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Life
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Cellular Senescence in Health, Disease and Aging: Blessing or Curse?
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Cellular Senescence in Health, Disease and Aging: Blessing or Curse?

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Cell Biology and Tissue Engineering".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 29941

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Markus Riessland

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Guest Editor
Department of Neurobiology and Behavior & Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY 11794, USA
Interests: neurogenetics; neuroscience; cellular senescence; neuro-immunology; genetic modifiers; Parkinson’s disease; dopaminergic neurons; selective vulnerability; spinal muscular atrophy

Special Issue Information

Dear Colleagues,

When Hayflick and Moorhead coined the term “cellular senescence” (CS) almost 60 years ago, this phenomenon was understood as a mechanism, usually induced by activation of the DNA-repair machinery, to prevent uncontrolled proliferation. Meanwhile, additional beneficial roles for CS have been identified, such as embryonic development and wound healing. The senescence associated secretory phenotype (SASP) activated in most senescent cells (SC) signals to the immune system “come here and remove me”. In organisms with young and functional immune systems, occurring SC are usually detected and removed. If SC remain in the tissue expressing the SASP, this will cause not just a damaging local inflammation but can also induce remodeling and regeneration of the surrounding tissue as well as spreading of senescence. Old organisms show reduced regenerative potential and immune function which leads to accumulation of SC. Accordingly, accumulation of SC was observed in tissues of aged individuals, but importantly also in the context of age-related disorders, neurodegenerative, or cardiovascular diseases and others. Because of its detrimental effect of the surrounding tissue, accumulation of SC is not just a consequence, but can rather been understood as a major driver of aging. In line with this, recent studies described that removal of SC showed beneficial effects on healthspan and lifespan. This exciting research led to the discovery of “senolytics”, drugs which can kill SC. Given the heterogeneity of cell types that show senescence-like phenotypes, including heart muscle and post-mitotic neuronal cells, further research is required to unravel the molecular background that renders a cell type vulnerable to senesce. Additionally, it will be important to understand how senescence is cell type-specifically induced and which molecules serve as drug targets to prevent senescence and its spreading, or actively kill SC. This special issue will shed light on the molecular pathways of CS and inflammaging and on possible strategies to interfere with these processes.

Dr. Markus Riessland
Guest Editor

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Keywords

  • cellular senescence 
  • senolytics 
  • senescence associated secretory phenotype (SASP) 
  • spreading of senescence 
  • neuronal senescence 
  • brain senescence 
  • cell cycle inhibitors 
  • inflammation 
  • inflammaging

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Published Papers (7 papers)

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Editorial

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3 pages, 188 KiB  
Editorial
Cellular Senescence in Health, Disease and Aging: Blessing or Curse?
by Markus Riessland
Life 2021, 11(6), 541; https://doi.org/10.3390/life11060541 - 9 Jun 2021
Cited by 5 | Viewed by 2173
Abstract
Sixty years ago (1961), Hayflick and Moorhead reported that primary cells terminate their growth and stop dividing after ~50 passages or one year in culture [...] Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)

Research

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11 pages, 667 KiB  
Article
Human Prostate Epithelial Cells Activate the AIM2 Inflammasome upon Cellular Senescence: Role of POP3 Protein in Aging-Related Prostatic Inflammation
by Ravichandran Panchanathan, Vaikundamoorthy Ramalingam, Hongzhu Liu and Divaker Choubey
Life 2021, 11(4), 366; https://doi.org/10.3390/life11040366 - 20 Apr 2021
Cited by 13 | Viewed by 2588
Abstract
Increased levels of type I (T1) interferon (IFN)-inducible POP3 protein in myeloid cells inhibit activation of the AIM2 inflammasome and production of IL-1β and IL-18 proinflammatory cytokines. The AIM2 mRNA levels were significantly higher in benign prostate hyperplasia (BPH) than the normal prostate. [...] Read more.
Increased levels of type I (T1) interferon (IFN)-inducible POP3 protein in myeloid cells inhibit activation of the AIM2 inflammasome and production of IL-1β and IL-18 proinflammatory cytokines. The AIM2 mRNA levels were significantly higher in benign prostate hyperplasia (BPH) than the normal prostate. Further, human normal prostate epithelial cells (PrECs), upon becoming senescent, activated an inflammasome. Because in aging related BPH senescent PrECs accumulate, we investigated the role of POP3 and AIM2 proteins in pre-senescent and senescent PrECs. Here we report that the basal levels of the POP3 mRNA and protein were lower in senescent (versus young or old) PrECs that exhibited activation of the T1 IFN response. Further, treatment of PrECs and a BPH cell line (BPH-1) that expresses the androgen receptor (AR) with the male sex hormone dihydrotestosterone (DHT) increased the basal levels of POP3 mRNA and protein, but not AIM2, and inhibited activation of the AIM2 inflammasome. Of interest, a stable knockdown of POP3 protein expression in the BPH-1 cell line increased cytosolic DNA-induced activation of AIM2 inflammasome. These observations suggest a potential role of POP3 protein in aging-related prostatic inflammation. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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19 pages, 1378 KiB  
Article
Evaluation of GammaH2AX in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer’s Disease in the AIBL Study of Ageing
by Mohammad Sabbir Siddiqui, Maxime Francois, Stephanie Rainey-Smith, Ralph Martins, Colin L. Masters, David Ames, Christopher C. Rowe, Lance S. Macaulay, Michael F. Fenech and Wayne R. Leifert
Life 2020, 10(8), 141; https://doi.org/10.3390/life10080141 - 6 Aug 2020
Cited by 2 | Viewed by 3111
Abstract
In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses [...] Read more.
In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in P-trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 (p = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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Review

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10 pages, 627 KiB  
Review
Loss of p16: A Bouncer of the Immunological Surveillance?
by Kelly E. Leon, Naveen Kumar Tangudu, Katherine M. Aird and Raquel Buj
Life 2021, 11(4), 309; https://doi.org/10.3390/life11040309 - 2 Apr 2021
Cited by 12 | Viewed by 4342
Abstract
p16INK4A (hereafter called p16) is an important tumor suppressor protein frequently suppressed in human cancer and highly upregulated in many types of senescence. Although its role as a cell cycle regulator is very well delineated, little is known about its other non-cell [...] Read more.
p16INK4A (hereafter called p16) is an important tumor suppressor protein frequently suppressed in human cancer and highly upregulated in many types of senescence. Although its role as a cell cycle regulator is very well delineated, little is known about its other non-cell cycle-related roles. Importantly, recent correlative studies suggest that p16 may be a regulator of tissue immunological surveillance through the transcriptional regulation of different chemokines, interleukins and other factors secreted as part of the senescence-associated secretory phenotype (SASP). Here, we summarize the current evidence supporting the hypothesis that p16 is a regulator of tumor immunity. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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24 pages, 826 KiB  
Review
The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration
by Eric Sah, Sudarshan Krishnamurthy, Mohamed Y. Ahmidouch, Gregory J. Gillispie, Carol Milligan and Miranda E. Orr
Life 2021, 11(3), 229; https://doi.org/10.3390/life11030229 - 11 Mar 2021
Cited by 34 | Viewed by 7044
Abstract
In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, [...] Read more.
In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as “senescence”) now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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26 pages, 750 KiB  
Review
Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration
by Gregory J. Gillispie, Eric Sah, Sudarshan Krishnamurthy, Mohamed Y. Ahmidouch, Bin Zhang and Miranda E. Orr
Life 2021, 11(2), 153; https://doi.org/10.3390/life11020153 - 17 Feb 2021
Cited by 16 | Viewed by 6201
Abstract
Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one [...] Read more.
Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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Other

7 pages, 256 KiB  
Opinion
Secreted Protein Acidic and Rich in Cysteine as A Regeneration Factor: Beyond the Tissue Repair
by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand
Life 2021, 11(1), 38; https://doi.org/10.3390/life11010038 - 8 Jan 2021
Cited by 23 | Viewed by 3259
Abstract
Diverse pathologies (inflammation, tissues injuries, cancer, etc.) and physiological conditions (obesity, physical activity, etc.) induce the expression/secretion of the matricellular protein, secrete protein acidic and rich in cysteine (SPARC). SPARC contributes to the creation of an environment that is suitable for tissue regeneration [...] Read more.
Diverse pathologies (inflammation, tissues injuries, cancer, etc.) and physiological conditions (obesity, physical activity, etc.) induce the expression/secretion of the matricellular protein, secrete protein acidic and rich in cysteine (SPARC). SPARC contributes to the creation of an environment that is suitable for tissue regeneration through a variety of roles, including metabolic homeostasis, inflammation reduction, extracellular matrix remodeling and collagen maturation. Such a homeostatic environment optimizes tissue regeneration and improves tissues’ repair ability. These properties that SPARC has within the regeneration contexts could have a variety of applications, such as in obesity, cancer, sarcopenia, diabetes and bioengineering. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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