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Aging induces a distinct gene expression program in mouse islets.

ABSTRACT: The role of aging in the pathogenesis of type 2 diabetes remains poorly understood. In the past adult ?-cells were assumed to undergo frequent turnover. However, we find that ?-cell turnover declines to very low levels in middle-aged mice. We therefore hypothesized that aged islets could exhibit a distinct gene expression program. We compared gene expression in islets from young mice to islets from aged mice under basal conditions. Aging was associated with differential expression of many genes in islets, including mRNAs encoding for chromatin remodeling components, RNA binding proteins, and pancreatic endocrine transcription factors. We previously observed that cell cycle entry of ?-cells is severely restricted by middle age, with minimal of ?-cell proliferation in response to regenerative stimuli such as 50% partial pancreatectomy. To characterize the effect of age in adaptive ?-cell proliferation, we measured gene expression in islets from young mice after pancreatectomy. As expected, partial pancreatectomy induced differential expression of many genes, including those encoding Reg (regenerating) proteins. Surprisingly, partial pancreatectomy also induced expression of Reg genes in islets from aged mice, which have greatly reduced capacity for adaptive ?-cell proliferation. However, there was little overlap (besides the Reg genes) in between the partial pancreatectomy induced islet genes in young mice versus old mice. Thus, partial pancreatectomy does not induce the same gene expression program in young mice vs old mice. Taken together, our results reveal that aged islets exhibit a unique gene expression signature that could contribute to the limited regenerative capacity of mature ?-cells.

SUBMITTER: Rankin MM

PROVIDER: S-EPMC3062249 | biostudies-literature | 2010 Nov-Dec

REPOSITORIES: biostudies-literature

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Aging induces a distinct gene expression program in mouse islets.

Rankin Matthew M MM Kushner Jake A JA

Islets 20101101 6

The role of aging in the pathogenesis of type 2 diabetes remains poorly understood. In the past adult β-cells were assumed to undergo frequent turnover. However, we find that β-cell turnover declines to very low levels in middle-aged mice. We therefore hypothesized that aged islets could exhibit a distinct gene expression program. We compared gene expression in islets from young mice to islets from aged mice under basal conditions. Aging was associated with differential expression of many genes ...[more]

PMID: 21099336

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Project description:BackgroundLight exposure induces oxidative stress, which contributes to ocular diseases of aging. Blue light provides a model for light-induced oxidative stress, lipid peroxidation and retinal degeneration in Drosophila melanogaster. In contrast to mature adults, which undergo retinal degeneration when exposed to prolonged blue light, newly-eclosed flies are resistant to blue light-induced retinal degeneration. Here, we sought to characterize the gene expression programs induced by blue light in flies of different ages to identify neuroprotective pathways utilized by photoreceptors to cope with light-induced oxidative stress.ResultsTo identify gene expression changes induced by blue light exposure, we profiled the nuclear transcriptome of Drosophila photoreceptors from one- and six-day-old flies exposed to blue light and compared these with dark controls. Flies were exposed to 3 h blue light, which increases levels of reactive oxygen species but does not cause retinal degeneration. We identified substantial gene expression changes in response to blue light only in six-day-old flies. In six-day-old flies, blue light induced a neuroprotective gene expression program that included upregulation of stress response pathways and downregulation of genes involved in light response, calcium influx and ion transport. An intact phototransduction pathway and calcium influx were required for upregulation, but not downregulation, of genes in response to blue light, suggesting that distinct pathways mediate the blue light-associated transcriptional response.ConclusionOur data demonstrate that under phototoxic conditions, Drosophila photoreceptors upregulate stress response pathways and simultaneously, downregulate expression of phototransduction components, ion transporters, and calcium channels. Together, this gene expression program both counteracts the calcium influx resulting from prolonged light exposure, and ameliorates the oxidative stress resulting from this calcium influx. Thus, six-day-old flies can withstand up to 3 h blue light exposure without undergoing retinal degeneration. Developmental transitions during the first week of adult Drosophila life lead to an altered gene expression program in photoreceptors that includes reduced expression of genes that maintain redox and calcium homeostasis, reducing the capacity of six-day-old flies to cope with longer periods (8 h) of light exposure. Together, these data provide insight into the neuroprotective gene regulatory mechanisms that enable photoreceptors to withstand light-induced oxidative stress.

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Aging induces a distinct gene expression program in mouse islets.

Publications

Aging induces a distinct gene expression program in mouse islets.

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