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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.
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Envelhecimento/genética , Envelhecimento/fisiologia , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Animais , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Feminino , Cadeias J de Imunoglobulina/genética , Cadeias J de Imunoglobulina/metabolismo , Masculino , Camundongos , Plasmócitos/citologia , Plasmócitos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA-Seq , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , TranscriptomaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call 'lipid-droplet-accumulating microglia' (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.
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Envelhecimento/patologia , Encéfalo/patologia , Lipídeos , Microglia/patologia , Animais , Humanos , Inflamação/patologia , CamundongosRESUMO
PURPOSE: The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS: The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E(-/-) db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS: Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS: In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.
Assuntos
Apolipoproteínas E/metabolismo , Retinopatia Diabética/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hiperglicemia/metabolismo , Hiperlipidemias/metabolismo , Receptores Imunológicos/metabolismo , Animais , Retinopatia Diabética/fisiopatologia , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Feminino , Fluorescência , Técnica Indireta de Fluorescência para Anticorpo , Expressão Gênica , Produtos Finais de Glicação Avançada/genética , Hiperglicemia/patologia , Hiperlipidemias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Vasos Retinianos/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
PURPOSE: To determine the role of pars plana vitrectomy (PPV) in the treatment of Klebsiella pneumoniae endogenous endophthalmitis. METHODS: Records of seven consecutive patients (10 eyes) diagnosed with Klebsiella endogenous endophthalmitis were retrospectively reviewed. RESULTS: Five patients (71%) had diabetes, and four (57%) had a liver abscess as the source. In most cases, the inflammation progressed within days and resulted in decreased vision worse than hand motions and a total vitreous abscess, despite systemic and intravitreal antibiotic injections. A PPV with subretinal abscess drainage and silicone oil tamponade was performed within 2 weeks. After 6 months, the retina remained attached in all eyes (100%), and vision was counting fingers or better in five eyes (50%). Two eyes recovered visual acuity between 20/63 and 20/125. CONCLUSIONS: Physicians should be alerted to the development of endogenous endophthalmitis in patients with Klebsiella septicemia, especially in diabetics with a hepatobiliary abscess. Aggressive therapy, including early vitrectomy with antibiotic injection, may improve the final outcome in this otherwise devastating ocular condition.
