Impaired immune surveillance accelerates accumulation of senescent cells and aging

Ovadya, Yossi; Landsberger, Tomer; Leins, Hanna; Vadai, Ezra; Gal, Hilah; Biran, Anat; Yosef, Reut; Sagiv, Adi; Agrawal, Amit; Shapira, Alon; Windheim, Joseph; Tsoory, Michael; Schirmbeck, Reinhold; Amit, Ido; Geiger, Hartmut; Krizhanovsky, Valery

doi:10.1038/s41467-018-07825-3

Cited by 394 publications

(340 citation statements)

References 70 publications

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“…It will be interesting to determine if senolytic-treatment can also improve such cases of severe damage. Indeed, senolytics have already been shown to function in the liver of mouse models with immune dysfunction (Ovadya et al, 2018), and in ameliorating age-related hepatic steatosis (Ogrodnik et al, 2017). Interestingly, as PH is associated with induction of steatosis in older animals as shown here and elsewhere (Loforese et al, 2017), our study further supports that these drugs could aid in liver regeneration in elderly patients.…”

Section: Discussionsupporting

confidence: 82%

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Senolytic treatment targets aberrant p21-expression to restore liver regeneration in adult mice

Ritschka

Knauer-Meyer

Mas

et al. 2019

Preprint

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Young mammals possess a limited regenerative capacity in tissues such as the liver, heart and limbs, but which is quickly lost upon maturation or transition to adulthood. Chronic cellular senescence is a known mediator of decreased tissue function in aging and disease. Here we investigated whether senescence plays a role in the progressive loss of liver regenerative capacity that develops in young adult mice. We find that following partial hepatectomy, the senescence markers p21, p16 Ink4a and p19 Arf become dynamically expressed at an age when regenerative capacity decreases. In addition, we demonstrate that treatment with a senescence-inhibiting drug improves regenerative capacity, through targeting of aberrant p21 expression. Surprisingly, we also find that the senescence marker p16 Ink4a is expressed in a different cell-population to p21, and is unaffected by senescence targeting. This work suggests that senescence may initially develop as a heterogeneous cellular response, and that treatment with senolytic drugs may aid in promoting organ regeneration.

show abstract

Section: Discussionsupporting

confidence: 82%

“…on 2 consecutive days immediately before PH with DMSO (2%) or ABT-737 (25 mg/kg body weight; AdooQ Bioscience). DMSO and ABT-737 were prepared in the following working solution: 30% propylene glycol, 5% Tween 80, 5% dextrose in water (pH 4-5) as previously reported (Ovadya et al, 2018).…”

Section: Elimination Of Senescent Cells In Vivomentioning

confidence: 99%

Senolytic treatment targets aberrant p21-expression to restore liver regeneration in adult mice

Ritschka

Knauer-Meyer

Mas

et al. 2019

Preprint

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“…Under physiological conditions, senescence eliminates damaged cells and is involved in tissue restoration on acute stress or injury. The secretion of chemokines and cytokines such as IL‐1b, IL‐8, and MCP‐1 through SASP attracts immune cells, leading to immunological clearance of the senescent cells . Consistently, aging and chronic stress induce telomere attrition and excessive SASP, leading to accumulation of senescent cells and insufficient tissue regeneration .…”

Section: Senescence In Health and Diseasementioning

confidence: 99%

“…The secretion of chemokines and cytokines such as IL-1b, IL-8, and MCP-1 through SASP attracts immune cells, leading to immunological clearance of the senescent cells. (14,15) Consistently, aging and chronic stress induce telomere attrition and excessive SASP, leading to accumulation of senescent cells and insufficient tissue regeneration. (14,16) Concurrently, hematopoietic stem cells decrease with age, resulting in fewer immune cells and a decline in the immune response, provoking a vicious cycle of defective clearance of senescent cells.…”

Section: Senescence In Health and Disease General Aspectsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…In addition, studies have indicated that the activation of pathways, downstream of the DNA damage response (DDR), accelerate the process of aging . On the other end, elimination of senescent cells in mice displaying premature aging due to genomic instability increases animal life span, and elimination of senescent cells in wild‐type mice increases their health span . Moreover, supporting further the causal relationship between accumulation of senescent cells and the aging phenotype, it was shown that elimination of p16 Ink4a ‐positive senescent cells decreased the onset of age‐related pathologies in both progeroid and wild‐type mice .…”

Section: Organismal Aging and Cellular Senescencementioning

confidence: 77%

Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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The relationship between oxidants and organismal aging was first articulated through the free radical theory of aging. One of the major predictions of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of an increased level of oxidants, which are damaging to macromolecules. However, challenging the role of oxidants in age‐related diseases, there is now sufficient evidence that antioxidant supplements do not provide significant health benefits. Interestingly, in addition to an increase in oxidant‐mediated macromolecules damage, there is convincing experimental data to support the role of senescent cells in the process of aging. Here, the current knowledge regarding the role of oxidants and cellular senescence in organismal aging is reviewed and it is proposed that, in addition to the role of oxidants as inducers of macromolecular damage, oxidants may also function as regulators of signaling pathways involved in the establishment of cellular senescence. If this role for oxidants is established, it may be necessary to modify the free radical theory of aging from “Organisms age because cells accumulate reactive oxygen species‐dependent damage over time” to: “Organisms age because cells accumulate oxidants’‐dependent damage and oxidants’‐dependent senescent characteristics over time.”

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Impaired immune surveillance accelerates accumulation of senescent cells and aging

Cited by 394 publications

References 70 publications

Senolytic treatment targets aberrant p21-expression to restore liver regeneration in adult mice

Senolytic treatment targets aberrant p21-expression to restore liver regeneration in adult mice

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

Organismal Aging and Oxidants beyond Macromolecules Damage

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