2023.e22005.

[15] Fu Y, Kong Y, Li J, et al. Mesenchymal stem cells combined with traditional Chinese medicine (Qi-Fang-Bi-Min-Tang) alleviates rodent allergic rhinitis. J Cell Biochem. 2020; 121(2):1541-1551. https://doi.org/10.1002/jcb.29389.

[16] He H, Yang T, Li F, et al. A novel study on the immunomodulatory effect of umbilical cord derived mesenchymal stem cells pretreated with traditional Chinese medicine asarinin. Int Immunopharmacol. 2021;100:108054. https://doi.org/10.1016/j.intimp.2021.108054.

[17] Zhao H, Luo Y. Traditional Chinese medicine and aging intervention. Aging Dis. 2017; 8(6):688-690. https://doi.org/10.14336/AD.2017.1002.

[18] Su J, Su Q, Hu S, et al. Research progress on the anti-aging potential of the active components of ginseng. Nutrients. 2023; 15(15):3286. https://doi.org/10.3390/nu15153286.

[19] Wang J, Cao B, Zhao H, et al. Emerging roles of Ganoderma lucidum in anti-aging. Aging Dis. 2017; 8(6):691-707. https://doi.org/10.14336/AD.2017.0410.

[20] Berezutsky MA, Durnova NA, Vlasova IA. Experimental and clinical studies of mechanisms of the anti-aging effects of chemical compounds in Astragalus membranaceus. Adv Gerontol. 2019; 32(5):702-710. https://doi.org/10.1134/S2079057020020046.

[21] Chen G, Huang C, Shi P, et al. Mechanism of Chinese yam for the treatment of aging-related diseases based on network pharmacology. Eur J Integr Med. 2021;41:101254. https://doi.org/10.1016/j.eujim.2020.101254.

[22] Liu BH, Gu YH, Tu Y, et al. Molecular regulative mechanisms of aging and interventional effects of Chinese herbal medicine. Chin J Chin Mater Med. 2017; 42(16):3065-3071. https://doi.org/10.19540/j.cnki.cjcmm.20170731.001.

[23] Yang YHK, Ogando CR, Wang SC, et al. Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro. Stem Cell Res Ther. 2018; 9(1):131. https://doi.org/10.1186/s13287-018-0876-3.

[24] Stolzing A, Jones E, McGonagle D, et al. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 2008; 129(3):163-173. https://doi.org/10.1016/j.mad.2007.12.002.

[25] Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-9367. https://doi.org/10.1073/pnas.92.20.9363.

[26] Brenner AJ, Stampfer MR, Aldaz CM. Increased p 16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene. 1998; 17(2):199-205. https://doi.org/10.1038/sj.onc.1201919.

[27] Özcan S, Alessio N, Acar MB, et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging (Albany NY). 2016; 8(7):1316-1329. https://doi.org/10.18632/aging.100971.

[28] Coussens M, Maresh JG, Yanagimachi R, et al. Sirt1 deficiency attenuates spermatogenesis and germ cell function. PLoS One. 2008; 3(2):e1571. https://doi.org/10.1371/journal.pone.0001571.

[29] Pérez-Garijo A, Steller H. The benefits of aging: cellular senescence in normal development. EMBO J. 2014; 33(2):99-100. https://doi.org/10.1002/embj.201387401.

[30] Schellenberg A, Lin Q, Schüler H, et al. Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks. Aging (Albany NY). 2011; 3(9):873-888. https://doi.org/10.18632/aging.100391.

[31] Zhao Q, Wang XY, Yu XX, et al. Expression of human telomerase reverse transcriptase mediates the senescence of mesenchymal stem cells through the PI3K/AKT signaling pathway. Int J Mol Med. 2015; 36(3):857-864. https://doi.org/10.3892/ijmm.2015.2284.

[32] Larsson LG. Oncogene and tumor suppressor gene-mediated suppression of cellular senescence. Semin Cancer Biol. 2011; 21(6):367-376. https://doi.org/10.1016/j.semcancer.2011.10.005.

[33] Vono R, Garcia EJ, Gaia Spinetti, et al. Oxidative stress in mesenchymal stem cell senescence: regulation by coding and noncoding RNAs. Antioxid Redox Signal. 2018; 29(9):864-879. https://doi.org/10.1089/ars.2017.7294.

[34] Demaria M, O'Leary MN, Chang J, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017; 7(2):165-176. https://doi.org/10.1158/2159-8290.CD-16-0241.

[35] d'Adda di FF. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008; 8(7):512-522. https://doi.org/10.1038/nrc2440.

[36] Reinhardt HC, Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 2012; 28(3):128-136. https://doi.org/10.1016/j.tig.2011.12.002.

[37] Zhou L, Chen X, Liu T, et al. Melatonin reverses H₂O₂-induced premature senescence in mesenchymal stem cells via the SIRT1-dependent pathway. J Pineal Res. 2015; 59(2):190-205. https://doi.org/10.1111/jpi.12250.

[38] Wang Z, Wang L, Jiang R, et al. Ginsenoside Rg 1 prevents bone marrow mesenchymal stem cell senescence via NRF2 and PI3K/Akt signaling. Free Radic Biol Med. 2021; 174:182-194. https://doi.org/10.1016/j.freeradbiomed.2021.08.007.

[39] Racz LZ, Racz CP, Pop LC, et al. Strategies for improving bioavailability, bioactivity, and physical-chemical behavior of curcumin. Molecules. 2022; 27(20):6854. https://doi.org/10.3390/molecules27206854.

[40] Fathi E, Charoudeh HN, Sanaat Z, et al. Telomere shortening as a hallmark of stem cell senescence. Stem Cell Investig. 2019;6:7. https://doi.org/10.21037/sci.2019.02.04.

[41] Cheung HH, Liu X, Canterel-Thouennon L, et al. Telomerase protects werner syndrome lineage-specific stem cells from premature aging. Stem Cell Rep. 2014; 2(4):534-546. https://doi.org/10.1016/j.stemcr.2014.02.006.

[42] Deng J, Ouyang P, Li W, et al. Curcumin alleviates the senescence of canine bone marrow mesenchymal stem cells during in vitro expansion by activating the autophagy pathway. Int J Mol Sci. 2021; 22(21):11356. https://doi.org/10.3390/ijms222111356.

[43] Chen K, Ling J, Zhou X, et al. Deciphering the anti-senescence immune paradigm: kidney yin-yang equilibrium in traditional Chinese medicine. J Holist Integr Pharm. 2024; 5(2):77-89. https://doi.org/10.1016/j.jhip.2024.05.001.

[44] Ho TJ, Tsai BCK, Debakshee G, et al. Ohwia caudata aqueous extract attenuates senescence in aging adipose-derived mesenchymal stem cells. Heliyon. 2024; 10(9):e29729. https://doi.org/10.1016/j.heliyon.2024.e29729.

[45] Sun Y, Zhang H, Qiu T, et al. Epigenetic regulation of mesenchymal stem cell aging through histone modifications. Genes Dis. 2022; 10(6):2443-2456. https://doi.org/10.1016/j.gendis.2022.10.030.

[46] Bork S, Pfister S, Witt H, et al. DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell. 2010; 9(1):54-63. https://doi.org/10.1111/j.1474-9726.2009.00535.x.

[47] Li Z, Liu C, Xie Z, et al. Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PLoS One. 2011; 6(6):e20526. https://doi.org/10.1371/journal.pone.0020526.

[48] Wang J, Liu L, Ding Z, et al. Exogenous NAD⁺postpones the D-Gal-induced senescence of bone marrow-derived mesenchymal stem cells via sirt1 signaling. Antioxidants. 2021; 10(2):254. https://doi.org/10.3390/antiox10020254.

[49] Qi J, Xue Q, Kuang L, et al. Berberine alleviates cisplatin-induced acute kidney injury by regulating mitophagy via PINK1/Parkin pathway. Transl Androl Urol. 2020; 9(4):1712-1724. https://doi.org/10.21037/tau-20-1129.

[50] Shin JH, Jeon HJ, Park J, et al.Epigallocatechin-3-gallate prevents oxidative stress-induced cellular senescence in human mesenchymal stem cells via Nrf2. Int J Mol Med. 2016; 38(4):1075-1082. https://doi.org/10.3892/ijmm.2016.2694.

[51] Maharajan N, Cho GW. Camphorquinone promotes the antisenescence effect via activating AMPK/SIRT1 in stem cells and D-galactose-induced aging mice. Antioxidants. 2021; 10(12):1916. https://doi.org/10.3390/antiox10121916.

[52] Hu C, Zhao L, Peng C, et al. Regulation of the mitochondrial reactive oxygen species: strategies to control mesenchymal stem cell fates ex vivo and in vivo. J Cell Mol Med. 2018; 22(11):5196-5207. https://doi.org/10.1111/jcmm.13835.

[53] Stab BR, Martinez L, Grismaldo A, et al. Mitochondrial functional changes characterization in young and senescent human adipose derived MSCs. Front Aging Neurosci. 2016;8:299. https://doi.org/10.3389/fnagi.2016.00299.

[54] Ren L, Chen X, Chen X, et al. Mitochondrial dynamics: fission and fusion in fate determination of mesenchymal stem cells. Front Cell Dev Biol. 2020;8:580070. https://doi.org/10.3389/fcell.2020.580070.

[55] Branco A, Moniz I, Ramalho-Santos J. Mitochondria as biological targets for stem cell and organismal senescence. Eur J Cell Biol. 2023; 102(2):151289. https://doi.org/10.1016/j.ejcb.2023.151289.

[56] Yan W, Diao S, Fan Z. The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells. Stem Cell Res Ther. 2021; 12(1):140. https://doi.org/10.1186/s13287-021-02194-z.

[57] Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013; 20(1):31-42. https://doi.org/10.1038/cdd.2012.81.

[58] Wang Y, Liu Y, Chen E, et al. The role of mitochondrial dysfunction in mesenchymal stem cell senescence. Cell Tissue Res. 2020; 382(3):457-462. https://doi.org/10.1007/s00441-020-03272-z.

[59] Poole AC, Thomas RE, Andrews LA, et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008; 105(5):1638-1643. https://doi.org/10.1073/pnas.0709336105.

[60] Lin Q, Chen J, Gu L, et al. New insights into mitophagy and stem cells. Stem Cell Res Ther. 2021; 12(1):452. https://doi.org/10.1186/s13287-021-02520-5.

[61] Maharajan N, Ganesan CD, Moon C, et al. Licochalcone D ameliorates oxidative stress-induced senescence via AMPK activation. Int J Mol Sci. 2021; 22(14):7324. https://doi.org/10.3390/ijms22147324.

[62] Ashrafizadeh M, Ahmadi Z, Mohammadinejad R, et al. Curcumin activates the Nrf2 pathway and induces cellular protection against oxidative injury. Curr Mol Med. 2020; 20(2):116-133. https://doi.org/10.2174/1566524019666191016150757.

[63] Revuelta M, Matheu A.Autophagy in stem cell aging. Aging Cell. 2017; 16(5):912-915. https://doi.org/10.1111/acel.12655.

[64] Zhang D, Chen Y, Xu X, et al. Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling. Clin Exper Pharmacol Physiol. 2020; 47(3):466-477. https://doi.org/10.1111/1440-1681.13207.

[65] Ma Y, Qi M, An Y, et al. Autophagy controls mesenchymal stem cell properties and senescence during bone aging. Aging Cell. 2018; 17(1):e12709. https://doi.org/10.1111/acel.12709.

[66] Rastaldo R, Vitale E, Giachino C. Dual role of autophagy in regulation of mesenchymal stem cell senescence. Front Cell Dev Biol. 2020;8:276. https://doi.org/10.3389/fcell.2020.00276.

[67] Zhang D, Lin J, Wang Y, et al. Effects of resveratrol on aging of mesenchymal stem cells and its mechanism. J Zhejiang Univer (Med Sci). 2019; 48(6):617-624. https://doi.org/10.3785/j.issn.1008-9292.2019.12.05.

[68] Chang YM, Chang HH, Kuo WW, et al. Anti-apoptotic and pro-survival effect of Alpinate Oxyphyllae Fructus (AOF) in a D-galactose-induced aging heart. Int J Mol Sci. 2016; 17(4):466. https://doi.org/10.3390/ijms17040466.

[69] Lin HJ, Ramesh S, Chang YM, et al. D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells. Environ Toxicol. 2021; 36(1):86-94. https://doi.org/10.1002/tox.23014.

[70] Chang YM, Asokan SM, Tsai CT, et al. Alpinate oxyphyllae extracts enhance the longevity and homing of mesenchymal stem cells and augment their protection against senescence in H9c2 cells. J Cell Physiol. 2019; 234(7):12042-12050. https://doi.org/10.1002/jcp.27867.

[71] Lu PH, Tseng CW, Lee JL, et al. Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: molecular evidence and mechanisms. Pharmacol Res Modern Chin Med. 2022;2:100024. https://doi.org/10.1016/j.prmcm.2021.100024.

[72] Shibu MA, Lin YJ, Chiang CY, et al. Novel anti-aging herbal formulation Jing Si displays pleiotropic effects against aging associated disorders. Biomed Pharmacother. 2022;146:112427. https://doi.org/10.1016/j.biopha.2021.112427.

[73] Kang X, Chen L, Yang S, et al. Zuogui Wan slowed senescence of bone marrow mesenchymal stem cells by suppressing Wnt/β-catenin signaling. J Ethnopharmacol. 2022;294:115323. https://doi.org/10.1016/j.jep.2022.115323.

[74] Yang YH, Wen CS, Kuo YL, et al. GuiLu-ErXian Glue extract promotes mesenchymal stem cells (MSC)-induced chondrogenesis via exosomes release and delays aging in the MSC senescence process. J Ethnopharmacol. 2023;317:116784. https://doi.org/10.1016/j.jep.2023.116784.

[75] Gershenzon J, Dudareva N. The function of terpene natural products in the natural world. Nat Chem Biol. 2007; 3(7):408-414. https://doi.org/10.1038/nchembio.2007.5.

[76] Leung KW, Wong AST. Pharmacology of ginsenosides: a literature review. Chin Med. 2010;5:20. https://doi.org/10.1186/1749-8546-5-20.

[77] Li X, Chu S, Lin M, et al. Anticancer property of ginsenoside Rh2 from ginseng. Eur J Med Chem. 2020;203:112627. https://doi.org/10.1016/j.ejmech.2020.112627.

[78] Sun Y, Liu Y, Chen K. Roles and mechanisms of ginsenoside in cardiovascular diseases: progress and perspectives. Sci Chin Life Sci. 2016; 59(3):292-298. https://doi.org/10.1007/s11427-016-5007-8.

[79] Tian T, Ko CN, Li D, et al. The anti-aging mechanism of ginsenosides with medicine and food homology. Food Funct. 2023; 14(20):9123-9136. https://doi.org/10.1039/d3fo02580b.

[80] Lou T, Huang Q, Su H, et al. Targeting sirtuin 1 signaling pathway by ginsenosides. J Ethnopharmacol. 2021;268:113657. https://doi.org/10.1016/j.jep.2020.113657.

[81] Wang Z, Jiang R, Wang L, et al. Ginsenoside Rg 1 improves differentiation by inhibiting senescence of human bone marrow mesenchymal stem cell via GSK-3β and β-catenin. Stem Cells Int. 2020;2020:2365814. https://doi.org/10.1155/2020/2365814.

[82] Ling L, Shu H, Huang Y, et al. Effects of ginsenoside Rg1 on the biological behavior of human amnion-derived mesenchymal stem/stromal cells (hAD-MSCs). Stem Cells Int. 2023;2023:7074703. https://doi.org/10.1155/2023/7074703.

[83] Che L, Zhu C, Huang L, et al. Ginsenoside Rg 2 promotes the proliferation and stemness maintenance of porcine mesenchymal stem cells through autophagy induction. Foods. 2023; 12(5):1075. https://doi.org/10.3390/foods12051075.

[84] Xu Y, Yuan H, Luo Y, et al. Ganoderic acid D protects human amniotic mesenchymal stem cells against oxidative stress-induced senescence through the PERK/NRF2 signaling pathway. Oxid Med Cell Longev. 2020;2020:8291413. https://doi.org/10.1155/2020/8291413.

[85] Yuan H, Xu Y, Luo Y, et al. Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells. Aging Cell. 2022; 21(9):e13686. https://doi.org/10.1111/acel.13686.

[86] Ertani A, Pizzeghello D, Francioso O, et al. Biological activity of vegetal extracts containing phenols on plant metabolism. Molecules. 2016; 21(2):205. https://doi.org/10.3390/molecules21020205.

[87] Ali D, Chen L, Kowal JM, et al. Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells. Bone. 2020;133:115252. https://doi.org/10.1016/j.bone.2020.115252.

[88] Alessio N, Squillaro T, Lettiero I, et al. Biomolecular evaluation of piceatannol’s effects in counteracting the senescence of mesenchymal stromal cells: a new candidate for senotherapeutics? Int J Mol Sci. 2021; 22(21):11619. https://doi.org/10.3390/ijms222111619.

[89] Lei L, Chen J, Zhao Y, et al.Resveratrol attenuates senescence of adipose-derived mesenchymal stem cells and restores their paracrine effects on promoting insulin secretion of INS-1 cells through Pim-1. Eur Rev Med Pharmacol Sci. 2016; 20(6):1203-1213.

[90] Pirmoradi S, Fathi E, Farahzadi R, et al. Curcumin affects adipose tissue-derived mesenchymal stem cell aging through TERT gene expression. Drug Res. 2018; 68(4):213-221. https://doi.org/10.1055/s-0043-119635.

[91] Shi PZ, Wang JW, Wang PC, et al. Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1α pathway. World J Stem Cells. 2021; 13(12):1928. https://doi.org/10.4252/wjsc.v13.i12.1928.

[92] Shan H, Geng L, Jiang X, et al. Large-scale chemical screen identifies gallic acid as a geroprotector for human stem cells. Protein Cell. 2022; 13(7):532-539. https://doi.org/10.1007/s13238-021-00872-5.

[93] Martens S, Mithöfer A.Flavones and flavone synthases. Phytochemistry. 2005; 66(20):2399-2407. https://doi.org/10.1016/j.phytochem.2005.07.013.

[94] Geng L, Liu Z, Zhang W, et al. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell. 2019; 10(6):417-435. https://doi.org/10.1007/s13238-018-0567-y.

[95] Li M, Yu Y, Xue K, et al. Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats. Redox Biol. 2023;61:102649. https://doi.org/10.1016/j.redox.2023.102649.

[96] Song X, Wang J, Zhang Y, et al. Protective effect of hydroxysafflor yellow A on MSCs against senescence induced by D-galactose. Chin Herb Med. 2023; 15(1):86-93. https://doi.org/10.1016/j.chmed.2022.06.011.

[97] Sasidharan S, Chen Y, Saravanan D, et al. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. Afr J Tradit Complement Altern Med. 2011; 8(1):1-10. https://doi.org/10.4314/ajtcam.v8i1.60483.

[98] Opara EI, White KN, Uvere PO. Chemical analyses and therapeutic properties of plant extracts. Molecules.. 2025; 30(3):610. https://doi.org/10.3390/molecules30030610.

[99] Jeong SG, Oh YS, Joe IS, et al. Functional restoration of replicative senescent mesenchymal stem cells by the brown alga Undaria pinnatifida. Anim Cells Syst. 2017; 21(2):108-114. https://doi.org/10.1080/19768354.2017.1292951.

[100] Askari N, Asadi F, Nazer A, et al. Anti-aging effects of the pistachio extract on mesenchymal stem cells proliferation and telomerase activity. Arch Gerontol Geriatr. 2023;111:105016. https://doi.org/10.1016/j.archger.2023.105016.

[101] Weng Z, Wang Y, Ouchi T, et al. Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies. Stem Cells Transl Med. 2022; 11(4):356-371. https://doi.org/10.1093/stcltm/szac004.

[102] Liu R, Li X, Huang N, Fan M, et al. Toxicity of traditional Chinese medicine herbal and mineral products. Adv Pharmacol. 2020; 87:301-346. https://doi.org/10.1016/bs.apha.2019.08.001.

[103] Muralikumar M, Manoj JS, Ganesan H, et al. Current understanding of the mesenchymal stem cell-derived exosomes in cancer and aging. Biotechnol Rep. 2021;31:e00658. https://doi.org/10.1016/j.btre.2021.e00658.

[104] Li X, Liu Z, Liao J, et al. Network pharmacology approaches for research of traditional Chinese medicines. Chin J Nat Med. 2023; 21(5):323-332. https://doi.org/10.1016/S1875-5364(23)60429-7.

[105] Qiu Z, Li S, Luo M, et al. Detection of differentially expressed genes in spatial transcriptomics data by spatial analysis of spatial transcriptomics: a novel method based on spatial statistics. Front Neurosci. 2022;16:1086168. https://doi.org/10.3389/fnins.2022.1086168.