Stress resistance and lifespan enhanced by downregulation of antimicrobial peptide genes in the Imd pathway

Lin, Yuh-Ru; Parikh, Hardik I.; Park, Yongkyu

doi:10.18632/aging.101417

Cited by 23 publications

(20 citation statements)

References 37 publications

(59 reference statements)

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“…Although the interplay between immunity and aging in Drosophila is well established, despite that the mechanism that underlie such reciprocity remain unknown, there is a lack of literature specific to the head tissue. In this study, gradually increasing levels of AMP expression in the head of healthy aging Drosophila were observed by mining transcriptome sequencing data from the GEO database, which were subsequently verified by RNA-seq and qPCR analyses, consistent with the available literature [29][30][31].…”

Section: Discussionsupporting

confidence: 76%

Dysregulation of antimicrobial peptide expression distinguishes Alzheimer’s disease from normal aging

Wang

Peng²,

et al. 2020

Aging

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Alzheimer's disease (AD) is an age-related neurodegenerative disease with unknown mechanism that is characterized by the aggregation of abnormal proteins and dysfunction of immune responses. In this study, an integrative approach employing in silico analysis and wet-lab experiment was conducted to estimate the degrees of innate immune system relevant gene expression, neurotoxic Aβ42 generation and neuronal apoptosis in normal Drosophila melanogaster and a transgenic model of AD. Results demonstrated mRNA levels of antimicrobial peptide (AMP) genes gradually increased with age in wild-type flies, while which exhibited a trend for an initial decrease followed by subsequent increase during aging in the AD group. Time series and correlation analysis illustrated indicated a potential relationship between variation in AMP expression and Aβ42 concentration. In conclusion, our study provides evidence for abnormal gene expression of AMPs in AD flies with age, which is distinct from the expression profiles in the normal aging process. Aberrant AMP expression may participate in the onset and development of AD by inducing or accelerating Aβ deposition. These findings suggest that AMPs may serve as potential diagnostic biomarkers and therapeutic targets. However, further studies are required to elucidate the pathological effects and underlying mechanisms of AMP dysregulation in AD progression. GEO accession Sample Age Age group GSE122470 GSM3466957,

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“…) or when the IMD AMPs AttacinC ( AttC ) and Diptericin B ( DiptB ) are downregulated in the fat body (Lin et al. ). The evidence available to date therefore suggests that decreased activity of the immune system can promote lifespan (DeVeale 2004), possibly by reducing the costs of immune deployment (McKean and Lazzaro ).…”

Section: Resultsmentioning

confidence: 99%

Evolution of longevity improves immunity in Drosophila

et al. 2018

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Much has been learned about the genetics of aging from studies in model organisms, but still little is known about naturally occurring alleles that contribute to variation in longevity. For example, analysis of mutants and transgenes has identified insulin signaling as a major regulator of longevity, yet whether standing variation in this pathway underlies microevolutionary changes in lifespan and correlated fitness traits remains largely unclear. Here, we have analyzed the genomes of a set of Drosophila melanogaster lines that have been maintained under direct selection for postponed reproduction and indirect selection for longevity, relative to unselected control lines, for over 35 years. We identified many candidate loci shaped by selection for longevity and late‐life fertility, but – contrary to expectation – we did not find overrepresentation of canonical longevity genes. Instead, we found an enrichment of immunity genes, particularly in the Toll pathway, suggesting that evolutionary changes in immune function might underpin – in part – the evolution of late‐life fertility and longevity. To test whether this genomic signature is causative, we performed functional experiments. In contrast to control flies, long‐lived flies tended to downregulate the expression of antimicrobial peptides upon infection with age yet survived fungal, bacterial, and viral infections significantly better, consistent with alleviated immunosenescence. To examine whether genes of the Toll pathway directly affect longevity, we employed conditional knockdown using in vivo RNAi. In adults, RNAi against the Toll receptor extended lifespan, whereas silencing the pathway antagonist cactus‐–causing immune hyperactivation – dramatically shortened lifespan. Together, our results suggest that genetic changes in the age‐dependent regulation of immune homeostasis might contribute to the evolution of longer life.

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“…As defending mechanisms, these proteins are essential to protect flies against toxins and bacterial infections [27-29], and the AMP expressions increase during the aging process [22], which may prepare pathogen defenses promptly in the old-aged flies that have weak immune responses. However, it has been reported that lesser expressions of AMP genes are found in longer-lived flies [22] and the AMP downregulation enhances stress resistance, lifespan, and fat content in adult flies [30]. Lifespan extension through hormesis (the beneficial effects of low-level toxins and stressors) also occurs with reduced immune function [31].…”

Section: Resultsmentioning

confidence: 99%

Longer lifespan in the Rpd3 and Loco signaling results from the reduced catabolism in young age with noncoding RNA

Kopp

Park

2019

Aging

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Downregulation of Rpd3 (histone deacetylase) or Loco (regulator of G-protein signaling protein) extends Drosophila lifespan with higher stress resistance. We found rpd3-downregulated long-lived flies genetically interact with loco-upregulated short-lived flies in stress resistance and lifespan. Gene expression profiles between those flies revealed that they regulate common target genes in metabolic enzymes and signaling pathways, showing an opposite expression pattern in their contrasting lifespans. Functional analyses of more significantly changed genes indicated that the activities of catabolic enzymes and uptake/storage proteins are reduced in long-lived flies with Rpd3 downregulation. This reduced catabolism exhibited from a young age is considered to be necessary for the resultant longer lifespan of the Rpd3- and Loco-downregulated old flies, which mimics the dietary restriction (DR) effect that extends lifespan in the several species. Inversely, those catabolic activities that break down carbohydrates, lipids, and peptides were high in the short lifespan of Loco-upregulated flies. Long noncoding gene, dntRL (CR45923), was also found as a putative target modulated by Rpd3 and Loco for the longevity. Interestingly, this dntRL could affect stress resistance and lifespan, suggesting that the dntRL lncRNA may be involved in the metabolic mechanism of Rpd3 and Loco signaling.

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“…Selective breeding for long-lived flies reduces agedependent increase in antimicrobial peptide expression (Fabian et al 2018). Furthermore, knockdown of individual antimicrobial peptides extends lifespan (Lin et al 2018). The effect of overexpression of antimicrobial peptides on lifespan may be context-dependent as evidence suggests either detrimental (Badinloo et al 2018) or beneficial outcomes (Loch et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Glucose extends lifespan through enhanced intestinal barrier integrity in Drosophila

Galenza

Foley

2020

Preprint

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Dietary intervention has received considerable attention as an approach to extend lifespan and improve aging. However, questions remain regarding optimal dietary regime and underlying mechanism of lifespan extension. Here, we asked how glucose-enriched food extends the lifespan of Drosophila. We showed that glucose-dependent lifespan extension is independent of caloric restriction, or insulin activity, two established mechanisms of lifespan extension. Instead, we found that flies raised on glucoseenriched food increased the expression of cell junction proteins, and extended intestinal barrier integrity with age. Furthermore, chemical disruption of the intestinal barrier removed the lifespan extension associated with glucose-treatment, suggesting that glucose-enriched food prolongs adult viability by enhancing the intestinal barrier. We believe our data contribute to our understanding of intestinal health and may help efforts to develop preventative measures to limit the effects of aging and disease.

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“…The authors also reported that overexpression of individual AMPs like attacin A , defensin , metchnikowin , and cecropin A1 shortened the lifespan of flies. Similarly, mild downregulation of the IMD pathway or AMP downregulation of the IMD pathway extended the lifespan of flies [ 39 ]. In contrast, overexpression of drosocin increased fly lifespan, possibly by reducing bacterial challenge [ 40 ].…”

Section: Innate Immunity In Drosophilamentioning

confidence: 99%

Unraveling the Molecular Mechanism of Immunosenescence in Drosophila

Min

Tatar

2018

IJMS

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A common feature of the aging process is a decline in immune system performance. Extensive research has sought to elucidate how changes in adaptive immunity contribute to aging and to provide evidence showing that changes in innate immunity have an important role in the overall decline of net immune function. Drosophila is an emerging model used to address questions related to immunosenescence via research that integrates its capacity for genetic dissection of aging with groundbreaking molecular biology related to innate immunity. Herein, we review information on the immunosenescence of Drosophila and suggest its possible mechanisms that involve changes in insulin/IGF(insulin-like growth factor)-1 signaling, hormones such as juvenile hormone and 20-hydroxyecdysone, and feedback system degeneration. Lastly, the emerging role of microbiota on the regulation of immunity and aging in Drosophila is discussed.

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Stress resistance and lifespan enhanced by downregulation of antimicrobial peptide genes in the Imd pathway

Cited by 23 publications

References 37 publications

Dysregulation of antimicrobial peptide expression distinguishes Alzheimer’s disease from normal aging

Evolution of longevity improves immunity in Drosophila

Longer lifespan in the Rpd3 and Loco signaling results from the reduced catabolism in young age with noncoding RNA

Glucose extends lifespan through enhanced intestinal barrier integrity in Drosophila

Unraveling the Molecular Mechanism of Immunosenescence in Drosophila

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