达沙替尼（Dasatinib）是一种第二代酪氨酸激酶抑制剂，最初开发用于治疗慢性髓性白血病（CML）和费城染色体阳性急性淋巴细胞白血病。近年来，达沙替尼作为一种用于长寿领域的 senolytic（衰老细胞清除）剂备受关注，通常与槲皮素（quercetin）联合使用，以选择性地消除随衰老而积累的衰老细胞。
达沙替尼通过靶向衰老细胞赖以生存的多种激酶通路来发挥 senolytic 作用。当与槲皮素结合使用时，它会产生一种强大的 senolytic 鸡尾酒疗法，能够选择性地诱导衰老细胞凋亡，同时保留健康细胞。这种机制使其成为治疗年龄相关疾病和潜在延长健康寿命（healthspan）的极具前景的干预措施。
- 衰老细胞负荷 (D+Q) — ↓ 脂肪/肾脏组织中 — C.[335][391]
- 身体机能（初步研究） — ↑ 轻微 — C.[334][346]
- 高危老年人的认知/活动能力 — 已证明可行性；信号不确定 — C.[^334]
- 人类寿命 — 证据不足 — F.
酪氨酸激酶抑制：
- BCR-ABL 融合蛋白（费城染色体）
- Src 家族激酶
- c-Kit 受体
- Ephrin 受体
- PDGFR（血小板衍生生长因子受体）¹
Src 激酶抑制：
- 破坏衰老细胞中的生存通路
- 靶向 PI3K/AKT 生存通路
- 抑制黏着斑激酶（FAK）信号传导²
与槲皮素（Quercetin）联用：
- 达沙替尼（Dasatinib）抑制依赖于 Src 激酶的生存通路
- 槲皮素抑制抗凋亡蛋白（BCL-xL、BCL-2）
- 协同作用对衰老细胞产生选择性毒性³
细胞选择性：
- 衰老细胞更依赖于生存通路
- 正常细胞具有冗余的生存机制
- 为选择性消除创造了治疗窗口⁴
动物模型：
- 改善老年小鼠的心血管功能
- 增强身体机能和活动能力
- 减少组织炎症和纤维化
- 在多种衰老模型中延长了健康寿命⁵
衰老细胞清除：
- 各种组织中的衰老细胞负荷减少 25-50%
- 改善组织再生和功能
- 逆转部分与年龄相关的表型⁶
STAMINA 研究（2025年）：
- 12 名年龄 ≥65 岁且有阿尔茨海默病风险的参与者
- 方案：100 mg 达沙替尼（dasatinib） + 1250 mg 槲皮素（quercetin），连续服用 2 天，每 2 周一次，持续 12 周
- 结果：可行且安全；潜在的认知改善与炎症减少相关⁷
糖尿病肾病研究：
- 开放标签 1 期初步研究
- 3 天口服疗程在 11 天后减少了衰老细胞负荷
- 改善了代谢参数和肾功能标志物⁸
特发性肺纤维化试验：
- I 期、单盲、安慰剂对照初步研究
- 证明了可行性和耐受性
- 部分参与者表现出肺功能改善⁹
阿尔茨海默病研究：
- 已完成多项 I 期试验
- 证明了良好的安全性
- 认知结果喜忧参半¹⁰
2024年纵向研究：
- 19名参与者接受了为期6个月的达沙替尼（dasatinib）+ 槲皮素（quercetin）治疗
- 第一代衰老表观遗传时钟发生显著变化
- 端粒长度显著缩短
- 对不同衰老生物标志物产生混合效应¹¹
研究记录了衰老相关生物标志物的改善：
- 炎症标志物（TNF-α、IL-6、IL-1β）¹²
- 衰老相关分泌表型（SASP）因子¹³
- 脂肪组织炎症标志物¹⁴
- 心血管功能参数¹⁵
达沙替尼（Dasatinib）在数十年的癌症治疗应用中具有充分表征的安全性概况。在使用间歇性给药的抗衰老（senolytic）应用中，其安全性概况似乎比连续的癌症给药更有利，尽管针对抗衰老用途的具体长期数据仍然有限¹⁶。
血液学影响：
- 中性粒细胞减少症（白细胞偏低） - 21%的患者¹⁷
- 血小板减少症（血小板偏低） - 10-19%的患者¹⁸
- 贫血（红细胞偏低）¹⁹
- 通常可通过调整剂量逆转²⁰
胃肠道影响：
- 腹泻（常见）²¹
- 恶心和呕吐²²
- 腹痛²³
- 通常为轻度至中度²⁴
全身症状：
- 疲劳和虚弱²⁵
- 头痛²⁶
- 发热²⁷
- 肌肉和关节疼痛²⁸
皮肤和软组织：
- 皮疹²⁹
- 腿部、手臂和面部肿胀（水肿）³⁰
- 通常可通过支持性护理控制³¹
肺部并发症：
- 胸腔积液（肺部周围积液）- 在某些研究中发生率为 18%³²
- 肺动脉高压 (PAH) - 罕见但严重³³
- 肺水肿³⁴
- 呼吸困难（呼吸费力）³⁵
心血管影响：
- QT 间期延长³⁶
- 心力衰竭（罕见）³⁷
- 心律失常³⁸
- 需要心脏监测³⁹
出血并发症：
- 出血（Hemorrhage）⁴⁰
- 由于血小板影响导致出血风险增加⁴¹
- 胃肠道出血（不常见）⁴²
肾脏并发症：
- 肾病综合征（罕见）⁴³
- 肾功能损害⁴⁴
- 停药后通常可逆⁴⁵
Senolytic 方案安全性：
- 总药物暴露量低于癌症治疗
- 慢性副作用的发生率降低
- 大多数不良事件是轻微且短暂的⁴⁶
监测要求：
- 每个周期前进行全血细胞计数
- 肝肾功能检查
- 如果存在危险因素，需进行心脏评估⁴⁷
- 对 dasatinib 或其成分过敏⁴⁸
- 怀孕和哺乳期⁴⁹
- 严重肝功能损害⁵⁰
心脏疾病：
- 既往存在 QT 间期延长⁵¹
- 先天性长 QT 综合征⁵²
- 未控制的心力衰竭⁵³
- 近期心肌梗死⁵⁴
肺部疾病：
- 既往存在肺动脉高压⁵⁵
- 严重肺部疾病⁵⁶
- 复发性胸腔积液病史⁵⁷
血液系统疾病：
- 严重血细胞减少症⁵⁸
- 活动性出血性疾病⁵⁹
- 近期接受过重大手术⁶⁰
老年患者：
- 可能需要调整剂量
- 增加对副作用的监测
- 考虑合并症和药物相互作用⁶¹
肾功能不全：
肝功能不全：
达沙替尼 + 槲皮素组合：
- 达沙替尼：口服 100 mg
- 槲皮素：口服 1000-1250 mg
- 每 2 周连续给药 2 天
- 初始疗程：12-24 周⁶⁴
替代方案：
- 每月 3 天的周期
- 针对敏感患者的低剂量方案
- 用于研究应用的扩展方案⁶⁵
治疗前评估：
- 完整的病史和体格检查
- 带有白细胞分类的全血细胞计数
- 综合代谢检查
- 肝功能检查
- 心电图⁶⁶
治疗期间：
- 每个周期前进行全血细胞计数 (CBC)
- 每月进行代谢检查
- 如有指征，进行心脏监测
- 症状评估⁶⁷
治疗后随访：
- 恢复情况评估
- 长期安全性监测
- 疗效生物标志物评估⁶⁸
CYP3A4 抑制剂：
- 酮康唑 (Ketoconazole)、伊曲康唑 (Itraconazole)
- 克拉霉素 (Clarithromycin)、红霉素 (Erythromycin)
- 西柚汁
- 可能显著增加达沙替尼水平⁶⁹
CYP3A4 诱导剂：
- 利福平 (Rifampin)、苯妥英 (Phenytoin)
- 卡马西平 (Carbamazepine)、圣约翰草 (St. John's wort)
- 可能降低达沙替尼的疗效⁷⁰
延长 QT 间期的药物：
- 胺碘酮 (Amiodarone)、索他洛尔 (Sotalol)
- 氟哌啶醇 (Haloperidol)、齐拉西酮 (Ziprasidone)
- 增加心律失常的风险⁷¹
抗凝血剂：
- 华法林 (Warfarin)、肝素 (Heparin)
- 增加出血风险
- 需密切监测 INR⁷²
质子泵抑制剂：
- 可能降低达沙替尼的吸收
- 考虑改用 H2 受体阻滞剂⁷³
- 达沙替尼（仿制药）：每个周期 50-200 美元
- 槲皮素补充剂：每个周期 20-50 美元
- 监测成本：每个周期 200-500 美元
- 每月总成本：150-400 美元⁷⁴
- 达沙替尼仿制药广泛供应
- 需要具备资质的医生开具处方
- 仅限于研究机构或专科诊所
- 用于抗衰老领域的超适应症使用 (Off-label use)⁷⁵
- 缺乏关于使用 senolytic 的长期安全性数据
- 尚未建立最佳给药方案
- 尚未明确个体反应差异
- 与其他干预措施联合使用的数据有限⁷⁶
- FDA 仅批准用于癌症治疗
- 抗衰老应用属于超适应症使用（off-label use）
- 尚无针对长寿应用的标准化方案
- 需要在医疗监督下进行⁷⁷
- 更大规模的随机对照试验
- 生物标志物指导的治疗方案
- 与其他 senolytics 联合使用
- 长期安全性和有效性研究⁷⁸
- 优化的 senolytic 组合
- 个性化给药策略
- 新型递送系统
- 组织特异性 senolytic 方法⁷⁹
达沙替尼（Dasatinib）与槲皮素（quercetin）联用，代表了一种在长寿应用方面极具前景的 senolytic 干预手段。虽然初步临床数据显示间歇性给药具有良好的耐受性，但由于潜在的严重不良事件，该疗法需要严密的医疗监督。Senolytic 领域正在快速发展，在下一代 senolytics 研发出来之前，达沙替尼可能会作为一种重要的桥接疗法发挥作用。
- Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658-6661.
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-658.
- Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15(3):428-435.
- Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536.
- Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256.
- Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017;9(3):955-963.
- Justice JN, Niedernhofer LJ, Robbins PD, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease. eBioMedicine. 2025;101:105056.
- Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456.
- Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: results of a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-563.
- Gonzales MM, Garbarino VR, Marques Zilli E, et al. Senolytic therapy to modulate the progression of Alzheimer's disease (SToMP-AD): a pilot clinical trial. J Prev Alzheimers Dis. 2022;9(1):22-29.
- Raffaele M, Kovacovicova K, Frohlich J, et al. Exploring the effects of dasatinib, quercetin, and fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions. Aging (Albany NY). 2024;16(3):2317-2336.
- Xu M, Tchkonia T, Ding H, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A. 2015;112(46):E6301-E6310.
- Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966-972.
- Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019;18(3):e12950.
- Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973-977.
- Dasatinib, a multikinase inhibitor: therapy, safety, and appropriate management of adverse events. Ther Adv Hematol. 2010;1(1):7-17.
- Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305(5682):399-401.
- Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541.
- Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109(12):5143-5150.
- Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303-2309.
- Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270.
- Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259.
- Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898-3905.
- Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123(4):494-500.
- Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333-2340.
- Hughes TP, Saglio G, Quintás-Cardama A, et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia. 2015;29(9):1832-1838.
- Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91(9):869-874.
- Quintas-Cardama A, Kantarjian H, Jones D, et al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007;109(2):497-499.
- Porkka K, Khoury HJ, Paquette RL, et al. Dasatinib 100 mg once daily minimizes the incidence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116(2):377-386.
- de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26(20):3358-3363.
- Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908-3914.
- Ibid.
- Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128-2137.
- Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res. 2009;33(6):861-864.
- Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908-3914.
- Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf. 2013;36(5):295-316.
- Quintas-Cardama A, Han X, Kantarjian H, et al. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114(2):261-263.
- Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf. 2013;36(5):295-316.
- Ibid.
- Quintas-Cardama A, Han X, Kantarjian H, et al. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114(2):261-263.
- Ibid.
- Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270.
- Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469-471.
- Ibid.
- Vaz de Castro PA, Bitencourt R, Saldanha AC, et al. Dasatinib-induced nephrotic syndrome in chronic myeloid leukemia. J Oncol Pharm Pract. 2015;21(1):61-64.
- Justice JN, Niedernhofer LJ, Robbins PD, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease. eBioMedicine. 2025;101:105056.
- Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- Ibid.
- Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf. 2013;36(5):295-316.
- Ibid.
- Ibid.
- Ibid.
- Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128-2137.
- Ibid.
- Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908-3914.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- Ibid.
- Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333-2340.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- Justice JN, Niedernhofer LJ, Robbins PD, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease. eBioMedicine. 2025;101:105056.
- Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- Justice JN, Niedernhofer LJ, Robbins PD, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease. eBioMedicine. 2025;101:105056.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf. 2013;36(5):295-316.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Ibid.
- GoodRx. Dasatinib prices, coupons, and patient assistance programs. 2024.
- Justice JN, Niedernhofer LJ, Robbins PD, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease. eBioMedicine. 2025;101:105056.
- Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536.
- Bristol-Myers Squibb. Sprycel (dasatinib) prescribing information. 2021.
- Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536.
- Niedernhofer LJ, Robbins PD. Senotherapeutics for healthy ageing. Nat Rev Drug Discov. 2018;17(5):377.