Project description:The aging of mammalian epigenomes fundamentally alters cellular functions, implicating organismal fitness and disease risk. However, the studies of this process typically use mouse models in the laboratory environment and neglect the impact of variation in social, physical, microbial, and other aspects of the living environment. We examined the aging differences between lab mice and “re-wilded” mice, which are C57BL6/J mice reintroduced into a controlled field environment with enhanced realism. Systematic analysis of age-associated methylation dynamics in the liver tissues suggests a genomic region-conditioned, faster epigenetic aging rate in field mice than in lab mice, implicating a 3D genome conformation change. The predicted age of lab mice by epigenetic clocks is closer to their actual age than that of field mice. These observations underscore the overlooked role of the social and physical environment in epigenetic aging.
Project description:Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) null mouse hepatic gene expression was compared with control C57BL/6J mice To determine if there were differences in gene expression between ARSB null mice and matched control mice. ARSB is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate and dermatan sulfate and thereby regulates their degradation. comparison between ARSB-null mice on C57BL/6J background and control C57BL/6J mice matched for age and gender
Project description:Here, we reveal that age-associated shifts in plasma composition remodel the protein corona of liposomes, leading to divergent biodistribution and immune responses. Using plasma from young (1-month), middle-aged (9-month), and aged (18-month) mice, we demonstrate that liposomes incubated in aged plasma acquire coronas enriched with immunoglobulins, particularly IgG. This age-dependent IgG enrichment enhances macrophage uptake via Fc receptor-mediated endocytosis and amplifies complement activation through the alternative pathway, triggering NF-κB signaling and a pro-inflammatory cascade marked by M1 macrophage polarization.
Project description:Aging profoundly influences the composition of biological fluids, including the plasma proteome and lipidome, yet its effects on the protein coronas (PC) forming around nanoparticles (NPs) remain poorly understood. Here, we investigate how age-dependent changes in plasma proteins and lipids modulate the PC on silica NPs, affecting their physicochemical properties, cellular interactions, immune responses, and in vivo pharmacokinetics. Using plasma from C57 mice at 1, 9, and 18 months of age, we demonstrate that while lipid composition remains relatively stable, the PCs have subtle distinct age-related shifts. Proteomic analyses reveal altered abundances of proteins involved in endocytosis, cell adhesion, and immune regulation, ultimately influencing macrophage uptake and activation. In vitro experiments show that younger plasma-derived coronas enhance NP internalization, whereas older coronas diminish uptake but promote a stronger inflammatory response via complement activation and NF-κB signaling. In senescent macrophages, the pattern of NP internalization and immune activation differs, highlighting the complexity of age-associated changes in host-NP interactions. In vivo studies further confirm that NPs biodistribution, biocompatibility, and immunogenicity vary significantly with host age. our findings suggest age as a crucial yet underexplored factor in the design of nanomedicine, with significant implications for enhancing the safety and efficacy of both diagnostic and therapeutic nanomedicine technologies.
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
Project description:Background: In the event of an improvised nuclear device or radiological dirty bomb detonation large numbers of people will be exposed to radiation that would require a timely and accurate biodosimetry to identify the highly exposed individuals who would require medical treatment from those who have received low or no radiation (the “worried well”). Gene expression signatures in response to radiation have been derived from mice and human peripheral blood and the impact of a number of variables, such as dose, time, genotype, and gender, on gene expression has been analyzed. However, the impact of aging on radiation gene profiling has not been taken into consideration. Results: Global gene expression was measured in the blood of young (2 mo) and old (21 mo) male C57BL/6J mice 1 day after they were exposed to 4 Gy x-rays or they were sham irradiated (control) using the Agilent Mouse Whole Genome microarrays. Animals exposed to radiation suppressed expression of DNA repair genes with fold-changes being very similar to the two age groups. A notable exception was Mismatch Repair (MMR) that was significantly enriched among the downregulated genes in irradiated old mice (p = 2.34E-09) compared with irradiated young mice (p = 1.62E-04). Furthermore, cardiac hypertrophy signaling (p < 0.002) and the role of NFAT in cardiac hypertrophy (p = 0.01) were predicted to be enriched among the upregulated differentially expressed genes in irradiated old mice, but not irradiated young mice. In contrast, young mice respond to x-ray exposure by significantly upregulating genes involved in phagosome formation (p = 3.09E-07), phagosome maturation (p = 0.001), and Fcγ receptor-mediated phagocytosis (p = 0.03), all crucial processes that eliminates apoptotic cells and preserve tissue homeostasis. Conclusions: We show that age is a variable that has the potential to fundamentally alter the transcriptomic profile of irradiated mouse blood. A number of biological processes, including phagocytosis, are differentially represented in young and old mice exposed to x-ray radiation. Our results highlight the significance of age as a variable that can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency.
Project description:Sex and age are critical factors in a variety of retinal diseases but have garnered little attention in preclinical models. The current lack of knowledge impairs informed decision making on inclusion and design of studies incorporating both sexes and aging. The goal of this study was to examine mouse retina normative gene expression in both sexes with advancing age.