Project description:Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This study found that age-associated changes of the gut microbiome of BALB/c and C57BL/6 mice could be reverted by co-housing of aged (22 months old) and adult (3 months old) mice for 30-40 days or faecal microbiota transplantation (FMT) from adult into aged mice. This was demonstrated using high-throughput sequencing of the V3-V4 hypervariable region of bacterial 16S rRNA gene isolated from faecal pellets collected from 3-4 months old adult and 22-23 months old aged mice before and after co-housing or FMT.
Project description:<p><strong>BACKGROUND:</strong> The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems, however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients affected the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process, and related functions.</p><p><strong>METHODS AND FINDINGS: </strong>Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. Gut permeability, levels of circulating cytokines and expression of markers of microglia cells were also assessed. FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (<em>Lachnospiraceae</em>, <em>Faecalibaculum</em> and <em>Ruminococcaceae</em>) and disorders of the CNS (<em>Prevotellaceae</em> and <em>Ruminococcaceae</em>) was observed. Finally, microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype, while gut permeability and levels of circulating cytokines remained unaffected.</p><p><strong>CONCLUSIONS:</strong> These results demonstrate a direct effect of the age-associated shifts of the microbiota on protein expression and key functions of the central nervous system. Furthermore, these results additionally highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions in the elderly.</p>
Project description:Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has been recently reported to impact hematopoiesis. However, there is currently no empirical evidence elucidating the direct impact of gut microbiome on aging hematopoiesis. To assess these potential effects, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed an increment in both the absolute number and the engraftment ability of HSCs. Single cell RNA sequencing depicted overall transcriptional changes of HSCs as well as the bone marrow microenvironment and indicated that gut microbiota from young mice enhanced cell cycle activity of HSCs, attenuated canonical inflammatory signals and mitigated inflammation-associated phenotypes in aging hematopoiesis. Integrated microbiome-metabolome analysis uncovered that FMT reshaped gut microbiota construction and metabolite landscape, while the administration of Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our results highlighted the paramount importance of the gut microbiota in HSC aging and provided a strong rationale to limit hematopoietic exhaustion and treat hematologic disorders.
Project description:Label-free expression proteomics of mouse brain. Three individuals per group, young mice, aged mice, and aged mice treated with spermidine were compared by bottom-up proteomics.
Project description:Aging and the chronic diseases associated with aging have become a great burden to modern society. Recent animal studies on heterochronic parabiosis have revealed that young blood has a powerful rejuvenating effect on aged tissues, but which components of the young blood are responsible for the rejuvenating effects remains unclear. In this study, we found that small extracellular vesicles (sEVs) purified from the plasma of young mice could counteract pre-existing aging at the molecular, mitochondrial, cellular and physiological levels. In detail, injection of young sEVs into aged mice extended lifespan, attenuated senescent phenotypes and mitigate age-associated impairments on various tissues (hippocampus, muscle, heart, testis, bone, etc). Mechanistical studies using iTRAQ-based quantitative proteomic analyses combined with GO term cluster revealed that the altered proteomes in aged tissues of young sEVs-treated mice were specifically related to their roles in regulating cellular senescence, metabolic process, epigenetic modification, genomic stability, etc, which are the cardinal features associated with aging. Particularly, the sEVs derived from young mice and young human donors could stimulate PGC-1α (a master regulator of mitochondrial biogenesis and energy metabolism) expression in vitro and in vivo through their rejuvenating miRNA cargos, thereby facilitating mitochondrial regeneration and counteracting mitochondrial deficits in aged tissues. Taken together, this study demonstrates that young sEVs can reverse degenerative changes and age-related dysfunctions through stimulating PGC-1α expression and regenerating intact mitochondria.
Project description:To study the protective effects of preoperative fasting against renal ischemia-reperfusion injury, young-lean as well as aged overweight mice were subjected to three days of fasting or ad libitum food consumption, and gene expressions in kidneys of male mice were analyzed 19 samples (5 young control, 4 young fasted, 5 aged control, 5 aged fasted), each from individual mice