Project description:Changes in DNA methylation (DNAm) are linked to aging. Here, we profile highly conserved CpGs in 339 predominantly female mice belonging to the BXD family for which we have deep longevity and genomic data. We use a 'pan-mammalian' microarray that provides a common platform for assaying the methylome across mammalian clades. We computed epigenetic clocks and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. We describe the multifactorial variance of methylation at these CpGs and show that high-fat diet augments the age-related changes. Entropy increases with age. The progression to disorder, particularly at CpGs that gain methylation over time, was predictive of genotype-dependent life expectancy. The longer-lived BXD strains had comparatively lower entropy at a given age. We identified two genetic loci that modulate epigenetic age acceleration (EAA): one on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and the other on Chr19 that contains a cytochrome P450 cluster. Both loci harbor genes associated with EAA in humans, including STXBP4, NKX2-3, and CUTC. Transcriptome and proteome analyses revealed correlations with oxidation-reduction, metabolic, and immune response pathways. Our results highlight concordant loci for EAA in humans and mice, and demonstrate a tight coupling between the metabolic state and epigenetic aging.
Project description:This is the proteomics component of a multi-omics analysis of the aging murine retina. Age is a critical risk factor for vision-threatening retinopathies. Susceptibility to age-related retinal neurodegeneration is genetically influenced, however, no studies have addressed molecular retinal aging signatures across genetically diverse populations. Here, we profile retinal proteomics in an array of genetically diverse mice with age. Proteomics were employed to profile retinal aging signatures in C57BL/6J (B6), 129S1/SvImJ, NZO/HlLtJ (NZO), WSB/EiJ (WSB), CAST/EiJ, PWK/PhJ, NOD/ShiLtJ, A/J, and BALB/cJ mouse strains at 4, 12, and 18M. These data were collated into a publicly available resource.
Project description:Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host–microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in the metabolic output of the microbiome. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate potential microbiome–host interactions that may influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics.
Project description:This SuperSeries is composed of the following subset Series: GSE25323: Biological Aging and Circadian Mechanisms in Murine Brown Adipose Tissue, Inguinal White Adipose Tissue, and Liver (Nov 2009 dataset) GSE25324: Biological Aging and Circadian Mechanisms in Murine Brown Adipose Tissue, Inguinal White Adipose Tissue, and Liver (Jan 2010 dataset) Refer to individual Series
Project description:Aging is the predominant cause of morbidity and mortality in industrialized countries, yet the molecular mechanisms driving aging and especially the contribution by the microbiome remain unclear. We combined multi-omics with metabolic modeling to comprehensively characterize host–microbiome interactions during aging in mice. Our findings reveal a complex dependency of host metabolism on known and novel microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These microbial changes coincided with increased inflammaging as well as a corresponding downregulation of key host pathways, predicted by our model to be microbiome-dependent, that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome–host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.
Project description:To investigate the global transcriptome changes in mouse hematopoietic stem cell aging, we performed high-throughput sequencing of Poly A+ RNA (RNA-Seq) from purified 4 month, and 24 month-old HSCs (SP-KSL-CD150+). With biological duplicates, more than 200 million reads in total for each age of HSC were obtained. Comparison of the young and old HSC transcriptomes revealed that 1,337 genes that were up-regulated, and 1,297 genes were down-regulated with HSC aging. The most highly represented upstream regulator was growth factor TGFB1, accounting for ~ 19% of differential gene expression in young versus old HSC (p-value = 1.96E-33). Gene ontology (GO) analyses indicated that up-regulated genes in 24mo HSCs are highly enriched in Regulation of Cell Adhesion, Regulation of Cell Proliferation and Ribosome, while down-regulated genes are enriched in DNA Base Excision Repair, DNA replication and Cell Cycle. RNA-seq also allowed us to examine alternative isoforms with aging including alternative splicing, promoter usage and pre-mRNA abundance. Mouse hematopoietic stem cell mRNA profiles of 4 month and 24 month old WT mice were generated generated by deep sequencing, in duplicate, using Illumina Hiseq 2000
Project description:How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here we show that CD38, a NAD+ metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism at young age. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration due to compromised mitochondrial stress management. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system. Blocking mitochondrial Ca2+ influx inhibits HSC proliferation at young age yet prevents HSC aging. Our study highlights a NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.