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Bioprocess 2026
细胞衰老在阿尔茨海默病发生发展中的作用及治疗前景
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Abstract:
阿尔茨海默病(Alzheimer’s disease, AD)作为一种以进行性认知功能障碍和记忆丧失为核心的神经退行性疾病，其发病机制错综复杂，目前临床仍缺乏有效的根治手段。细胞衰老作为机体老化的重要生物学标志，近年来的研究证据日益凸显其在AD发生与进展中的关键作用。本文以AD病理进程中胶质细胞、血管内皮细胞发生经典细胞衰老、神经元出现衰老样状态的分子机制为切入点，衰老细胞通过分泌衰老相关分泌表型(Senescence-Associated Secretory Phenotype, SASP)因子，如何加剧神经炎症反应、促进β-淀粉样蛋白(Amyloid-beta protein, Aβ)沉积以及驱动Tau蛋白过度磷酸化的病理过程进行综述。在此基础上，进一步探讨了基于清除衰老细胞的Senolytics疗法在AD治疗中的潜在应用与挑战。本文旨在整合现有研究成果，为AD的预防策略与治疗靶点开发提供新的理论视角与实践方向。
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and memory loss as its core symptoms. It has an intricate and complex pathogenesis, and there is still a lack of effective radical cure methods in clinical practice. As an important biological marker of organism aging, cellular senescence has been proven by growing research evidence in recent years to play a pivotal role in the occurrence and progression of AD. This article focuses on the molecular mechanisms underlying classic cellular senescence in glial cells and vascular endothelial cells, as well as the emergence of senility-like states in neurons during the pathological progression of AD, and elaborates on how senescent cells exacerbate neuroinflammation, promote amyloid-beta (Aβ) protein deposition and drive the pathological process of Tau protein hyperphosphorylation by secreting Senescence-Associated Secretory Phenotype (SASP) factors. On this basis, it further discusses the potential applications and challenges of Senolytics therapy based on senescent cell clearance in the treatment of AD. This paper aims to integrate existing research findings and provide novel theoretical perspectives and practical directions for the development of prevention strategies and therapeutic targets for AD.
| [1] | Zhang, X. and Pan, M. (2025) Changes and Forecast of the Disease Burden of Senile Dementias among Chinese Residents from 1992 to 2021. Journal of Central South University. Medical Sciences, 50, 2071-2081. |
| [2] | GBD 2019 Dementia Forecasting Collaborators (2022) Estimation of the Global Prevalence of Dementia in 2019 and Forecasted Prevalence in 2050: An Analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 7, e105-e125. |
| [3] | Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L. and Peng, W. (2024) The Interaction between Ageing and Alzheimer’s Disease: Insights from the Hallmarks of Ageing. Translational Neurodegeneration, 13, Article No. 7. https://doi.org/10.1186/s40035-024-00397-x |
| [4] | Karran, E. and De Strooper, B. (2022) The Amyloid Hypothesis in Alzheimer Disease: New Insights from New Therapeutics. Nature Reviews Drug Discovery, 21, 306-318. https://doi.org/10.1038/s41573-022-00391-w |
| [5] | Gao, P., Yao, F., Pang, J., Yin, K. and Zhu, X. (2023) m6A Methylation in Cellular Senescence of Age-Associated Diseases. Acta Biochimica et Biophysica Sinica, 55, 1168-1183. https://doi.org/10.3724/abbs.2023107 |
| [6] | Abbatecola, A.M., Giuliani, A., Biscetti, L., Scisciola, L., Battista, P., Barbieri, M., et al. (2024) Circulating Biomarkers of Inflammaging and Alzheimer’s Disease to Track Age-Related Trajectories of Dementia: Can We Develop a Clinically Relevant Composite Combination? Ageing Research Reviews, 96, Article ID: 102257. https://doi.org/10.1016/j.arr.2024.102257 |
| [7] | Sun, R., Feng, J. and Wang, J. (2024) Underlying Mechanisms and Treatment of Cellular Senescence-Induced Biological Barrier Interruption and Related Diseases. Aging and Disease, 15, 612-639. https://doi.org/10.14336/ad.2023.0621 |
| [8] | Bhatt, L.K. and Singh, S. (2024) Targeting Cellular Senescence: A Potential Therapeutic Approach for Alzheimer’s Disease. Current Molecular Pharmacology, 17, e2033282951. https://doi.org/10.2174/1874467217666230601113430 |
| [9] | Rim, C., You, M., Nahm, M. and Kwon, M. (2024) Emerging Role of Senescent Microglia in Brain Aging-Related Neurodegenerative Diseases. Translational Neurodegeneration, 13, Article No. 10. https://doi.org/10.1186/s40035-024-00402-3 |
| [10] | 林洁双, 卓桂锋, 陈炜. 细胞衰老与小胶质细胞极化在阿尔茨海默病发病机制中的研究进展[J]. 中国医药导报, 2025, 22(31): 136-141. |
| [11] | 赵珺琦, 叶田园, 齐冬梅, 等. 细胞衰老在阿尔茨海默病发病机制及防治中的作用研究进展[J]. 中国现代应用药学, 2022, 39(9): 1235-1246. |
| [12] | Thapa, R., Bhat, A.A., Shahwan, M., Ali, H., PadmaPriya, G., Bansal, P., et al. (2024) Proteostasis Disruption and Senescence in Alzheimer’s Disease Pathways to Neurodegeneration. Brain Research, 1845, Article ID: 149202. https://doi.org/10.1016/j.brainres.2024.149202 |
| [13] | Tangavelou, K. and Bhaskar, K. (2024) The Mechanistic Link between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer’s Disease. International Journal of Molecular Sciences, 25, Article No. 12335. https://doi.org/10.3390/ijms252212335 |
| [14] | Gaikwad, S., Senapati, S., Haque, M.A. and Kayed, R. (2024) Senescence, Brain Inflammation, and Oligomeric Tau Drive Cognitive Decline in Alzheimer’s Disease: Evidence from Clinical and Preclinical Studies. Alzheimer’s & Dementia, 20, 709-727. https://doi.org/10.1002/alz.13490 |
| [15] | Richardson, M. and Richardson, D.R. (2024) Pharmacological Targeting of Senescence with Senolytics as a New Therapeutic Strategy for Neurodegeneration. Molecular Pharmacology, 105, 64-74. https://doi.org/10.1124/molpharm.123.000803 |
| [16] | Millar, C.L., Iloputaife, I., Baldyga, K., Kuo, J., Tchkonia, T., Kirkland, J.L., et al. (2023) Rationale and Design of STAMINA: Senolytics to Alleviate Mobility Issues and Neurological Impairments in Aging, a Geroscience Feasibility Study. Translational Medicine of Aging, 7, 109-117. https://doi.org/10.1016/j.tma.2023.10.004 |
| [17] | Ogrodnik, M., Carlos Acosta, J., Adams, P.D., d’Adda di Fagagna, F., Baker, D.J., Bishop, C.L., et al. (2024) Guidelines for Minimal Information on Cellular Senescence Experimentation in Vivo. Cell, 187, 4150-4175. https://doi.org/10.1016/j.cell.2024.05.059 |
| [18] | González‐Gualda, E., Baker, A.G., Fruk, L. and Muñoz‐Espín, D. (2021) A Guide to Assessing Cellular Senescence in Vitro and in Vivo. The FEBS Journal, 288, 56-80. https://doi.org/10.1111/febs.15570 |
| [19] | Hernandez-Segura, A., Nehme, J. and Demaria, M. (2018) Hallmarks of Cellular Senescence. Trends in Cell Biology, 28, 436-453. https://doi.org/10.1016/j.tcb.2018.02.001 |
| [20] | Hudson, H.R., Correia-Melo, C. and Hewitt, G. (2025) Defining and Characterizing Neuronal Senescence, “Neurescence”, as a Distinct Cellular State in the Ageing Brain. The FEBS Journal, 292, 3430-3444. |
| [21] | Sun, L. and Chen, C. (2025) Senescence in Aging and Alzheimer’s Disease. Aging and Disease, Advance Online Publication. |
| [22] | Hughes, J.-W.B., Sandholm, A., Croll, D., Senchyna, F., Schneider, K., Butterfield, R., et al. (2026) DNA Damage Drives a Unique, Alzheimer’s Disease-Relevant Senescent State in Neurons. https://pmc.ncbi.nlm.nih.gov/articles/PMC13060347/ |
| [23] | Some, A., Naskar, N., Thomas, D.M., Jeengar, M.K. and Nassar, A. (2026) Senescence as a Central Node in Alzheimer’s Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions. Neurochemical Research, 51, Article No. 116. https://doi.org/10.1007/s11064-026-04737-3 |
| [24] | Firdous, S.M., Chakrabortty, S., Undale, V.R., Mallik, S. and Gouda, M. (2026) Interplay of Oxidative Stress and Neuroinflammation in Alzheimer’s: Insights into Age-Driven Pathogenesis. Inflammopharmacology, 34, 2243-2263. https://doi.org/10.1007/s10787-026-02169-7 |
| [25] | Alshaebi, F., Sciortino, A. and Kayed, R. (2025) The Role of Glial Cell Senescence in Alzheimer’s Disease. Journal of Neurochemistry, 169, e70051. https://doi.org/10.1111/jnc.70051 |
| [26] | Ristori, S., Bertoni, G., Bigi, A., Cecchi, C., Sollazzo, M., Iommarini, L., et al. (2025) Human Astrocytes from Healthy Individuals and Alzheimer’s Patients Respond Differently to Aβ 1-42 Oligomers, Triggering Distinct Paths of Reactivity and Senescence. Mechanisms of Ageing and Development, 228, Article ID: 112116. https://doi.org/10.1016/j.mad.2025.112116 |
| [27] | Ma, J., Yang, B., Jiang, X., Wang, L., Wei, W., Cao, Y., et al. (2026) Microglial Senescence and Epigenetic Reprogramming in Alzheimer’s Disease: An Immunometabolic Perspective. Experimental Gerontology, 221, Article ID: 113177. https://doi.org/10.1016/j.exger.2026.113177 |
| [28] | Li, Z., Wang, T., Du, S., Miao, Z., Zhao, Y., Tang, Y., et al. (2025) Tgm2‐Catalyzed Covalent Cross‐Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia. Aging Cell, 24, e14463. https://doi.org/10.1111/acel.14463 |
| [29] | Wei, L., Yang, X., Wang, J., Wang, Z., Wang, Q., Ding, Y., et al. (2023) H3K18 Lactylation of Senescent Microglia Potentiates Brain Aging and Alzheimer’s Disease through the NF-κB Signaling Pathway. Journal of Neuroinflammation, 20, Article No. 208. https://doi.org/10.1186/s12974-023-02879-7 |
| [30] | Doshi, P.P., Desale, S.H., Khutale, A.A., Sabarathinam, S. and Suresh, S. (2026) Evaluating Senescence-Targeted Approaches in Alzheimer’s Disease: What We Know and What Lies Ahead. Ageing Research Reviews, 115, Article ID: 103029. https://doi.org/10.1016/j.arr.2026.103029 |
| [31] | Hussong, S.A., Banh, A.Q., Van Skike, C.E., Dorigatti, A.O., Hernandez, S.F., Hart, M.J., et al. (2023) Soluble Pathogenic Tau Enters Brain Vascular Endothelial Cells and Drives Cellular Senescence and Brain Microvascular Dysfunction in a Mouse Model of Tauopathy. Nature Communications, 14, Article No. 2367. https://doi.org/10.1038/s41467-023-37840-y |
| [32] | Zhou, R., Lin, X., Liao, Z., Lin, J., Zheng, R., Ni, H., et al. (2026) Decoding Senescent Drivers in Alzheimer’s Disease: From Bench to Bedside. Ageing Research Reviews, 114, Article ID: 102978. https://doi.org/10.1016/j.arr.2025.102978 |
| [33] | Zhang, Y., Jin, Z., Rao, R., Si, L., Zhang, Z., Ma, R., et al. (2026) Single-Nucleus Profiling Reveals a BBB Senescence Unit Driving AD Pathology in Human Brain. Molecular Neurobiology, 63, Article No. 665. https://doi.org/10.1007/s12035-026-05956-z |
| [34] | Wang, Y., Kuca, K., You, L., Nepovimova, E., Heger, Z., Valko, M., et al. (2024) The Role of Cellular Senescence in Neurodegenerative Diseases. Archives of Toxicology, 98, 2393-2408. https://doi.org/10.1007/s00204-024-03768-5 |
| [35] | Riessland, M. and Orr, M.E. (2023) Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics. The Journal of Prevention of Alzheimer’s Disease, 10, 633-646. https://doi.org/10.14283/jpad.2023.104 |
| [36] | Yu, N., Pasha, M. and Chua, J.J.E. (2024) Redox Changes and Cellular Senescence in Alzheimer’s Disease. Redox Biology, 70, Article ID: 103048. https://doi.org/10.1016/j.redox.2024.103048 |
| [37] | Singh, M., Ali, H., Renuka Jyothi, S., Kaur, I., Kumar, S., Sharma, N., et al. (2024) Tau Proteins and Senescent Cells: Targeting Aging Pathways in Alzheimer’s Disease. Brain Research, 1844, Article ID: 149165. https://doi.org/10.1016/j.brainres.2024.149165 |
| [38] | Karabag, D., Heneka, M.T. and Ising, C. (2024) The Putative Contribution of Cellular Senescence to Driving Tauopathies. Trends in Immunology, 45, 837-848. https://doi.org/10.1016/j.it.2024.08.006 |
| [39] | Hussain, M.S., Agrawal, N., Ilma, B., Nayak, P.P., Kaur, M., et al. (2025) Autophagy and Cellular Senescence in Alzheimer’s Disease: Key Drivers of Neurodegeneration. CNS Neuroscience & Therapeutics, 31, e70503. https://doi.org/10.1111/cns.70503 |
| [40] | Kuźniar, J., Kozubek, P., Czaja, M., Sitka, H., Kochman, U. and Leszek, J. (2025) Connections between Cellular Senescence and Alzheimer’s Disease—A Narrative Review. International Journal of Molecular Sciences, 26, Article No. 8638. https://doi.org/10.3390/ijms26178638 |
| [41] | Liu, Y., Hong, T., Lv, M., Guo, X., Zhang, P., Yan, A., et al. (2025) Delphinidin Attenuates Cognitive Deficits and Pathology of Alzheimer’s Disease by Preventing Microglial Senescence via AMPK/SIRT1 Pathway. Alzheimer’s Research & Therapy, 17, Article No. 138. https://doi.org/10.1186/s13195-025-01783-x |
| [42] | Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R.G., Zhang, S., et al. (2019) Senolytic Therapy Alleviates Aβ-Associated Oligodendrocyte Progenitor Cell Senescence and Cognitive Deficits in an Alzheimer’s Disease Model. Nature Neuroscience, 22, 719-728. https://doi.org/10.1038/s41593-019-0372-9 |
| [43] | Bussian, T.J., Aziz, A., Meyer, C.F., Swenson, B.L., van Deursen, J.M. and Baker, D.J. (2018) Clearance of Senescent Glial Cells Prevents Tau-Dependent Pathology and Cognitive Decline. Nature, 562, 578-582. https://doi.org/10.1038/s41586-018-0543-y |
| [44] | Gonzales, M.M., Garbarino, V.R., Kautz, T.F., Palavicini, J.P., Lopez-Cruzan, M., Dehkordi, S.K., et al. (2023) Senolytic Therapy in Mild Alzheimer’s Disease: A Phase 1 Feasibility Trial. Nature Medicine, 29, 2481-2488. https://doi.org/10.1038/s41591-023-02543-w |
| [45] | Niu, Q., Li, D., Zhang, J., Piao, Z., Xu, B., Xi, Y., et al. (2024) The New Perspective of Alzheimer’s Disease Research: Mechanism and Therapeutic Strategy of Neuronal Senescence. Ageing Research Reviews, 102, Article ID: 102593. https://doi.org/10.1016/j.arr.2024.102593 |
| [46] | Alum, E.U., Izah, S.C., Uti, D.E., Ugwu, O., Betiang, P., Basajja, M., et al. (2025) Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics and Senomorphics. Drug Design, Development and Therapy, 19, 8489-8522. https://doi.org/10.2147/dddt.s543211 |
| [47] | Cantero-Fortiz, Y., Butler, C., Montalbán, X. and Boada, M. (2026) Cellular Senescence in Brain Aging and Neurodegeneration: From Molecular Mechanisms to Translational Opportunities. Frontiers in Cellular Neuroscience, 20, Article ID: 1805691. https://doi.org/10.3389/fncel.2026.1805691 |
| [48] | Twarowski, B. and Herbet, M. (2023) Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review. International Journal of Molecular Sciences, 24, Article No. 6518. https://doi.org/10.3390/ijms24076518 |
| [49] | Antón-Fernández, A., Ruiz de Alegría, Á., Mariscal-Casero, A., Roldán-Lázaro, M., Peinado-Cauchola, R., Ávila, J., et al. (2025) Partial Reprogramming by Cyclical Overexpression of Yamanaka Factors Improves Pathological Phenotypes of Tauopathy Mouse Model of Human Alzheimer’s Disease. Progress in Neurobiology, 247, Article ID: 102743. https://doi.org/10.1016/j.pneurobio.2025.102743 |
