​1. Cell—这是“趋利避害”的神经环路基础！！纹状体介导的基于价值的学习行为在衰老和亨廷顿病模型中显著退化

Abstract

Learningvalence-based responses to favorable and unfavorable options requires judgmentsof the relative value of the options, a process necessary for species survival.We found, using engineered mice, that circuit connectivity and function of thestriosome compartment of the striatum are critical for this type of learning.Calcium imaging during valence-based learning exhibited a selective correlationbetween learning and striosomal but not matrix signals. This striosomalactivity encoded discrimination learning and was correlated with taskengagement, which, in turn, could be regulated by chemogenetic excitation andinhibition. Striosomal function during discrimination learning was disturbedwith aging and severely so in a mouse model of Huntington's disease. Anatomicaland functional connectivity of parvalbumin-positive, putative fast-spikinginterneurons (FSIs) to striatal projection neurons was enhanced in striosomescompared with matrix in mice that learned. Computational modeling of thesefindings suggests that FSIs can modulate the striosomal signal-to-noise ratio,crucial for discrimination and learning.

参考文献：StriosomesMediate Value-Based Learning Vulnerable in Age and a Huntington's Disease Model.Cell. 2020 Nov 12;183(4):918-934.e49.

2. Science—外周-中枢交互再获突破（有视频）！！身体锻炼诱导肝脏产生Gpld1进而促进衰老大脑神经新生并改善认知功能

Abstract

Reversingbrain aging may be possible through systemic interventions such as exercise. Wefound that administration of circulating blood factors in plasma from exercisedaged mice transferred the effects of exercise on adult neurogenesis andcognition to sedentary aged mice. Plasma concentrations ofglycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), aGPI-degrading enzyme derived from liver, were found to increase after exerciseand to correlate with improved cognitive function in aged mice, andconcentrations of Gpld1 in blood were increased in active, healthy elderlyhumans. Increasing systemic concentrations of Gpld1 in aged mice amelioratedage-related regenerative and cognitive impairments by altering signalingcascades downstream of GPI-anchored substrate cleavage. We thus identify aliver-to-brain axis by which blood factors can transfer the benefits ofexercise in old age.

参考文献：Blood factors transfer beneficial effects of exercise on neurogenesis and cognitionto the aged brain. Science. 2020 Jul 10;369(6500):167-173.

3.Nature—外周中枢交互再获突破！！生理性血-脑间蛋白转运随着衰老过程中BBB跨细胞运输功能的下降而下降

Abstract

Thevascular interface of the brain, known as the blood-brain barrier (BBB), isunderstood to maintain brain function in part via its low transcellularpermeability1-3. Yet, recent studies have demonstrated that brain ageing issensitive to circulatory proteins4,5. Thus, it is unclear whether permeabilityto individually injected exogenous tracers-as is standard in BBB studies-fullyrepresents blood-to-brain transport. Here we label hundreds of proteinsconstituting the mouse blood plasma proteome, and upon their systemic administration,study the BBB with its physiological ligand. We find that plasma proteinsreadily permeate the healthy brain parenchyma, with transport maintained byBBB-specific transcriptional programmes. Unlike IgG antibody, plasma proteinuptake diminishes in the aged brain, driven by an age-related shift intransport from ligand-specific receptor-mediated to non-specific caveolartranscytosis. This age-related shift occurs alongside a specific loss ofpericyte coverage. Pharmacological inhibition of the age-upregulatedphosphatase ALPL, a predicted negative regulator of transport, enhances brainuptake of therapeutically relevant transferrin, transferrin receptor antibodyand plasma. These findings reveal the extent of physiological proteintranscytosis to the healthy brain, a mechanism of widespread BBB dysfunctionwith age and a strategy for enhanced drug delivery.

参考文献：Physiologicalblood-brain transport is impaired with age by a shift in transcytosis. Nature.2020 Jul;583(7816):425-430.

4. Nature—中国科学家研究发现遏制健康衰老的两个保守的表观遗传学调节分子

Abstract

It haslong been assumed that lifespan and healthspan correlate strongly, yet the twocan be clearly dissociated1-6. Although there has been a global increase inhuman life expectancy, increasing longevity is rarely accompanied by anextended healthspan4,7. Thus, understanding the origin of healthy behaviours inold people remains an important and challenging task. Here we report aconserved epigenetic mechanism underlying healthy ageing. Through genome-wideRNA-interference-based screening of genes that regulate behaviouraldeterioration in ageing Caenorhabditis elegans, we identify 59 genes aspotential modulators of the rate of age-related behavioural deterioration.Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, anda neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behaviouraldeterioration in C. elegans by reducing mitochondrial function, repressing theexpression of nuclear-encoded mitochondrial proteins. This mechanism isconserved in cultured mouse neurons and human cells. Examination of humandatabases8,9 shows that expression of the human orthologues of these C. elegansregulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlatespositively with the progression of Alzheimer's disease. Furthermore, ablationof Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weightgain and prevents cognitive decline in ageing mice. Thus our genome-wideRNA-interference screen in C. elegans has unravelled conserved epigeneticnegative regulators of ageing, suggesting possible ways to achieve healthyageing.

参考文献：Two conserved epigenetic regulators prevent healthy ageing. Nature. 2020Mar;579(7797):118-122.

5.Nature—逆转衰老不是梦！！哈佛科学家通过重编程修复青春期表观遗传学信息以逆转衰老和眼科疾病诱导的视觉缺陷

Abstract

Ageing isa degenerative process that leads to tissue dysfunction and death. A proposedcause of ageing is the accumulation of epigenetic noise that disrupts geneexpression patterns, leading to decreases in tissue function and regenerativecapacity1-3. Changes to DNA methylation patterns over time form the basis ofageing clocks4, but whether older individuals retain the information needed torestore these patterns-and, if so, whether this could improve tissuefunction-is not known. Over time, the central nervous system (CNS) losesfunction and regenerative capacity5-7. Using the eye as a model CNS tissue,here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 andKlf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNAmethylation patterns and transcriptomes, promotes axon regeneration afterinjury, and reverses vision loss in a mouse model of glaucoma and in aged mice.The beneficial effects of OSK-induced reprogramming in axon regeneration andvision require the DNA demethylases TET1 and TET2. These data indicate thatmammalian tissues retain a record of youthful epigenetic information-encoded inpart by DNA methylation-that can be accessed to improve tissue function andpromote regeneration in vivo.

参考文献：Reprogrammingto recover youthful epigenetic information and restore vision. Nature. 2020Dec;588(7836):124-129.

6. Science—科学家完善单细胞衰老“稳态”理论！！单细胞酵母的衰老受核染色质和线粒体联合调控

Abstract

Chromatininstability and mitochondrial decline are conserved processes that contributeto cellular aging. Although both processes have been explored individually inthe context of their distinct signaling pathways, the mechanism that determineswhich process dominates during aging of individual cells is unknown. We showthat interactions between the chromatin silencing and mitochondrial pathwayslead to an epigenetic landscape of yeast replicative aging with multipleequilibrium states that represent different types of terminal states of aging.The structure of the landscape drives single-cell differentiation toward one ofthese states during aging, whereby the fate is determined quite early and is insensitiveto intracellular noise. Guided by a quantitative model of the aging landscape,we genetically engineered a long-lived equilibrium state characterized by anextended life span.

参考文献：A programmable fate decision landscape underlies single-cell aging in yeast. Science.2020 Jul 17;369(6501):325-329.

7. Nature—细胞外蛋白稳态也很重要！！细胞外蛋白稳态可以抑制病理性攻击引起的蛋白聚集

Abstract

Inmetazoans, the secreted proteome participates in intercellular signalling andinnate immunity, and builds the extracellular matrix scaffold around cells.Compared with the relatively constant intracellular environment, conditions forproteins in the extracellular space are harsher, and low concentrations of ATPprevent the activity of intracellular components of the protein quality-controlmachinery. Until now, only a few bona fide extracellular chaperones andproteases have been shown to limit the aggregation of extracellular proteins1-5.Here we performed a systematic analysis of the extracellular proteostasisnetwork in Caenorhabditis elegans with an RNA interference screen that targetsgenes that encode the secreted proteome. We discovered 57 regulators ofextracellular protein aggregation, including several proteins related to innateimmunity. Because intracellular proteostasis is upregulated in response topathogens6-9, we investigated whether pathogens also stimulate extracellularproteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we foundthat C. elegans responded by increasing the expression of components ofextracellular proteostasis and by limiting aggregation of extracellularproteins. The activation of extracellular proteostasis was dependent on stress-activatedMAP kinase signalling. Notably, the overexpression of components ofextracellular proteostasis delayed ageing and rendered worms resistant tointoxication. We propose that enhanced extracellular proteostasis contributesto systemic host defence by maintaining a functional secreted proteome andavoiding proteotoxicity.

参考文献：Extracellular proteostasis prevents aggregation during pathogenic attack. Nature. 2020Aug;584(7821):410-414.

8. Cell—哈佛大学发现！！睡眠不足可能通过增加肠道活性氧化合物加速衰老，甚至引起“英年早逝”

Abstract

The viewthat sleep is essential for survival is supported by the ubiquity of thisbehavior, the apparent existence of sleep-like states in the earliest animals,and the fact that severe sleep loss can be lethal. The cause of this lethalityis unknown. Here we show, using flies and mice, that sleep deprivation leads toaccumulation of reactive oxygen species (ROS) and consequent oxidative stress,specifically in the gut. ROS are not just correlates of sleep deprivation butdrivers of death: their neutralization prevents oxidative stress and allowsflies to have a normal lifespan with little to no sleep. The rescue can beachieved with oral antioxidant compounds or with gut-targeted transgenicexpression of antioxidant enzymes. We conclude that death upon severe sleeprestriction can be caused by oxidative stress, that the gut is central in thisprocess, and that survival without sleep is possible when ROS accumulation isprevented. VIDEO ABSTRACT.

参考文献：Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut. Cell.2020 Jun 11;181(6):1307-1328.e15.

9. Nature—抗衰老CAR T细胞可逆转衰老相关的病理改变

Abstract

Cellularsenescence is characterized by stable cell-cycle arrest and a secretory programthat modulates the tissue microenvironment1,2. Physiologically, senescenceserves as a tumour-suppressive mechanism that prevents the expansion ofpremalignant cells3,4 and has a beneficial role in wound-healing responses5,6.Pathologically, the aberrant accumulation of senescent cells generates aninflammatory milieu that leads to chronic tissue damage and contributes todiseases such as liver and lung fibrosis, atherosclerosis, diabetes andosteoarthritis1,7. Accordingly, eliminating senescent cells from damagedtissues in mice ameliorates the symptoms of these pathologies and even promoteslongevity1,2,8-10. Here we test the therapeutic concept that chimeric antigenreceptor (CAR) T cells that target senescent cells can be effective senolyticagents. We identify the urokinase-type plasminogen activator receptor (uPAR)11as a cell-surface protein that is broadly induced during senescence and showthat uPAR-specific CAR T cells efficiently ablate senescent cells in vitro andin vivo. CAR T cells that target uPAR extend the survival of mice with lungadenocarcinoma that are treated with a senescence-inducing combination ofdrugs, and restore tissue homeostasis in mice in which liver fibrosis isinduced chemically or by diet. These results establish the therapeuticpotential of senolytic CAR T cells for senescence-associated diseases.

参考文献：Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020Jul;583(7814):127-132.

10. Science—线粒体功能障碍的T细胞可诱导多种病理状态和早老症

Abstract

The effectof immunometabolism on age-associated diseases remains uncertain. In this work,we show that T cells with dysfunctional mitochondria owing to mitochondrialtranscription factor A (TFAM) deficiency act as accelerators of senescence. Inmice, these cells instigate multiple aging-related features, includingmetabolic, cognitive, physical, and cardiovascular alterations, which togetherresult in premature death. T cell metabolic failure induces the accumulation ofcirculating cytokines, which resembles the chronic inflammation that ischaracteristic of aging ("inflammaging"). This cytokine storm itselfacts as a systemic inducer of senescence. Blocking tumor necrosis factor-αsignaling or preventing senescence with nicotinamide adenine dinucleotideprecursors partially rescues premature aging in mice with Tfam-deficient Tcells. Thus, T cells can regulate organismal fitness and life span, whichhighlights the importance of tight immunometabolic control in both aging andthe onset of age-associated diseases.

参考文献：T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science. 2020 Jun 19;368(6497):1371-1376.

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2020年十大研究进展名录

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

8. 年终盘点：2019年神经炎症领域十大基础研究进展

9. 年终盘点：2019年神经活动记录十大基础研究进展

10. 年终盘点：2019年ALS/FTD十大基础研究进展

11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展

12. 年终盘点：2019年神经内科十大临床研究突破

13. 年终盘点：2019年疼痛防治和痛觉机制十大研究突破

14. 年终盘点：2019年睡眠和失眠领域十大研究突破

15.年终盘点：2019年神经发育及成年神经再生十大研究突破

16. 年终盘点：2019年大脑学习和记忆的十大研究突破

17. 年终盘点：2019年衰老和长寿十大研究突破

18. 年终盘点：2019年自闭症十大研究突破

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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14. 运动神经元病等神经变性病机制研究及其干预。

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