p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

Davalos, Albert R.; Kawahara, Misako; Malhotra, Gautam; Schaum, Nicholas; Huang, Joe; Ved, Urvi; Beauséjour, Christian; Coppé, Jean‐Philippe; Rodier, Francis; Campisi, Judith

doi:10.1083/jcb.201206006

Cited by 375 publications

(274 citation statements)

References 83 publications

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“…The discrepancy with our current results could be attributed to intrinsic factors such as tissue specificity, species, and gender in the measure of telomere length (Sanders & Newman, 2013). Nevertheless, the combination of decreased HMGB1 (Davalos et al., 2013) and increased cell cycle inhibitors [p53 and p16 Ink4a (Childs et al., 2017)] are in line with the emergence of cellular senescence that can be associated with the development of tissue pathology and earlier mortality in subordinate mice. This hypothesis is supported by studies demonstrating that accumulation of senescent cells is causal in driving aging‐associated pathologies.…”

Section: Discussionmentioning

confidence: 99%

Social stress shortens lifespan in mice

et al. 2018

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SummaryStress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

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Section: Discussionmentioning

confidence: 99%

Social stress shortens lifespan in mice

et al. 2018

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“…Recent reports from several laboratories indicate that fully-reduced HMGB1 (also called all-cysteine-reduced HMGB1) acts as a chemokine by forming a heterocomplex with CXCL12 to bind CXCR4; disulfide HMGB1 with a disulfide bond connecting C23 and C45 acts as a proinflammatory cytokine by binding to TLR4 or NDMAR; sulfonyl HMGB1 (also called oxidized HMGB1) has no activity in cell migration or cytokine induction (Figure 9B) (Balosso et al, 2014; Liu et al, 2012a; Schiraldi et al, 2012; Venereau et al, 2012; Yang et al, 2010a). However, other reports indicate that oxidized HMGB1 still has the ability to activate neutrophils, vascular inflammation, and age-associated inflammation (Davalos et al, 2013; Maugeri et al, 2014). The different HMGB1 redox forms can be identified in serum, saliva, and cell culture medium by mass spectrometry (Balosso et al, 2014; Liu et al, 2012a; Schiraldi et al, 2012; Venereau et al, 2012; Yang et al, 2010a) and nuclear magnetic resonance (NMR) spectroscopy (Zandarashvili et al, 2013), although currently there is no convenient method.…”

Section: Hmgb1 Post-translational Modificationmentioning

confidence: 96%

“…In addition to cell death, senescence is considered an important mechanism for mammalian cells to suppress tumorigenesis. During senescence, HMGB1 translocates from the nucleus to the cytoplasm and is then released to the extracellular space (Davalos et al, 2013). Once released, oxidized HMGB1 binds to TLR4 and induces IL-6 production and release, which promotes age-associated inflammation.…”

Section: Hmgb1 Functionmentioning

confidence: 99%

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HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

822

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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“…The study of fetal and neonatal β cells has provided a lot of information about the major phenotypic changes that occur 4 , 5 and markers of aging are also being found such as p16 12 . There are other markers of aging that may prove valuable including senescence-associated β-galactosidase (SA-βgal) 13 among others 14 , 15 . These differences are, however, only the tip of the iceberg; we look forward to the identification of many more markers.…”

Section: Normal Differences In β-Cell Differentiation: β-Cell Maturatmentioning

confidence: 99%

β-cell dedifferentiation in diabetes is important, but what is it?

Weir

Aguayo-Mazzucato

Bonner-Weir

2013

Islets

113

100

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This commentary discusses the concept of β-cell dedifferentiation in diabetes, which is important but not well defined. A broad interpretation is that a state of differentiation has been lost, which means changes in gene expression as well as in structural and functional elements. Thus, a fully mature healthy β cell will have its unique differentiation characteristics, but maturing cells and old β cells will have different patterns of gene expression and might therefore be considered as dedifferentiated. The meaning of dedifferentiation is now being debated because β cells in the diabetic state lose components of their differentiated state, which results in severe dysfunction of insulin secretion. The major cause of this change is thought to be glucose toxicity (glucotoxicity) and that lowering glucose levels with treatment results in some restoration of function. An issue to be discussed is whether dedifferentiated β cells return to a multipotent precursor cell phenotype or whether they follow a different pathway of dedifferentiation.

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p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

Abstract: In addition to allowing immune cells to signal tissue damage, HMBG1 is secreted by senescent cells to initiate inflammatory cytokine secretion.

Cited by 375 publications

References 83 publications

Social stress shortens lifespan in mice

Social stress shortens lifespan in mice

HMGB1 in health and disease

β-cell dedifferentiation in diabetes is important, but what is it?

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