A comprehensive multiomics approach toward understanding the relationship between aging and dementia

Currais, Antonio; Goldberg, Joshua; Farrokhi, Catherine; Chang, Max W.; Prior, Marguerite; Dargusch, Richard; Daugherty, Daniel; Armando, Aaron M.; Quehenberger, Oswald; Maher, Pamela; Schubert, David

doi:10.18632/aging.100838

Cited by 63 publications

(113 citation statements)

References 49 publications

(69 reference statements)

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“…This approach led to J147 having a half life of 2 and a half hours in the brain, a t max of 2 h and a C max of 203 ng/mL after administration of 20 mg/kg in mice (Prior et al, 2013). J147 has previously demonstrated efficacy in multiple mouse models of Alzheimer’s disease and associated CNS inflammation, and has neurotrophic properties (Chen et al, 2011; Currais et al, 2015). The potential of J147 to impact multiple pathogenic pathways associated with diabetic neuropathy prompted us to investigate it in a mouse model of type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…J147 reverses cognitive impairment in a mouse model of Alzheimer’s disease, and enhances memory in both transgenic AD mice, and aged wild type mice. It also reduces inflammation and old age-associated metabolic decline in a mouse model of aging (Currais et al, 2015; Prior et al, 2013) and is neurogenic (Prior et al, 2016). The wide-ranging effects of J147 suggest that it has a strong therapeutic potential to reduce the multiple pathogenic pathways associated with diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

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A novel curcumin derivative for the treatment of diabetic neuropathy

et al. 2018

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Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel curcumin derivative for the treatment of diabetic neuropathy

et al. 2018

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“…These results suggest that humanin could improve cognitive function during aging and age-related diseases like Alzheimer's disease through these signaling pathways [46]. Why humanin only effects signaling in old mice is still unknown, but it is possible that humanin may have improved brain availability due to the leakier blood brain barrier found in old mice [47]. Alternatively, endogenous humanin levels are higher in young mice and these pathways may already be activated, while the lower endogenous humanin levels in old mice, associated with lower levels of activation, allow for a more notable induction (Figures S7A and S7B).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

et al. 2016

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Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.

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“…Throughout this manuscript, we utilize two simulated data sets and four experimental data sets (Bottomly 14 [ Data set 3], GSE64570 15 [ Data set 4], GSE69244 16 [ Data set 5], GSE72165 17 [ Data set 6], see Supplementary File 1 for further details) for illustration. Details on the data generation and full records of the analyses are provided in the data sets and Supplementary File 1.…”

Section: Datamentioning

confidence: 99%

Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences

2015

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High-throughput sequencing of cDNA (RNA-seq) is used extensively to characterize the transcriptome of cells. Many transcriptomic studies aim at comparing either abundance levels or the transcriptome composition between given conditions, and as a first step, the sequencing reads must be used as the basis for abundance quantification of transcriptomic features of interest, such as genes or transcripts. Several different quantification approaches have been proposed, ranging from simple counting of reads that overlap given genomic regions to more complex estimation of underlying transcript abundances. In this paper, we show that gene-level abundance estimates and statistical inference offer advantages over transcript-level analyses, in terms of performance and interpretability. We also illustrate that while the presence of differential isoform usage can lead to inflated false discovery rates in differential expression analyses on simple count matrices and transcript-level abundance estimates improve the performance in simulated data, the difference is relatively minor in several real data sets. Finally, we provide an R package ( tximport) to help users integrate transcript-level abundance estimates from common quantification pipelines into count-based statistical inference engines.

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A comprehensive multiomics approach toward understanding the relationship between aging and dementia

Cited by 63 publications

References 49 publications

A novel curcumin derivative for the treatment of diabetic neuropathy

A novel curcumin derivative for the treatment of diabetic neuropathy

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences

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