SRT-2104

作者：金汉卿 美工：何国红 罗真真 排版：马超 一、引言 人类对抗衰老的探索贯穿了整个文明史，从古代炼金术士对“贤者之石”与长生神药的神秘追寻，演变为现代生物医学中最具颠覆性的前沿学科——老年科学（Geroscience）。随着分子生物学、遗传学及系统生物学的飞速发展，衰老不再被视为一种不可逆转的熵增宿命，而被重新定义为一组可被生物学机制解释、量化乃至干预的复杂病理生理过程。 人类对衰老的认知，从衰老的源头损伤（如基因组不稳定性与表观遗传漂移）、中游的代谢失调（如营养感应通路异常与线粒体功能障碍），到下游的功能衰退（如细胞衰老与慢性炎症），早已经构建了一个多层次的系统性认知框架。 ▲ Figure 1. Molecular mechanisms of aging and anti-aging strategies[1] 二、衰老的生物学架构 为了系统地干预衰老，首先必须精确地定义它。2013年，López-Otín等人在《Cell》杂志上发表了里程碑式的综述《The Hallmarks of Aging》，总结了九大衰老标识。2023年，这一框架被进一步扩展和细化为十二大标识。这些标识不仅在分子层面定义了衰老，更提供了药物开发的具体靶点。它们被分为三个层次：源头损伤、拮抗性反应（中游的代谢失调）和综合性表型（下游的功能衰退）[2]。 01 源头损伤：基因组与表观遗传的熵增 衰老的始发点往往在于遗传信息的完整性受损。这如同复印机反复复印文件，随着次数增加，噪点和错误逐渐累积。这些遗传信息的损伤包括基因组不稳定性（Genomic Instability）、表观遗传改变（Epigenetic Alterations）以及端粒磨损（Telomere Attrition）。源头损伤会触发一系列细胞内的应激反应和稳态失衡，这些反应在初期可能是保护性的，但长期持续则转变为破坏性。 02 代谢与细胞稳态的失调：中游的调控紊乱 随着源头损伤的逐步发展，细胞内的代谢与稳态开始逐渐产生偏差，蛋白稳态开始失衡，代谢途径逐渐瓦解，而作为细胞的能量工程，线粒体的功能也出现障碍。衰老导致分子伴侣功能下降，无法协助蛋白正确折叠；同时，负责清除垃圾的蛋白酶体和溶酶体自噬系统活性减弱。结果是错误折叠的蛋白质无法被修复也无法被清除，它们聚集成毒性团块（如阿茨海默病中的β-淀粉样蛋白和Tau蛋白，帕金森病中的α-突触核蛋白），直接干扰细胞功能并诱导细胞死亡。衰老导致的线粒体DNA突变、电子传递链效率降低和线粒体动力学异常，导致能量供给不足和过量ROS泄漏，引发炎症和细胞死亡。 03 功能衰退与系统性效应：下游的病理表现 随着分子层面的损伤不断叠加汇总，最终汇聚为细胞和组织层面的功能衰竭，表现为临床可见的衰老表型。首先是细胞衰老，衰老的细胞会分泌大量的促炎因子、生长因子和蛋白酶，统称为衰老相关分泌表型（SASP）。SASP不仅破坏局部组织微环境（降解细胞外基质），还会诱导邻近健康细胞发生衰老（旁分泌效应），并招募免疫细胞引发慢性炎症。同时，由于DNA损伤累积、端粒极度缩短以及衰老微环境（SASP）的抑制，干细胞逐渐失去增殖和分化能力，甚至直接衰竭。这直接导致了造血功能下降（免疫衰老）、肌肉萎缩（少肌症）、骨质疏松和皮肤愈合能力差。而由衰老细胞与干细胞耗竭导致的慢性炎症则是连接分子损伤与宏观疾病，例如动脉粥样硬化、胰岛素抵抗和神经退行性疾病的桥梁。 三、小分子药物：从模糊干预到精准代谢调控 随着对衰老机制认知的深入，干预手段也从早期的“全系统模糊调节”（如热量限制）进化为针对特定核心信号通路甚至特定的细胞群体的精准药物干预。小分子药物和大分子生物药基于其不同的特性，被应用于不同机制的治疗手段，小分子药物聚焦于代谢层面的调控。 ▲ Figure 2. Metabolic alterations of Aging[2] 01 mTOR通路与雷帕霉素：细胞生长的“主开关”与双刃剑 mTOR是目前抗衰老领域研究最深入、证据最确凿的靶点。作为一种丝氨酸/苏氨酸激酶，mTOR整合了营养（氨基酸）、能量（ATP）、生长因子（胰岛素）等多重信号。当营养充足时，mTORC1被激活，它磷酸化下游底物如S6K1和4E-BP1，极大地促进蛋白质和脂质的合成，推动细胞生长。衰老过程中，mTORC1往往处于持续的过度激活状态，导致细胞不断合成蛋白却无法清除累积的废物，最终引发功能崩溃。而针对mTOR的雷帕霉素是目前唯一在NIA的干预测试计划（ITP）中，在遗传异质性小鼠中无论雌雄、无论给药起始时间（甚至是晚年给药），都能稳健延长寿命的药物，延长幅度可达10%-30%[3]。 02 AMPK通路与二甲双胍：能量感应与“老药新用” AMP活化蛋白激酶（AMPK）是细胞的“能量感受器”。当细胞能量耗竭，AMP/ATP比值升高时，AMPK被激活。激活的AMPK就像细胞的“节能模式”开关：它关闭合成代谢（耗能），开启分解代谢（产修），包括促进葡萄糖摄取、脂肪酸氧化，此外AMPK能直接磷酸化抑制mTORC1，并激活SIRT1和PGC-1α（线粒体生物合成主控因子），从而形成一个抗衰老的信号网络。作为全球使用最广的降糖药，二甲双胍被发现具有惊人的抗衰老潜力。它轻度抑制线粒体复合物I，导致ATP生成微降、AMP上升，从而激活AMPK。越来越多的证据表明，二甲双胍可以调节关键的衰老相关过程，包括能量调节、炎症和自噬，从而延缓衰老并减轻衰老相关疾病[4]。于二甲双胍具有延长寿命和改善健康状况的潜力，它成为首个针对抗衰老干预措施的大型临床试验——“二甲双胍靶向衰老”（TAME）试验计划的重点研究对象[5]。 03 Sirtuins与NAD+代谢：线粒体复兴的希望 Sirtuins是一类依赖NAD+的去乙酰化酶（SIRT1-SIRT7），被称为“长寿蛋白”。它们在DNA修复、线粒体维护和炎症控制中起关键作用。Sirtuins的活性受限于其辅酶NAD+（烟酰胺腺嘌呤二核苷酸）的水平，随年龄增长，NAD+合成酶（NAMPT）活性下降，而消耗酶（如CD38）活性飙升，导致NAD+水平断崖式下跌。针对Sirtuins的合成激活剂（如SRT1720、SRT2104）在动物实验中显示出更好的效力，但临床转化尚在探索中[6]。 04 胰岛素/IGF-1信号通路（IIS）：生长与长寿的权衡 IGF-1（胰岛素样生长因子-1）是促进生长、发育和组织合成的关键激素。然而，由于一种名为“拮抗基因多效性”（Antagonistic Pleiotropy）的进化机制，年轻时有益的IGF-1，在老年时却成为帮凶：高水平的IGF-1会抑制FOXO转录因子（负责抗压和DNA修复），并促进细胞分裂，从而增加癌症风险和加速衰老。相反，百岁老人往往携带IGF-1受体功能减弱的基因突变。抑制IIS通路在蠕虫和果蝇中能成倍延长寿命，但在哺乳动物中，过度抑制会导致生长迟缓、肌肉量减少（少肌症）、骨质疏松和代谢异常，因此如何在保持肌肉骨骼健康的合成代谢与延缓衰老的抗压代谢之间找到平衡点，是药物开发的巨大挑战。 四、生物药与系统干预：抑制炎症、阻断纤维化、清除衰老细胞 随着科学技术的发展，生物医药例如抗体、细胞治疗、基因治疗等技术逐步的进入了大众的视野，适应症不断地从肿瘤、自免、神经等方向，向代谢、衰老等领域延申。而生物大分子所关注更多的是系统干预。 01 炎症因子——从“标志物”走向“可被工程化的干预” 在细胞层面，细胞衰老伴随的SASP（Senescence-Associated Secretory Phenotype，衰老相关分泌表型）会释放大量炎症因子，其中最典型、最常被当作“药靶候选”的就包括IL-6与IL-1β。 IL-6常被视为炎症衰老的“典型指标”，也是SASP的核心成分之一。在稳态下血液与组织间隙中的IL-6水平非常低，但在衰老与炎症等病理状态（尤其在肝脏相关病理中）IL-6会显著升高，并参与炎症、纤维化与肿瘤发生过程。衰老相关肝脏IL-6的升高，主要来自衰老细胞（包括肝细胞、巨噬细胞、内皮细胞等）的表达与分泌，并推动老年相关慢性肝病的发展。针对IL-6通路的抗体疗法（如抗IL-6R单抗托珠单抗）虽已广泛应用于类风湿关节炎等炎症疾病，并被视为缓解炎症衰老的潜在手段，但系统性抑制也带来了免疫抑制的风险。近期一项针对膝骨关节炎患者的主动抗IL-6免疫疗法（疫苗）I期研究显示了良好的安全性，并成功诱导了中和IL-6的抗体，这进一步印证了通过工程化手段抑制IL-6以对抗老年慢性炎症的可行性，也为后续更精准靶点的开发铺平了道路。 ▲ Figure 3. The pro-inflammatory and anti-inflammatory effects of IL-6 in the liver pathological process[7] 如果说IL-6是炎症衰老在血液中的“广播员”，那么白细胞介素-1β（IL-1β）就是细胞内的“点火器”。不同于持续分泌的细胞因子，IL-1β的产生受到极其严格的调控，其核心枢纽是NLRP3炎症小体。在衰老过程中，这一精密的防御机制逐渐失控，成为驱动血管硬化与心力衰竭的元凶。IL-1β作为抗衰老靶点的临床价值，在具有里程碑意义的CANTOS（Canakinumab Anti-inflammatory Thrombosis Outcome Study）试验中得到了确证[8]。Canakinumab显著降低了hsCRP（降幅达37-41%）和IL-6水平，且不改变LDL胆固醇水平。这一干预使得主要不良心血管事件（MACE）的相对风险降低了15%。同时Canakinumab治疗组的肺癌发生率和死亡率呈剂量依赖性显著下降，最高剂量组的致死性肺癌发生率降低了77%。这提示IL-1β驱动的炎症微环境在肿瘤的发生发展（尤其是老年性癌症）中起到了关键的作用。 02 IL-11与纤维化：“促衰老的隐形杀手” 长期以来，白细胞介素-11（IL-11）在IL-6家族中地位边缘，甚至一度被误认为是抗炎因子。然而，随着2024年Stuart Cook团队在《Nature》上发表的突破性研究，IL-11被“验明正身”：它是随着年龄增长在多器官中积聚、驱动纤维化与代谢衰退的核心因子。这一发现颠覆了教科书，将IL-11推向了长寿药物研发的舞台中央。 随着年龄增长，IL-11在肝脏、内脏脂肪和骨骼肌中的表达量逐渐攀升。这种上调并非无害的伴随现象，而是多种老年性病理（Multimorbidity）的驱动力： ▶ 纤维化（Fibrosis）：IL-11是TGF-β1下游的关键效应因子。它驱动成纤维细胞向肌成纤维细胞转化，导致胶原蛋白在心、肺、肾等器官的过度沉积。这种纤维化不仅破坏组织结构，更是器官功能衰竭的直接原因。 ▶ 代谢障碍：在脂肪组织中，IL-11抑制白色脂肪的“棕色化（Beiging）”，促进内脏脂肪堆积；在肝脏中，它驱动脂肪变性与炎症。去除IL-11信号可使老年小鼠恢复线粒体功能，减少脂肪堆积，维持代谢灵活性。 ▶ 肌肉减少症（Sarcopenia）：IL-11信号直接抑制肌肉再生程序，促进肌肉萎缩。阻断IL-11可显著改善老年小鼠的肌肉力量与物理机能。 最具说服力的数据来自干预实验。Widjaja等人不仅在基因敲除小鼠中观察到了寿命延长，更在75周龄（相当于人类55岁）的老年小鼠中进行了抗体干预实验[9]。接受抗IL-11抗体治疗的小鼠，其中位寿命延长了22.5%（雄性）至25%（雌性），治疗组小鼠不仅活得更久，而且活得更健康。它们表现出更低的虚弱指数、更少的肿瘤发生率、更好的毛发色泽与肌肉功能，被研究人员戏称为“超模奶奶（Supermodel Granny）”。与系统性抑制IL-1β不同，IL-11主要在基质细胞中发挥作用，其阻断似乎不影响适应性免疫系统的核心功能，提示其作为长期抗衰药物的安全性可能优于广谱抗炎药。 ▲ Figure 4. Blocking IL-11 signaling extends healthspan and lifespan in mice[10] 03 uPAR-衰老细胞的精准清除 寻找广谱且特异的衰老细胞表面标志物一直是Senolytics（衰老细胞清除剂）研发的痛点。Scott Lowe与Corina Amor团队通过对治疗诱导、致癌基因诱导及复制性衰老三种模型进行转录组测序，发现PLAUR（编码uPAR的基因）在衰老细胞中普遍且特异地高表达。生理状态下，uPAR主要参与细胞外基质（ECM）的降解与重塑。在衰老细胞中，uPAR的高表达不仅促进了SASP因子的释放，还协助衰老细胞在组织中“扎根”并重塑周围微环境，往往导致病理性的纤维化。由于uPAR在健康的重要脏器中表达极低，这为利用免疫疗法进行靶向清除提供了极佳的治疗窗口。 2024年1月，Corina Amor团队在《Nature Aging》发表的研究展示了利用靶向uPAR的嵌合抗原受体T细胞（CAR-T）清除衰老细胞的惊人潜力。uPAR CAR-T细胞能够精准识别并裂解表达uPAR的衰老细胞（SA-β-gal+）。在20月龄的老年小鼠中，单次输注即可显著降低肝脏、脂肪和胰腺中的衰老细胞负荷。治疗后的小鼠展现出代谢功能的全面回春，包括葡萄糖耐量的改善和运动耐力的显著提升（在跑步机上的力竭时间延长）。最引人注目的是，研究人员在3月龄的年轻小鼠中输注了低剂量的uPAR CAR-T细胞。这些经过工程改造的T细胞在小鼠体内持续存活超过12个月，如同巡逻的卫兵，在衰老细胞出现的瞬间即将其清除。结果显示，这种“疫苗式”的干预成功预防了中年时期的代谢衰退，而无需反复给药。 ▲ Figure 5. uPAR-targeting CAR T cells eliminate uPAR-expressing senescent cells and reduce metabolic dysfunction[11] 04 GD3-恢复机体的自身清洁 针对GD3的干预策略不再是直接杀死衰老细胞，而是“松开刹车”，恢复机体自身的清洁能力。在体外和体内实验中，使用抗GD3抗体阻断GD3与Siglec-7的结合，能够重新激活NK细胞对衰老细胞的识别和裂解能力。在小鼠模型中，抗GD3免疫疗法显著减少了肝脏和肺部的衰老细胞负荷，进而减轻了组织纤维化，并改善了老年性骨质疏松（通过减少衰老细胞对骨稳态的干扰）。这一发现具有极高的临床转化潜力，因为GD3是一种脂质抗原，其在健康成人组织中的表达相对受限（主要在脑部和黑色素瘤中），而在衰老组织中特异性上调。这为开发具有高治疗指数的抗衰老抗体提供了理论基础。 ▲ Figure 6. Mechanisms of interaction between senescent cells and NK cells[12] 五、总结：从生物学观察到工程化重塑 回顾抗衰老靶点的演变历程，我们清晰地看到了一条从全身性模糊干预走向细胞级精准工程的技术路线图。衰老已不再是不可逾越的鸿沟。随着这些靶点从实验室走向临床，我们正处于生物医药历史上的一个奇点：人类首次拥有了能够从分子层面解码、重写并逆转时间印记的工具箱。这不仅是生物医药的终极命题，更是人类文明向生命极限发起的理性挑战。 Sanyou 10th Anniversary: Anti-Aging: From Elixirs of Immortality to Systematic and Precision Interventions 1. Introduction Humanity’s quest to resist aging has spanned the entire history of civilization—from ancient alchemists’ mystical search for the “Philosopher’s Stone” and elixirs of immortality to one of the most disruptive frontiers of modern biomedicine: geroscience. With rapid advances in molecular biology, genetics, and systems biology, aging is no longer viewed as an irreversible entropic fate. Instead, it is being redefined as a set of complex pathophysiological processes that can be explained by biological mechanisms, quantified, and even intervened upon. Our understanding of aging—from upstream damage (such as genomic instability and epigenetic drift), through midstream metabolic dysregulation (such as aberrant nutrient-sensing pathways and mitochondrial dysfunction), to downstream functional decline (such as cellular senescence and chronic inflammation)—has long formed a multilayered, systems-level framework. ▲ Figure 1. Molecular mechanisms of aging and anti-aging strategies[1] 2. The Biological Architecture of Aging To intervene systematically in aging, we must first define it precisely. In 2013, López-Otín and colleagues published the landmark review The Hallmarks of Aging in Cell, summarizing ninehallmarks of aging. In 2023, this framework was further expanded and refined totwelve hallmarks. These hallmarks define aging not only at the molecular level but also provide concrete targets for drug development. They can be organized into three tiers: primary damage, antagonistic responses (midstream metabolic dysregulation), and integrated phenotypes (downstream functional decline)[2]. 01 Primary damage: Entropy increase in the genome and epigenome Aging often begins with compromised integrity of genetic information—like repeatedly photocopying a document: with each copy, noise and errors accumulate. Such damage includes genomic instability, epigenetic alterations, and telomere attrition. Primary damage triggers a series of intracellular stress responses and homeostatic imbalances that may be protective initially but become destructive when chronically sustained. 02 Metabolic and cellular homeostasis dysregulation: Midstream regulatory breakdown As primary damage progresses, cellular metabolism and homeostasis gradually drift off course. Proteostasis becomes imbalanced, metabolic pathways begin to fail, and mitochondrial function—central to cellular energy production—becomes impaired. Aging reduces chaperone function, weakening proper protein folding; meanwhile, the proteasome and lysosome–autophagy systems responsible for waste clearance lose activity. As a result, misfolded proteins can neither be repaired nor cleared; they aggregate into toxic species (e.g., amyloid-β and Tau in Alzheimer’s disease, and α-synuclein in Parkinson’s disease), directly disrupting cellular function and inducing cell death. Aging-associated mitochondrial DNA mutations, reduced electron transport chain efficiency, and abnormal mitochondrial dynamics lead to energy deficits and excessive ROS leakage, triggering inflammation and cell death. 03 Functional decline and systemic effects: Downstream pathological manifestations As molecular-level damage accumulates and converges, it ultimately manifests as functional failure at cellular and tissue levels, producing clinically visible aging phenotypes. One key process is cellular senescence: senescent cells secrete large amounts of pro-inflammatory cytokines, growth factors, and proteases—collectively termed the senescence-associated secretory phenotype (SASP). SASP not only disrupts the local tissue microenvironment (e.g., by degrading extracellular matrix) but also induces senescence in neighboring healthy cells (paracrine effects) and recruits immune cells, driving chronic inflammation. Meanwhile, due to accumulated DNA damage, critically shortened telomeres, and inhibitory effects of the senescent milieu (SASP), stem cells gradually lose proliferative and differentiation capacity and may become exhausted. This directly contributes to reduced hematopoietic function (immunosenescence), muscle wasting (sarcopenia), osteoporosis, and poor skin wound healing. Chronic inflammation driven by senescent cells and stem cell exhaustion forms a bridge between molecular damage and macroscopic disease, such as atherosclerosis, insulin resistance, and neurodegenerative disorders. 3. Small-Molecule Drugs: From Broad Modulation to Precision Metabolic Control As mechanisms of aging become clearer, interventions have evolved from early, “whole-system, fuzzy modulation” (e.g., caloric restriction) toward precision pharmacologic interventions targeting specific core signaling pathways—or even specific cell populations. Small molecules and biologics differ in properties and are therefore applied to different mechanisms; small-molecule drugs primarily focus on metabolic regulation. ▲ Figure 2. Metabolic alterations of Aging[2] 01 The mTOR pathway and rapamycin: A “master switch” for growth—and a double-edged sword mTOR is among the most deeply studied and best-evidenced targets in anti-aging research. As a serine/threonine kinase, mTOR integrates multiple signals: nutrients (amino acids), energy (ATP), and growth factors (insulin). When nutrients are abundant, mTORC1 is activated and phosphorylates downstream substrates such as S6K1 and 4E-BP1, strongly promoting protein and lipid synthesis and driving cellular growth. During aging, mTORC1 is often chronically hyperactivated, causing cells to continuously synthesize proteins while failing to clear accumulated waste—eventually leading to functional collapse. Rapamycin, an mTOR-targeting drug, is currently the only agent in the NIA Interventions Testing Program (ITP) that robustly extends lifespan in genetically heterogeneous mice across sexes and across different starting ages (including late-life administration), with lifespan extension reported at approximately 10%–30%[3]. 02 The AMPK pathway and metformin: Energy sensing and “new uses for an old drug” AMP-activated protein kinase (AMPK) is the cell’s “energy sensor.” When cellular energy is depleted and the AMP/ATP ratio rises, AMPK is activated. Activated AMPK acts like a cellular “power-saving mode” switch: it turns off energy-consuming anabolic processes and turns on catabolic processes that generate energy and support repair, including promoting glucose uptake and fatty acid oxidation. AMPK can also directly inhibit mTORC1 via phosphorylation and activate SIRT1 and PGC-1α (a master regulator of mitochondrial biogenesis), forming an anti-aging signaling network. As the most widely used glucose-lowering drug worldwide, metformin has shown striking anti-aging potential. It mildly inhibits mitochondrial complex I, slightly reducing ATP production and increasing AMP, thereby activating AMPK. Growing evidence suggests metformin modulates key aging-related processes—including energy regulation, inflammation, and autophagy—thereby delaying aging and alleviating age-related diseases[4]. Because metformin may extend lifespan and improve health, it became the focal candidate for the first large clinical trial specifically targeting aging interventions: the Targeting Aging with Metformin (TAME) trial initiative[5]. 03 Sirtuins and NAD⁺ metabolism: Hope for mitochondrial rejuvenation Sirtuins are a family of NAD⁺-dependent deacetylases (SIRT1–SIRT7), often called “longevity proteins.” They play critical roles in DNA repair, mitochondrial maintenance, and inflammatory control. Their activity is constrained by levels of the cofactor NAD⁺(nicotinamide adenine dinucleotide). With aging, the activity of the NAD⁺ biosynthetic enzyme NAMPT declines, while NAD⁺-consuming enzymes (e.g., CD38) become highly active, causing a precipitous drop in NAD⁺. Synthetic sirtuin activators (e.g., SRT1720, SRT2104) have shown stronger efficacy in animal studies, but clinical translation remains under exploration[6]. 04 Insulin/IGF-1 signaling (IIS): The trade-off between growth and longevity IGF-1 (insulin-like growth factor 1) is a key hormone promoting growth, development, and tissue anabolism. However, due to an evolutionary mechanism termed antagonistic pleiotropy, IGF-1 that is beneficial in youth can become harmful in old age: high IGF-1 suppresses FOXO transcription factors (responsible for stress resistance and DNA repair) and promotes cell proliferation, increasing cancer risk and accelerating aging. In contrast, centenarians often carry genetic variants that reduce IGF-1 receptor function. In worms and flies, IIS inhibition can multiply lifespan, but in mammals excessive inhibition can cause growth retardation, reduced muscle mass (sarcopenia), osteoporosis, and metabolic abnormalities. Thus, a major challenge in drug development is finding a balance between preserving musculoskeletal anabolic health and promoting stress-resistant, longevity-associated metabolism. 4. Biologics and Systemic Interventions: Suppressing Inflammation, Blocking Fibrosis, Eliminating Senescent Cells With advances in science and technology, biomedicine—such as antibodies, cell therapy, and gene therapy—has increasingly entered the public view. Indications have expanded from oncology, autoimmunity, and neurology into metabolism and aging. Compared with small molecules, large-molecule biologics focus more on system-level interventions. 01 Inflammatory factors: From “biomarkers” to engineerable interventions At the cellular level, SASP (Senescence-Associated Secretory Phenotype) releases abundant inflammatory factors, among which IL-6 and IL-1β are among the most typical and frequently proposed “drug target candidates.” IL-6 is often regarded as a “canonical indicator” of inflammaging and a core SASP component. Under homeostasis, IL-6 levels in blood and interstitial spaces are very low. In pathological states such as aging and inflammation—especially in liver-related pathology—IL-6 rises markedly and participates in inflammation, fibrosis, and tumorigenesis. Age-related elevation of hepatic IL-6 mainly arises from expression and secretion by senescent cells (including hepatocytes, macrophages, endothelial cells, etc.), promoting the progression of chronic liver diseases in older adults. Antibody therapies targeting the IL-6 pathway (e.g., the anti-IL-6R monoclonal antibody tocilizumab) are widely used in inflammatory diseases such as rheumatoid arthritis and are considered potential approaches to mitigate inflammaging, but systemic inhibition carries immunosuppression risk. A recent Phase I study of an active anti-IL-6 immunotherapy (vaccine) in knee osteoarthritis patients showed good safety and successfully induced IL-6-neutralizing antibodies, further supporting the feasibility of engineering IL-6 suppression to counter chronic age-related inflammation and paving the way for more precise target development. ▲ Figure 3. The pro-inflammatory and anti-inflammatory effects of IL-6 in the liver pathological process[7] If IL-6 is the “broadcaster” of inflammaging in the bloodstream, then interleukin-1β (IL-1β) is the intracellular “igniter.” Unlike continuously secreted cytokines, IL-1β production is under extremely strict control, with the NLRP3 inflammasomeas the central hub. During aging, this finely tuned defense system gradually becomes dysregulated, turning into a key driver of vascular stiffening and heart failure. The clinical value of IL-1β as an anti-aging target was confirmed by the landmark CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial[8].Canakinumab significantly reduced hsCRP (by 37%–41%) and IL-6 levels without changing LDL cholesterol. This intervention reduced the relative risk of major adverse cardiovascular events (MACE) by 15%. Meanwhile, lung cancer incidence and mortality in the canakinumab group decreased in a dose-dependent manner; in the highest-dose group, fatal lung cancer incidence fell by 77%. These findings suggest that IL-1β-driven inflammatory microenvironments play a key role in tumor initiation and progression, particularly in age-associated cancers. 02 IL-11 and fibrosis: An “invisible killer” that promotes aging For a long time, interleukin-11 (IL-11) occupied a marginal position within the IL-6 family and was even once mischaracterized as anti-inflammatory. However, a breakthrough study by Stuart Cook’s team published in Nature in 2024 “set the record straight”: IL-11 accumulates with age across multiple organs and is a core driver of fibrosis and metabolic decline—overturning textbook views and moving IL-11 to center stage in longevity drug development. With aging, IL-11 expression gradually increases in the liver, visceral adipose tissue, and skeletal muscle. This upregulation is not a harmless bystander effect; it drives multimorbidity: ▶ Fibrosis: IL-11 is a key downstream effector of TGF-β1. It drives fibroblasts to differentiate into myofibroblasts, causing excessive collagen deposition in the heart, lung, kidney, and other organs. This fibrosis disrupts tissue architecture and directly contributes to organ failure. ▶ Metabolic dysfunction: In adipose tissue, IL-11 suppresses “beiging” of white fat and promotes visceral fat accumulation; in the liver, it drives steatosis and inflammation. Removing IL-11 signaling restores mitochondrial function in aged mice, reduces fat accumulation, and maintains metabolic flexibility. ▶ Sarcopenia: IL-11 signaling directly suppresses muscle regeneration programs and promotes muscle atrophy. Blocking IL-11 significantly improves muscle strength and physical performance in aged mice. The most persuasive data come from intervention experiments. Widjaja and colleagues not only observed lifespan extension in IL-11 knockout mice, but also performed antibody intervention in 75-week-old mice (roughly equivalent to humans around age 55)[9]. Anti–IL-11 antibody treatment extended median lifespan by 22.5% (males) to 25% (females). Treated mice not only lived longer but also healthier: they showed lower frailty indices, fewer tumors, better coat coloration, and improved muscle function—earning the nickname “Supermodel Granny.” Unlike systemic IL-1β inhibition, IL-11 primarily acts in stromal cells, and its blockade appears not to impair core adaptive immune functions, suggesting it may offer better long-term safety than broad-spectrum anti-inflammatory drugs. ▲ Figure 4. Blocking IL-11 signaling extends healthspan and lifespan in mice[10] 03 uPAR: Precise elimination of senescent cells Finding broad yet specific surface markers for senescent cells has been a major bottleneck in developing senolytics. Scott Lowe and Corina Amor’s team performed transcriptomic sequencing across three models—therapy-induced, oncogene-induced, and replicative senescence—and found that PLAUR (the gene encoding uPAR) is broadly and specifically upregulated in senescent cells. Under physiological conditions, uPAR mainly participates in extracellular matrix (ECM) degradation and remodeling. In senescent cells, high uPAR expression not only promotes SASP factor release but also helps senescent cells “take root” in tissues and remodel the surrounding microenvironment, often leading to pathological fibrosis. Because uPAR expression is very low in essential healthy organs, it provides an excellent therapeutic window for targeted clearance via immunotherapy. In January 2024, Corina Amor’s team published a study in Nature Aging demonstrating the remarkable potential of uPAR-targeting CAR-T cells to eliminate senescent cells. uPAR CAR-T cells precisely recognized and lysed uPAR-expressing senescent cells (SA-β-gal⁺). In 20-month-old mice, a single infusion significantly reduced senescent cell burden in the liver, adipose tissue, and pancreas. Treated mice exhibited broad metabolic rejuvenation, including improved glucose tolerance and significantly increased exercise endurance (longer time to exhaustion on a treadmill). Most strikingly, researchers infused low-dose uPAR CAR-T cells into 3-month-old young mice. These engineered T cells persisted for over 12 months, acting like patrolling guards that cleared senescent cells as soon as they emerged. This “vaccine-like” intervention successfully prevented midlife metabolic decline without repeated dosing. ▲ Figure 5. uPAR-targeting CAR T cells eliminate uPAR-expressing senescent cells and reduce metabolic dysfunction[11] 04 GD3: Restoring the body’s own clearance Strategies targeting GD3 do not aim to directly kill senescent cells; instead, they “release the brakes” to restore the body’s intrinsic cleaning capacity. In vitro and in vivo, blocking GD3–Siglec-7 binding with anti-GD3 antibodies reactivates NK cells’ ability to recognize and lyse senescent cells. In mouse models, anti-GD3 immunotherapy significantly reduced senescent cell burden in the liver and lung, alleviated tissue fibrosis, and improved age-related osteoporosis (by reducing senescent-cell disruption of bone homeostasis). This discovery has strong translational potential because GD3 is a lipid antigen with relatively restricted expression in healthy adult tissues (mainly in the brain and melanoma), while being specifically upregulated in aged tissues—providing a theoretical basis for developing anti-aging antibodies with high therapeutic index. ▲ Figure 6. Mechanisms of interaction between senescent cells and NK cells[12] 5. Conclusion: From Biological Observation to Engineered Remodeling Looking back at the evolution of anti-aging targets, we can clearly see a technology roadmap moving from whole-body, imprecise interventions toward cell-level precision engineering. Aging is no longer an insurmountable chasm. As these targets move from laboratories into clinics, we are approaching a singular point in biomedical history: for the first time, humanity has a toolbox capable of decoding, rewriting, and reversing the imprints of time at the molecular level. This is not only the ultimate question of biomedicine, but also a rational challenge by human civilization to the limits of life. ▶ Reference 1. Li, Y. et al. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal22, 285 (2024). https://doi.org/10.1186/s12964-024-01663-1 2. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: An expanding universe. Cell186, 243-278 (2023). https://doi.org/10.1016/j.cell.2022.11.001 3. Roark, K. M. & Iffland, P. H., 2nd. Rapamycin for longevity: the pros, the cons, and future perspectives. Front Aging6, 1628187 (2025). https://doi.org/10.3389/fragi.2025.1628187 4. Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metab32, 15-30 (2020). https://doi.org/10.1016/j.cmet.2020.04.001 5. Onken, B. et al. Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes. Aging Cell21, e13488 (2022). https://doi.org/10.1111/acel.13488 6. Ungurianu, A., Zanfirescu, A. & Margina, D. Sirtuins, resveratrol and the intertwining cellular pathways connecting them. Ageing Res Rev88, 101936 (2023). https://doi.org/10.1016/j.arr.2023.101936 7. Wang, M. J. et al. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Exp Hematol Oncol13, 62 (2024). https://doi.org/10.1186/s40164-024-00527-1 8. Hassan, M. CANTOS: A breakthrough that proves the inflammatory hypothesis of atherosclerosis. Glob Cardiol Sci Pract2018, 2 (2018). https://doi.org/10.21542/gcsp.2018.2 9. Widjaja, A. A. et al. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature632, 157-165 (2024). https://doi.org/10.1038/s41586-024-07701-9 10. Kim, H. H. & Dixit, V. D. Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity. Cell Metab36, 1911-1913 (2024). https://doi.org/10.1016/j.cmet.2024.08.003 11. Bartley, J. M. & Xu, M. Unleashing CAR T cells to delay metabolic aging. Nat Aging4, 284-286 (2024). https://doi.org/10.1038/s43587-024-00576-5 12. Majewska, J. & Krizhanovsky, V. GD3 ganglioside checkpoints in immune surveillance of senescent cells. Nat Aging5, 182-183 (2025). https://doi.org/10.1038/s43587-025-00803-7 关于三优生物 三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。 公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。 推荐阅读 战略跃迁｜打造全球顶尖的原创新药创新工场 三优十周年｜恶病质的代谢紊乱与靶向药物的研发态势 三优十周年｜中国药企撬动千亿美元赛道 三优十周年｜平台篇-创新抗体产生平台 三优十周年｜眼科治疗前沿：用抗体药物精准点亮未来 三优十周年｜磁阵列全人源小鼠抗体发现平台 三优十周年｜新“药王”加冕：减重增肌 三优十周年｜抗体药物如何实现精准“狙击”炎症？ 三优十周年｜血液肿瘤治疗革命-精准分层治疗新时代 三优十周年｜抗体药免疫原性全方位解析 三优十周年｜肿瘤免疫2025及2018双诺奖解析 三优十周年｜TCE药物-重塑免疫治疗版图的新力量 三优十周年｜神经系统疾病治疗进展 三优十周年｜AI-STAL 智能超万亿分子库发展历程 三优十周年｜打造全球顶尖的原创新药创新工场 三优十周年｜抗体治疗50年风雨江湖