Fenofibrate

衰老是多种慢性疾病的主要风险因素，比如心脏病、糖尿病和关节炎。想象一下，你的身体就像一台老旧的机器，随着时间的推移，各个部件开始出现问题。而在这台机器中，有一个特别重要的零件——骨髓中的巨噬细胞（BMMs），它们在老化过程中扮演了“捣蛋鬼”的角色。 骨髓巨噬细胞负责清理我们身体中的废物清除和维护秩序。而随着年龄的增长，这些“指挥者”开始变得不灵敏，它们释放出细胞外囊泡（EVs）这一“信使”，携带着一些特殊的分子，比如微小RNA（miRNAs），传播到身体的其他部位。但当这些“信使”被老化的骨髓巨噬细胞派出时，它们带去的信息却是“老化”的信号。这些信号会导致其他细胞也变老，从而加速全身的衰老过程。 近日，中南大学湘雅医院李长俊研究团队在Nat Aging发表了题为Aged bone marrow macrophages drive systemic aging and age-related dysfunction via ext racellular vesicle-mediated induction of paracrine senescence的研究论文，揭示了BMMs通过EVs载有的miRNA驱动全身性衰老的机制，并提出了非诺贝特（fenofibrate）作为延缓衰老相关疾病的潜在治疗手段，为未来通过靶向骨髓巨噬细胞及其分泌的EVs以抗击衰老及相关疾病提供了新的思路。 研究通过将老年（24个月）和年轻（3个月）小鼠的骨髓分别移植至年轻小鼠体内，评估老年骨髓对全身衰老的影响。 结果显示，接受老年骨髓移植的小鼠（ABMT组）在肝脏、骨骼肌和白色脂肪组织中，衰老相关基因（如Cdkn2a、Cdkn1a）和SASP因子（如Il-1β、Il-6、Mmp13）显著上调。 此外，这些小鼠表现出胰岛素信号通路的失活、高血糖水平、骨小梁体积减少及大脑中神经元尼氏体和谷氨酸受体1（GluR-1）的表达降低，表明老年骨髓可通过传播衰老来诱导系统性老化。 图 1：老年骨髓可通过传播衰老来诱导系统性老化 为了验证清除衰老细胞是否能阻止衰老传播，研究使用了达沙替尼和槲皮素（D+Q）对老年小鼠进行处理，然后将这些处理过的骨髓移植到年轻小鼠体内。 结果表明，去除衰老细胞后，年轻小鼠体内的衰老标志物和SASP因子（如Il-1β、Il-6、Tnf-α等）的表达显著降低，组织中的SA-β-半乳糖苷酶（SA-β-gal）阳性细胞数量减少。此外，D+Q预处理还改善了年轻小鼠的系统性胰岛素敏感性，减少了肝脏脂肪变性，恢复了骨骼质量，显示去除骨髓中的衰老细胞可以显著缓解全身衰老效应。 通过单细胞RNA测序（scRNA-seq）分析，研究人员发现，老化的骨髓巨噬细胞中，衰老相关基因的表达显著高于其他细胞类型。这表明，骨髓巨噬细胞在老化过程中起到了关键作用，它们通过释放EVs传播衰老信号，影响全身的健康。 图 2：骨髓巨噬细胞是导致衰老的主要因素 图 3：衰老BMM分泌的 EV 传播衰老和衰老，而YBMM-EV缓解衰老 进一步的实验表明，将老化的骨髓巨噬细胞（BMMs）移植到年轻小鼠体内，会导致多种组织的衰老标志物升高，包括骨骼、肝脏、肌肉、脂肪和大脑。这些小鼠还会表现出高血糖、肝脏脂肪变性和胰岛素敏感性降低等问题。相反，将年轻的BMM-EVs移植到老年小鼠体内，可以部分缓解老年小鼠的衰老表型，改善胰岛素敏感性和骨质密度，显示年轻BMM-EVs具有延缓衰老的潜力。 通过测序分析，研究人员发现，BMM-EVs中的微小RNA（miRNAs）在调节衰老和代谢紊乱中起关键作用。老化的BMM-EVs中富含miR-378a-3p，而年轻的BMM-EVs中富含miR-191-5p。进一步实验表明，过表达miR-378a的巨噬细胞分泌的EVs会导致小鼠血糖升高、肝脏脂肪变性和胰岛素敏感性降低，表明miR-378a在老年BMM-EVs中促进了衰老效应。 图 4：BMM-EVs中miRNAs在调节衰老和代谢紊乱中的作用 接着，通过生物信息学分析，研究人员发现，miR-378a和miR-191可能靶向过氧化物酶体增殖物激活受体α（PPARα），该受体在脂质代谢、炎症和与衰老相关的疾病中发挥重要作用。 代谢组学分析表明，PPAR信号通路在衰老过程中受到抑制，过表达miR-378a会抑制PPARα表达，而抑制miR-378a可恢复其水平，miR-191过表达则上调PPARα。 图 5：非诺贝特延缓了人类年龄相关疾病的发作 基于上述研究结果，研究人员进一步验证了非诺贝特（fenofibrate）对衰老的影响。非诺贝特是一种PPARα激动剂，可以激活过氧化物酶体增殖物激活受体α（PPARα）。 结果显示，经过非诺贝特处理的老年小鼠（23个月）在多个器官中表现出衰老标志物和炎症因子的减少，胰岛素敏感性提高，骨质流失和认知功能减退也得到了缓解。 总体而言，这项研究发现，老化的骨髓巨噬细胞通过细胞外囊泡（EVs）传播衰老信号，导致多种组织功能障碍。PPARα激动剂非诺贝特（fenofibrate）不仅能改善脂质代谢，还能延缓衰老和相关疾病的发生，显示出降低年龄相关慢性病风险和提高预期寿命的潜力。这一发现为抗击衰老及相关疾病的治疗提供了新的思路。 参考文献： Hou, J., Chen, KX., He, C. et al. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00694-0 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

For the past century, heart disease has remained the leading cause of death in the United States. Fortunately, as our understanding of the disease has evolved over time, we have made advances in treatment options to help people reduce their risk for a devastating cardiovascular event, like a heart attack or stroke. But staying one step ahead of this disease requires both providers and patients to continually follow and implement the latest science and regulatory guidance on what treatment options are safe, effective, and FDA-approved. Sadly, this isn’t happening and misinformation about treatment options poses a significant public health concern, which the FDA has acknowledged and in July issued new guidance on how companies can combat it. This is why HealthyWomen, the nation’s leading independent nonprofit health information source for women, recently filed a citizen petition with the FDA urging regulators to take further action on the labeling of fibrates, a class of medication commonly prescribed to address cardiovascular disease risk factors. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health While fibrates are proven to lower triglyceride levels, which can serve as a biomarker for cardiovascular disease risk, several major clinical studies from the past 20 years have failed to show a benefit of fenofibrates over and above statins in further reducing heart-related events. As a result of these failed outcomes studies, the FDA took significant action. In 2015, the agency removed the statin co-administration indication from the labeling of fenofibrates. When announcing the withdrawal of the indication in 2016, the FDA explained that it had determined that the benefits of fenofibrates with statins no longer outweighed the risks to patients. But despite the significance of the FDA’s withdrawal more than eight years ago, prescribing behavior has lagged, ultimately putting patients at risk. Even with a slight decline in fenofibrate use since 2015, more than 1 million patients are being treated today with the drug off-label to reduce cardiovascular disease risk. In fact, prescription rates are actually increasing year-over-year among some providers like nurse practitioners. Sponsored Post What Healthcare Can Learn from Costco The path forward is clear: employers must evaluate their health plan the same way they do their Saturday shopping excursion. By Jeff Bak, Imagine360 CEO and President Adding more concern, the 2022 Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial reinforced the FDA’s finding that fibrates did not reduce cardiovascular disease risk over and above statins. This was especially shocking because the trial specifically enrolled a population that was most likely to benefit: those with type 2 diabetes and high triglycerides and low HDL-cholesterol. Even in this high-risk population, the trial had to be stopped early for futility, or lack of benefit. Several other studies have shown how fibrate therapy can potentially cause harm, like adverse kidney events and blood clots, or even liver injury and hospitalization when used concurrently with a statin. And unnecessary use of fibrates with statins exposes people to potentially needless, serious side effects including myopathy, venous thromboembolism (VTE), and rhabdomyolysis, which pose significant risks to patients, particularly those from communities of color who already face barriers to quality care and experience disproportionate rates of cardiovascular disease. Furthermore, these patients should not have to spend their hard-earned dollars at the pharmacy counter for a drug proven ineffective in lowering their risk for having a cardiovascular event while also demonstrating consistent signals of harm across multiple studies. HealthyWomen’s citizen petition to the FDA is putting a spotlight on this problem by asking for two key changes: updating the label for fibrates to reflect the latest data and benefit-risk information and communicating to healthcare providers that fibrates do not lower cardiovascular event risk over and above statins. As a clinician, I applaud this action. The fact is, there are numerous alternative safe and effective FDA-approved therapies available that actually reduce risk for cardiovascular events for patients and not just lower biomarker scores. Increased awareness and following the latest science will help ensure patients have the best chance at achieving their healthiest outcomes.