Volume 12 Issue 9
Sep.  2021
Turn off MathJax
Article Contents
Hui Zhang, Jiaming Li, Jie Ren, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Yusheng Cai, Kaowen Yan, Wei Li, Baoyang Hu, Piu Chan, Guo-Guang Zhao, Juan Carlos Izpisua Belmonte, Qi Zhou, Jing Qu, Si Wang, Guang-Hui Liu. Single-nucleus transcriptomic landscape of primate hippocampal aging[J]. Protein&Cell, 2021, 12(9): 695-716. doi: 10.1007/s13238-021-00852-9
Citation: Hui Zhang, Jiaming Li, Jie Ren, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Yusheng Cai, Kaowen Yan, Wei Li, Baoyang Hu, Piu Chan, Guo-Guang Zhao, Juan Carlos Izpisua Belmonte, Qi Zhou, Jing Qu, Si Wang, Guang-Hui Liu. Single-nucleus transcriptomic landscape of primate hippocampal aging[J]. Protein&Cell, 2021, 12(9): 695-716. doi: 10.1007/s13238-021-00852-9

Single-nucleus transcriptomic landscape of primate hippocampal aging

doi: 10.1007/s13238-021-00852-9

We thank Shanshan Che, Liyun Zhao, Xiaoyan Sun, and Yixin Zhang for their help in immunofluorescence staining, Ruotong Ren, Liping Deng and Xiaojuan He for their help in tissue collection, Junying Jia from the Institute of Biophysics, Chinese Academy of Sciences for his help in fluorescence-activated cell sorting (FACS), as well as Shiwen Li from the Institute of Zoology, Chinese Academy of Sciences for her help in image scanning of immunohistochemical staining. We thank Profs. Fuchou Tang, Xiaoqun Wang, Young Shen, Moshi Song, Fudong Shi and Junying Yuan for their helpful suggestions and discussions. We are grateful to Lei Bai, Qun Chu, Xiao Zhuo, Jing Lu, Ying Yang, Ruijun Bai, and Shikun Ma for administrative assistance. This work was supported by the National Key Research and Development Program of China (2020YFA0804000), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000), the National Key Research and Development Program of China (2019YFA0110100, 2020YFA0112201, 2018YFC2000100, 2017YFA0103304, 2017YFA0102802, 2018Y FA0107203, 2020YFA0803401, and 2019YFA0802202), the National Natural Science Foundation of China (Grant Nos. 81921006, 81625009, 91749202, 81861168034, 91949209, 92049304, 81822018, 82071588, 92049116, 31900523, 32000500, 31970597, 82030037, and 81801534), the Program of the Beijing Municipal Science and Technology Commission (Z191100001519005), Beijing Natural Science Foundation (Z190019), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221), K. C. Wong Education Foundation (GJTD-2019-06, GJTD-2019-08), the International Partnership Program of Chinese Academy of Sciences (152111KYSB20160004), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-JKCS-011), the State Key Laboratory of Stem Cell and Reproductive Biology, the State Key Laboratory of Membrane Biology, the Milky Way Research Foundation (MWRF), and the Moxie Foundation (for J.C.I.B.).

  • Received Date: 2020-10-07
  • Accepted Date: 2020-11-13
  • The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealedimpairedTAPCdivisionandcompromisedneuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.
  • loading
  • [1]
    Aging Atlas C (2021) Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 49:D825–D830
    Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J et al (2017) SCENIC: single-cell regulatory network inference and clustering. Nat Methods 14:1083–1086
    Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH (2014) Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 94:991–1026
    Angelidis I, Simon LM, Fernandez IE, Strunz M, Mayr CH, Greiffo FR, Tsitsiridis G, Ansari M, Graf E, Strom TM et al (2019) An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun 10:963
    Artegiani B, Lyubimova A, Muraro M, van Es JH, van Oudenaarden A, Clevers H (2017) A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep 21:3271–3284
    Baird GS, Nelson SK, Keeney TR, Stewart A, Williams S, Kraemer S, Peskind ER, Montine TJ (2012) Age-dependent changes in the cerebrospinal fluid proteome by slow off-rate modified aptamer array. Am J Pathol 180:446–456
    Baker DJ, Petersen RC (2018) Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Investig 128:1208–1216
    Bedrosian TA, Houtman J, Eguiguren JS, Ghassemzadeh S, Rund N, Novaresi NM, Hu L, Parylak SL, Denli AM, Randolph-Moore L et al (2021) Lamin B1 decline underlies age-related loss of adult hippocampal neurogenesis. EMBO J 40:e105819
    Bengoa-Vergniory N, Kypta RM (2015) Canonical and noncanonical Wnt signaling in neural stem/progenitor cells. Cell Mol Life Sci 72:4157–4172
    Bi S, Liu Z, Wu Z, Wang Z, Liu X, Wang S, Ren J, Yao Y, Zhang W, Song M et al (2020) SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell 11:483–504
    Bin Imtiaz MK, Jaeger BN, Bottes S, Machado RAC, Vidmar M, Moore DL, Jessberger S (2021) Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell. https://doi.org/10.1016/j.stem.2021.01.015
    Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ et al (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22(589–599):e585
    Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging. Eur J Biochem 269:1996–2002
    Bryan KJ, Zhu X, Harris PL, Perry G, Castellani RJ, Smith MA, Casadesus G (2008) Expression of CD74 is increased in neurofibrillary tangles in Alzheimer’s disease. Mol Neurodegener 3:13
    Buchwalter A, Kaneshiro JM, Hetzer MW (2019) Coaching from the sidelines: the nuclear periphery in genome regulation. Nat Rev Genet 20:39–50
    Buckig A, Tikkanen R, Herzog V, Schmitz A (2002) Cytosolic and nuclear aggregation of the amyloid beta-peptide following its expression in the endoplasmic reticulum. Histochem Cell Biol 118:353–360
    Butler A, Hoffman P, Smibert P, Papalexi E, Satija R (2018) Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36:411–420
    Chen Y, Niu Y, Ji W (2012) Transgenic nonhuman primate models for human diseases: approaches and contributing factors. J Genet Genom 39:247–251
    Chen Y, Niu Y, Ji W (2016) Genome editing in nonhuman primates: approach to generating human disease models. J Intern Med 280:246–251
    Chen Y, Yu J, Niu Y, Qin D, Liu H, Li G, Hu Y, Wang J, Lu Y, Kang Y et al (2017) Modeling Rett syndrome using TALEN-edited MECP2 mutant cynomolgus monkeys. Cell 169(945–955):
    Chen WT, Lu A, Craessaerts K, Pavie B, Sala Frigerio C, Corthout N, Qian X, Lalakova J, Kuhnemund M, Voytyuk I et al (2020) Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 182(976–991):e919
    Chow HM, Shi M, Cheng A, Gao Y, Chen G, Song X, So RWL, Zhang J, Herrup K (2019) Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nat Neurosci 22:1806–1819
    Colman RJ (2018) Non-human primates as a model for aging. Biochim Biophys Acta Mol Basis Dis 1864:2733–2741
    Costa-Mattioli M, Walter P (2020) The integrated stress response: from mechanism to disease. Science 368:eaat5314
    De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD et al (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:73–78
    Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O (2009) Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4:1798–1806
    Deng L, Ren R, Liu Z, Song M, Li J, Wu Z, Ren X, Fu L, Li W, Zhang W et al (2019) Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Nat Commun 10:3329
    Diao Z, Ji Q, Wu Z, Zhang W, Cai Y, Wang Z, Hu J, Liu Z, Wang Q, Bi S et al (2021) SIRT3 consolidates heterochromatin and counteracts senescence. Nucleic Acids Res 49:4203–4219
    Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, Ivanov A, Capell BC, Drake AM, Shah PP et al (2015) Autophagy mediates degradation of nuclear lamina. Nature 527:105–109
    Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, George BM, Boutet SC, Hebestreit K, Pluvinage JV et al (2019) Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571:205–210
    Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R (2020) Cell PhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat Protoc 15:1484–1506
    Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A, Enikolopov G (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8:566–579
    Fan X, Wheatley EG, Villeda SA (2017) Mechanisms of hippocampal aging and the potential for rejuvenation. Annu Rev Neurosci 40:251–272
    Frost B (2016) Alzheimer’s disease: an acquired neurodegenerative laminopathy. Nucleus 7:275–283
    Geng L, Liu Z, Wang S, Sun S, Ma S, Liu X, Chan P, Sun L, Song M, Zhang W et al (2019) Low-dose quercetin positively regulates mouse healthspan. Protein Cell 10:770–775
    Geutskens SB, Hordijk PL, van Hennik PB (2010) The chemorepellent Slit3 promotes monocyte migration. J Immunol 185:7691–7698
    Giacobini E, Gold G (2013) Alzheimer disease therapy–moving from amyloid-beta to tau. Nat Rev Neurol 9:677–686
    Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S et al (2021) Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol 18:194–209
    Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, Yeung C, Liles WC, Wurfel M, Lopez JA et al (2017) Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 7:1404–1419
    Habib N, Li Y, Heidenreich M, Swiech L, Avraham-Davidi I, Trombetta JJ, Hession C, Zhang F, Regev A (2016) Div-Seq: single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons. Science 353:925–928
    Harris L, Genovesi LA, Gronostajski RM, Wainwright BJ, Piper M (2015) Nuclear factor one transcription factors: divergent functions in developmental versus adult stem cell populations. Dev Dyn 244:227–238
    He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP et al (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 467:95–98
    He X, Memczak S, Qu J, Belmonte JCI, Liu GH (2020) Single-cell omics in ageing: a young and growing field. Nat Metab 2:293–302
    Head D, Snyder AZ, Girton LE, Morris JC, Buckner RL (2005) Frontal-hippocampal double dissociation between normal aging and Alzheimer’s disease. Cereb Cortex 15:732–739
    Herculano-Houzel S (2009) The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 3:31
    Hoppe B, Dorner T (2012) Coagulation and the fibrin network in rheumatic disease: a role beyond haemostasis. Nat Rev Rheumatol 8:738–746
    Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA (2019) Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15:565–581
    Hu H, Ji Q, Song M, Ren J, Liu Z, Wang Z, Liu X, Yan K, Hu J, Jing Y et al (2020) ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin. Nucleic Acids Res 48:6001–6018
    Hwang IK, Park JH, Lee TK, Kim DW, Yoo KY, Ahn JH, Kim YH, Cho JH, Kim YM, Won MH et al (2017) CD74-immunoreactive activated M1 microglia are shown late in the gerbil hippocampal CA1 region following transient cerebral ischemia. Mol Med Rep 15:4148–4154
    Ibrayeva A, Bay M, Pu E, Jorg DJ, Peng L, Jun H, Zhang N, Aaron D, Lin C, Resler G et al (2021) Early stem cell aging in the mature brain. Cell Stem Cell. https://doi.org/10.1016/j.stem.2021.03.018
    Jin WN, Shi K, He W, Sun JH, Van Kaer L, Shi FD, Liu Q (2021) Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat Neurosci 24:61–73
    Kempermann G, Song H, Gage FH (2015) Neurogenesis in the Adult Hippocampus. Cold Spring Harb Perspect Biol 7:a018812
    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290
    Krishnaswami SR, Grindberg RV, Novotny M, Venepally P, Lacar B, Bhutani K, Linker SB, Pham S, Erwin JA, Miller JA et al (2016) Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc 11:499–524
    Kruithof EK, Dunoyer-Geindre S (2014) Human tissue-type plasminogen activator. Thromb Haemost 112:243–254
    Kuhn HG, Toda T, Gage FH (2018) Adult hippocampal neurogenesis: a coming-of-age story. J Neurosci 38:10401–10410
    Leng F, Edison P (2021) Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 17:157–172
    Leuner B, Kozorovitskiy Y, Gross CG, Gould E (2007) Diminished adult neurogenesis in the marmoset brain precedes old age. Proc Natl Acad Sci USA 104:17169–17173
    Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM (2017) TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci USA 114:11524–11529
    Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H et al (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 101:3632–3637
    Li D, Takeda N, Jain R, Manderfield LJ, Liu F, Li L, Anderson SA, Epstein JA (2015) Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res 15:522–529
    Li J, Zheng Y, Yan P, Song M, Wang S, Sun L, Liu Z, Ma S, Belmonte JCI, Chan P et al (2020) A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev 8(2):127
    Liang C, Liu Z, Song M, Li W, Wu Z, Wang Z, Wang Q, Wang S, Yan K, Sun L et al (2021) Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration. Cell Res 31:187–205
    Linnartz-Gerlach B, Bodea LG, Klaus C, Ginolhac A, Halder R, Sinkkonen L, Walter J, Colonna M, Neumann H (2019) TREM2 triggers microglial density and age-related neuronal loss. Glia 67:539–550
    Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W et al (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491:603–607
    Liu X, Liu Z, Sun L, Ren J, Wu Z, Jiang X, Ji Q, Wang Q, Fan Y, Cai Y et al (2021) Resurrection of human endogenous retroviruses during aging reinforces senescence. bioRxiv. https://doi.org/10.1101/2021.02.22.432260v1.abstract
    Lubbe SJ, Bustos B, Hu J, Krainc D, Joseph T, Hehir J, Tan M, Zhang W, Escott-Price V, Williams NM et al (2021) Assessing the relationship between monoallelic PRKN mutations and Parkinson’s risk. Human Mol Genet 30:78–86
    Ma S, Sun S, Geng L, Song M, Wang W, Ye Y, Ji Q, Zou Z, Wang S, He X et al (2020a) Caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus aging. Cell 180(984–1001):e1022
    Ma S, Sun S, Li J, Fan Y, Qu J, Sun L, Wang S, Zhang Y, Yang S, Liu Z et al (2020b) Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 31(4):415–432
    Malykhin NV, Bouchard TP, Camicioli R, Coupland NJ (2008) Aging hippocampus and amygdala. NeuroReport 19:543–547
    Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J et al (2016) Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism. Blood 128:2423–2434
    Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcao A, Xiao L, Li H, Haring M, Hochgerner H, Romanov RA et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352:1326–1329
    Martinelli P, Real FX (2019) Mouse models shed light on the SLIT/ROBO pathway in pancreatic development and cancer. Trends Cancer 5:145–148
    Mauffrey P, Tchitchek N, Barroca V, Bemelmans A-P, Firlej V, Allory Y, Roméo P-H, Magnon C (2019) Progenitors from the central nervous system drive neurogenesis in cancer. Nature 569:672–678
    McGinnis CS, Murrow LM, Gartner ZJ (2019) DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 8:329–337.e324
    Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250
    Nakamura R, Nakamoto C, Obama H, Durward E, Nakamoto M (2012) Structure-function analysis of Nel, a thrombospondin-1-like glycoprotein involved in neural development and functions. J Biol Chem 287:3282–3291
    Navarro Negredo P, Yeo RW, Brunet A (2020) Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27:202–223
    Ofengeim D, Yuan J (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14:727–736
    Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353:777–783
    Rivero O, Sich S, Popp S, Schmitt A, Franke B, Lesch KP (2013) Impact of the ADHD-susceptibility gene CDH13 on development and function of brain networks. Eur Neuropsychopharmacol 23:492–507
    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504
    Shi Z, Geng Y, Liu J, Zhang H, Zhou L, Lin Q, Yu J, Zhang K, Liu J, Gao X et al (2018) Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations. Protein Cell 9:351–364
    Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL et al (2019) LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab 29:871–885
    Stahl PL, Salmen F, Vickovic S, Lundmark A, Navarro JF, Magnusson J, Giacomello S, Asp M, Westholm JO, Huss M et al (2016) Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353:78–82
    Su H, Na N, Zhang X, Zhao Y (2017) The biological function and significance of CD74 in immune diseases. Inflamm Res 66:209–216
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 102:15545
    Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150
    Tanaka T, Biancotto A, Moaddel R, Moore AZ, Gonzalez-Freire M, Aon MA, Candia J, Zhang P, Cheung F, Fantoni G et al (2018) Plasma proteomic signature of age in healthy humans. Aging Cell 17:
    Tiensuu H, Haapalainen AM, Karjalainen MK, Pasanen A, Huusko JM, Marttila R, Ojaniemi M, Muglia LJ, Hallman M, Ramet M (2019) Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2. PLoS Genet 15:e1008107
    Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD (2011) NF-kappaB in aging and disease. Aging Dis 2:449–465
    Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, Lennon NJ, Livak KJ, Mikkelsen TS, Rinn JL (2014) The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 32:381–386
    Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675
    Vanlandewijck M, He L, Mae MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Lavina B, Gouveia L et al (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:475–480
    Végh MJ, Rausell A, Loos M, Heldring CM, Jurkowski W, van Nierop P, Paliukhovich I, Li KW, del Sol A, Smit AB et al (2014) Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline. Mol Cell Proteom 13:2975–2985
    Volkman HE, Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol 15:415–422
    Wang L, Song G, Zhang X, Feng T, Pan J, Chen W, Yang M, Bai X, Pang Y, Yu J et al (2017) PADI2-mediated citrullination promotes prostate cancer progression. Cancer Res 77:5755–5768
    Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M, Liu Z, Min Z, Hu H, Jing Y et al (2020a) Single-cell transcriptomic atlas of primate ovarian aging. Cell 180(585–600):e519
    Wang S, Zheng Y, Li Q, He X, Ren R, Zhang W, Song M, Hu H, Liu F, Sun G et al (2020b) Deciphering primate retinal aging at single-cell resolution. Protein Cell. https://doi.org/10.1007/s13238-020-00791-x
    Wegiel J, Frackowiak J, Mazur-Kolecka B, Schanen NC, Cook EH Jr, Sigman M, Brown WT, Kuchna I, Wegiel J, Nowicki K et al (2012) Abnormal intracellular accumulation and extracellular Abeta deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders. PLoS One 7:e35414
    Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Hornig S, Bauer S et al (2021) Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation. J Exp Med. https://doi.org/10.1084/jem.20201290
    Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180–186
    Yang X, Goh A, Chen SH, Qiu A (2013) Evolution of hippocampal shapes across the human lifespan. Hum Brain Mapp 34:3075–3085
    Yang AC, Stevens MY, Chen MB, Lee DP, Stahli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L et al (2020) Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 583:425–430
    Young MD, Behjati S (2020) SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data. GigaScience 9:giaa151
    Yu HC, Tung CH, Huang KY, Huang HB, Lu MC (2020) The essential role of peptidylarginine deiminases 2 for cytokines secretion, apoptosis, and cell adhesion in macrophage. Int J Mol Sci 21:5720
    Yuan J, Amin P, Ofengeim D (2019) Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 20:19–33
    Zenker M, Bunt J, Schanze I, Schanze D, Piper M, Priolo M, Gerkes EH, Gronostajski RM, Richards LJ, Vogt J et al (2019) Variants in nuclear factor I genes influence growth and development. Am J Med Genet C Semin Med Genet 181:611–626
    Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A et al (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163
    Zhang W, Wan H, Feng G, Qu J, Wang J, Jing Y, Ren R, Liu Z, Zhang L, Chen Z et al (2018) SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 560:661–665
    Zhang K, Wang Y, Fan T, Zeng C, Sun ZS (2020a) The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders. Protein Cell. https://doi.org/10.1007/s13238-020-00812-9
    Zhang W, Qu J, Liu GH, Belmonte JCI (2020b) The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 21:137–150
    Zhang W, Zhang S, Yan P, Ren J, Song M, Li J, Lei J, Pan H, Wang S, Ma X et al (2020c) A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 11:2202
    Zhong S, Ding W, Sun L, Lu Y, Dong H, Fan X, Liu Z, Chen R, Zhang S, Ma Q et al (2020) Decoding the development of the human hippocampus. Nature 577:531–536
    Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523
  • PAC-0695-21203-LGH_Supple.pdf
    PAC-0695-21203-LGH_Supple_Table S1.xlsx
    PAC-0695-21203-LGH_Supple_Table S2.xlsx
    PAC-0695-21203-LGH_Supple_Table S3.xlsx
    PAC-0695-21203-LGH_Supple_Table S6.xlsx
    PAC-0695-21203-LGH_Supple_Table S4.xlsx
    PAC-0695-21203-LGH_Supple_Table S5.xlsx
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (186) PDF downloads(55) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint