Project description:To understand why asthma remit with aging, we exposed mice across a range of ages to viral and allergic triggers of asthma exacerbations and inflammatory airway pathology. We found that pathology induced by Sendai virus (SeV) or influenza A virus (IAV) occurred selectively in juvenile mice in a microbiome-independent manner, while the same phenotypes induced by allergens were relatively insensitive to age. Age-specific responses to SeV included a juvenile bias towards type-2 airway inflammation that emerged early in infection and was lost with maturation. With aging, we observed progressive transcriptional changes to alveolar macrophages (AMs) including the acquisition of high-level MHC-II expression. Importantly, depleting AMs before SeV infection canceled the protective effects of maturity on post-viral airway pathology. Thus, age-related changes to the lung immune micro-environment alter host responses to viruses and may drive childhood asthma remission.
Project description:This study utilized a standard rat model of aging and global gene expression analyses to attempt to identify the most appropriate time points to study vascular aging and to identify molecules associated with the development of pathology. Recent studies have established that age is the major risk factor for vascular disease. Numerous changes occur in vascular structure and function during aging, and animal models, including rodents, are the primary means to determine the underlying mechanisms of age-mediated vascular pathology. This study utilized a standard rat model of aging and both morphometric and global gene expression analyses to attempt to identify the most appropriate time points to study vascular aging and to identify molecules associated with the development of pathology. Morphometric analysis of Fischer 344/Brown Norway F1 hybrid (F344xBN) rat thoracic aorta indicated, in contrast to some previous studies, that progressive increases in intimal and medial thickness, as well as smooth muscle cell-containing intimal protrusions, occurred with age. This structural vascular pathology was associated with a progressive increase in global differential gene expression. Specific molecules with altered mRNA and protein expression included the adhesion molecules ICAM-1 and VCAM-1, and the bone morphogenic proteins osteopontin and bone sialoprotein-1. Intimal-associated macrophages were detected with immunohistochemistry in paraffin sections of thoracic aorta and were found to increase significantly in number with age. Both systemic and tissue markers of oxidant stress, serum 8-isoprostane and 3-nitrotyrosine, respectively, were found to increase during aging. The results demonstrate that increased inflammation and oxidant stress occur progressively during vascular aging, and suggest therapeutic targets to limit or reverse aging-associated vascular pathology and dysfunction. Experiment Overall Design: Samples were taken from rats at 4 ages, 3mo, 6mo, 15mo and 28 mo, with 4 replicates in each age group.
Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice
Project description:(Phospho)proteomic studies in the human aging brain are based on the comparison between controls of bain aging usually affected by early stages of neurofibrillary tangle (NFT) pathology and subjects with moderate or advanced Alzheimer’s disease (AD).
(Phospho)proteomics using conventional label‐free‐ and SWATH‐MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs and SPs, and comorbidities classified by age (years) in four groups; group 1 (young, 30-44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64-70); and group 4 (late-elderly, 75-85).
Project description:This study utilized a standard rat model of aging and global gene expression analyses to attempt to identify the most appropriate time points to study vascular aging and to identify molecules associated with the development of pathology. Recent studies have established that age is the major risk factor for vascular disease. Numerous changes occur in vascular structure and function during aging, and animal models, including rodents, are the primary means to determine the underlying mechanisms of age-mediated vascular pathology. This study utilized a standard rat model of aging and both morphometric and global gene expression analyses to attempt to identify the most appropriate time points to study vascular aging and to identify molecules associated with the development of pathology. Morphometric analysis of Fischer 344/Brown Norway F1 hybrid (F344xBN) rat thoracic aorta indicated, in contrast to some previous studies, that progressive increases in intimal and medial thickness, as well as smooth muscle cell-containing intimal protrusions, occurred with age. This structural vascular pathology was associated with a progressive increase in global differential gene expression. Specific molecules with altered mRNA and protein expression included the adhesion molecules ICAM-1 and VCAM-1, and the bone morphogenic proteins osteopontin and bone sialoprotein-1. Intimal-associated macrophages were detected with immunohistochemistry in paraffin sections of thoracic aorta and were found to increase significantly in number with age. Both systemic and tissue markers of oxidant stress, serum 8-isoprostane and 3-nitrotyrosine, respectively, were found to increase during aging. The results demonstrate that increased inflammation and oxidant stress occur progressively during vascular aging, and suggest therapeutic targets to limit or reverse aging-associated vascular pathology and dysfunction. Keywords: time course
Project description:Alveolar macrophages maintain lung homeostasis and are critical for host defense to respiratory pathogens, including influenza virus. Yet how aging impacts alveolar macrophages remains unclear. Here, we found that aging reduces the proliferation and concentration of alveolar macrophages under basal conditions in mice. Transcriptomic analysis revealed that aging induces a down regulation in cell cycling pathways in alveolar macrophages. Functionally, aging impaired the capacity of alveolar macrophages to phagocytose in vivo, and also increased influenza virus-induced lung damage, morbidity and mortality. Depleting alveolar macrophages indicated that these cells were critical for accelerated mortality during influenza viral lung infection with aging. Adoptive transfer experiments demonstrated that aging impaired the ability of alveolar macrophages to reduce lung damage after influenza viral infection. Thus, our study has revealed that aging impairs alveolar macrophages to resolve damageand increases mortality after influenza viral infection.
Project description:Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia were the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification (TRAP)-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was also enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in AD mouse models and human AD data is evident across numerous mouse models, methods, and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
Project description:Transcriptome analysis using the liver from young versus old mice, fed either normally or under caloric restriction reveals reorganization of distinct circadian signatures related to metabolic aging and nutrient-dependent counterbalance of aging by caloric restriction