Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Chemical constituents from leaves of Craibiodendron yunnanense / 中国中药杂志

The present study investigated the chemical constituents from the leaves of Craibiodendron yunnanense. The compounds were isolated and purified from the leaves of C. yunnanense by a combination of various chromatographic techniques including column chromatography over polyamide, silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were identified by extensive spectroscopic analyses including MS and NMR data. As a result, 10 compounds, including melionoside F(1), meliosmaionol D(2), naringenin(3), quercetin-3-O-α-L-arabinopyranoside(4), epicatechin(5), quercetin-3'-glucoside(6), corbulain Ib(7), loliolide(8), asiatic acid(9), and ursolic acid(10), were isolated. Compounds 1 and 2 were two new compounds, and compound 7 was isolated from this genus for the first time. All compounds showed no significant cytotoxic activity by MTT assay.

Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

Single-cell transcriptomic atlas of mouse cochlear aging

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging

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 profiles. 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 cellular 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.

Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration

Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth.

A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

Epidemiological analysis on death cases of pneumoconiosis during 1959‒2019 in Chongming District of Shanghai / 上海预防医学

ObjectiveTo study the epidemiological characteristics of deaths due to pneumoconiosis and its complications in order to improve the prevention and management of pneumoconiosis. MethodsThe pneumoconiosis deaths who died during 1959‒2019 in Chongming District of Shanghai were investigated and analyzed retrospectively by the descriptive epidemiological methods. The correlation of the age of onset and the course of disease was analyzed by Spearman rank correlation，as well as the duration of dust exposure and the course of disease in pneumoconiosis patients. ResultsFrom 1959 to 2019， there were 226 pneumoconiosis deaths， 223 males （98.67%）. The mortality of silicosis was the highest （82.07%）. The age of onset of pneumoconiosis was negatively correlated with the course of disease （rs=-0.596，P<0.001）.There was no correlation between the duration of dust exposure and the course of disease in pneumoconiosis patients （rs=-0.107，P=0.109）.There were statistically significant differences in mortality among groups in different types and stages of pneumoconiosis（χ2=59.250，27.666，both P<0.05）. The mortality increased with the increase of stage of pneumoconiosis. The mortality of pneumoconiosis was significantly different in 1959‒1979， 1980‒1989， 1990‒1999， 2000‒2009 and 2010‒2019 （χ2=29.750， P<0.05）. The top three causes of death in pneumoconiosis cases were respiratory diseases， malignant tumor and cardiovascular and cerebrovascular diseases.ConclusionIt is suggested to further strengthen the health monitoring and management of pneumoconiosis patients，control lung and chronic respiratory diseases to delay the life expectancy and improve quality of life of pneumoconiosis patients.

Aging weakens Th17 cell pathogenicity and ameliorates experimental autoimmune uveitis in mice

Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure. Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process. However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking. We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU). We found extensive and complicated changes in the cellular constituents of CDLNs during aging. When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice. Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice. The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs' effects on facilitating the pathogenicity of Th17 cells. Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs. Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.

Single-nucleus transcriptomic landscape of primate hippocampal aging

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 revealed impaired TAPC division and compromised neuronal 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.

The efficacy of hemostatic powder for chronic rhinosinusitis in endoscopic sinus surgery: a prospective, randomised, controlled and single blinded clinical trial / 中华耳鼻咽喉头颈外科杂志

Objective: To study the efficacy and patient comfort of absorbable hemostatic powder after endoscopic sinus surgery (ESS). Methods: A total of 21 (17 males, 4 females) patients with an average age of 42(ranging from 18 to 65) underwent bilateral ESS for chronic rhinosinusitis(CRS) in Beijing Tongren Hospital, Capital Medical University between October 2015 and July 2019 were enrolled to compare the effect of absorbable hemostasis powder with Nasopore using an intrapatient control design. A randomized controlled trial was conducted in the left and right nasal cavities of the same patient. If hemostatic powder was applied in the experiment nasal cavity, the Nasopore was applied in the control nasal cavity. The mean preoperative sinus computed tomography (CT) score was 6.25. All patients competed for symptom diaries using a visual analog scale (VAS, score out of 10) at baseline, through 1, 7, 14 and 30 days. Outcomes including bleeding, facial pain, nasal obstruction, nasal discharges using VAS were recorded separately for both sides. Postoperative endoscopic scores were also investigated. SPSS 22 and Graphpad prism 8.0 statistical softwares were used for the analysis. Paired t-test or nonparametric test was used between the test side and the control side. The difference was statistically significant (P<0.05). Results: The bleeding score and total nasal symptom VAS scores at postoperative days (POD) 1, 7, 14 and 30 were not significantly different(t=1.341, 0.552, 0.631, 0.158, all P>0.05;t=0.944, 1.471, 1.612, 2.251, all P>0.05). There was no significant difference between absorbable hemostasis powder and Nasopore side on POD 1, 7, 14 and 30 in terms of each nasal symptom VAS scores(all P>0.05). On POD 1, 7 and 14, the packing material degeneration scores of the absorbable hemostasis powder side were significantly lower than those of the Nasopore side [(1.33±0.21)vs(2.00±0.00),(0.38±0.18) vs (1.95±0.22), 0 vs (1.80±0.13), all P<0.01]. There were significant differences between absorbable hemostasis powder and Nasopore side on POD 1, 7, 14 and 30 in terms of endoscopic scores (edema, crusting, discharges, scar, polyps and material degeneration, t=3.07, 7.00, 6.41, 2.69, all P<0.05). Conclusions: The absorbable hemostasis powder and Nasopore has similar postoperative hemostasis effect. The absorbable hemostasis powder is rapidly cleared and without negative effects on mucosal wound healing 14 days postoperatively.

High resolution CT findings and clinical features of novel coronavirus pneumonia in Guangzhou / 中华放射学杂志

Objective@#To investigate the initial HRCT manifestations and clinical features of imported novel coronavirus pneumonia (NCP) in Guangzhou.@*Methods@#A retrospective analysis of 91 NCP patients admitted to the Guangzhou Eighth People’s Hospital from January 22 to 30, 2020 was performed including 39 males and 52 females, with a median age of 50 (33-62) years, then their clinical features and HRCT characteristics were analyzed.@*Results@#The main clinical presentations included fever in 70 cases and cough in 57 cases(mainly dry coughin39 cases). The first time HRCT showed that 24 cases with NCP were normal, however other 67 cases were abnormal. The ground glass opacity in the lung on HRCT was found in 65 cases, including 64 cases with dilated blood vessel crossing the lesion, 50 cases with thickened adjacent pleura, and 47 cases with thickening of interstitial septum. The patchy opacity was seen in 42 cases, and no enlarged lymph nodes were observed in all patients. As for the lesion distribution, there were two cases with bilateral diffuse changes, 57 cases with multiple lesions, 8 cases with the lesion in only one lobe. The lesions were mainly located under the pleura area in 46 cases, including 39 cases in the lower lobe and other 7 cases in the upper lobe. And there were 13 cases without characteristic distribution in the lung.@*Conclusions@#The initial images of NCP in Guangzhou mainly showed multiple ground glass opacity, which were mostly seen in the subpleural and lower lung fields, most of them with thickened pulmonary interstitium. Guangzhou has a higher proportion of NCP patients with mild and general patients, and some confirmed patients show negative HRCT for the first time. Patients without HRCT changes should be reviewed in a timely manner.

Generation of a Hutchinson-Gilford progeria syndrome monkey model by base editing

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.

High resolution CT findings and clinical features of COVID-19 in Guangzhou / 中华放射学杂志

Objective:To investigate the initial high resolution CT (HRCT) manifestations and clinical features of imported COVID-19 in Guangzhou.Methods:A retrospective analysis of 91 COVID-19 patients admitted to the Guangzhou Eighth People's Hospital from January 22 to 30, 2020 was performed including 39 males and 52 females, with a median age of 50 (33-62) years,then their clinical features and HRCT characteristics were analyzed.Results:The main clinical presentations included fever in 70 cases and cough in 57 cases(mainly dry cough in 39 cases). The first time HRCT showed that 24 cases with COVID-19 were normal, however other 67 cases were abnormal. The ground glass opacity in the lung on HRCT was found in 65 cases, including 64 cases with dilated blood vessel crossing the lesion, 50 cases with thickened adjacent pleura, and 47 cases with thickening of interstitial septum. The patchy opacity was seen in 42 cases, and no enlarged lymph nodes were observed in all patients. As for the lesion distribution, there were two cases with bilateral diffuse changes, 57 cases with multiple lesions, 8 cases with the lesion in only one lobe. The lesions were mainly located under the pleura area in 46 cases, including 39 cases in the lower lobe and other 7 cases in the upper lobe. And there were 13 cases without characteristic distribution in the lung.Conclusion:The initial images of COVID-19 in Guangzhou mainly showed multiple ground glass opacity, which were mostly seen in the subpleural and lower lung fields, most of them with thickened pulmonary interstitium. Guangzhou has a higher proportion of COVID-19 patients with mild and general patients, and some confirmed patients show negative HRCT for the first time. Patients without HRCT changes should be reviewed in a timely manner.

A human circulating immune cell landscape in aging and COVID-19

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 regulatory 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 coronavirus 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 senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

Analysis of Clinical Characteristics and Prognostic Risk Factors of HLH Children with Central Nervous System Involvement / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics and prognostic risk factors of HLH children with central nervous system (CNS) involvement so as to provide more reference for further improving the prognosis of HLH children.@*METHODS@#The clinical data of 45 HLH children with CNS involvement treated in our hospital from January 2006 to October 2016 were collected and analyzed retrospectively. The clinical characteristics of HLH children with CNS involvement were recorded, moreover the possible factors influencing the prognosis of HLH children with CNS involvement were analyzed using univariate and multivariate analysis through the establishment of Cox risk ratio model.@*RESULTS@#Among 45 HLH children with CNS involvement, male was 19 cases and female was 26 cases. The median age of 4.0 years old (1.0-15.1). The detection showed that EBV found in 38 cases (84.44%), CMV infection in 1 case (2.22%), bacterial infection in 3 cases (6.67%), connection tissue disease in 1 case (2.22%) and indefinite etiology infection in 2 cases (4.44%). After lumbar puncture of 27 HLH children with CNS involvement, 10 cases (37.04%) showed cerebrospinal fluid abnormality. In addition, 22 cases showed the craniography abnormality. The follow-up results showed that the OS rate of 1 year was 46.67% (21/45), the OS rate of 3 years was 44.44% (20/45); the median survival time was 5.0 months. The OS analysis indicated that 1 years OS rate of diseased children with cerebrospinal fluid abnormality was significantly lower than that of diseased children with cerebrospinal fluid normality (10/45 vs 17/45) (P＜0.05), and 1 years OS rate of diseased children who not received intrathecal injection was significantly lower that of diseased children who received intrathecal (10/45 vs 17/45) (P＜0.05). The univariate analysis showed that the symptoms of nervous system, abnormal cerebrospinal fluid, absence of intrathecal injection and treatment schedule all were the risk factors affecting the prognosis of HLH children with CNS involvement (P＜0.05). The multivariate analysis by Cox risk model showed that abnormal cerebrospinal fluid and absence of intrathecal injection were independent risk factors for of HLH children with CNS involvement (P＜0.05).@*CONCLUSION@#The clinical prognosis of HLH children with CNS involvement is relatively poor, moreover some of HLH children with CNS involvement have neural sequelae. The cerebrospinal fluid abnormality and absence of intrathecal injection are independent risk factors leading to poor prognosis for HLH clildren with CNS involvement.

Overexpression of miR-130a-3p attenuates cardiomyocyte hypertrophy / 生物医学工程学杂志

This study aimed to explore the role of miR-130a-3p in cardiomyocyte hypertrophy and its underlying mechanisms. Pressure-overload induced myocardial hypertrophy mice model was constructed by thoracic aortic constriction (TAC). , norepinephrine (NE) was used to stimulate neonatal rat cardiomyocytes (NRCMs) and H9c2 rat cardiomyocytes to induce hypertrophic phenotypes. The expression of miR-130a-3p was detected in mice hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. The mimics and inhibitors of miR-130a-3p were transfected into H9c2 cells to observe the role of miR-130a-3p on the hypertrophic phenotype change of cardiomyocytes separately. Furthermore, whether miR-130a-3p regulated hypertrophic related signaling pathways was explored. The results showed that the expression of miR-130a-3p was significantly decreased in hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. After transfection of miR-130a-3p mimics, the expression of hypertrophic marker genes, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), and the cell surface area were notably down-regulated compared with the control group (mimics N.C. + NE group). But after transfection of miR-130a-3p inhibitor, the expression of ANP, BNP and β-MHC in H9c2 cells increased significantly, and the cell area increased further. By Western blot, it was found that the protein phosphorylation level of Akt and mTOR were down-regulated after over-expression of miR-130a-3p. These results suggest that miR-130a-3p mimics may alleviate the degree of cardiomyocyte hypertrophy, meanwhile its inhibitor can further aggravate cardiomyocyte hypertrophy. Over-expression of miR-130a-3p may attenuate cardiomyocytes hypertrophy by affecting the Akt pathway.

A human circulating immune cell landscape in aging and COVID-19

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 regulatory 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 coronavirus 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 senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.