Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain.
Loss of miR-210 leads to progressive retinal degeneration in Drosophila melanogaster
LIFE SCIENCE ALLIANCE
2019; 2 (1)
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.
View details for DOI 10.1038/s41593-019-0566-1
View details for PubMedID 31959936
A nutritional memory effect counteracts benefits of dietary restriction in old mice.
2019; 1 (11): 1059?73
miRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally. We used small RNA sequencing to identify tissue-specific miRNAs in the adult brain, thorax, gut, and fat body of Drosophila melanogaster One of the most brain-specific miRNAs that we identified was miR-210, an evolutionarily highly conserved miRNA implicated in the regulation of hypoxia in mammals. In Drosophila, we show that miR-210 is specifically expressed in sensory organs, including photoreceptors. miR-210 knockout mutants are not sensitive toward hypoxia but show progressive degradation of photoreceptor cells, accompanied by decreased photoreceptor potential, demonstrating an important function of miR-210 in photoreceptor maintenance and survival.
View details for DOI 10.26508/lsa.201800149
View details for Web of Science ID 000457337300004
View details for PubMedID 30670478
View details for PubMedCentralID PMC6343102
Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.
2018; 14 (11): e1007766
Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa. Strikingly, the switch from DR-to-AL acutely increases mortality, whereas the switch from AL-to-DR causes only a weak and gradual increase in survival, suggesting a memory of earlier nutrition. RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrate a largely refractory transcriptional and metabolic response to DR after AL feeding in fat tissue, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.
View details for DOI 10.1038/s42255-019-0121-0
View details for PubMedID 31742247
View details for PubMedCentralID PMC6861129
Expression of N471D strumpellin leads to defects in the endolysosomal system.
Disease models & mechanisms
2018; 11 (9)
Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.
View details for DOI 10.1371/journal.pgen.1007766
View details for PubMedID 30462643
Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.
2017; 18 (1): 56
Hereditary spastic paraplegias (HSPs) are genetically diverse and clinically characterised by lower limb weakness and spasticity. The N471D and several other point mutations of human strumpellin (Str; also known as WASHC5), a member of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex, have been shown to cause a form of HSP known as spastic paraplegia 8 (SPG8). To investigate the molecular functions of wild-type (WT) and N417D Str, we generated Dictyostelium Str- cells and ectopically expressed StrWT-GFP or StrN471D-GFP in Str- and WT cells. Overexpression of both proteins apparently caused a defect in cell division, as we observed a clear increase in multinucleate cells. Real-time PCR analyses revealed no transcriptional changes in WASH complex subunits in Str- cells, but western blots showed a twofold decrease in the SWIP subunit. GFP-trap experiments in conjunction with mass-spectrometric analysis revealed many previously known, as well as new, Str-interacting proteins, and also proteins that no longer bind to StrN471D At the cellular level, Str- cells displayed defects in cell growth, phagocytosis, macropinocytosis, exocytosis and lysosomal function. Expression of StrWT-GFP in Str- cells rescued all observed defects. In contrast, expression of StrN471D-GFP could not rescue lysosome morphology and exocytosis of indigestible material. Our results underscore a key role for the WASH complex and its core subunit, Str, in the endolysosomal system, and highlight the fundamental importance of the Str N471 residue for maintaining lysosome morphology and dynamics. Our data indicate that the SPG8-causing N471D mutation leads to a partial loss of Str function in the endolysosomal system. This article has an associated First Person interview with the first author of the paper.
View details for PubMedID 30061306
The Sense of Smell Impacts Metabolic Health and Obesity.
2017; 26 (1): 198?211.e5
Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age.Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.
View details for DOI 10.1186/s13059-017-1187-1
View details for PubMedID 28351387
View details for PubMedCentralID PMC5370449
Fluoxetine treatment prevents the inflammatory response in a mouse model of posttraumatic stress disorder.
Journal of psychiatric research
2016; 76: 74?83
Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of ?-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.
View details for DOI 10.1016/j.cmet.2017.06.015
View details for PubMedID 28683287
Despite intense research efforts the molecular mechanisms affecting stress-vulnerable brain regions in posttraumatic stress disorder (PTSD) remain elusive. In the current study we have applied global transcriptomic profiling to a PTSD mouse model induced by foot shock fear conditioning. We compared the transcriptomes of prelimbic cortex, anterior cingulate cortex (ACC), basolateral amygdala, central nucleus of amygdala, nucleus accumbens (NAc) and CA1 of the dorsal hippocampus between shocked and non-shocked (control) mice, with and without fluoxetine treatment by RNA sequencing. Differentially expressed (DE) genes were identified and clustered for in silico pathway analysis. Findings in relevant brain regions were further validated with immunohistochemistry. DE genes belonging to 11 clusters were identified including increased inflammatory response in ACC in shocked mice. In line with this finding, we noted higher microglial activation in ACC of shocked mice. Chronic fluoxetine treatment initiated in the aftermath of the trauma prevented inflammatory gene expression alterations in ACC and ameliorated PTSD-like symptoms, implying an important role of the immune response in PTSD pathobiology. Our results provide novel insights into molecular mechanisms affected in PTSD and suggest therapeutic applications with anti-inflammatory agents.
View details for DOI 10.1016/j.jpsychires.2016.02.003
View details for PubMedID 26897419