Research Progress on the Regulation Mechanism of Senescence-associated Secretory Phenotype in Osteoporosis

doi:10.12114/j.issn.1007-9572.2023.0721

Abstract

Abstract:

Senescence-associated secretory phenotype (SASP) is an important feature of cellular senescence and plays an important role in regulating the disease microenvironment. At present, the role of SASP in intervening bone metabolism and inducing bone loss is very limited. Therefore, this paper discusses the regulatory mechanism of SASP in osteoporosis models and summarizes its regulatory characteristics: SASP is fully expressed in senescent bone cells and transmits aging effects to mesenchymal stem cells in an autocrine/paracrine manner, thereby interfering with osteogenic differentiation. SASP activates immune cells and promotes their aging, thus inducing the formation of inflammatory tissue microenvironment and aggravating bone loss. Mitochondrial homeostasis, pathologic hyperglycemia, and obesity-induced fat accumulation all promote SASP expression, thus disrupting microenvironmental homeostasis and transmitting aging effects to bone tissue. To sum up, understanding the role of SASP in osteoporosis lays a solid foundation for us to develop anti-SASP therapy for osteoporosis in the future.

Key words: Osteoporosis, Senescence-associated secretory phenotype, Cell senescence, Metabolic disorders, Immunomodulation

摘要：

衰老相关分泌表型（SASP）是细胞衰老的重要特征，在调控疾病微环境中具有重要作用。目前，对于SASP干预骨代谢、诱导骨流失的作用机制了解有限，因此，本文探讨了在骨质疏松模型中SASP的调控机制，并归纳总结了其调控特点：SASP在衰老骨细胞中充分表达，以自分泌/旁分泌的方式将衰老效应传递到间充质干细胞，从而干预其成骨分化；SASP激活免疫细胞，并促进其衰老，从而诱导炎性组织微环境的形成，加重骨流失；线粒体稳态失调、病理性血糖升高、肥胖诱导的脂肪蓄积均会促进SASP的表达，从而扰乱微环境稳态，将衰老效应传递到骨组织。所以，有必要深入了解SASP在骨质疏松中的作用，为后续开发抗SASP疗法治疗骨质疏松提供借鉴。

YANG Chaofu,TAN Guoqing,XU Zhanwang. Research Progress on the Regulation Mechanism of Senescence-associated Secretory Phenotype in Osteoporosis[J]. Chinese General Practice, 2024, 27(29): 3685-3695. DOI: 10.12114/j.issn.1007-9572.2023.0721.
杨超富,谭国庆,徐展望. 骨质疏松中衰老相关分泌表型调控机制的研究进展[J]. 中国全科医学, 2024, 27(29): 3685-3695. DOI: 10.12114/j.issn.1007-9572.2023.0721.

Figures/Tables 2

References 99

[1]	WANG L H，YU W，YIN X J，et al. Prevalence of osteoporosis and fracture in China：the China osteoporosis prevalence study[J]. JAMA Netw Open，2021，4（8）：e2121106. DOI：10.1001/jamanetworkopen.2021.21106.
[2]	CONTI V，RUSSOMANNO G，CORBI G，et al. A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy[J]. Int J Mol Sci，2015，16（3）：5452-5466. DOI：10.3390/ijms16035452.
[3]	COPPÉ J P，PATIL C K，RODIER F，et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor[J]. PLoS Biol，2008，6（12）：2853-2868. DOI：10.1371/journal.pbio.0060301.
[4]	ZHAO R L，JIN X Y，LI A，et al. Precise diabetic wound therapy：PLS nanospheres eliminate senescent cells via DPP4 targeting and PARP1 activation[J]. Adv Sci，2022，9（1）：e2104128. DOI：10.1002/advs.202104128.
[5]	JIN W N，SHI K B，HE W Y，et al. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition[J]. Nat Neurosci，2021，24（1）：61-73. DOI：10.1038/s41593-020-00745-w.
[6]	HU L F，YIN C，ZHAO F，et al. Mesenchymal stem cells：cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment[J]. Int J Mol Sci，2018，19（2）：360. DOI：10.3390/ijms19020360.
[7]	DING P，GAO C，GAO Y S，et al. Osteocytes regulate senescence of bone and bone marrow[J]. eLife，2022，11：e81480. DOI：10.7554/eLife.81480.
[8]	SINHA S，SINHA A，DONGRE P，et al. Organelle dysfunction upon asrij depletion causes aging-like changes in mouse hematopoietic stem cells[J]. Aging Cell，2022，21（4）：e13570. DOI：10.1111/acel.13570.
[9]	TRESGUERRES F G F，TORRES J，LÓPEZ-QUILES J，et al. The osteocyte：a multifunctional cell within the bone[J]. Ann Anat，2020，227：151422. DOI：10.1016/j.aanat.2019.151422.
[10]	BLOCK T J，MARINKOVIC M，TRAN O N，et al. Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies[J]. Stem Cell Res Ther，2017，8（1）：239. DOI：10.1186/s13287-017-0688-x.
[11]	ZHUANG Y，LI D，FU J Q，et al. Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages：immunomodulatory ability is enhanced in aged cells[J]. Mol Med Rep，2015，11（1）：166-174. DOI：10.3892/mmr.2014.2755.
[12]	WANG L P，ZHANG H，XIAO X，et al. Small extracellular vesicles maintain homeostasis of senescent mesenchymal stem cells at least through excreting harmful lipids[J]. Stem Cells Dev，2023，32（17/18）：565-579. DOI：10.1089/scd.2023.0079.
[13]	KIM M，BAE Y K，UM S，et al. A small-sized population of human umbilical cord blood-derived mesenchymal stem cells shows high stemness properties and therapeutic benefit[J]. Stem Cells Int，2020，2020：5924983. DOI：10.1155/2020/5924983.
[14]	LUNYAK V V，AMARO-ORTIZ A，GAUR M. Mesenchymal stem cells secretory responses：senescence messaging secretome and immunomodulation perspective[J]. Front Genet，2017，8：220. DOI：10.3389/fgene.2017.00220.
[15]	KWON J H，KIM M，UM S，et al. Senescence-associated secretory phenotype suppression mediated by small-sized mesenchymal stem cells delays cellular senescence through TLR2 and TLR5 signaling[J]. Cells，2021，10（1）：63. DOI：10.3390/cells10010063.
[16]	CHOU L Y，HO C T，HUNG S C. Paracrine senescence of mesenchymal stromal cells involves inflammatory cytokines and the NF-κB pathway[J]. Cells，2022，11（20）：3324. DOI：10.3390/cells11203324.
[17]	LEHMANN J，NARCISI R，FRANCESCHINI N，et al. WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion[J]. Cell Mol Life Sci，2022，79（2）：82. DOI：10.1007/s00018-021-04035-x.
[18]	VOSKAMP C，ANDERSON L A，KOEVOET W J，et al. TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells[J]. Eur Cell Mater，2021，42：401-414. DOI：10.22203/eCM.v042a25.
[19]	LEE J Y，YU K R，LEE B C，et al. GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging[J]. Exp Mol Med，2018，50（5）：1-12. DOI：10.1038/s12276-018-0092-3.
[20]	ZHENG X L，WANG Q X，XIE Z，et al. The elevated level of IL-1α in the bone marrow of aged mice leads to MSC senescence partly by down-regulating Bmi-1[J]. Exp Gerontol，2021，148：111313. DOI：10.1016/j.exger.2021.111313.
[21]	SHANG J，YAO Y，FAN X，et al. MiR-29c-3p promotes senescence of human mesenchymal stem cells by targeting CNOT6 through p53-p21 and p16-pRB pathways[J]. Biochim Biophys Acta，2016，1863（4）：520-532. DOI：10.1016/j.bbamcr.2016.01.005.
[22]	WEILNER S，SCHRAML E，WIESER M，et al. Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells[J]. Aging Cell，2016，15（4）：744-754. DOI：10.1111/acel.12484.
[23]	TOMÉ M，SEPÚLVEDA J C，DELGADO M，et al. MiR-335 correlates with senescence/aging in human mesenchymal stem cells and inhibits their therapeutic actions through inhibition of AP-1 activity[J]. Stem Cells，2014，32（8）：2229-2244. DOI：10.1002/stem.1699.
[24]	MATO-BASALO R，MORENTE-LÓPEZ M，ARNTZ O J，et al. Therapeutic potential for regulation of the nuclear factor kappa-B transcription factor p65 to prevent cellular senescence and activation of pro-inflammatory in mesenchymal stem cells[J]. Int J Mol Sci，2021，22（7）：3367. DOI：10.3390/ijms22073367.
[25]	SORIANI A，IANNITTO M L，RICCI B，et al. Reactive oxygen species- and DNA damage response-dependent NK cell activating ligand upregulation occurs at transcriptional levels and requires the transcriptional factor E2F1[J]. J Immunol，2014，193（2）：950-960. DOI：10.4049/jimmunol.1400271.
[26]	SHARMA C，WANG H X，LI Q L，et al. Protein acyltransferase DHHC3 regulates breast tumor growth，oxidative stress，and senescence[J]. Cancer Res，2017，77（24）：6880-6890. DOI：10.1158/0008-5472.CAN-17-1536.
[27]	LEFÈVRE L，IACOVONI J S，MARTINI H，et al. Kidney inflammaging is promoted by CCR2+ macrophages and tissue-derived micro-environmental factors[J]. Cell Mol Life Sci，2021，78（7）：3485-3501. DOI：10.1007/s00018-020-03719-0.
[28]	FUJIU K，MANABE I，NAGAI R. Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice[J]. J Clin Investig，2011，121（9）：3425-3441. DOI：10.1172/JCI57582.
[29]	HEARPS A C，MARTIN G E，ANGELOVICH T A，et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function[J]. Aging Cell，2012，11（5）：867-875. DOI：10.1111/j.1474-9726.2012.00851.x.
[30]	ZHANG B，BAILEY W M，BRAUN K J，et al. Age decreases macrophage IL-10 expression：implications for functional recovery and tissue repair in spinal cord injury[J]. Exp Neurol，2015，273：83-91. DOI：10.1016/j.expneurol.2015.08.001.
[31]	HOLT D J，GRAINGER D W. Senescence and quiescence induced compromised function in cultured macrophages[J]. Biomaterials，2012，33（30）：7497-7507. DOI：10.1016/j.biomaterials.2012.06.099.
[32]	BOADA-ROMERO E，MARTINEZ J，HECKMANN B L，et al. The clearance of dead cells by efferocytosis[J]. Nat Rev Mol Cell Biol，2020，21（7）：398-414. DOI：10.1038/s41580-020-0232-1.
[33]	DORAN A C，YURDAGUL A Jr，TABAS I. Efferocytosis in health and disease[J]. Nat Rev Immunol，2020，20（4）：254-267. DOI：10.1038/s41577-019-0240-6.
[34]	MORIOKA S，MAUERÖDER C，RAVICHANDRAN K S. Living on the edge：efferocytosis at the interface of homeostasis and pathology[J]. Immunity，2019，50（5）：1149-1162. DOI：10.1016/j.immuni.2019.04.018.
[35]	SCHLOESSER D，LINDENTHAL L，SAUER J，et al. Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis[J]. J Cell Biol，2023，222（2）：e202207097. DOI：10.1083/jcb.202207097.
[36]	ORECCHIONI M，GHOSHEH Y，PRAMOD A B，et al. Macrophage polarization：different gene signatures in M1（LPS+） vs. classically and M2（LPS-） vs. alternatively activated macrophages[J]. Front Immunol，2019，10：1084. DOI：10.3389/fimmu.2019.01084.
[37]	MONTANARO M，MELONI M，ANEMONA L，et al. Macrophage activation and M2 polarization in wound bed of diabetic patients treated by dermal/epidermal substitute nevelia[J]. Int J Low Extrem Wounds，2022，21（4）：377-383. DOI：10.1177/1534734620945559.
[38]	TAMAKI S，KUROSHIMA S，HAYANO H，et al. Dynamic polarization shifting from M1 to M2 macrophages in reduced osteonecrosis of the jaw-like lesions by cessation of anti-RANKL antibody in mice[J]. Bone，2020，141：115560. DOI：10.1016/j.bone.2020.115560.
[39]	KOHNO K，KOYA-MIYATA S，HARASHIMA A，et al. Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells[J]. J Inflamm，2021，18（1）：2. DOI：10.1186/s12950-020-00267-z.
[40]	DING L，YUAN X Y，YAN J H，et al. Nrf2 exerts mixed inflammation and glucose metabolism regulatory effects on murine RAW264.7 macrophages[J]. Int Immunopharmacol，2019，71：198-204. DOI：10.1016/j.intimp.2019.03.023.
[41]	SPRANGERS S，DE VRIES T J，EVERTS V. Monocyte heterogeneity：consequences for monocyte-derived immune cells[J]. J Immunol Res，2016，2016：1475435. DOI：10.1155/2016/1475435.
[42]	GEBRAAD A，KORNILOV R，KAUR S，et al. Monocyte-derived extracellular vesicles stimulate cytokinesecretion and gene expression of matrixmetalloproteinases by mesenchymal stem/stromal cells[J]. FEBS J，2018，285（12）：2337-2359. DOI：10.1111/febs.14485.
[43]	ONG S M，HADADI E，DANG T M，et al. The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence[J]. Cell Death Dis，2018，9（3）：266. DOI：10.1038/s41419-018-0327-1.
[44]	PENCE B D，YARBRO J R，EMMONS R S. Growth differentiation factor-15 is associated with age-related monocyte dysfunction[J]. Aging Med，2021，4（1）：47-52. DOI：10.1002/agm2.12128.
[45]	TSUKASAKI M，KOMATSU N，NAGASHIMA K，et al. Host defense against oral microbiota by bone-damaging T cells[J]. Nat Commun，2018，9（1）：701. DOI：10.1038/s41467-018-03147-6.
[46]	GARLET G P，CARDOSO C R，MARIANO F S，et al. Regulatory T cells attenuate experimental periodontitis progression in mice[J]. J Clin Periodontol，2010，37（7）：591-600. DOI：10.1111/j.1600-051X.2010.01586.x.
[47]	KOMATSU N，TAKAYANAGI H. Immune-bone interplay in the structural damage in rheumatoid arthritis[J]. Clin Exp Immunol，2018，194（1）：1-8. DOI：10.1111/cei.13188.
[48]	JANG H M，PARK J Y，LEE Y J，et al. TLR2 and the NLRP3 inflammasome mediate IL-1β production in Prevotella nigrescens-infected dendritic cells[J]. Int J Med Sci，2021，18（2）：432-440. DOI：10.7150/ijms.47197.
[49]	ELSAYED R，ELASHIRY M，LIU Y T，et al. Porphyromonas gingivalis provokes exosome secretion and paracrine immune senescence in bystander dendritic cells[J]. Front Cell Infect Microbiol，2021，11：669989. DOI：10.3389/fcimb.2021.669989.
[50]	SÖDERSTRÖM K，STEIN E，COLMENERO P，et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis[J]. Proc Natl Acad Sci U S A，2010，107（29）：13028-13033. DOI：10.1073/pnas.1000546107.
[51]	ZANG J F，YE J，ZHANG C，et al. Senescent hepatocytes enhance natural killer cell activity via the CXCL-10/CXCR3 axis[J]. Exp Ther Med，2019，18（5）：3845-3852. DOI：10.3892/etm.2019.8037.
[52]	RAJAGOPALAN S，LEE E C，DUPRIE M L，et al. TNFR-associated factor 6 and TGF-β-activated kinase 1 control signals for a senescence response by an endosomal NK cell receptor[J]. J Immunol，2014，192（2）：714-721. DOI：10.4049/jimmunol.1302384.
[53]	RAJAGOPALAN S，LONG E O. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling[J]. Proc Natl Acad Sci U S A，2012，109（50）：20596-20601. DOI：10.1073/pnas.1208248109.
[54]	DAR H Y，SINGH A，SHUKLA P，et al. High dietary salt intake correlates with modulated Th17-Treg cell balance resulting in enhanced bone loss and impaired bone-microarchitecture in male mice[J]. Sci Rep，2018，8（1）：2503. DOI：10.1038/s41598-018-20896-y.
[55]	DAR H Y，SHUKLA P，MISHRA P K，et al. Lactobacillus acidophilus inhibits bone loss and increases bone heterogeneity in osteoporotic mice via modulating Treg-Th17 cell balance[J]. Bone Rep，2018，8：46-56. DOI：10.1016/j.bonr.2018.02.001.
[56]	SHASHKOVA E V，TRIVEDI J，CLINE-SMITH A B，et al. Osteoclast-primed Foxp3+ CD8 T cells induce T-bet，eomesodermin，and IFN-γ to regulate bone resorption[J]. J Immunol，2016，197（3）：726-735. DOI：10.4049/jimmunol.1600253.
[57]	FUKUSHIMA Y，MINATO N，HATTORI M. The impact of senescence-associated T cells on immunosenescence and age-related disorders[J]. Inflamm Regen，2018，38：24. DOI：10.1186/s41232-018-0082-9.
[58]	CALLENDER L A，CARROLL E C，BEAL R W J，et al. Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK[J]. Aging Cell，2018，17（1）：e12675. DOI：10.1111/acel.12675.
[59]	FRASCA D，DIAZ A，ROMERO M，et al. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways[J]. Exp Gerontol，2017，87（Pt A）：113-120. DOI：10.1016/j.exger.2016.12.001.
[60]	LI Y，TERAUCHI M，VIKULINA T，et al. B cell production of both OPG and RANKL is significantly increased in aged mice[J]. Open Bone J，2014，6：8-17. DOI：10.2174/1876525401406010008.
[61]	ZHANG Z，YUAN W，DENG J J，et al. Granulocyte colony stimulating factor （G-CSF） regulates neutrophils infiltration and periodontal tissue destruction in an experimental periodontitis[J]. Mol Immunol，2020，117：110-121. DOI：10.1016/j.molimm.2019.11.003.
[62]	BREUIL V，TICCHIONI M，TESTA J，et al. Immune changes in post-menopausal osteoporosis：the Immunos study[J]. Osteoporos Int，2010，21（5）：805-814. DOI：10.1007/s00198-009-1018-7.
[63]	BHAUMIK D，SCOTT G K，SCHOKRPUR S，et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8[J]. Aging，2009，1（4）：402-411. DOI：10.18632/aging.100042.
[64]	LANG A，GRETHER-BECK S，SINGH M，et al. MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4[J]. Aging，2016，8（3）：484-505. DOI：10.18632/aging.100905.
[65]	NOH J H，KIM K M，IDDA M L，et al. GRSF1 suppresses cell senescence[J]. Aging，2018，10（8）：1856-1866. DOI：10.18632/aging.101516.
[66]	NELSON G，KUCHERYAVENKO O，WORDSWORTH J，et al. The senescent bystander effect is caused by ROS-activated NF-κB signalling[J]. Mech Ageing Dev，2018，170：30-36. DOI：10.1016/j.mad.2017.08.005.
[67]	NACARELLI T，LAU L，FUKUMOTO T，et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome[J]. Nat Cell Biol，2019，21（3）：397-407. DOI：10.1038/s41556-019-0287-4.
[68]	KIM S J，MEHTA H H，WAN J X，et al. Mitochondrial peptides modulate mitochondrial function during cellular senescence[J]. Aging，2018，10（6）：1239-1256. DOI：10.18632/aging.101463.
[69]	PLAFKER K S，ZYLA K，BERRY W，et al. Loss of the ubiquitin conjugating enzyme UBE2E3 induces cellular senescence[J]. Redox Biol，2018，17：411-422. DOI：10.1016/j.redox.2018.05.008.
[70]	VIZIOLI M G，LIU T H，MILLER K N，et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence[J]. Genes Dev，2020，34（5/6）：428-445. DOI：10.1101/gad.331272.119.
[71]	JOY J，BARRIO L，SANTOS-TAPIA C，et al. Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence[J]. Dev Cell，2021，56（14）：2043-2058.e7. DOI：10.1016/j.devcel.2021.06.009.
[72]	YAMASHITA R，FUJII S，USHIODA R，et al. Ca2+ imbalance caused by ERdj5 deletion affects mitochondrial fragmentation[J]. Sci Rep，2021，11（1）：20772. DOI：10.1038/s41598-021-99980-9.
[73]	GAN X Q，HUANG S B，YU Q，et al. Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction[J]. Biochem Biophys Res Commun，2015，468（4）：719-725. DOI：10.1016/j.bbrc.2015.11.022.
[74]	ZHANG L，GAN X Q，HE Y T，et al. Drp1-dependent mitochondrial fission mediates osteogenic dysfunction in inflammation through elevated production of reactive oxygen species[J]. PLoS One，2017，12（4）：e0175262. DOI：10.1371/journal.pone.0175262.
[75]	JEONG S，SEONG J H，KANG J H，et al. Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss[J]. FEBS Lett，2021，595（1）：58-67. DOI：10.1002/1873-3468.13963.
[76]	BADER V，WINKLHOFER K F. PINK1 and Parkin：team players in stress-induced mitophagy[J]. Biol Chem，2020，401（6/7）：891-899. DOI：10.1515/hsz-2020-0135.
[77]	LEE S Y，AN H J，KIM J M，et al. PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis[J]. Stem Cell Res Ther，2021，12（1）：589. DOI：10.1186/s13287-021-02656-4.
[78]	WANG X，LI H，ZHENG A，et al. Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration：preventative effect of hydroxytyrosol acetate[J]. Cell Death Dis，2014，5（11）：e1521. DOI：10.1038/cddis.2014.473.
[79]	CAI W J，CHEN Y，SHI L X，et al. AKT-GSK3 β signaling pathway regulates mitochondrial dysfunction-associated OPA1 cleavage contributing to osteoblast apoptosis：preventative effects of hydroxytyrosol[J]. Oxid Med Cell Longev，2019，2019：4101738. DOI：10.1155/2019/4101738.
[80]	MAO Y X，CAI W J，SUN X Y，et al. RAGE-dependent mitochondria pathway：a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products[J]. Cell Death Dis，2018，9（6）：674. DOI：10.1038/s41419-018-0718-3.
[81]	WANG W D，KANG W B，ZHOU X Q，et al. Mitochondrial protein OPA mediates osteoporosis induced by radiation through the P38 signaling pathway[J]. Eur Rev Med Pharmacol Sci，2018，22（23）：8091-8097. DOI：10.26355/eurrev_201812_16499.
[82]	MIDHA A，PAN H，ABARCA C，et al. Unique human and mouse β-cell senescence-associated secretory phenotype （SASP） reveal conserved signaling pathways and heterogeneous factors[J]. Diabetes，2021，70（5）：1098-1116. DOI：10.2337/db20-0553.
[83]	BRAWERMAN G，NTRANOS V，THOMPSON P J. Alpha cell dysfunction in type 1 diabetes is independent of a senescence program[J]. Front Endocrinol，2022，13：932516. DOI：10.3389/fendo.2022.932516.
[84]	BAHOUR N，BLEICHMAR L，ABARCA C，et al. Clearance of p16Ink4a-positive cells in a mouse transgenic model does not change β-cell mass and has limited effects on their proliferative capacity[J]. Aging，2023，15（2）：441-458. DOI：10.18632/aging.204483.
[85]	PRATTICHIZZO F，DE NIGRIS V，MANCUSO E，et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages[J]. Redox Biol，2018，15：170-181. DOI：10.1016/j.redox.2017.12.001.
[86]	WANG Q，NIE L，ZHAO P F，et al. Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging[J]. Int J Oral Sci，2021，13（1）：11. DOI：10.1038/s41368-021-00116-6.
[87]	ZHANG P，WANG Q，NIE L，et al. Hyperglycemia-induced inflamm-aging accelerates gingival senescence via NLRC4 phosphorylation[J]. J Biol Chem，2019，294（49）：18807-18819. DOI：10.1074/jbc.RA119.010648.
[88]	FRASCA D，ROMERO M，DIAZ A，et al. B cells with a senescent-associated secretory phenotype accumulate in the adipose tissue of individuals with obesity[J]. Int J Mol Sci，2021，22（4）：1839. DOI：10.3390/ijms22041839.
[89]	RABHI N，DESEVIN K，BELKINA A C，et al. Obesity-induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors[J]. Life Sci Alliance，2022，5（5）：e202101286. DOI：10.26508/lsa.202101286.
[90]	BOULET N，BRIOT A，JARGAUD V，et al. Notch activation shifts the fate decision of senescent progenitors toward myofibrogenesis in human adipose tissue[J]. Aging Cell，2023，22（3）：e13776. DOI：10.1111/acel.13776.
[91]	XU M，TCHKONIA T，DING H S，et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age[J]. Proc Natl Acad Sci U S A，2015，112（46）：E6301-E6310. DOI：10.1073/pnas.1515386112.
[92]	MANDL M，WAGNER S A，HATZMANN F M，et al. Sprouty1 prevents cellular senescence maintaining proliferation and differentiation capacity of human adipose stem/progenitor cells[J]. J Gerontol A Biol Sci Med Sci，2020，75（12）：2308-2319. DOI：10.1093/gerona/glaa098.
[93]	CONLEY S M，HICKSON L J，KELLOGG T A，et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells[J]. Front Cell Dev Biol，2020，8：197. DOI：10.3389/fcell.2020.00197.
[94]	RATUSHNYY A，EZDAKOVA M，BURAVKOVA L. Secretome of senescent adipose-derived mesenchymal stem cells negatively regulates angiogenesis[J]. Int J Mol Sci，2020，21（5）：1802. DOI：10.3390/ijms21051802.
[95]	LI Y J，LU L Y，XIE Y，et al. Interleukin-6 knockout inhibits senescence of bone mesenchymal stem cells in high-fat diet-induced bone loss[J]. Front Endocrinol，2020，11：622950. DOI：10.3389/fendo.2020.622950.
[96]	VALVERDE M，SÁNCHEZ-BRITO A. Sustained activation of TNFα-induced DNA damage response in newly differentiated adipocytes[J]. Int J Mol Sci，2021，22（19）：10548. DOI：10.3390/ijms221910548.
[97]	VELDHUIS-VLUG A G，ROSEN C J. Clinical implications of bone marrow adiposity[J]. J Intern Med，2018，283（2）：121-139. DOI：10.1111/joim.12718.
[98]	TENCEROVA M，FIGEAC F，DITZEL N，et al. High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice[J]. J Bone Miner Res，2018，33（6）：1154-1165. DOI：10.1002/jbmr.3408.
[99]	LIU X N，GU Y R，KUMAR S，et al. Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow[J]. Cell Metab，2023，35（4）：667-684.e6. DOI：10.1016/j.cmet.2023.03.005.