Research Progress On Chinese Medicine Intervention in Mesenchymal Stem Cell Aging

2 Mechanism of action of Chinese medicine in Intervening MSC aging

2.1 Kidney-tonifying Chinese medicine

Most of the Chinese medicines currently studied are kidney-tonifying drugs. Icariin, the active ingredient of epimedium, can activate autophagy and reduce macrophage SASP secretion, reduce microenvironmental inflammatory response, and can also enhance the expression of Wnt/β-Catenin pathway through Foxo3a transcription factor, slowing down bone marrow mesenchymal stem cell (BMSC) aging［25］. Icariin can also play an estrogen-like role and play an anti-BMSC aging effect mediated by estrogen receptor［26］, but its molecular mechanism still needs further study.
Quercetin, the active ingredient of Eucommia ulmoides, has antioxidant and mitochondrial function protection effects, and can delay microgravity-induced BMSC aging［27］. Zhao Wenjie [28] found that quercetin can reverse the inhibition of SIＲT1 caused by miＲ-34a-5p, reduce inflammation and oxidative stress, and thus delay the aging of nucleus pulposus MSC. Qiu Yunge [29] found that quercetin combined with dasatinib can delay the replicative aging of dental pulp MSC by upregulating the expression of YAP and TAZ, enhancing cell stemness and differentiation ability.

HERBAL SUPPLEMENTS FOR KIDNEY-TONIFYING

The active ingredient cordycepin in Cordyceps militaris and Cordyceps sinensis can activate the AMPK/SIＲT1 signaling pathway, increase SIＲT1 expression, and then delay MSC aging by enhancing autophagy and telomerase activity [30].
The active ingredient curculigo glycoside in Curculigo orchioides can promote bone differentiation, reduce adipogenic differentiation, and delay BMSC aging by activating the MAPK/ERK signaling pathway [31]. The Chinese medicine compound for tonifying kidney yang, Wenshentongluozhitongfang (composed of Drynaria fortunei, Cibotium barometz, Epimedium brevicornum, etc.), can activate the AMPK/mTOR pathway, enhance cell autophagy, promote BMSC differentiation and delay aging [15]. Other prescriptions for tonifying kidney yang include Erxian decoction and Bushenhuatan decoction. Erxian decoction can promote mitochondrial autophagy [32], and Bushenhuatan decoction can inhibit SASP secretion and improve the inflammatory microenvironment [33], effectively delaying the aging process of BMSC, but the specific signaling pathways involved still need to be further clarified.

Some kidney yin nourishing prescriptions such as Liuwei Dihuang Pills and Zuogui Pills also have anti-aging effects. Liang et al. [34] proved that Liuwei Dihuang Pills can activate YAP-mediated autophagy, activate the cell cycle, and delay BMSC aging. Zuogui Pills can activate the Wnt/β-Catenin pathway, improve the stemness of BMSCs, and reduce DNA damage and inflammatory response [35].

2.2 Blood-activating Chinese medicines

Resveratrol is the active ingredient of the Chinese medicine Polygonum cuspidatum. Studies [36] have shown that resveratrol reverses BMSC aging by activating the MAPK pathway, reducing ROS and SASP. Yun et al. [37] found that BMSCs in patients with amyotrophic lateral sclerosis showed aging symptoms. Resveratrol can upregulate the SIＲT1/AMPK pathway, delay BMSC aging and promote their differentiation into neuron-like cells. Guo Liling [11] found that resveratrol can enhance Foxo1-mediated SIＲT1 transcriptional expression or directly inhibit SIＲT1 nitrosation by regulating the Akt/Foxo1 signaling pathway, thereby counteracting the premature senescence of adipose MSC induced by postprandial triglyceride. Lei et al. [38] found that resveratrol promotes the expression of Pim-1 kinase through the PI3K/AKT signaling pathway and restores the paracrine effect of aged adipose MSC, thereby promoting cell proliferation.
Curcumin, the active ingredient of turmeric, can promote autophagy and increase the expression of telomere reverse transcriptase, prolong the life span of rat adipose MSC, and improve cartilage aging damage in mice [39-40].
Angelica polysaccharide, the active ingredient of the Chinese medicine Angelica sinensis, can activate the Wnt/β-Catenin pathway and resist 5-fluorouracil-induced BMSC senescence [41]. Ligustrazine, the active ingredient of Chuanxiong, can inhibit the NF-κB pathway, inhibit the secretion of inflammatory factors, regulate the cell cycle, and improve the self-renewal ability of aged BMSCs and their potential to differentiate into neurons [42]. Camphor's active ingredient camphorquinone can activate the AMPK/SIＲT1 pathway, enhance autophagy, and inhibit BMSC aging [43]. Cannabidiol, the active ingredient of cannabis, can activate autophagy, delay BMSC aging and promote its osteogenic differentiation [44], but the specific signaling pathway involved is still unclear. Danshensu borneol ester is a compound synthesized by modern pharmacological technology from the active components of Danshen and borneol. Wang Xue et al. [45] found that danshensu borneol ester can improve oxidative stress and reverse BMSC aging, and the mechanism is related to the activation of PI3K/Akt and downstream NF-κB pathway. Ho et al. [46] found that mugwort can reduce mitochondrial ROS production, repair aging DNA damage and telomere shortening, and reverse human adipose MSC aging. Yanghe decoction has the effect of dispelling cold and relieving stagnation, which can inhibit the p38MAPK signaling pathway, reduce inflammatory stimulation, reverse BMSC aging and promote differentiation［47］.

2.3 Qi-replenishing Chinese medicine

The mechanism by which the active ingredient of Ganoderma lucidum, ganoderic acid D, inhibits the aging of human amniotic membrane MSC is related to the NＲF2-related signaling pathway. Xu et al.［48］ found that ganoderic acid D can activate the PERK/NＲF2 signaling pathway, reduce ROS production, alleviate cell cycle arrest caused by oxidative stress, and enhance telomerase activity. Yuan et al.［49］ found that ganoderic acid D can target 14-3-3ε to activate calmodulin (CaM)/CaM-dependent protein kinase II (CAMKⅡ), thereby activating the Nrf2/HO-1/NQO1 pathway, inhibiting the oxidative stress response of human amniotic membrane MSC, and reducing the damage of oxidative stress to calcium ion homeostasis.
Ginsenoside Rg1 is the active ingredient of ginseng. Wang Ziling [50] confirmed that ginsenoside Rg1 activates the PI3K/Akt/mTOR pathway, enhances p62-dependent autophagy, and then activates the NRF2 pathway, reducing DNA damage, SASP secretion and oxidative stress, thereby delaying BMSC aging. Licorice flavonoids are abundant in the traditional Chinese medicine licorice. Licorice chalcone A activates the PI3K/Akt pathway to increase glycolysis, inhibit telomere shortening and ROS production, thereby delaying human adipose MSC aging [51]. Licorice chalcone D can activate the AMPK pathway, promote autophagy, improve oxidative stress and RAGE-mediated inflammatory response, and inhibit BMSC premature aging [52]. Astragalus membranaceus improves the vitality and bone formation of aged BMSCs by regulating the vitamin D/FGF23-Klotho axis, thus exerting an anti-osteoporosis effect. [53] Astragalus polysaccharide is the active ingredient of Astragalus membranaceus. Yang et al. [54] found that astragalus polysaccharide can reverse the senescence of iron-overloaded BMSCs induced by ammonium ferric citrate.

2.4 Other Chinese medicines

The heat-clearing Chinese medicine Menghua glycoside is a natural component of wild chrysanthemum, which can effectively reduce DNA damage in aging BMSCs [55].

Epigallocatechin gallate inhibits BMSC aging by promoting Nrf2 nuclear translocation [56].

The warming Chinese medicine capsaicin regulates the Hippo pathway, reduces SASP secretion, and delays human placental MSC aging [57].

The active ingredient of the Chinese medicine Inula japonica is total flavonoids

It reduces oxidative damage in aging BMSCs and inhibits cell apoptosis by upregulating SIＲT1 expression [58]. The mechanism of action of common Chinese medicines in regulating MSC aging is shown in Table 1.

Table 1 Cell types used in studies on the regulation of MSC aging by common traditional Chinese medicines

3 Summary and Outlook

MSC aging involves multiple mechanisms and multiple signaling pathways, but how to apply these theories to the anti-aging of traditional Chinese medicine still faces many challenges. First, the research on the effective ingredients or traditional Chinese medicine compound is still insufficient, and the molecular mechanism of some traditional Chinese medicine has not yet been clarified. Therefore, in the future, it is necessary to further combine modern molecular biology techniques to deeply explore the specific mechanism of traditional Chinese medicine regulation in MSC aging. Secondly, the precise regulation of signaling pathways is the focus of anti-aging research. Some signaling pathways such as Wnt/β-Catenin, NF-κB and STAT3 show dual effects in regulation. Therefore, it is necessary to screen out targets that have both beneficial regulation and inhibition of harmful effects in order to achieve precise intervention in MSC aging. Finally, multiple signaling pathways may interact in the regulation of MSC aging. Exploring the intervention strategies of these cross-acting pathways may provide more effective anti-aging methods.

References

［1］ ＷAGNEＲ W, HOＲN P, CASTOLDI M, et al． Replicative senescence of mesenchymal stem cells: a continuous and organized process［J］． PLoS One, 2008, 3( 5) : e2213

［2］ WENG ZJ,WANG YG,OUCHI T,et al． Mesenchymal stem/stromal cell senescence: hallmarks,mechanisms,and combating strategies［J］． Stem Cells Transl Med,2022,11( 4) : 356

［3］ PAN Xiaolong,FAN Feiyan,YING Chunmiao,et al． Effect and mechanism of traditional Chinese medicine on inhibiting the aging of mesenchymal stem cells［J］． Chinese Journal of Tissue Engineering Research,2024,28( 7) :1091
PAN XL,FAN FY,YING CM,et al． Effect and mechanism of traditional Chinese medicine on inhibiting the aging of mesenchymal stem cells［J］． Chinese Journal of Tissue Engineering Ｒsearch, 2024, 28(7): 1091

[4] BANIMOHAMAD-SHOTORBANI B, KAHROBA H, SADEGHZADEH H, et al. DNA damage repair response in mesenchymal stromal cells: from cellular senescence and Aging to apoptosis and differentiation ability［J］． Ageing Res Rev, 2020, 62: 101125

[5] AL-AZAB M, SAFI M, IDIIATULLINA E, et al. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting［J］． Cell Mol Biol Lett, 2022, 27(1): 69

[6] JIN HJ, LEE HJ, HEO J, et al. Senescence-associated MCP-1 secretion is dependent on a decline in BMI1 in human mesenchymal stromal cells［J］． Antioxid Ｒdox Signal, 2016, 24(9): 471

[7] KUBBEN N, ZHANG W, WANG L, et al. Repression of the antioxidant NRF2 pathway in premature aging［J］． Cell, 2016, 165(6): 1361

[8] LIU GX, LI XX, YANG FH, et al. C-phycocyanin ameliorates the senescence of mesenchymal stem cells through ZDHHC5-mediated autophagy via PI3K/AKT/mTOR pathway［J］． Aging Dis, 2023, 14(4): 1425 [9] HUANG DY, ZHAO Q, YANG K, et al. CRL2-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence［J］． Sci China Life Sci, 2024, 67(3): 460 [10] ZHANG DY, LU HF, CHEN ZX, et al. High glucose induces the aging of mesenchymal stem cells via Akt /mTORＲ signaling［J］． Mol Med Rep, 2017, 16(2): 1685