神经科学日报第1期：今日焦点+5项最佳研究突破（虐猴实验+外泌体+抗衰老疗法+AD+减肥+肌苷+棕色脂肪+清除衰老细胞）

今日焦点

据Science News报告，哈佛大学神经学家、美国科学院院士 Margaret Livingstone 因在实验中涉及把幼年猴子从母猴身边带走，以及在 2016 年的 2 项实验中将幼猴的眼睑缝合，引发谴责。

今日突破1

中文摘要

异时性血液交换（HBE）已证明循环因子可恢复衰老组织的年轻特征。然而，这些具有恢复机体活力的系统性介质仍不明确。研究人员在此表明，当血清中细胞外囊泡（EVs）耗尽时，年轻血液对老年肌肉再生的有益作用减弱。年轻动物的EV使衰老细胞生物能量学和骨骼肌再生恢复活力，而衰老改变了EV亚群的异质性，并损害了受体细胞的下游益处。机器学习分类器显示，衰老改变了循环EV的核酸指纹，而不是蛋白质指纹。亚群体异质性的改变伴随着促长寿蛋白α-Klotho转录水平的下降，并且注射含有 Klotho mRNA的EVs促进肌肉再生。这些研究表明，EV在HBE的恢复作用中起着关键作用，EV中的Klotho转录物介导了年轻血清对老年骨骼肌的影响。

英文摘要

Heterochronic blood exchange (HBE) has demonstrated that circulating factors restore youthful features to aged tissues. However, the systemic mediators of those rejuvenating effects remain poorly defined. We show here that the beneficial effect of young blood on aged muscle regeneration was diminished when serum was depleted of extracellular vesicles (EVs). Whereas EVs from young animals rejuvenate aged cell bioenergetics and skeletal muscle regeneration, aging shifts EV subpopulation heterogeneity and compromises downstream benefits on recipient cells. Machine learning classifiers revealed that aging shifts the nucleic acid, but not protein, fingerprint of circulating EVs. Alterations in sub-population heterogeneity were accompanied by declines in transcript levels of the pro-longevity protein, α-Klotho, and injection of EVs improved muscle regeneration in a Klotho mRNA-dependent manner. These studies demonstrate that EVs play a key role in the rejuvenating effects of HBE and that Klotho transcripts within EVs phenocopy the effects of young serum on aged skeletal muscle.

参考文献：Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles. Nat Aging. 2021 Dec;1(12):1148-1161. doi: 10.1038/s43587-021-00143-2. Epub 2021 Dec 6.

今日突破2

中文摘要

衰老与虚弱、残疾和死亡的风险增加有关。延缓与衰老和虚弱相关的退行性变化的策略特别有趣。研究人员用来自幼年动物脂肪间充质干细胞（ADSC）的小细胞外囊泡（sEVs）治疗老年动物，他们发现一些随年龄变化的参数有所改善，如运动协调性、握力、抗疲劳性、皮毛再生和肾功能，以及脆弱性的显著降低。ADSC sEVs在肌肉和肾脏中诱导了促再生效应和氧化应激、炎症和衰老标记物的减少。此外，用ADSC sEVs治疗的老年小鼠的组织中预测的表观遗传年龄较低，其代谢组改变为青年样模式。最后，他们发现了sEV中可能存在导致观察到的效应的微小RNA。他们认为年轻的sEV治疗可以促进健康的衰老。

英文摘要

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging.

参考文献：Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice. Sci Adv. 2022 Oct 21;8(42):eabq2226. doi: 10.1126/sciadv.abq2226. Epub 2022 Oct 19.

今日突破3

中文摘要

为了表征阿尔茨海默病（AD）中染色质可及性的失调，研究人员从153例AD患者和56例对照组的颞上回和内嗅皮质分离的神经元和非神经元核中生成了636个ATAC-seq文库。通过分析总共200亿个读对，他们扩展了人脑中已知开放染色质区（OCR）的储备，并确定了细胞类型特异性增强子-启动子相互作用。他们的研究表明，OCR的个体间变异性可用于识别捕获基因组三维结构（3D基因组）的顺式调控域（CRD）。他们确定了AD对染色质可及性、3D基因组和转录因子（TF）调控网络的相关影响。对于AD干扰最严重的TF之一USF2，他们验证了其对溶酶体基因的调节作用。总的来说，他们采用了一种系统的方法来理解3D基因组在AD中的作用。他们将所有数据作为在线资源提供给广泛的社区分析。

英文摘要

To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.

参考文献：The three-dimensional landscape of cortical chromatin accessibility in Alzheimer's disease.Nat Neurosci. 2022 Oct;25(10):1366-1378.

今日突破4

中文摘要

棕色脂肪组织（BAT）消耗能量并促进心脏代谢健康。肥胖和衰老过程中BAT的丢失是以BAT为中心的肥胖治疗策略的主要障碍，但目前科学家对BAT的凋亡机制知之甚少。在这 项研究中，非靶向代谢组学证明凋亡的棕色脂肪细胞释放出特定的嘌呤代谢产物。这种凋亡的分泌组增强了健康脂肪细胞中产热程序的表达。这种效应由嘌呤肌苷介导，嘌呤-肌苷通过环磷酸腺苷蛋白激酶A信号通路刺激棕色脂肪细胞的能量消耗。用肌苷干预小鼠增加了BAT依赖性能量消耗，并诱导了白色脂肪组织的“褐变”。从机制上讲，平衡核苷转运蛋白1（ENT1，SLC29A1）调节BAT中的肌苷水平：ENT1缺乏增加细胞外肌苷水平，从而增强热原性脂肪细胞分化。在小鼠中，ENT1的药理学抑制以及全身和脂肪特异性消融分别增强了BAT活性和抵消了饮食诱导的肥胖。在人类棕色脂肪细胞中，ENT1的敲除或阻断增加了细胞外肌苷，从而增强了产热能力。相反，高ENT1水平与人类脂肪组织中生热标志物UCP1的低表达相关。最后，人类ENT1中Ile216Thr功能缺失突变与携带Thr变异的个体体重指数显著降低和肥胖率降低59%相关。我们的数据表明，肌苷是细胞凋亡过程中释放的一种代谢物，具有“替代我”的信号功能，可以调节产热脂肪并对抗肥胖。

英文摘要

Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardiometabolic health3. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate-protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure and induced 'browning' of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a 'replace me' signalling function that regulates thermogenic fat and counteracts obesity.

参考文献：Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. Nature. 2022 Sep;609(7926):361-368.

今日突破5

研究人员设计了一个超敏感的p16INK4a报告子，这是细胞衰老的生物标志物。他们的报告子检测到p16INK4a表达的成纤维细胞具有某些衰老特征，这些成纤维细胞在出生后不久就出现在邻近肺上皮干细胞的基底膜中。此外，这些p16INK4a+成纤维细胞增强了感知组织炎症的能力，并通过增加分泌能力来促进上皮再生。此外，成纤维细胞中需要p16INK4a的表达以促进上皮再生。这项研究强调了p16INK4a+成纤维细胞作为干细胞生态位中的组织驻留哨兵的作用，该哨兵监测屏障完整性并快速响应炎症以促进组织再生。

We engineered an ultrasensitive reporter of p16INK4a, a biomarker of cellular senescence. Our reporter detected p16INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these p16INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, p16INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.

参考文献： Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science. 2022 Oct 14;378(6616):192-201. doi: 10.1126/science.abf3326. Epub 2022 Oct 13.

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