Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking....Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.展开更多
Werner syndrome （WS） is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells （MSCs）. This...Werner syndrome （WS） is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells （MSCs）. This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, teiomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN- deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.展开更多
Aging poses a major risk factor for cardiovascular diseases,the leading cause of death in the aged population.However,the cell type-specific changes underlying cardiac aging are far from being clear.Here,we performed ...Aging poses a major risk factor for cardiovascular diseases,the leading cause of death in the aged population.However,the cell type-specific changes underlying cardiac aging are far from being clear.Here,we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age.We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profles.Via transcription regulatory network analysis,we identified FOxP1,a core transcription factor in organ development,as a key downregulated factor in aged cardiomyocytes,concomitant with the dysregulation of FoxP1 target genes associated with heart function and cardiac diseases.Consistently,the deficiency of FOxP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes.Altogether,our findings depict the celiular and molecular landscape of ventricular aging at the single-cell resolution,and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.展开更多
基金This work was supported by the National Key Research and Development Program of China(2017YFA0105804)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+8 种基金the National Key Research and Development Program of China(2018YFC2000100,2017YFA0103304,2017YFA0102802,2018YFA0107203)the National Natural Science Foundation of China(81670897,81625009,91749202.81861168034,81921006,31671429,91949209,91749123,81671377,81822018,81870228,81922027,81701388,81601233)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Bejing Natural Science Foun-dation(Z190019)Bejing Municipal Commission of Health and Family Planning(PXM2018026283_000002)Advanced Innovation Center for Human Brain Protection(3500-1192012)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08),Youth Innovation Promotion Association of CAS(2016093)the State Key Laboratory of Membrane Biology and the State Key Laboratory of Stem Cell and Reproductive Biology.
文摘Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
基金the National Basic Research Program of China （973 Program） （Nos. 2015CB964800 and 2014CB910503）, the Strategic Priority Research Program of the Chinese Academy of Sciences （XDA01020312）, the National High Technology Research and Development Program of China （2015AA020307）, the National Nat- ural Science Foundation of China （Grant Nos. 81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, and 81401159）, the Program of Beijing Municipal Science and Technology Commission （Z151100003915072）, the Beijing Nat- ural Science Foundation （7141005 and 5142016）, the Key Research Program of the Chinese Academy of Sciences （KJZDEW-TZ-L05）, the Thousand Young Talents program of China, Youth Innovation Pro- motion Association of CAS. WZ was supported by NIH grants CA158055, CA200673, and CA203834, the V Scholar award, Breast Cancer Research Award and Oberley Award （National Cancer Insti- tute Award P30CA086862） from Holden Comprehensive Cancer Center at the University of Iowa, and startup fund from the Department of Pathology, University of lowa.
文摘Werner syndrome （WS） is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells （MSCs）. This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, teiomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN- deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000)+6 种基金the National Natural Science Foundation of China(81921006,92149301,92168201,82125011,91949209,92049304,92049116,32121001,82192863,82122024,82071588,81901432,32000510,81861168034,32000500,81901433,81870228,81922027)the National Key Research and Development Program of China(2020YFA0804000,2020YFA0113400,2018YFA0107203,2020YFA0112200,2021YFF1201005,2021ZD0202401)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08),Young Elite Scientists Sponsorship Program by CAST(YESS20200012,YESS20210002)The Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(11000022T000000461062)CAS Project for Young Scientists in Basic Research(YSBR-012),Youth Innovation Promotion Association of CAS(E1CAZW0401,2022083)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CASWX2022SDC-XK14),the Tencent Foundation(2021-1045).
文摘Aging poses a major risk factor for cardiovascular diseases,the leading cause of death in the aged population.However,the cell type-specific changes underlying cardiac aging are far from being clear.Here,we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age.We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profles.Via transcription regulatory network analysis,we identified FOxP1,a core transcription factor in organ development,as a key downregulated factor in aged cardiomyocytes,concomitant with the dysregulation of FoxP1 target genes associated with heart function and cardiac diseases.Consistently,the deficiency of FOxP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes.Altogether,our findings depict the celiular and molecular landscape of ventricular aging at the single-cell resolution,and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
