Apoptosis in the aging liver

Zhong, Huahua; Hu, Song; Yu, Bo; Jiang, Shasha; Zhang, Jin; Luo, Dongmei; Yang, Mei-wen; Su, Wei; Shao, Ya-Lan; Deng, Hao-Lin; Hong, Fashui; Yang, Shu‐Long

doi:10.18632/oncotarget.21123

Cited by 22 publications

(17 citation statements)

References 95 publications

(102 reference statements)

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“…IPF is thought to be an age-related disease, mostly because a large majority of IPF patients are aged 50 years and older [39,40]. Therefore, the possibility that age per se plays a confounding role in influencing resistance to apoptosis, as is the case in aberrant senescent cells [41], cannot be excluded. Accordingly, the resolution of fibrosis detected in the BLM experimental model should be assessed in aged-mice, where responses are known to more accurately resemble that of human-IPF, since they do not resolve fibrosis [42].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis

et al. 2020

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In contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (H355Y-Sirt1y/y), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis

et al. 2020

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“…75 It is however expected that a balance of apoptosis should be maintained to achieve liver homeostasis. 76 Accordingly, inducing activated stellate cell senescence limits liver fibrosis 77 and targeting autophagy, which declines with age, could also be an interesting therapeutic consideration. 78 Susceptibility to liver fibrosis also increases with age, whatever the aetiology.…”

Section: Age Of the Donormentioning

confidence: 99%

Age and liver transplantation

Durand

Levitsky

Cauchy

et al. 2019

Journal of Hepatology

195

190

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The average age of liver transplant donors and recipients has increased over the years. Independent of the cause of liver disease, older candidates have more comorbidities, higher waitlist mortality and higher post-transplant mortality than younger patients. However, transplant benefit may be similar in older and younger recipients, provided older recipients are carefully selected. The cohort of elderly patients transplanted decades ago is also increasingly raising issues concerning long-term exposure to immunosuppression and aging of the transplanted liver. Excellent results can be achieved with elderly donors and there is virtually no upper age limit for donors after brain death liver transplantation. The issue is how to optimise selection, procurement and matching to ensure good results with elderly donors. The impact of old donor age is more pronounced in younger recipients and patients with a high model for end-stage liver disease score. Age matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach. However, age matching may vary depending on the objectives of different allocation policies. In addition, age matching must be revisited in the era of direct-acting antivirals. More restrictive limits have been adopted in donation after circulatory death. Perfusion machines which are currently under investigation may help expand these limits. In living donor liver transplantation, donor age limit is essentially guided by morbidity related to procurement. In this review we summarise changing trends in recipient and donor age. We discuss the implications of older age donors and recipients. We also consider different options for age matching in liver transplantation that could improve outcomes.

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“…Therefore, it could be suggested that genome-wide hypomethylation occurs in an age-dependent fashion in many types of cells from various organs, which could lead to retrotransposon activation, induction of genomic instability [ 99 ], aberrant transcription patterns [ 100 ] and increase in cell apoptosis [ 101 ]. On the other hand, the opposite process, hypermethylation of certain promoter regions including those of tumor suppressor genes, can occur during aging and result in the development of various pathologies [ 102 ].…”

Section: Circulating Dna As a Source Of Cancer Biomarkersmentioning

confidence: 99%

Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers

Ponomaryova

Rykova

Gervas

et al. 2020

Cells

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Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade. Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the reactivation of retroelements and subsequent genomic instability. Accumulating data on LINE-1 aberrant methylation in different tumor types indicates its significant role in cancer initiation and progression. However, direct evidence that LINE-1 activation can be used as a cancer biomarker is still limited. The objective of this review was to critically evaluate the published results regarding the diagnostic/prognostic potential of the LINE-1 methylation status in cancer. Our analysis indicates that LINE-1 hypomethylation is a promising candidate biomarker of cancer development, which, however, needs validation in both clinical and laboratory studies to confirm its applicability to different cancer types and/or stages. As LINE-1 is present in multiple cell-free copies in blood, it has advantages over single-copy genes regarding perspectives of using its methylation status as an epigenetic cancer biomarker for cell-free DNA liquid biopsy.

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Apoptosis in the aging liver

Cited by 22 publications

References 95 publications

SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis

SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis

Age and liver transplantation

Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers

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