Liver regeneration in aged mice: new insights

Pibiri, Monica

doi:10.18632/aging.101524

Cited by 40 publications

(27 citation statements)

References 234 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sirtuin 1 (Sirt1) is a histone-deacetylase involved in the transcriptional control of metabolism, and its low activity has been associated with senescent phenotypes in several organs. (15,16) Supporting aging-mediated changes in Sirt1, we found that it was down-regulated in older mice on FFD and that Shc down-regulation in the LV or AAV8-injected model reversed this (Supporting Fig. S7A).…”

Section: Hepatocyte-specific Shc-deleted Mice Show Improvement In Nasmentioning

confidence: 70%

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

et al. 2020

View full text Add to dashboard Cite

BaCKgRoUND aND aIMS: Older patients with obesity/ type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored. appRoaCH aND ReSUltS: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47 phox (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47 phox , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47 phox interaction using RosettaDock was generated. CoNClUSIoNS: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47 phox subunit that results in redox stress and accelerated fibrosis in the aged. (Hepatology 2020;72:1204-1218). N ASH and associated cirrhosis are the leading causes of liver-related mortality in the United States and worldwide. (1) The incidence of NASH rises strikingly with age, contributing significantly to elder mortality. (2) Older patients are often excluded from liver transplantation because of comorbidities and the age limit for transplantation; therefore, a significant increase in NASH-related mortality is expected because NASH has no approved medical treatment. Most of the preclinical data in NASH/fibrosis research is derived from experiments employing young mice. In clinical trials, however, the target population is usually middle-aged or elderly. To

show abstract

Section: Hepatocyte-specific Shc-deleted Mice Show Improvement In Nasmentioning

confidence: 70%

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Conversely, prolonged exposure of keratinocytes to SASP provoked maintenance of the cells to a senescent status, implying overall that SASP acts as a double‐edged sword for tissue regeneration in a time‐dependent manner . In addition, chronic activation of HSCs due to aging or NASH and their subsequent chemokine and ROS production leads to decreased activation and proliferation of liver progenitor cells, which are required for liver regeneration following hepatic injury . Overall, further studies are essential to reveal the role of senescence in liver regeneration during NASH resolution.…”

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

“…(76) In addition, chronic activation of HSCs due to aging or NASH and their subsequent chemokine and ROS production leads to decreased activation and proliferation of liver progenitor cells, which are required for liver regeneration following hepatic injury. (77) Overall, further studies are essential to reveal the role of senescence in liver regeneration during NASH resolution.…”

Section: Nash Resolution and The Role Of Senescencementioning

confidence: 99%

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

View full text Add to dashboard Cite

In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.

show abstract

“…On the one hand, there are significant changes in expression of crucial proteins like Yap or Sirt1, and lncRNAs in the aged mice and humans. [196][197][198] On the other hand, there is a clinical evidence that orthotopic liver transplants from aged donors are comparable to those from young donors. 199 We propose significant progress on the roles of ncRNA in aging liver as many transplants in clinic are from people more than 70 to 80 years old.…”

Section: Resultsmentioning

confidence: 99%

Noncoding RNA in Liver Regeneration—From Molecular Mechanisms to Clinical Implications

2019

View full text Add to dashboard Cite

The unique ability of the adult liver to regenerate after injury is the basis for efficient surgical resection and liver transplantation and provides solutions for the treatment of liver cancer and acute liver failure. Current success in surgical treatments could be enhanced by directed regulation of liver regeneration. A number of small molecules and growth factors have been tested in mice models to improve liver regeneration. Noncoding ribonucleic acids (ncRNA) are less studied regulators of various cellular processes. Here, the authors carefully review ncRNA involved in liver regeneration and discuss molecular mechanisms and regulatory networks. These ncRNAs modulate the expression of pro- and antiproliferative genes allowing to orchestrate precisely the proliferation of hepatocytes. The authors expect that ncRNA will become new targets in liver regeneration due to recent progress in therapeutic nucleic acids. Among a large number of preclinical studies on ncRNA, only a few entered clinical trials, and further studies are needed to uncover their potential as therapeutic targets.

show abstract

Liver regeneration in aged mice: new insights

Cited by 40 publications

References 234 publications

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

Noncoding RNA in Liver Regeneration—From Molecular Mechanisms to Clinical Implications

Contact Info

Product

Resources

About