**About the Editor**

**Riessland, Markus** is a trained molecular biologist with a background in neuroscience, human genetics and neurodegenerative diseases. Dr. Riessland received his PhD from the Clinic of the University of Cologne, Institute for Human Genetics, Germany. Early in his career, Dr. Riessland was involved in several internationally funded projects, where he performed and published studies on epigenetic modifiers as a potential therapy for the neurodegenerative disease spinal muscular atrophy (SMA). His research is particularly focused on the identification and characterization of neuron-specific disease-modifying factors that may facilitate the development of novel therapeutic strategies for degenerative disorders of the central nervous system. Dr. Riessland focuses on the understanding of cellular senescence. Cellular senescence is a common biological process in which mitotic cells may shut down the cell cycle when they recognize they have suffered DNA damage during division. This process causes a generation of "undead cells" (also known as "Zombie Cells"). This helps to prevent damaged cells from growing uncontrollably and causing problems such as cancer. Undead cells are, in fact, common and they are found all over the body. However, senescence is not typically seen in the nerve cells of the brain. Unlike most other cells in the body, neurons stop dividing once they are fully formed. In the lab of Nobel Laureate Paul Greengard at Rockefeller University, Dr. Riessland discovered that, surprisingly, post-mitotic dopaminergic neurons—which regulate motivation, memory, and movement by producing the chemical messenger dopamine—can nevertheless become senescent. This finding could have widespread implications for the understanding of many age-related neurodegenerative disorders (e.g., Parkinson's disease) and the aging process itself. Currently, his lab in the Center for Nervous System Disorders at the Department of Neurobiology and Behavior at Stony Brook University uses stem cell-based approaches as well as mouse models and next generation sequencing techniques (TRAP-seq, RNA-seq, ATAC-seq, scRNA-seq, etc.) to tackle the questions where and how cellular senescence in the brain could occur and spread, which cell types are involved and what the molecular triggers are. Additionally, research in the lab focuses on the identification and molecular characterization of genetic modifiers that influence the vulnerability of neuronal subtypes. The knowledge of molecular modifiers helps us to understand the underlying reasons of vulnerability that could be leveraged to protect cells from neurodegeneration. Moreover, the lab's research aims to interfere with the aging process by ameliorating the unwanted negative effects of cellular senescence.

## *Editorial* **Cellular Senescence in Health, Disease and Aging: Blessing or Curse?**

**Markus Riessland 1,2**


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. This seminal study described the phenomenon that we now refer to as "cellular senescence" [1]. More specifically, the description by Hayflick and Moorhead unraveled "replicative senescence", which is caused by cell-division-dependent telomere attrition. Since then, increasing numbers of additional senescence-inducing factors have been identified. In parallel, a plethora of cell types have been recognized to possess the ability to enter a state of cellular senescence. These studies revealed diverse senescence-related cellular phenotypes and identified various metabolic changes, gene-activity alterations and other molecular markers [2–4]. Although some gene expression changes are characteristic hallmarks of cellular senescence, a single molecular marker has not been identified. Accordingly, the univocal identification of a senescent cell remains challenging. To address this problem, the International Cell Senescence Association (ICSA) assembled a list of key features observed in senescent cells [2].

A particularly interesting feature of senescent cells is the so-called senescence-associated secretory phenotype (SASP), which remodels the gene epression profile of a senescent cell causing the secretion of proinflammatory molecules to signal to the immune system "come here and remove me". During development, and in organisms with fully functional immune systems, senescent cells are usually detected and cleared from the tissue [5]. In case where immune cells do not remove the senescent cells, they remain in the tissue and continue to express the SASP. In turn, this would cause a damaging local inflammation and could also induce remodeling of the surrounding tissue as well as the spreading of senescence. Aged organisms possess a significantly reduced regenerative potential and immune function resulting in the accumulation of senescent cells [5]. Interestingly, this accumulation has also been observed in age-related disorders, neurodegenerative diseases, cardiovascular diseases, and others [6,7]. Because of its detrimental effect on the surrounding tissue, the accumulation of senescent cells is not just a consequence, but can instead be understood as a major driver of aging. Accordingly, recent studies described that the removal of senescent cells showed beneficial effects on healthspan and lifespan [8]. This exciting research led to the discovery of "senolytics", drugs which can kill senescent cells. Moreover, because of the heterogeneity of cell types that show senescencelike phenotypes, including cardiovascular cells and post-mitotic neuronal cells [6,9,10], further research is required to unravel the molecular background that renders a cell type vulnerable to senescence and to determine the pathways that induce senescence in a cell type-specific manner.

Given that there are many open questions in the field, this Special Issue of *Life* was created to shed light on the molecular pathways of cellular senescence, inflammaging, and the possible strategies to interfere with these processes. The work published in this Special Issue of *Life*, entitled "Cellular Senescence in Health, Disease and Aging: Blessing or Curse?", mirrors the broad interest in the field of cellular senescence since the presented

**Citation:** Riessland, M. Cellular Senescence in Health, Disease and Aging: Blessing or Curse?. *Life* **2021**, *11*, 541. https://doi.org/10.3390/ life11060541

Received: 28 May 2021 Accepted: 7 June 2021 Published: 9 June 2021

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**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

studies highlight quite diverse aspects of senescence and related pathways from various areas of research.

The manuscript by Panchanathan et al. reports observations that identify the interferon inducible POP3 PYHIN protein as a potential negative regulator of the AIM2 inflammasome and SASP in senescent human prostate epithelial cells. This study provides insight into the age-related development of prostatic inflammatory diseases [11].

Senescence DNA damage foci (SDF) and telomere-dysfunction-induced foci (TIF) can be identified by the histone marker γH2AX for cellular senescence and DNA damage, respectively, which makes γH2AX a useful tool for the identification of these traits in diverse tissues [12]. In this Special Issue, Siddiqui and colleagues determine the feasibility of using γH2AX as a molecular biomarker of DNA damage in Alzheimer's disease (AD). The authors report a protocol that employs laser scanning cytometry (LSC) to measure endogenous γH2AX in buccal cell nuclei from mild cognitive impairment (MCI) patients, AD patients, and healthy controls [13].

Secreted protein acidic and rich in cysteine (SPARC), a molecule that has been described to be overexpressed in senescent cells [14], was the topic of an Opinion manuscript by Ghanemi et al. [15]. The authors emphasize that SPARC not only acts as a regeneration factor but also counteracts the aging-related decrease in regeneration ability, and thus can be seen as a potential factor for preventing age-related conditions.

p16INK4A, which is often highly upregulated in many types of cellular senescence, acts as a tumor suppressor and is frequently reduced in human cancers. In this Special Issue, Leon et al. review the potential role of p16 in the regulation of immunological surveillance. In brief, the authors discuss the hypothesis that a p16-positive tumor would foster immunosurveillance by inviting immune cells into the tumor microenvironment, whereas a p16-null tumor would reduce immunosurveillance and promote tumor growth [16].

Finally, two reviews from the Orr lab highlight the importance of cellular senescence in the human brain. Gillispie et al. summarize the role of mitotic cells in brain senescence and discuss implications in neurodegenerative diseases and cancer [17]. The second manuscript reviews the recent discovery of post-mitotic senescence in the brain. In short, Sah et al. provide a comprehensive overview of the current knowledge of the cellular senescence of brain cells, including neurons [18]. Additionally, this manuscript gives an elegant introduction into the field of cellular senescence.

Generally, I hope that this Special Issue of *Life* will capture the attention of both specialists and non-specialists who are interested in understanding the molecular processes involved in cellular senescence and inflammaging. As seen in the diverse articles in this Special Issue, cellular senescence and the molecules that are crucial in its underlying pathways are of high interest in many areas of research. The rising interest in a more thorough understanding of cellular senescence is reflected by the fact that the National Institutes of Health (NIH) have recently established the Common Fund's Cellular Senescence Network (SenNet) Program to identify and characterize the differences in senescent cells within the body, across various states of human health, and throughout lifespan. It is an exciting time for researchers working on senescence and aging, and overall, there is great hope that the outcome of this research can translate into strategies that provide beneficial effects on healthspan and lifespan in humans.

**Funding:** This research received no external funding.

**Acknowledgments:** I would like to thank all the contributors of the Special Issue of *Life* (ISSN 2075-1729): "Cellular Senescence in Health, Disease and Aging: Blessing or Curse?"), belonging to the section "Cell Biology and Tissue Engineering".

**Conflicts of Interest:** The author declares no conflict of interest.

#### **References**

