Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan

Yamashita, Kyoko; Oi, Ayano; Kosakamoto, Hina; Yamauchi, Teruaki; Kadoguchi, Hibiki; Kuraishi, Takayuki; Miura, Masayuki; Obata, Fumiaki

doi:10.1242/dmm.049103

Cited by 14 publications

(10 citation statements)

References 67 publications

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“…Collectively, these results well accord with the previous reports of positive association of the pathways of ribosome and autophagy with longevity [52] and negative association of genome instability [53,54] and activated immune reaction [55,56] with lifespan. Among the alteration of the expression levels of the genes, the pathways of genome stability were most notable (Fig.…”

Section: Discussionsupporting

confidence: 92%

Genetic Association of Intelligence with Longevity in Drosophila melanogaster

Khan

Lkhagva

Siddiqui

et al. 2022

Preprint

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Epidemiological studies in different populations, in different countries, and in different epochs consistently showed that high intelligence is positively correlated with longevity. The link between high intelligence and longevity has remained unknown, only to be assumed as a consequence of the socioeconomic difference associated with intelligence in human population. Here, we report that genome stability contributes both to lifespan and intelligence in Drosophila melanogaster. The intelligence of the genetically heterogenous flies was determined by T-maze olfactory memory assay, and the flies moving to the right direction defined as intelligent flies (INT) were separated from the flies moving to the wrong direction defined as non-intelligent flies (NINT). INT male and female lived 26.40% and 21.35% longer than NINT male and female, respectively, suggesting a possible genetic linkage between intelligence and longevity. The bidirectional selective breeding based on intelligence extended lifespans gradually generation by generation in INT breeding contrast to the reversed pattern in NINT breeding. INT of F12 generation lived longer than NINT of F12 generation, 63.91% for male and 67.88% for female, as a result from slower aging. The whole-genome transcriptome analysis showed the activation of the genes in ribosome and autophagy in INT and the pathways of genome stability and immune reaction in NINT. Especially, the genetic pathway associated with genome stability was most noticeable, indicating that genome stability contributes both to lifespan and intelligence in D. melanogaster.

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Section: Discussionsupporting

confidence: 92%

Genetic Association of Intelligence with Longevity in Drosophila melanogaster

Khan

Lkhagva

Siddiqui

et al. 2022

Preprint

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“…Consistent with this, we did not see major differences between axenic and conventionally raised wild-type flies in this study. Previous studies have already revealed the role of Imd signalling in controlling microbiome load and diversity, preventing dysbiosis [46,88–90]. More recently, use of ΔAMP14 flies revealed a key role of AMPs to control bacteria in the gut, notably the Gram-negative bacterium Acetobacter , and accordingly, ΔAMP14 flies have increased microbiome load upon aging ([25] and Fig.…”

Section: Discussionmentioning

confidence: 96%

“…Consistent with this, we did not see major differences between germ-free and conventionally raised wild-type flies in this study. Previous studies have already revealed the role of Imd signalling in controlling microbiome load and diversity, preventing dysbiosis (Guo et al, 2014; Li et al, 2016; Liu et al, 2022; Yamashita et al, 2021). The specific microbiome of a given research group could also change the impact of germ-free conditions.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial peptides do not directly contribute to aging inDrosophila, but improve lifespan by preventing dysbiosis

Hanson

Lemaître

2022

Preprint

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Antimicrobial peptides (AMPs) are innate immune effectors first studied for their role in host defense against bacterial and fungal infections. Recent studies have implicated these peptides in the clearance of aberrant cells and various neurological processes including neurodegenerative syndromes. In Drosophila, an array of AMPs are produced downstream of the Toll and Imd NF-κB pathways in response to infection. Many studies have suggested a role for the Imd pathway and AMPs in aging in this insect, supported by the upregulation of AMPs with aging (so-called inflammaging). However, functional studies using RNAi or over-expression have been inconclusive on whether and how these immune effectors impact aging. Leveraging a new set of single and compound AMP gene deletions in a controlled genetic background, we have investigated how AMPs contribute to aging. Overall, we found no major effect of individual AMPs on lifespan, with a possible exception of Defensin. However, ΔAMP14 flies lacking 14 AMP genes from seven families display a reduced lifespan. Interestingly, we found an increased bacterial load in the food medium of aged ΔAMP14 flies, suggesting that the lifespan reduction of these flies was due to a failure in controlling the microbiome. Consistent with this idea, use of germ-free conditions extends the lifespan of ΔAMP14 flies. Overall, our results do not point to an overt role of individual AMPs in lifespan. Instead, we find that AMPs collectively impact lifespan by preventing dysbiosis over aging. This is consistent with previous studies that have shown that AMPs control the gut microbiome, and that dysbiosis is detrimental upon aging. In the course of our experiments, we also uncovered a strong impact of a cryptic Drosophila nora virus infection on lifespan that should be taken into consideration in aging studies.

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“…Canton-S, w Dah , w CS (Canton-S backcrossed to w iso31 eight times), w iso31 , and yw flies were used as control strains. Other fly lines used in this study were Dredd B118 [26], 5966 GS , UAS-GFP [44], WBFB GS (S106+S32) [45], Uro GS [46], Su(H)GBE-LacZ, esg ts , NP1-Gal4 [47], UAS-caudal-RNAi (VDRC, v3361), UAS-Rel-RNAi (BDSC, 33661), PGRP-LC-RNAi (BDSC, 33383), and UAS-PGRP-LE-RNA i (BDSC, 60038). The Rel E20 , PGRP-LC E12 , and PGRP-LE 112 lines have been described previously [17,48].…”

Section: Methodsmentioning

confidence: 99%

Recognition of commensal bacterial peptidoglycans definesDrosophilagut homeostasis and lifespan

Onuma

Yamauchi

Kosakamoto³

et al. 2023

Preprint

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Commensal microbes in animals have a profound impact on tissue homeostasis, stress resistance, and ageing. We previously showed in Drosophila melanogaster that Acetobacter persici is a member of the gut microbiota that promotes ageing and shortens fly lifespan. However, the molecular mechanism by which this specific bacterial species changes lifespan and physiology remains unclear. The difficulty in studying longevity using gnotobiotic flies is the high risk of contamination during ageing. To overcome this technical challenge, we used a bacteria-conditioned diet enriched with bacterial products and cell wall components. Here, we demonstrate that an A. persici-conditioned diet shortens lifespan and increases intestinal stem cell (ISC) proliferation. Feeding adult flies a diet conditioned with A. persici, but not with Lactiplantibacillus plantarum, can decrease lifespan but increase resistance to paraquat or oral infection of Pseudomonas entomophila, indicating that the bacterium alters the trade-off between lifespan and host defence. A transcriptomic analysis using fly intestine revealed that A. persici preferably induces antimicrobial peptides (AMPs), while L. plantarum upregulates amidase peptidoglycan recognition proteins (PGRPs). The specific induction of these Imd target genes by peptidoglycans from two bacterial species is due to the stimulation of the receptor PGRP-LC in the anterior midgut for AMPs or PGRP-LE from the posterior midgut for amidase PGRPs. Heat-killed A. persici also shortens lifespan and increases ISC proliferation via PGRP-LC, but it is not sufficient to alter the stress resistance. Our study emphasizes the significance of peptidoglycan specificity in determining the gut bacterial impact on healthspan. It also unveils the postbiotic effect of specific gut bacterial species, which turns flies into a "live fast, die young" lifestyle.

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Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan

Cited by 14 publications

References 67 publications

Genetic Association of Intelligence with Longevity in Drosophila melanogaster

Genetic Association of Intelligence with Longevity in Drosophila melanogaster

Antimicrobial peptides do not directly contribute to aging inDrosophila, but improve lifespan by preventing dysbiosis

Recognition of commensal bacterial peptidoglycans definesDrosophilagut homeostasis and lifespan

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