Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

Delire, Bénédicte; Lebrun, Valérie; Selvais, Charlotte; Henriet, Patrick; Bertrand, Amélie; Horsmans, Yves; Leclercq, Isabelle

doi:10.18632/aging.101124

Cited by 34 publications

(33 citation statements)

References 54 publications

(65 reference statements)

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“…These include increased inflammation and immune response-related proteins [23], and accumulation of extracellular matrix proteins [32]. Interestingly, we found a statistically significant overlap between proteins differentially abundant in NMR vs. GP, and proteins whose abundance is affected by NMR aging (99 proteins, p=2x10 -4 , Fisher's exact test, Figure 3C).…”

Section: Cross-species-and Aging-related Changes Correlatementioning

confidence: 78%

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

Heinze

Bens

Calzia

et al. 2017

Preprint

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Mammals display wide range of variation in their lifespan. Lifespan is generally 29 correlated to body size, but outliers such as human and the naked mole-rat 30 (NMR, Heterocephalus glaber) exist. Investigating the molecular networks that 31 distinguish long-from short-lived species has proven useful to identify 32 determinants of longevity. Here, we compared the liver of long-lived NMRs and 33 the phylogenetically closely related, shorter-lived, guinea pigs (GP, Cavia 34 porcellus) using an integrated transcriptomic and proteomic approach. We found 35 that NMRs express substantially higher levels (up to 30 fold) of a restricted 36 number of longevity-associated proteins that confer enhanced buffering against 37 oxidative stress. Moreover, NMR livers display a unique expression pattern of 38 mitochondrial proteins that result in distinct metabolic features of their 39 mitochondria. For instance, we observed a generally reduced respiration rate 40 associated with lower protein levels of respiratory chain components, 41 particularly complex I, and increased capacity to utilize fatty acids. Interestingly, 42 the same molecular networks are affected during aging in both NMR and 43 humans, supporting a direct link to the extraordinary longevity of both species. 44Finally, we used our analysis to identify novel longevity pathways, and validated 45 one of them experimentally in the phylogenetically distantly related nematode C. 46 elegans. 47 48 . CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/220343 doi: bioRxiv preprint first posted online Nov. 17, 2017; Heinze, Bens, Calzia, et al. 2Introduction: 49 50Among mammals lifespan generally correlates with other life-history parameters 51 such as gestation period and body mass [1]. In this perspective, a subterranean 52 rodent, the naked mole-rat (Heterocephalus glaber, NMR), and humans represent 53 two species outliers by having an exceptionally long lifespan relatively to their 54 body mass. NMRs are eusocial animals that live in colonies where only a 55 subgroup of animals is devoted to reproduction (usually a queen and one male 56 called pasha) [2]. NMRs exhibit other exceptional traits including lifelong 57 fertility, resistance to infection, high regenerative capacity, resistance to cancer 58 and diabetes, reviewed in [3,4]. For these reasons, NMRs have drawn attention of 59 multiple studies aimed at identifying the molecular mechanisms behind their 60 extreme longevity and resistance to age-related diseases. Comparative genome 61 analysis has revealed positively selected genes in NMR [5,6], and RNA-seq 62 analysis revealed minimal changes in gene expression during aging [5,7], 63 supporting the view of enhanced maintenance of homeostasis in NMRs at the 64 molecular level. NMRs possess enhanced protein stability and increased 65 proteasomal activity [8,9], negligible levels of cellular senescence [10], over-66 activation of pathways...

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Section: Cross-species-and Aging-related Changes Correlatementioning

confidence: 78%

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

Heinze

Bens

Calzia

et al. 2017

Preprint

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“…Young animals have a different ECM composition, higher regenerative capacity, and higher collagen turnover rate compared to old animals. (53,54) To address this issue, future studies using aged mice for evaluation of the RGD inhibitors are warranted.…”

Section: Discussionmentioning

confidence: 99%

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

et al. 2018

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The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.

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“…We focused on a subset of tissues (i.e. heart, liver, cerebellum, olfactory bulb) that are known to display age-related functional decline (Enwere et al 2004;Sussman and Anversa 2004;Zhang et al 2010;Shioi and Inuzuka 2012;Mobley et al 2014;Delire et al 2016), and that are clearly anatomically defined. We also derived primary cultures of neural stem and progenitor (NSCs) from these young, middle-aged, and old mice.…”

Section: A Genome-wide Epigenomic and Transcriptomic Landscape Of In mentioning

confidence: 99%

“…NSCs cultures derived from the Subventricular Zone (SVZ) because (i) these tissues and cells are known to display age-related functional decline(Enwere et al 2004;Sussman and Anversa 2004;Zhang et al 2010;Shioi and Inuzuka 2012;Mobley et al 2014;Delire et al 2016) and (ii) the tissues are all clearly defined anatomically, which guarantees reproducible isolation across animals of different ages and minimizes the risk that observed differences comes from dissection differences. For the heart, we dissected the ventricle tissue for chromatin and RNA extraction.…”

mentioning

confidence: 99%

Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses

Benayoun

Pollina

Singh

et al. 2018

Preprint

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(max 250 words)Aging is accompanied by the functional decline of tissues. However, a systematic study of epigenomic and transcriptomic changes across tissues during aging is missing. Here we generated chromatin maps and transcriptomes from 4 tissues and one cell type from young, middle-age, and old mice, yielding 143 high-quality datasets. We focused specifically on chromatin marks linked to gene expression regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a mark enriched at active enhancers. Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of datasets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the upregulation of immune system response pathways such as the interferon signaling pathway. The upregulation of interferon response pathway with age was accompanied by increased transcription of various endogenous retroviral sequences.Pathways deregulated during mouse aging across tissues, notably innate immune pathways, were also deregulated with aging in other vertebrate species -African turquoise killifish, rat, and humansindicating common signatures of age across species. To date, our dataset represents the largest multitissue epigenomic and transcriptomic dataset for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of youthful tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.

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Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

Cited by 34 publications

References 54 publications

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses

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