Transcriptional profiling reveals protective mechanisms in brains of long-lived mice

Frahm, Christiane; Srivastava, Akash; Schmidt, S.; Mueller, Jule; Groth, Marco; Guenther, Madlen; Ji, Youngmi; Priebe, Stefan; Platzer, Matthias; Witte, Otto W.

doi:10.1016/j.neurobiolaging.2016.12.016

Cited by 19 publications

(9 citation statements)

References 73 publications

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“…This observation indicates that the selected genes associated with inflammation and senescence have a more stable expression, suggesting that both age-driving processes are in fact more controlled in the long-lived individuals. Similar observations were recently made in brains of long-lived mice [10]. Exceptions are the skin samples of all species other than humans, which show the opposite pattern of a significantly increased variance in gene expression in the old-age time point.…”

Section: Resultssupporting

confidence: 80%

Conserved aging-related signatures of senescence and inflammation in different tissues and species

Barth

Srivastava

Stojiljkovic

et al. 2019

Aging

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Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual’s life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.

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Section: Resultssupporting

confidence: 80%

Conserved aging-related signatures of senescence and inflammation in different tissues and species

Barth

Srivastava

Stojiljkovic

et al. 2019

Aging

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“…We found increased levels of GSTP1, GSTM1, and PRDX6 in the hippocampus and A previous study also reported that the protein GSTP1 participating in the regulation of oxidative stress was significantly increased in the brain of aged rats [48]. Recent transcriptomics studies are in accordance with our results, since GST, subunits mu1, mu3, mu7, pi2, theta 1, and theta2 are all significantly increased in aged mouse brain tissue [49]. The increased levels of glutathione metabolism-related proteins GSTP1, GSTM1, and PRDX6 in aged vs. young brain suggest that a protective antioxidant compensatory mechanism becomes more active as aging advances [50].…”

Section: Oxidative Stresssupporting

confidence: 92%

Proteomic Profile of Mouse Brain Aging Contributions to Mitochondrial Dysfunction, DNA Oxidative Damage, Loss of Neurotrophic Factor, and Synaptic and Ribosomal Proteins

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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The deleterious effects of aging on the brain remain to be fully elucidated. In the present study, proteomic changes of young (4-month) and aged (16-month) B6129SF2/J male mouse hippocampus and cerebral cortex were investigated by using nano liquid chromatography tandem mass spectrometry (NanoLC-ESI-MS/MS) combined with tandem mass tag (TMT) labeling technology. Compared with the young animals, 390 hippocampal proteins (121 increased and 269 decreased) and 258 cortical proteins (149 increased and 109 decreased) changed significantly in the aged mouse. Bioinformatic analysis indicated that these proteins are mainly involved in mitochondrial functions (FIS1, DRP1), oxidative stress (PRDX6, GSTP1, and GSTM1), synapses (SYT12, GLUR2), ribosome (RPL4, RPS3), cytoskeletal integrity, transcriptional regulation, and GTPase function. The mitochondrial fission-related proteins FIS1 and DRP1 were significantly increased in the hippocampus and cerebral cortex of the aged mice. Further results in the hippocampus showed that ATP content was significantly reduced in aged mice. A neurotrophin brain-derived neurotrophic factor (BNDF), a protein closely related with synaptic plasticity and memory, was also significantly decreased in the hippocampus of the aged mice, with the tendency of synaptic protein markers including complexin-2, synaptophysin, GLUR2, PSD95, NMDAR2A, and NMDAR1. More interestingly, 8-hydroxydeoxyguanosine (8-OHdG), a marker of DNA oxidative damage, increased as shown by immunofluorescence staining. In summary, we demonstrated that aging is associated with systemic changes involving mitochondrial dysfunction, energy reduction, oxidative stress, loss of neurotrophic factor, synaptic proteins, and ribosomal proteins, as well as molecular deficits involved in various physiological/pathological processes.

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“…With a median lifespan of 3–7 months (Valdesalici & Cellerino, ; Terzibasi et al , ; Ripa et al , ; Hu & Brunet, ), it has emerged as a convenient model organism to investigate genetic and non‐genetic interventions on aging (Harel et al , ; Cellerino et al , ; Kim et al , ; Platzer & Englert, ; Ripa et al , ), since it replicates many typical aspects of vertebrate brain aging at the levels of behavior (Valenzano et al , ,b), neuroanatomy (Tozzini et al , ), and global gene expression (Baumgart et al , ; Aramillo Irizar et al , ). Age‐dependent processes are enhanced in this species, thus facilitating the detection of differentially expressed genes as compared to other model organisms (Wood et al , ; Baumgart et al , ; Frahm et al , ). Importantly, an age‐dependent formation of inclusion bodies containing α‐synuclein and spontaneous degeneration of dopaminergic neurons has been recently described in killifish (Matsui et al , ).…”

Section: Introductionmentioning

confidence: 99%

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Sacramento

Kirkpatrick

Mazzetto

et al. 2020

Molecular Systems Biology

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122

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A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to posttranscriptional mechanisms that account for over 40% of the ageregulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

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Transcriptional profiling reveals protective mechanisms in brains of long-lived mice

Cited by 19 publications

References 73 publications

Conserved aging-related signatures of senescence and inflammation in different tissues and species

Conserved aging-related signatures of senescence and inflammation in different tissues and species

Proteomic Profile of Mouse Brain Aging Contributions to Mitochondrial Dysfunction, DNA Oxidative Damage, Loss of Neurotrophic Factor, and Synaptic and Ribosomal Proteins

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

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