Core Insights - A groundbreaking study from Nankai University reveals a potential treatment for infertility in women over 34, linked to ribosomal dysfunction as a molecular clock of aging [1][2] - The research indicates that the drug rapamycin may serve as a safe and effective method to help women with repeated IVF failures achieve successful pregnancies and live births [1][2] Research Findings - The study identifies significant transcriptional changes in oocytes and surrounding cumulus cells after the age of 34, particularly an abnormal increase in ribosomal gene transcription [1] - Key gene expressions related to meiosis, actin, and adhesion proteins are downregulated, while lysosomal activity and protein homeostasis in cumulus cells are disrupted [1][2] Mechanism of Action - The research highlights that the abnormal function of ribosomes is a previously overlooked driver of declining oocyte quality, linked to epigenetic dysregulation [2] - Specific genomic loci exhibit DNA hypomethylation and reduced levels of heterochromatin H3K9me3, indicating a chaotic control system for gene expression [2] Clinical Application - The study includes a randomized controlled trial demonstrating that short-term treatment with rapamycin can lead to the production of high-quality blastocysts in women with repeated IVF failures, resulting in successful pregnancies [2] - The director of the Reproductive Medicine Center at Shanxi Children's Hospital emphasizes the encouraging preliminary results, suggesting a new pathway for understanding and treating age-related infertility [2]

Core Insights - A groundbreaking study by Nankai University reveals a new target for treating infertility in women due to age or unknown reasons, focusing on ribosomal dysregulation as a molecular clock affecting fertility after age 34 [1][2] - The study suggests that the drug rapamycin may serve as a potential, safe, and effective treatment method for patients experiencing repeated IVF failures, leading to successful pregnancies and live births [1][3] Group 1: Research Findings - The research indicates that significant transcriptomic changes occur in oocytes and surrounding cumulus cells after women reach 34 years of age, with a notable increase in ribosomal gene transcription levels [2] - The study identifies that the abnormal function of ribosomes is a previously overlooked driver of declining oocyte quality, affecting both oocytes and their surrounding supportive cells [2] Group 2: Mechanism and Treatment - Further investigation reveals that the overactivity of ribosomal genes is closely linked to epigenetic dysregulation, including DNA hypomethylation and reduced levels of heterochromatin H3K9me3, leading to chaotic gene expression [2] - The research team conducted mouse intervention trials using rapamycin, which effectively reduced overall translational activity and improved ovarian microenvironment and oocyte quality [3] - Clinical trials confirmed that short-term rapamycin treatment resulted in high-quality blastocysts and successful pregnancies in patients with repeated IVF failures [3]

Core Viewpoint - Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid protein and hyperphosphorylated tau protein, leading to neuronal dysfunction and cognitive decline. Current treatments only alleviate symptoms without altering disease progression, while emerging therapies face significant challenges [2]. Group 1: Current Treatments and Limitations - Approved therapies for Alzheimer's, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, only provide symptomatic relief and do not modify disease progression [2]. - Anti-Aβ monoclonal antibodies can reduce Aβ plaque burden and slow cognitive decline but have limitations, including low blood-brain barrier (BBB) permeability and ineffectiveness against newly generated Aβ [2]. - Emerging anti-tau therapies also face challenges, including off-target toxicity and poor clinical efficacy [2]. Group 2: Recent Research Developments - A study published by researchers from Sichuan University developed a method called Microglia-Liposome Fusion Extrusion (MiLi-FE) to create microglia-derived nanovesicles that can cross the BBB and co-deliver rapamycin and AR7 to treat Alzheimer's disease [3][4]. - The study confirmed that both macroautophagy and chaperone-mediated autophagy are impaired in Alzheimer's disease model mice, which precedes Aβ accumulation and drives disease progression [4]. Group 3: Mechanism and Efficacy of New Approach - The AR@ENV nanovesicles can effectively penetrate the BBB and target inflammatory sites in the brains of Alzheimer's patients, activating both autophagy pathways to enhance the clearance of Aβ and other toxic protein aggregates [5]. - This dual activation restores protein homeostasis and provides significant neuroprotection, improving neuroinflammation and cognitive deficits in two different Alzheimer's mouse models [5]. Group 4: Future Implications - The combination of synchronized dual autophagy activation and targeted biomimetic delivery positions AR@ENV as a promising candidate for Alzheimer's treatment. The MiLi-FE platform offers a flexible and scalable method for delivering various therapeutic agents to the central nervous system, potentially expanding its applicability to a range of neurological diseases [7].

Core Viewpoint - The study identifies ribosome dysregulation as a potential causal mechanism driving female reproductive aging, particularly highlighting the upregulation of ribosomal gene transcription in oocytes and cumulus cells around the age of 34, which correlates with a decline in fertility. It suggests that short-term intervention with rapamycin may serve as an effective treatment for age-related infertility [2][11]. Group 1: Mechanisms of Female Reproductive Aging - Female fertility declines with age, especially after 35, primarily due to decreased oocyte quality, which affects embryo development and leads to repeated failures in assisted reproduction [2][4]. - Chromosomal segregation errors increase with age, particularly after 35, contributing to aneuploidy in embryos, which often results in developmental arrest or miscarriage [4]. - Other factors contributing to ovarian aging include DNA damage response, oxidative stress, mitochondrial dysfunction, telomere shortening, autophagy, inflammation, and fibrosis [5]. Group 2: Molecular Changes in Oocytes and Cumulus Cells - The study utilized multi-omics analysis to discover molecular changes in aging oocytes and cumulus cells, revealing significant transcriptional alterations at age 34, including upregulation of ribosomal gene transcription [8][9]. - The research indicates that specific genomic loci exhibit DNA hypomethylation and abnormal heterochromatin deposition, closely associated with the activation of ribosomal gene transcription [8][9]. - The abundance of histone H3K9me3 decreases with age, which is linked to the upregulation of ribosomal genes [9]. Group 3: Implications for Treatment - Short-term treatment with the clinically approved immunosuppressant rapamycin can effectively inhibit protein translation in cumulus cells and restore protein homeostasis, leading to improved embryo quality and higher rates of pregnancy and live births [9][11].

Core Viewpoint - A recent study indicates that the combination of two cancer drugs, rapamycin and trametinib, can extend the lifespan of experimental mice by approximately 30% [1] Group 1: Research Findings - The study was conducted by the Max Planck Institute for Biology of Ageing in Germany and University College London [1] - The research was published in the latest issue of the journal "Nature Aging" [1] - Previous studies showed that trametinib alone could extend lifespan by 5%-10%, while rapamycin could achieve 15%-20% [1] Group 2: Synergistic Effects - The combination of rapamycin and trametinib produces a synergistic effect, resulting in a lifespan extension greater than the sum of their individual effects [1] - The treatment significantly improves the health status of older mice, with noticeable reductions in chronic inflammation in tissues and the brain [1] - The combination also delays the occurrence and progression of cancer in the treated mice [1]

| nature | | | | | --- | --- | --- | --- | | medicine | | 30 | | | | | | 385 2 | | 创刊30周年,医学的未来与挑战 | | | | | celebrating | | | | | 30 | | | | | vears | | | | | | Rober Referr 111 : " | HE EFF | | 撰文丨王聪 编辑丨王多鱼 排版丨水成文 沿 浓度梯度被动扩散穿过细胞的脂质双层膜，被广泛认为是小分子药物吸收的主要机制，尽管已发现少数 转运蛋白能促进营养物质和化学物质的扩散，但其作用有限。脂溶性小分子 （分子量 ≤ 500 道尔顿） 更 有可能通过被动扩散穿过细胞膜进入细胞内，而较大的分子 （例如分子量 > 800 道尔顿） 无法被动穿过 质膜，这限制了小分子药物能够作用的范围。 但实际上，也有许多大分子药物是能够被细胞吸收的，其中最典型的是 蛋白靶向降解嵌合体 （ PROTAC） ，这是一种异双功能化合物，由一个 （或多个） 靶向目标蛋白的配体和一个 E3 泛素连接酶 配体通过连接子 （linker） 连接而成。PROT ...