Cellular Senescence in Disease

Winner of the 2023 PROSE award in Biomedicine and Neuroscience!

 

Research in the field of senescence has boomed recently due to the gradual realization that senescent cells are associated with a significant number of diseases. The genetic or pharmacological elimination of senescent cells can cause widespread benefits and improves outcomes for most of those diseases. Cellular Senescence in Diseases presents an updated review of the role of cellular senescence in multiple pathologies. Focus is given to those diseases where the implication of senescence has been more extensively documented, such as (cancer, lung and liver diseases, diabetes, Neurodegenerative diseases and others).

The Editors recruited a group of worldwide experts in each individual pathology to review the role of cellular senescence in each one of them, aiming at identifying potential therapeutic pathways. The first two chapters provide an overview of the cellular senescence principles. Next, the chapters are divided into specific diseases. Cancer, including premalignant lesions (OIS), Advanced disease (TIS), and Metastasis are covered. The following condition covered is Lund diseases, including IPF, COPD, and Pulmonary Hypertension. Next Liver Diseases are covered, including Fibrosis and Cirrhosis, and Fatty liver disease. Next there is coverage for Kidney implications, including fibrosis and transplantation. Vascular diseases are covered next including infarction and hear fibrosis, and atherosclerosis. Both diabetes types 1 and 2 are covered next. Following chapters cover Obesity, Sarcopenia, and Bone and Cartilage disorders, respectively. Neurodegenerative diseases are covered next, focusing on Alzheimer and Parkinson. The next chapter discusses accumulation of senescent cell in tissues during aging. The two final chapters cover current developments and conclusions.

Cellular Senescence in Diseases is designed for researchers and clinicians with a focus on the cellular mechanisms of diseases.  All chapters cover current experimental therapeutic approaches to eliminate or cancel the pathological effects of senescent cells.  Pharmaceutical scientists may also benefit from the contents of the book in the exploration of novel therapeutic opportunities.

• 2023 PROSE Awards - Winner: Category: Biomedicine and Neuroscience: Association of American Publishers
• Provides a thorough introduction to Cellular Senescence
• Covers all major pathologies for which cellular senescence has shown evidence of involvement
• Focuses on possible therapeutic pathways
• Edited and authored by worldwide experts

• Language: English
• Publisher: Academic Press
• Release date: Nov 27, 2021
• ISBN: 9780128225158

Book preview

Cellular Senescence in Disease

Editors

Manuel Serrano

Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

Daniel Muñoz-Espín

CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Table of Contents

Cover image

Title page

Copyright

Contributors

Foreword

Part 1. Fundamentals

Chapter 1. Cellular senescence: from old to new testament

Old testament—genesis of senescence

New testament—from mechanisms and roles of senescence to therapies

Part 2. Cellular senescence in disease states

Chapter 2. Premalignant lesions and cellular senescence

Introduction

Cellular senescence in premalignant lesions: evidence in various organs

Future perspectives

Chapter 3. Lung aging and senescence in health and disease

Introduction

Normal lung development and aging

A brief introduction to COPD and IPF

Abnormal hallmarks of lung aging in COPD and IPF

Future treatment targeting lung senescence

Conclusions

Supported

Abbreviations

Chapter 4. Cell senescence in pulmonary hypertension

Introduction

Pulmonary hypertension, a non-aging-related proliferative vascular disorder at the crossroads of vascular disease and cancer

General considerations about aging of the systemic and pulmonary vascular systems

Considerations about constitutive cells of pulmonary vessels and the specificity of the pulmonary vasculature

Potential mechanisms accounting for cell senescence in PH and PAH

Role for senescent cells in PH and PAH

Conclusion

Chapter 5. Liver diseases fibrosis and cirrhosis

Liver structure and function

Cellular senescence

Liver diseases—epidemiology and clinical aspects

Senescence during aging of the healthy liver

Senescence in acute liver injury

Senescence in chronic liver disease

Role of senescence in hepatic dysfunction

Evolutionary role of senescence in the liver

Senescence during hepatic carcinogenesis

Summary and closing comments

Chapter 6. Cellular senescence during aging and chronic liver diseases: mechanisms and therapeutic opportunities

Introduction

Cellular senescence in the liver

Mechanisms contributing to cellular senescence in liver

Therapies: senolytic and senostatic drugs

Conclusions and outstanding questions

List of abbreviations

Chapter 7. Kidney diseases: fibrosis

Introduction

Fibrosis is a common feature of unresolved kidney damage and kidney aging

Glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis

ECM in renal homeostasis, injury, and repair

Cellular senescence in renal aging, AKI, and CKD

Different forms and different timing of cell-cycle arrest may have detrimental or beneficial effects in AKI and CKD

TIF and cellular senescence

Senescence and the cellular origin of TIF

Senescence-associated secretory phenotype

Transforming growth factor-β (TGF-β)

WNT/β-catenin signaling

The renin-angiotensin system (RAS)

The antiaging factor Klotho

Inflammation, innate immunity, and TIF

Senescence and TIF—physiology and pathology

Chapter 8. Kidney diseases: transplantation

Introduction

Factors determining donor organ quality and their association with senescence

Impact of cellular senescence on transplant-related injuries and transplant outcome

Rejuvenating and protecting kidney transplants

Chapter 9. Vascular diseases: atherosclerosis and atherosclerotic cardiovascular diseases

Introduction—a man is as old as his arteries

Features of cellular senescence in vascular cells

Evidence of cellular senescence in atherosclerosis

Factors involved in vascular senescence associated with the pathophysiology of atherosclerosis

Therapeutics targeting cellular senescence for atherosclerosis

Conclusions (limitations and perspectives)

Chapter 10. Diabetes: senescence in type 1 diabetes

Introduction

Senescent beta cell accumulation as a novel pathogenic mechanism in T1D

Outstanding questions and future directions

Conclusions and outlook

Chapter 11. Senescence in obesity: causes and consequences

Introduction

Adipose tissue function in obesity

Senescent cells accumulate in multiple tissues in obesity

Causes of cellular senescence in obesity

Threshold theory of senescent cell burden

Implications of senescence in obesity: downstream effects

Strategies to target obesity-related senescent cells

Chapter 12. A framework for addressing senescent cell burden in the osteoarthritic knee: therapeutics, immune signaling, and the local-systemic interface

Introduction

Main

Conclusion

Competing interests

Chapter 13. Osteoporosis and bone loss

Osteoporosis as a public health problem

The hallmarks of aging in bone

The role of cellular senescence in mediating age-related bone loss

Estrogen deficiency and cellular senescence

The role of cellular senescence in the effects of diabetes mellitus on bone

Cellular senescence and radiation- and chemotherapy-induced bone loss

Role of cellular senescence in the growth plate and regulation by parathyroid hormone–related peptide (PTHrP)

Summary and conclusions

Chapter 14. Cellular senescence in neurodegenerative diseases

Cellular senescence: driving force or beneficial response in neurodegeneration?

Postmitotic senescence in brain aging and neurodegenerative diseases

Replicative senescence in brain aging and neurodegenerative diseases

Demyelination, oligodendrocyte lineages, and Aβ plaque propagation in AD brains

Senolytics as AD therapy

Combination therapy for AD using senolytics and senomorphics

Conclusions

Chapter 15. Cell senescence is a cause of frailty

What is frailty?

How is frailty assessed in humans?

How is frailty defined and assessed in experimental animals?

What are the possible causes of frailty?

What is cell senescence?

Does cell senescence cause frailty? How good is the evidence for it?

Conclusions

Part 3. Conclusions

Chapter 16. Senescence as a therapeutic target: current state and future challenges

Biological interpretations of cellular senescence

Tissue remodeling by senescence is a two-step process

The two steps of senescence in cancer

The two steps of senescence in disease

SASP-induced tissue repair versus SASP-induced tissue dysfunction

Molecular triggers of senescence

Triggers of senescence in vivo

The challenge of detecting cellular senescence in clinical settings

Potential side effects of eliminating senescent cells

Senolytics as an anti-aging strategy

Index

Copyright

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Contributors

Shariq Abid,     Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Serge Adnot

Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

AP-HP Hôpital Henri Mondor, Département de Physiologie-Explorations Fonctionnelles, FHU SENEC, Créteil, France

Institute for Lung Health, Justus Liebig University, Giessen, Germany

Alvar Agusti

Department of Pulmonology, ICR, Hospital Clinic, Barcelona, Spain

IDIBAPS, Barcelona, Spain

University of Barcelona, Barcelona, Spain

CIBERES, Madrid, Spain

Delphine Beaulieu,     Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Anil Bhushan,     Department of Medicine, University of California San Francisco, San Francisco, CA, United States

Thomas G. Bird

Cancer Research UK Beatson Institute, Glasgow, United Kingdom

Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

Emmanuelle Born,     Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Marielle Breau,     Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Alexander F. Chin,     Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Jennifer H. Elisseeff

Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Zulrahman Erlangga,     Children's Hospital, Hannover Medical School, Hannover, Germany

Konstantinos Evangelou,     Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Rosa Faner

IDIBAPS, Barcelona, Spain

CIBERES, Madrid, Spain

Joshua N. Farr,     From the Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, MN, United States

Eleni Georgakopoulou,     Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Estela González-Gualda,     CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Vassilis G. Gorgoulis

Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Biomedical Research Foundation, Academy of Athens, Athens, Greece

Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom

Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Faculty of Health and Medical Sciences, University of Surrey, Surrey, United Kingdom

Elise Gray-Gaillard,     Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Jin Han,     Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Fernanda Hernandez-Gonzalez

Department of Pulmonology, ICR, Hospital Clinic, Barcelona, Spain

Institut de Recerca Biomedica, Barcelona, Spain

IDIBAPS, Barcelona, Spain

Amal Houssaini

Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Institute for Lung Health, Justus Liebig University, Giessen, Germany

Michael D. Jensen,     Endocrine Research Unit, Rochester, MN, United States

Diana Jurk

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States

Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States

Goro Katsuumi

Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Sundeep Khosla,     From the Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, MN, United States

Christos Kiourtis

Cancer Research UK Beatson Institute, Glasgow, United Kingdom

Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

James L. Kirkland,     Robert and Arlene Kogod Center on Aging, Rochester, MN, United States

Marta Kovatcheva,     Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Larissa Lipskaia

Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

AP-HP Hôpital Henri Mondor, Département de Physiologie-Explorations Fonctionnelles, FHU SENEC, Créteil, France

Jose Alberto López-Domínguez,     Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

David Macías,     CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Elisabeth Marcos,     Univ Paris Est Créteil, INSERM U955, IMRB, Créteil, France

Mate Maus,     Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Anette Melk,     Children's Hospital, Hannover Medical School, Hannover, Germany

Kathleen Meyer,     Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

John Michel,     Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Tohru Minamino

Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Satomi Miwa,     Newcastle University Biosciences Institute, Newcastle upon Tyne, United Kingdom

David G. Monroe,     From the Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, MN, United States

Daniel Muñoz-Espín,     CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Hui-Ling Ou,     CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Allyson K. Palmer,     Robert and Arlene Kogod Center on Aging, Rochester, MN, United States

Nayuta Saito,     Institut de Recerca Biomedica, Barcelona, Spain

Roland Schmitt,     Hannover Medical School Department of Nephrology and Hypertension, Hannover, Germany

Jacobo Sellares

Department of Pulmonology, ICR, Hospital Clinic, Barcelona, Spain

IDIBAPS, Barcelona, Spain

University of Barcelona, Barcelona, Spain

CIBERES, Madrid, Spain

Manuel Serrano

Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

Myong-Hee Sung,     Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States

Tamara Tchkonia,     Robert and Arlene Kogod Center on Aging, Rochester, MN, United States

Peter J. Thompson

Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, MB, Canada

Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada

Thomas von Zglinicki

Newcastle University Biosciences Institute, Newcastle upon Tyne, United Kingdom

Ageing Biology Laboratories, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom

Tengfei Wan,     Newcastle University Biosciences Institute, Newcastle upon Tyne, United Kingdom

Peisu Zhang,     Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States

Foreword

The concepts of aging, disease, and immortality have been intermingled since the early 1900s, when Carrel proposed that cells were immortal, despite the fact that organisms were mortal. ¹ Of course, much of that misconception was dispelled by Hayflick and colleagues in the 1960s ² , ³ , with the first formal description of what is now known as cellular senescence. This book captures our current understanding of this complex cellular phenomenon, as well as new exciting ideas that now mark the field with the promise of novel interventions into aging. Not quite immortality … but hope of a healthy life, relatively unscarred by the chronic disabilities that so often plague the elderly.

Cellular senescence is a multifaceted cell fate. Vertebrate cells adopt this fate in response to both endogenous and exogenous stressors, as well as evolutionarily selected physiological signals. Our understanding of cellular senescence, its deleterious effects, and its beneficial effects has virtually exploded in recent decades. The implications of this increase in knowledge is not only documented here, but, importantly, its implications for human health are explored in detail.

Whether and to what extent interventions that modify or eliminate cellular senescence will have an impact on life span remains a big unknown. But there is rising evidence, deftly described here, that cellular senescence does indeed contribute to many of the chronic diseases of aging, and that an increase in health span—years of healthy life—may well be on the horizon as a result of our still-evolving understanding of cellular senescence.

This book is especially suitable for those who practice biogerontology—whether as physicians dedicated to treating aged patients or as basic scientists interested in translational aspects of cellular senescence. It provides a wealth of knowledge from a wealth of leaders in the field. And it should also entice those curious about the aging process and the promises of new fact-based interventions.

Judith Campisi

Professor, The Buck Institute

Senior Scientist, Lawrence Berkeley National Laboratory

References

1. . Carrel A. On the permanent life of tissues outside of the organism.  J Exp Med . 1912;15:516–528.

2. . Hayflick L. The limited in vitro lifetime of human diploid cell strains.  Exp Cell Res . 1965;37:614–636.

3. . Hayflick L, Moorhead P.S. The serial cultivation of human diploid cell strains.  Exp Cell Res . 1961;25:585–621.

Part 1

Fundamentals

Outline

Chapter 1. Cellular senescence: from old to new testament

Chapter 1: Cellular senescence

from old to new testament

Estela González-Gualda, Hui-Ling Ou, David Macías, and Daniel Muñoz-Espín     CRUK Cambridge Centre Early Detection Programme, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

Abstract

Senescence is a cellular state in response to irreparable damage discovered 60 years ago and characterized by the implementation of a stable cell cycle arrest and a potent secretory phenotype affecting the nearby tissue. From its early days to date, our perception and definition of cellular senescence and its roles (see Box 1.1) have been subjected to constant and significant changes. The complexity of this process is exemplified by its close association with both physiological and pathological states in living organisms. Senescence plays a fundamental role in tissue repair, the maintenance of homeostasis, tumor suppression, and even embryonic development, but, in sharp contrast, it can also contribute to the progression and pathological manifestations of multiple chronic medical conditions, and has been convincingly shown to be a crucial hallmark of aging. Senescence is therefore a defining feature of a variety of age-related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. This introductory chapter will take the reader from the origins of cellular senescence to the landmark discoveries made by its Prophets over the past decades (Fig. 1.1), which have transformed the field of senescence into a new research paradigm that may change our vision of aging and disease, and yield novel therapeutic modalities for chronic—so far untreatable—disorders.

Keywords

Cell cycle arrest; Oncogene; Senescence; Senotherapy; Telomere; Tumor suppression

Old testament—genesis of senescence

The process of cellular senescence was described for the first time in a seminal study by Hayflick and Moorhead (1961). The authors cultured normal human diploid fibroblasts and, after serial passages in vitro, they realized that the cells entered a state of irreversible growth arrest, in contrast to cancer cells, which were able to proliferate indefinitely in culture. This ground-breaking study was the starting point of an entire research field and led the authors to conjecture a visionary hypothesis at the time: senescence was linked to organismal aging. Importantly, the authors also posed the idea that certain cellular factors may be lost or diluted through consecutive cellular divisions, thereby restricting the proliferative capacity of normal cells.

BOX 1.1

The 10 Commandments Of Cellular Senescence

This work laid the foundations for the concept of replicative senescence, and established the maximum number of potential cell doublings (around 50 divisions), which was coined the Hayflick limit (Hayflick, 1965). Through their observations, the authors speculated that the finite lifetime of diploid cell strains in vitro may be an expression of aging or senescence at the cellular level, and that the ultimate accrual of nondividing cells could be the result of accumulated damage to a single or multiple cellular targets.

For many years, the field of senescence stood largely abeyant, and the intrinsic molecular mechanisms remained unknown. During this time, the onset of cellular  senescence continued to be considered as one of the main cellular theories of aging, together with other cellular (e.g., free radical), evolutionary (e.g., mutation accumulation), and molecular (e.g., error-catastrophe) theories of aging (Martin, 1980). At this stage, despite reported in cell cultures, senescence had not formally been demonstrated in vivo. In 1979, impairment of cell proliferation was found in ex vivo cultures of skin fibroblasts derived from skin biopsy samples obtained from old individuals as part of a longitudinal study on human aging. Importantly, such halt in proliferation was not observed in young individuals, which suggested a connection between senescence and aging (Schneider et al., 1979). Further evidence of reduced clonogenic potential was generated with preadipocytes obtained from old rat adipose tissue (29 months old vs. 3 months old) in culture (Kirkland et al., 1990). These studies therefore represent the first evidence of senescence occurring in living organisms. However, the assessment of the senescent phenotype was restricted to the proliferative capacity of the cells in culture, given that the hallmarks of senescence (Fig. 1.2) and mechanistic insights of this program (Fig. 1.3) had not been discovered and described thus far, and therefore no reliable biomarkers were available at the time.

Figure 1.1 Landmark discoveries of cellular senescence.Timeline depicting the discovery of cellular senescence and the main findings over the past decades to date.

Figure 1.2 Hallmarks of cellular senescence.Senescence is a program that is elicited in response to various stimuli, including damage and stress. Depending on the trigger, it can be classified into different types: replicative senescence, which occurs when telomeres shorten or become dysfunctional after sequential replications; damage-induced senescence, which can be further subdivided into therapy-induced senescence or oxidative-stress senescence, for instance, and oncogene-induced senescence, which takes places upon the aberrant activation of an oncogene or the loss of a tumor suppressor. Despite being elicited by different insults, several traits and mechanisms are generally preserved among the different types, and they constitute the so-called hallmarks of senescence. These include a stable proliferative arrest at the G1 phase of the cell cycle, driven by the activation and cooperation of different proteins involved in the p21CIP1/p53 and p16INK4a/Rb pathways. Senescent cells also present epigenetic changes and chromatin reorganization, which includes the formation of well-established structures named SAHFs (Senescence-Associated Heterochromatin Foci) and DNA-SCARS (DNA Segments with Chromatin Alterations Reinforcing Senescence), as well as the disruption of the nuclear membrane by the downregulation of Lamin B1 expression and the presence of more than one nucleus in the cell (multinucleation). In addition, senescent cells are characterized by metabolic changes and the accumulation of macromolecular damage, which results in higher ROS levels and dysfunctional mitochondria. An additional hallmark is the well-described resistance to apoptosis, which results from the upregulation and activation of prosurvival signaling pathways. Senescent cells also display an increased lysosomal compartment and the overexpression of SA-β-gal (Senescence-Associated β-galactosidase), an enzymatic activity commonly used for the detection of senescence in vitro and in tissues. The senescent program also features the implementation of a strong paracrine secretion of factors to the surrounding tissue, termed SASP (Senescence-Associated Secretory Phenotype). Further to these traits, senescent cells in vitro generally adopt a flattened and enlarged cellular morphology, probably derived from the adoption of the different structural and metabolic changes. Finally, senescent cells have more recently been described to induce the expression of what is now surging as the senescent surfaceome. While all these elements are strongly associated to the senescent phenotype, they may not always be present or detected in senescent cells, as the majority are not exclusive nor indispensable for the implementation of the senescent program, except for the cell cycle arrest. As a consensus in the field, the presence of more than two of the hallmarks described above are generally sufficient to confirm the induction of cellular senescence in vitro and in vivo.

New testament—from mechanisms and roles of senescence to therapies

Replicative senescence and telomeres

Landmark studies performed in the late 1980s contemplated the possibility that the finite doubling capacity of normal mammalian cells could be due to a loss of telomeric DNA and the eventual degradation or deletion of essential genomic sequences (Cooke & Smith, 1986), and it was found that a mutation resulting in defective telomere elongation led to senescence in yeast (Lundblad & Szostak, 1989). Definitive evidence that the amount and length of telomeric DNA decreases as a function of serial passage in culture was obtained with human fibroblasts (Harley et al., 1990), thereby proposing the causality of the gradual loss of telomeric DNA in the implementation of the senescent program (Fig. 1.3A). This scenario was radically different from that of immortal or cancer cells, where the loss of telomeric DNA can be balanced by telomere elongation through the activation of telomerase, a ribonucleoprotein with DNA polymerase activity (Greider & Blackburn, 1985), detected in HeLa cells (Morin, 1989). The above observations were confirmed when retinal epithelial cells and foreskin fibroblasts were transfected with vectors driving the ectopic expression of the human telomerase catalytic subunit, which resulted in elongated telomeres and eventually led to the bypass of senescence and the immortalization of these cellular types (Bodnar et al., 1998). This experiment formally established a causal link between telomere shortening and cellular senescence in vitro, and introduced the possibility of manipulating differentiated cells to be maintained in a phenotypically healthy and youthful state.

Oncogene-induced senescence and tumor suppression

The findings on telomere shortening as an underlying mechanism for replicative senescence led the scientific community to hypothesize in the early 1990s that senescence could act as a tumor suppression response, thereby preventing cellular transformation and unlimited proliferation. Ground-breaking studies pointed at the p53/p21 and p16INK4/pRb axes to have a fundamental role in regulating how oncogenic signaling triggers senescence (Fig. 1.3A). p16INK4 is encoded by the INK4a/ARF locus and was firstly isolated and shown to inhibit the cyclin D/CDK4 complex, preventing retinoblastoma protein (Rb) phosphorylation and cell cycle progression (Serrano et al., 1993). On the other hand, p21 was shown to inhibit the activity of most members of the cyclin/CDK family in a p53-dependent manner (Xiong et al., 1993). In a follow-up study, the authors demonstrated that p16INK4 expression inhibited oncogenic ras-induced proliferation and cellular transformation (Serrano et al., 1995). Like the tumor suppressor p53, the cell cycle-inhibitor p16INK4 is mutated in numerous cancer types and, accordingly, p16-deficient mice were highly prone to develop spontaneous and carcinogen-induced tumors (Serrano et al., 1996).

Figure 1.3 Molecular mechanisms of cellular senescence. (A) Cell cycle arrest: Despite the multiple triggers of cellular senescence, most of the molecular cascades ultimately converge in the activation of p53 (encoded by TP53) and the cyclin-dependent kinase (CDK) inhibitors p16 (also known as INK4A; encoded by CDKN2A), p15 (also known as INK4B; encoded by CDKN2B), p21 (also known as WAF1; encoded by CDKN1A), and p27 (encoded by CDKN1B). These, in turn, result in the inhibition of CDK1, CDK2, CDK4, and CDK6 which prevents the phosphorylation of the retinoblastoma protein (RB), leading to the suppression of S-phase genes and an ensuing stable cell cycle arrest. DNA damaging triggers activate the DNA-damage response (DDR) pathway. The main mediators of the DDR are the DNA damage kinases ATM, ATR, which phosphorylate and activate the p53/p21 pathway. Aging and epigenetic derepression of the Ink4a/ARF locus also lead to the activation of cell cycle inhibitors p16 and p21. ROS lead to the activation of the MAPK signaling pathway and its downstream effector p38. The aberrant expression of oncogenes or the loss of tumor suppressors lead to p53 activation through the Ras-Raf-MEK-ERK or AKT-mTOR signaling pathways, and TGFβ, an important factor of the SASP, leads to p15, p21, and p27 upregulation via SMAD signaling. Other triggers such as developmental cues and polyploidy activate the AKT, SMAD, and/or Ras-Rad-MEK-ERK pathway for p21 upregulation, while processes such as cell fusion signal through the DDR for p53 activation. (B) SASP: A similar scenario occurs for the implementation of the SASP. SASP implementation is orchestrated by the activation of the transcription factors (TFs) NF-κB and C/EBPβ through a variety of upstream signaling pathways in response to different senescence stimuli. DNA-damaging agents, ROS and OIS, generally activate the expression of SASP TFs via the AKT and/or the Ras-Raf-MEK-ERK axis. Additionally, DNA fragments are also known to trigger the activation of the cGAS/STING signaling, resulting in the activation of the IRF3 TF and subsequent transcription of Type 1 IFN. OIS-derived SASP is dynamic and can also be orchestrated by NOTCH signaling, a process that restrains the inflammatory secretion by inhibiting C/EBPβ at initial stages, and allows the activation of SASP-related super enhancers through NF-κB later on. Finally, accumulating increased levels of TFs reinforce the senescent phenotype through autocrine and paracrine signaling. SASP-derived inflammatory chemokines such as IL-6 and IL-8 promote epigenetic modifications reinforcing the cell cycle arrest through the JAK/STAT cascade, while IL-1α stimulates the activity of NF-κB and C/EBPβ promoting a positive feedback loop on the secretion of other cytokines. OIS, oncogene-induced senescence; TS, tumor suppressor. ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype. 

Figure adapted from our previous work Páez-Ribes et al. EMBO Mol Med, 2019. https://creativecommons.org/licenses/by/4.0/.

These and other observations concluded with the discovery that oncogenic ras provokes premature senescence accompanied by the accumulation of p53 and p16INK4 (Serrano et al., 1997) (Fig. 1.3A), a process independent of telomere length, which led to the emergent concept of oncogene-induced senescence (OIS). Conceptually, this seminal study placed senescence as a crucial tumor suppressive mechanism, together with apoptosis, and was the inception for the research community to later suggest the possibility of promoting senescence induction as a barrier against cancer. Consistent with these results, oncogenic ras was found to promote senescence through activation of the MAPK cascade subsequently limiting the consequences of mitogenic signaling (Lin et al., 1998).

In 2005, a formal demonstration of the concept of OIS in living organisms, including both human and mice, was obtained through a variety of preclinical models and patient tissue samples. Remarkably, senescence was found to be a defining feature of multiple types of premalignant lesions, while malignant and advanced cancer states were characterized by bypassing the senescent program. This is the case of human naevi (Michaloglou et al., 2005), lung adenomas (Collado et al., 2005), hyperplasia in the pituitary gland (Lazzerini Denchi et al., 2005), and initial stages of lymphoma (Braig et al., 2005) and prostate cancer (Chen et al., 2005). Last but not least, further to its role as a barrier against early tumorigenesis, restoration of cellular senescence through the reactivation of endogenous p53 was described to result in tumor clearance and regression in advanced liver carcinoma (Xue et al., 2007), as well as sarcoma (Ventura et al., 2007) and lymphomas (Martins et al., 2006; Ventura et al., 2007). Altogether, the above studies confirmed senescence as a key tumor suppressive mechanism through the halt of the proliferation of precancerous cells, leading to tumor arrest and even regression. Intriguingly, these results also supported the idea to treat human cancers by pharmacologically active agents that could reactivate p53 and induce cellular senescence.

Damage-induced senescence

We now know that cellular senescence can be triggered by multiple stimuli, including a variety of sources of damage and stress resulting in DNA damage. It is important to note that mutations and other types of DNA damage cannot only contribute to the onset of senescence, but also to cancer initiation and progression. Further, organismal aging has been largely reported to be accompanied by relevant levels of genomic alterations, which, altogether, emphasizes the interplay between senescence, cancer, and aging. Importantly, early studies demonstrated that the infliction of a variety of forms of DNA damage had the capacity to trigger senescence in cell cultures, mouse models, and human tissues. These sources of damage included genotoxic and cytotoxic drugs as well as radiotherapy (Roberson et al., 2005; Schmitt et al., 2002; te Poele et al., 2002). Of note, telomeric damage was found to trigger senescence through the implementation of DNA-damage response (DDR) involving apical kinases ATM and ATR and transducer checkpoint kinases CHK1 and CHK2 (d'Adda di Fagagna et al., 2003) (Fig. 1.3A). Also, the rate of telomere shortening is accelerated by oxidative damage, leading to replicative senescence (von Zglinicki et al., 2003).

Hallmarks of cellular senescence

The above studies showed that senescence is a very heterogenous response triggered by different stressors and hence the assessment of bona fide senescent cells was dependent on the identification of a more universal biomarker of senescence, in particular, one suitable for detection in cell cultures and in vivo tissue samples. Although still imperfect, the most widely used biomarker of senescent cells is the senescence-associated β-galactosidase (SA-β-gal) activity (Dimri et al., 1995), which is present in most of the forms of senescence and cellular types described so far. Senescent cells are featured by an enlarged or aberrant morphology and by the significant accumulation of lysosomal content. Lysosomal β-galactosidase is encoded by GLB1, and this activity is typically measured at the acidic pH 4.5. However, senescence-associated lysosomal β-galactosidase is detectable at the restrictive pH 6.0 in a colorimetric reaction using the chromogenic substrate 5-bromo-4-chloro-3-indoyl β-D-galactopyranoside (X-gal), which yields an insoluble blue dye when cleaved by lysosomal β-galactosidase. A limitation of this biomarker is that SA-β-gal activity can also be detected in some cellular types/states unrelated to senescence and that this enzymatic reaction requires fresh tissues, so it is not suitable for archived material. Therefore, a formal assessment of cellular senescence is usually performed with a collection of hallmarks and biomarkers of senescent phenotypes (see Fig. 1.2). Despite these limitations, the identification of SA-β-gal activity was crucial for the development of the field.

SASP

Another key feature of senescent cells is the implementation of a complex and very active proinflammatory paracrine response, the so-called senescence-associated secretory phenotype (SASP), consisting of a cocktail of cytokines, chemokines, proteases, growth factors, and other tissue-remodeling factors (see Fig. 1.2). Remarkably, the underlying mechanisms and drivers governing the SASP are different and usually independent from those pathways controlling the implementation of a stable cell cycle arrest. Although the acronym of SASP was not initially introduced until 2008, preceding works already illustrated this concept. An early study that performed microarray analyses with fibroblasts, epithelial and endothelial cells showed evidence that replicative senescence triggers mRNA expression patterns mimicking inflammatory wound repair processes (Shelton et al., 1999). This finding was expanded by a pioneering study showing that senescent fibroblasts can promote epithelial cell growth and tumorigenesis of nearby cells by secreting a collection of soluble and insoluble tumor-promoting factors (Krtolica et al., 2001).

Later, in 2008, the secretory response of senescent cells and its underlying signaling pathways ballooned with the publication of three comprehensive studies (see Fig. 1.3B showing the main SASP drivers and underlying signaling pathways). The SASP was dissected more comprehensively and shown to induce epithelial-mesenchymal transitions (EMT) in recipient cells by a paracrine mechanism largely dependent on interleukin (IL)-6 and IL-8, which were amplified by cell-nonautonomous functions of oncogenic ras and functional loss of p53 tumor suppressor (Coppe et al., 2008). OIS was therefore linked to the activation of an inflammatory transcriptome, a process that requires the cooperation of transcription factor C/EBPβ with IL-6 to amplify the activation of the inflammatory network, including IL-8 expression (Kuilman et al., 2008). Of note, the effects of the SASP were also found to be autocrine, thereby reinforcing the senescent arrest through the secretion of multiple CXCR2-binding chemokines in a molecular program regulated by the NF-κB and C/EBPβ transcription factors, which cooperate to induce CXCR2 expression in senescent lesions (Acosta et al., 2008). Further unbiased screenings identified multiple SASP components that are controlled by inflammasome-mediated IL-1 signaling, including TGF-β family ligands, VEGF, CCL2, and CCL20. This secretory program had the ability to cause paracrine senescence and impact tumor suppression (Acosta et al., 2013). The senescence inflammatory secretome was further reported to modulate the immune system response, and it was found to be crucial for senescence surveillance of premalignant hepatocytes, limiting liver cancer development (Kang et al., 2011). Of note, this study denoted that senescence surveillance driven by the SASP secretome represents an important extrinsic component of the anticancer barrier, which emphasizes a central role of the senescent program in tumor suppression.

Senescence in physiology, repair, and embryonic development

In addition to a central function in tumor suppression, cellular senescence was also found to exert a variety of beneficial effects and even key physiological roles (Fig. 1.4). An innovative study analyzing the contribution of senescence in noncancer pathologies showed that senescent-activated stellate cells restrict liver fibrosis, a pathological condition that precedes cirrhosis, in mouse models (Krizhanovsky et al., 2008). This work then showed that senescence limits the fibrogenic response to acute organ tissue damage, and suggested reparative roles of senescence. Tissue repair functions were confirmed by a study that demonstrated that matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing (Jun & Lau, 2010). This conclusion was further supported in a subsequent work showing a key role of senescent cells in optimal wound healing through secretion of platelet-derived growth factor AA (PDGF-AA), which was identified as a SASP reparative component (Demaria et al., 2014). Altogether, these studies concluded a fundamental role of cell senescence in promoting tissue repair.

Besides the above processes, senescence can also participate in tissue regeneration. This was first observed in salamanders, organisms where an amputated limb can be fully regenerated. In this injury model, senescence was found to be abundant around the sectioned area, and it was proposed that the effective immunosurveillance of senescent cells by macrophages after paracrine reparative signaling contributes to salamander limb regeneration (Yun et al., 2015). It should be noted that physiological or beneficial roles of senescence, including tumor suppression, tissue repair, regeneration, or developmental senescence, are usually accompanied by an efficient SASP-mediated immunoclearance of senescent cells.

The close interplay between tissue damage, senescence, and tissue repair or regeneration has been further expanded by the finding that the senescent secretome can induce plasticity, dedifferentiation processes and promote stemness in nearby cells. In a reprogrammable mouse model (Abad et al., 2013), senescence was demonstrated to be in close proximity to reprogrammed cells upon the in vivo-induced expression of the Yamanaka factors, Oct4, Sox2, Klf4, and cMYC (OSKM) in the context of tissue injury and aging (Mosteiro et al., 2016). OSKM-induced senescence created a permissive environment for reprogramming and repair, a process involving the INK4a/ARF locus and IL-6. Additional studies confirmed that SASP factors in response to OIS or injury, including IL-6, induce cellular plasticity and regeneration in different tissues such as the skin and liver (Ritschka et al., 2017) and the skeletal muscle (Chiche et al., 2017), exhibiting increased expression of stem cell markers.

Figure 1.4 Antagonistic roles of cellular senescence in physiology and pathology.The SASP has been reported to play dual roles in physiology and disease. Senescent cells can implement a particular combination of factors that orchestrate crucial developmental processes during embryogenesis, tissue repair, and regeneration, and drive immune cell recruitment to promote immunosurveillance and tumor suppression. Importantly, the SASP can also induce cellular senescence in nearby cells, as well as it has also been reported to reinforce the senescent state and cell cycle arrest in an autocrine manner. Conversely, in chronic conditions, under persistent damage or stress and during aging, senescent cells accumulate and are not effectively cleared by the immune system. In such scenarios, the SASP has been shown to promote immune evasion, tissue dysfunction, chronic inflammation, and even drive tumor promotion and metastasis.

An unexpected finding was the physiological role of cellular senescence reported in multiple embryonic structures during mammalian and vertebrate's development, including in humans and mice (Muñoz-Espín et al., 2013; Storer et al., 2013). In these studies, senescence was shown to promote tissue remodeling and organogenesis (e.g., apical ectoderm ridge and the closing neural tube), driving the elimination of transient embryonic structures (e.g., mesonephros), and maintaining the cellular balance (e.g., endolymphatic sac). In contrast to OIS, damage-induced senescence, or replicative senescence, developmental senescence is a programmed process and not a response to stress or stochastic damage. Developmentally-programmed senescence was found to be driven by p21 in a p53-dependent manner and correlated with the upregulation of different developmental pathways. Other examples of physiological senescence include placental syncytiotrophoblasts (Chuprin et al., 2013) and normal megakaryocytes (Besancenot et al., 2010), which undergo senescence during their maturation and differentiation programs.

In conclusion, cellular senescence can not only play a variety of beneficial and physiological roles in the adult, instructing the nearby tissue to promote repair and regeneration, but it also serves as a crucial mechanism during embryonic development. This finding opened up the possibility that cellular senescence emerged as a developmental tissue remodeling process during evolution, and that it was later adapted as a reparative response to damage in the adult organism.

Senescence in aging and age-related disorders

Despite the above beneficial aspects of senescence, this cellular response can also drive detrimental processes (Fig. 1.4). This usually happens in the context of chronic disorders or during aging, when senescent cells are not effectively cleared by the immune system and accumulate in tissues in response to persistent and irreparable damage. When first discovered by Hayflick and Moorhead (1961) cellular senescence was associated with organismal aging and proposed to contribute to its progression. Indeed, the increased senescent burden during aging has since then been documented in multiple tissues in humans, primates, and mice (Herbig & Sedivy, 2006; Jeyapalan et al., 2007; Krishnamurthy et al., 2006; Lawless et al., 2010; Wang et al., 2010). An early study showed that INK4a/ARF expression (encoding for p16INK4 and ARF), key mediator of senescence, is a biomarker and potential effector of aging (Krishnamurthy et al., 2004), providing for the first time a functional link between senescence and aging. Remarkably, this report additionally showed that a delay in senescence accumulation in different mouse models (such as through caloric restriction) correlates with an increased healthspan and lifespan, suggesting for the first time that targeting senescent cells could ameliorate some age-related pathological manifestations. In 2011, this hypothesis was confirmed in a seminal study that represented the origin of senotherapies (see Section below). In this work, the authors developed a transgenic mouse model, namely INK-ATTAC that allowed the pharmacogenetic ablation of p16INK4-positive cells upon administration of a drug (Baker et al., 2011), which was examined in a BubR1 progeroid mouse background (Baker et al., 2008). Interestingly, life-long removal of p16INK4-positive cells in tissues, like skeletal muscle, the eye, and adipose tissue, delayed the onset of associated age-related pathologies (including sarcopenia, cataracts, and fat loss). These data demonstrated the causal implication of senescence as a direct driver of age-related phenotypes and that the removal of senescent cells could ameliorate or defer tissue dysfunction and promote healthspan. In a subsequent study, the same authors explored the consequences of senescence eradication in naturally aged INK-ATTAC mice (Baker et al., 2016). Importantly, the clearance of p16INK4-positive cells delayed tumorigenesis (lymphomas, sarcomas, and carcinomas) and attenuated age-related deterioration of several organs. These include attenuation of age-related lipodystrophy, amelioration of kidney dysfunction and glomerulosclerosis, as well as mitigation of cardiomyocyte hypertrophy in the heart. Of note, the ablation of senescent cells in naturally aged mice not only promoted healthspan, but also extended lifespan by up to 30%.

All these and related observations led the scientific community to examine the role of senescence in multiple chronic age-related disorders, by using animal models and the genetic and/or the pharmacological ablation of senescent cells. A number of studies have concluded that chronic senescence can contribute to the progression and even onset of numerous pathologies, including cardiovascular diseases (e.g., atherosclerosis), neurological disorders (e.g., Alzheimer and Parkinson disease), fibrosis (e.g., idiopathic pulmonary fibrosis and kidney fibrosis), metabolic syndromes, type I and II diabetes, obesity, inflammatory diseases, sarcopenia, osteoarthritis, osteoporosis, liver steatosis, and many others (for review see Muñoz-Espín and Serrano (2014)). In addition to these diseases, unresolved (i.e., noncleared) senescence can contribute to cancer by a variety of noncell autonomous (SASP-driven) effects (for review see Faget et al. (2019)) and cell autonomous effects (for review see Lee and Schmitt (2019)). These activities are exemplified by the contribution of senescence to adverse effects of chemotherapy and tumor relapse (Demaria et al., 2017), and by the ground-breaking proposal that senescent cancer cells in response to therapy have the potential to reenter the cell cycle with an enhanced proliferative potential and the acquisition of cancer-stemness properties (Milanovic et al., 2018). Interestingly, this work contrasts with the long-standing dogma that senescence is featured by a permanent and stable cell cycle arrest, at least for the particular case of therapy-induced senescent cancer cells. Finally, it is worth mentioning that an aged, senescent immune system (immunosenescence) has the potential to drive systemic aging and organ dysfunction, thereby promoting the emergence of pathological manifestations and age-related disorders (Yousefzadeh et al., 2021).

This section should only serve as an introduction to key discoveries, and the specific contributions of senescence to the above age-related disorders, original references, and detailed descriptions of such studies will be dissected in subsequent chapters.

Prosenescent and antisenescent therapies

In this section, we would like to stress that due to the antagonistic effects of senescence (Fig. 1.4), both prosenescent and antisenescent therapies can be beneficial, depending on the context. As described above, oncogene-induced senescence represents an important anticancer barrier, but eventually some cells can bypass this process, leading to malignant transformation and unlimited proliferation (i.e., cancer). Even in this case, and conceptually, senescence can still be restored in cancer cells by the appropriate stimulus (Serrano & Blasco, 2007), such as through the restoration or activation of p53 in response to radiation (Martins et al., 2006; Ventura et al., 2007; Xue et al., 2007) or via Nutlin-3a administration (Mouraret et al., 2013). In addition to radiation, there are multiple identified drugs and chemotherapeutic agents capable of efficiently inducing both senescence and apoptosis of cancer cells in patients, including etoposide, doxorubicin, cisplatin, bleomycin, palbociclib, and many others (for review see Ewald et al. (2010)). Besides the benefits reported for the treatment of numerous cancer types (see Nardella et al. (2011)), prosenescent therapies can also be useful for ongoing tissue repair processes in the context of chronic pathologies, as it is the case of preclinical strategies based on CDK4 inhibitor administration for kidney fibrosis (DiRocco et al., 2014) or IL-22 (Kong et al., 2012) and the extracellular matrix protein CCN1 (Kim et al., 2013) in liver fibrosis. Therefore, prosenescent therapies are well-established in the case of cancer and are emerging as promising approaches for the treatment of fibrotic disorders and related diseases.

On a different note, the work published by Baker and colleagues reporting that the eradication of persistent senescent cells can ameliorate, delay, and even revert age-associated disorders (Baker et al., 2011) has transformed the research field. This article established a direct link between senescence and aging and, conceptually, provided a new therapeutic strategy for chronic diseases with poor or unavailable treatments. In the last 5   years, multiple laboratories and pharmaceutical companies in the world have focused on the design, synthesis, development, and validation of a number of senotherapies, mostly based on senolytic drugs (i.e., pharmacologically active agents selectively targeting and inducing death in senescent cells). In 2015, the first drug combination with senolytic activity, namely Dasatinib   +   Quercetin (D   +   Q), was published in a landmark study (Zhu et al., 2015). By transcriptomics analysis, the authors found increased expression of prosurvival networks in senescent cells, consistent with their reported resistance to undergo apoptosis, and employed RNA interference and computational analyses by using the STRING database to identify potential senolytic targets. Screening of drugs that target these gene products showed that Dasatinib (inhibitor of tyrosine kinases) and Quercetin (a natural flavonoid) had particular promise in clearing different types of senescent cells. The capacity of the combination of