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年终盘点：2019年衰老和长寿十大研究突破
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2019年衰老和长寿十大研究突破
1. Cell—线粒体通透性决定了自噬是延长寿命还是缩短寿命
英文摘要：
Autophagyis required in diverse paradigms of lifespan extension, leading to theprevailing notion that autophagy is beneficial for longevity.However, why autophagy is harmful in certain contexts remains unexplained.Here, we show that mitochondrial permeability defines the impact of autophagyon aging. Elevated autophagy unexpectedly shortenslifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1(sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants,reducing levels of autophagy or mitochondrial permeability transition pore(mPTP) opening restores normal lifespan. Remarkably, low mitochondrialpermeability is required across all paradigms examined of autophagy-dependentlifespan extension. Genetically induced mPTP opening blocks autophagy-dependentlifespan extension resulting from caloric restriction or loss of germline stemcells. Mitochondrial permeability similarly transforms autophagy into adestructive force in mammals, as liver-specific Sgk knockout mice demonstratemarked enhancement of hepatocyte autophagy, mPTP opening, and death withischemia/reperfusion injury. Targeting mitochondrial permeability may maximizebenefits of autophagy in aging.
参考文献：
Zhou et al (2019). Mitochondrial Permeability UncouplesElevated Autophagy and Lifespan Extension. Cell. 2019 Apr 4;177(2):299-314.e16.
2. Nat Med—早老小鼠粪便微生物移植可延长其寿命和健康时长
英文摘要：
Thegut microbiome is emerging as a key regulator of several metabolic, immune andneuroendocrine pathways1,2. Gut microbiome deregulation has beenimplicated in major conditions such as obesity, type 2 diabetes, cardiovasculardisease, non-alcoholic fatty acid liver disease and cancer3-6, butits precise role in aging remains to beelucidated. Here, we find that two different mouse models of progeria arecharacterized by intestinal dysbiosis with alterations that include an increasein the abundance of Proteobacteria and Cyanobacteria, and a decrease in theabundance of Verrucomicrobia. Consistent with these findings, we found thathuman progeria patients also display intestinal dysbiosis and that long-livedhumans (that is, centenarians) exhibit a substantial increase inVerrucomicrobia and a reduction in Proteobacteria. Fecal microbiotatransplantation from wild-type mice enhanced healthspan and lifespan in bothprogeroid mouse models, and transplantation with the verrucomicrobiaAkkermansia muciniphila was sufficient to exert beneficial effects. Moreover,metabolomic analysis of ileal content points to the restoration of secondarybile acids as a possible mechanism for the beneficial effects of reestablishinga healthy microbiome. Our results demonstrate that correction of theaccelerated aging-associated intestinal dysbiosisis beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationalefor microbiome-based interventions against age-related diseases.
参考文献：
Bárcena et al (2019). Healthspan and lifespan extension by fecal microbiota transplantationinto progeroid mice. Nat Med. 2019 Aug;25(8):1234-1242.
3. Cell—透明质酸酶TMEM2可促进内质网内稳态并延长线虫寿命
英文摘要：
Cellshave evolved complex mechanisms to maintain protein homeostasis, such as theUPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-basedknockout (KO) screen to identify genes important for cells to survive ER-basedprotein misfolding stress. We identified the cell-surface hyaluronidase(HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stressresistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2within the extracellular matrix (ECM) altered ER stress resistance independentof canonical UPRER pathways but dependent upon the cell-surfacereceptor, CD44, a putative HA receptor, and the MAPK cell-signaling components,ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegansprotected animals from ER stress and increased both longevityand pathogen resistance independent of canonical UPRER activationbut dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.
参考文献：
Schinzelet al (2019). The Hyaluronidase, TMEM2, Promotes ER Homeostasis and LongevityIndependent of the UPRER. Cell. 2019 Nov 27;179(6):1306-1318.e18.
4. Nature—REST通过抑制神经元兴奋进而延长线虫寿命
英文摘要：
Themechanisms that extend lifespan in humans are poorly understood. Here we showthat extended longevity in humans is associatedwith a distinct transcriptome signature in the cerebral cortex that ischaracterized by downregulation of genes related to neural excitation andsynaptic function. In Caenorhabditis elegans, neural excitation increases withage and inhibition of excitation globally, or in glutamatergic or cholinergicneurons, increases longevity. Furthermore, longevity is dynamically regulated by theexcitatory-inhibitory balance of neural circuits. The transcription factor RESTis upregulated in humans with extended longevityand represses excitation-related genes. Notably, REST-deficient mice exhibitincreased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C.elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation andreduce the lifespan of long-lived daf-2 mutants. In wild-type worms,overexpression of spr-4 suppresses excitation and extends lifespan. REST,SPR-3, SPR-4 and reduced excitation activate the longevity-associatedtranscription factors FOXO1 and DAF-16 in mammals and worms, respectively.These findings reveal a conserved mechanism of ageingthat is mediated by neural circuit activity and regulated by REST.
参考文献：
Zulloet al (2019). Regulation of lifespan by neural excitation and REST. Nature.2019 Oct;574(7778):359-364.
5.Nature— Niche僵硬感在神经祖细胞的衰老中扮演关键角色
英文摘要：
Ageing causes a decline in tissue regeneration owing toa loss of function of adult stem cell and progenitor cell populations1.One example is the deterioration of the regenerative capacity of the widespreadand abundant population of central nervous system (CNS) multipotent stem cellsknown as oligodendrocyte progenitor cells (OPCs)2. A relatively overlookedpotential source of this loss of function is the stem cell 'niche'-a setof cell-extrinsic cues that include chemical and mechanical signals3,4.Here we show that the OPC microenvironment stiffens with age, and that thismechanical change is sufficient to cause age-related loss of function of OPCs.Using biological and synthetic scaffolds to mimic the stiffness of youngbrains, we find that isolated aged OPCs cultured on these scaffolds aremolecularly and functionally rejuvenated. When we disrupt mechanicalsignalling, the proliferation and differentiation rates of OPCs are increased.We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPCmechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivoand allows OPCs to maintain activity in the ageingCNS. We also show that PIEZO1 is important in regulating cell number during CNSdevelopment. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how thefunction of adult stem and progenitor cells changes with age. Our findingscould be important not only for the development of regenerative therapies, butalso for understanding the ageing process itself.
参考文献：
Segelet al (2019). Niche stiffness underlies the ageing of central nervous systemprogenitor cells. Nature. 2019 Sep;573(7772):130-134.
6. Cell—在长寿物种中，SIRT6可更高效的修复双链DNA断裂
英文摘要：
DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is basedlargely on accelerated aging phenotypes of DNArepair mutants. Here, using a panel of 18 rodent species with diverselifespans, we show that more robust DNA double-strand break (DSB) repair, butnot nucleotide excision repair (NER), coevolves with longevity.Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. Wefurther show that the capacity of the SIRT6 protein to promote DSB repairaccounts for a major part of the variation in DSB repair efficacy betweenshort- and long-lived species. We dissected the molecular differences between aweak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acidresidues that are fully responsible for their differential activities. Ourfindings demonstrate that DSB repair and SIRT6 have been optimized during theevolution of longevity, which provides new targetsfor anti-aging interventions.
参考文献：
Tian et al (2019). SIRT6 Is Responsible for MoreEfficient DNA Double-Strand Break Repair in Long-Lived Species. Cell. 2019 Apr18;177(3):622-638.e22.
7. Nature— 研究发现COL17A1是调控皮肤衰老的关键蛋白
英文摘要：
Stemcells underlie tissue homeostasis, but their dynamics during ageing-and the relevance of these dynamics to organ ageing-remain unknown. Here we report that theexpression of the hemidesmosome component collagen XVII (COL17A1) by epidermalstem cells fluctuates physiologically through genomic/oxidative stress-inducedproteolysis, and that the resulting differential expression of COL17A1 inindividual stem cells generates a driving force for cell competition. In vivoclonal analysis in mice and in vitro 3D modelling show that clones that expresshigh levels of COL17A1, which divide symmetrically, outcompete and eliminateadjacent stressed clones that express low levels of COL17A1, which divideasymmetrically. Stem cells with higher potential or quality are thus selectedfor homeostasis, but their eventual loss of COL17A1 limits their competition,thereby causing ageing. The resultanthemidesmosome fragility and stem cell delamination deplete adjacent melanocytesand fibroblasts to promote skin ageing.Conversely, the forced maintenance of COL17A1 rescues skin organ ageing, thereby indicating potential angles for anti-ageing therapeutic intervention.
参考文献：
Liuet al (2019). Stem cell competition orchestrates skin homeostasis and ageing. Nature.2019 Apr;568(7752):344-350.
8. Cell—过度细胞生长通过稀释细胞浆进而促进细胞衰老
英文摘要：
Cellsize varies greatly between cell types, yet within a specific cell type andgrowth condition, cell size is narrowly distributed. Why maintenance of acell-type specific cell size is important remains poorly understood. Here weshow that growing budding yeast and primary mammalian cells beyond a certainsize impairs gene induction, cell-cycle progression, and cell signaling. Thesedefects are due to the inability of large cells to scale nucleic acid andprotein biosynthesis in accordance with cell volume increase, which effectivelyleads to cytoplasm dilution. We further show that loss of scaling beyond acertain critical size is due to DNA becoming limiting. Based on the observationthat senescent cells are large and exhibit many of the phenotypes of largecells, we propose that the range of DNA:cytoplasm ratio that supports optimalcell function is limited and that ratios outside these bounds contribute to aging.
参考文献：
Neurohret al (2019). Excessive Cell Growth Causes Cytoplasm Dilution And Contributesto Senescence. Cell. 2019 Feb 21;176(5):1083-1097.e18.
9. Nature—L1 cDNA通过激活I型干扰素反应进而促进衰老相关的无菌性炎症反应
英文摘要：
Retrotransposableelements are deleterious at many levels, and the failure of host surveillancesystems for these elements can thus have negative consequences. However, thecontribution of retrotransposon activity to ageingand age-associated diseases is not known. Here we show that during cellularsenescence, L1 (also known as LINE-1) retrotransposable elements becometranscriptionally derepressed and activate a type-I interferon (IFN-I) response.The IFN-I response is a phenotype of late senescence and contributes to themaintenance of the senescence-associated secretory phenotype. The IFN-Iresponse is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitorsof the L1 reverse transcriptase. Treatment of aged mice with the nucleosidereverse transcriptase inhibitor lamivudine downregulated IFN-I activation andage-associated inflammation (inflammaging) in several tissues. We propose thatthe activation of retrotransposons is an important component of sterileinflammation that is a hallmark of ageing, andthat L1 reverse transcriptase is a relevant target for the treatment ofage-associated disorders.
参考文献：
De Cecco et al (2019). L1 drives IFN in senescent cellsand promotes age-associated inflammation. Nature. 2019 Feb;566(7742):73-78.
10. Cell Stem Cell —SATB1是抑制多巴胺能神经元细胞衰老的关键因子
英文摘要：
Cellularsenescence is a mechanism used by mitotic cells to prevent uncontrolled celldivision. As senescent cells persist in tissues, they cause local inflammationand are harmful to surrounding cells, contributing to aging.Generally, neurodegenerative diseases, such as Parkinson's, are disorders of aging. The contribution of cellular senescence toneurodegeneration is still unclear. SATB1 is a DNA binding protein associatedwith Parkinson's disease. We report that SATB1 prevents cellular senescence inpost-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellularsenescence transcriptional program in dopamine neurons both in human stemcell-derived dopaminergic neurons and in mice. We observed phenotypes that arecentral to cellular senescence in SATB1 knockout dopamine neurons in vitroand in vivo. Moreover, we found that SATB1 directly represses expressionof the pro-senescence factor p21 in dopaminergic neurons. Our data implicatesenescence of dopamine neurons as a contributing factor in the pathology ofParkinson's disease.
参考文献：
Riessland et al (2019). Loss of SATB1 Inducesp21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons. CellStem Cell. 2019 Oct 3;25(4):514-530.e8.
2019年十大研究进展名录
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）
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
15.年终盘点：2019年神经发育及成年神经再生十大研究突破
2018年十大研究进展名录
14. 2018年的十大睡眠研究突破
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