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E-grāmata: Cellular Senescence in Disease

Edited by (Senior Research Associate, Department of Oncology, University of Cambridge, Cambridge, UK), Edited by (Parc Cientķfic de Barcelona, Baldiri Reixa, Barcelona, Spain)
  • Formāts: PDF+DRM
  • Izdošanas datums: 27-Nov-2021
  • Izdevniecība: Academic Press Inc
  • Valoda: eng
  • ISBN-13: 9780128225158
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  • Formāts: PDF+DRM
  • Izdošanas datums: 27-Nov-2021
  • Izdevniecība: Academic Press Inc
  • Valoda: eng
  • ISBN-13: 9780128225158
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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.

  • 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
Contributors xv
Foreword xxi
Part 1 Fundamentals
Chapter 1 Cellular senescence: from old to new testament
3(26)
Estela Gonzalez-Gualda
Hui-Ling Ou
David Macias
Daniel Munoz-Espin
Old testament-genesis of senescence
3(4)
New testament-from mechanisms and roles of senescence to therapies
7(12)
Replicative senescence and telomeres
7(1)
Oncogene-induced senescence and tumor suppression
7(3)
Damage-induced senescence
10(1)
Hallmarks of cellular senescence
10(1)
SASP
11(1)
Senescence in physiology, repair, and embryonic development
12(2)
Senescence in aging and age-related disorders
14(1)
Prosenescent and antisenescent therapies
15(3)
Clinical trials
18(1)
References
19(10)
Part 2 Cellular senescence in disease states
Chapter 2 Premalignant lesions and cellular senescence
29(32)
Eleni Georgakopoulou
Konstantinos Evangelou
Vassilis G. Gorgoulis
Introduction
29(4)
Cellular senescence in premalignant lesions: evidence in various organs
33(14)
Skin
36(2)
Head and neck
38(1)
Lungs
39(1)
Gastrointestinal tract
40(2)
Liver
42(1)
Pancreas
43(1)
Mammary gland
44(1)
Prostate gland
45(1)
Cervix
46(1)
Thyroid
47(1)
Future perspectives
47(1)
Acknowledgments
48(1)
References
48(11)
Further reading
59(2)
Chapter 3 Lung aging and senescence in health and disease
61(20)
Fernanda Hernandez-Gonzalez
Nayuta Saito
Alvar Agusti
Jacobo Sellares
Rosa Faner
Introduction
61(2)
Normal lung development and aging
63(1)
A brief introduction to COPD and IPF
64(1)
Abnormal hallmarks of lung aging in COPD and IPF
65(6)
Cellular senescence
65(3)
Mitochondrial dysfunction
68(1)
Stem cell dysfunction
69(1)
Telomere dysfunction
69(1)
Epigenetic changes and miRNAs
70(1)
Loss of protein homeostasis (proteostasis)
70(1)
Deregulated nutrient sensing
70(1)
Extracellular matrix (ECM) dysregulation
71(1)
Future treatment targeting lung senescence
71(2)
Conclusions
73(1)
Supported
74(1)
Abbreviations
74(1)
References
75(6)
Chapter 4 Cell senescence in pulmonary hypertension
81(26)
Emmanuelle Born
Larissa Lipskaia
Shariq Abid
Amal Houssaini
Marielle Breau
Delphine Beaulieu
Elisabeth Marcos
Serge Adnot
Introduction
81(1)
Pulmonary hypertension, a non-aging-related proliferative vascular disorder at the crossroads of vascular disease and cancer
82(2)
General considerations about aging of the systemic and pulmonary vascular systems
84(1)
Considerations about constitutive cells of pulmonary vessels and the specificity of the pulmonary vasculature
85(1)
Potential mechanisms accounting for cell senescence in PH and PAH
86(6)
DNA damage is associated with PH
86(2)
Alteration in the BMPR2/TGF beta pathway
88(1)
Hypoxia
89(1)
Drugs
90(1)
Telomere dysfunction
91(1)
Shear stress
91(1)
HIV infection
92(1)
Role for senescent cells in PH and PAH
92(5)
General considerations
92(2)
Induction of lung cell senescence: effect on PH
94(1)
Telomerase inactivation
94(1)
Prevention or protection against lung cell senescence: effect on PH
95(2)
Conclusion
97(1)
References
98(9)
Chapter 5 Liver diseases fibrosis and cirrhosis
107(48)
Thomas G. Bird
Christos Kiourtis
Liver structure and function
107(3)
Cellular senescence
110(2)
Liver diseases-epidemiology and clinical aspects
112(4)
Senescence during aging of the healthy liver
116(2)
Senescence in acute liver injury
118(11)
Senescence in chronic liver disease
129(5)
Role of senescence in hepatic dysfunction
134(1)
Evolutionary role of senescence in the liver
135(2)
Senescence during hepatic carcinogenesis
137(5)
Summary and closing comments
142(1)
References
143(12)
Chapter 6 Cellular senescence during aging and chronic liver diseases: mechanisms and therapeutic opportunities
155(24)
Diana Jurk
Introduction
155(1)
Cellular senescence in the liver
156(2)
Mechanisms contributing to cellular senescence in liver
158(6)
Telomere dysfunction
158(2)
Autophagy impairment
160(1)
Mitochondrial dysfunction
161(2)
Chronic inflammation
163(1)
Therapies: senolytic and senostatic drugs
164(3)
Senolytic drugs
165(1)
Senostatic/senomorphic drugs
166(1)
Conclusions and outstanding questions
167(1)
List of abbreviations
168(1)
References
168(11)
Chapter 7 Kidney diseases: fibrosis
179(26)
Roland Schmitt
Introduction
179(1)
Fibrosis is a common feature of unresolved kidney damage and kidney aging
180(1)
Glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis
181(1)
ECM in renal homeostasis, injury, and repair
181(1)
Cellular senescence in renal aging, AKI, and CKD
182(1)
Different forms and different timing of cell-cycle arrest may have detrimental or beneficial effects in AM and CICD
183(2)
TIF and cellular senescence
185(3)
Senescence and the cellular origin of TIF
188(1)
Senescence-associated secretory phenotype
188(1)
Transforming growth factor-β (TGF-β)
189(1)
WNT/β-catenin signaling
190(1)
The renin-angiotensin system (RAS)
191(1)
The antiaging factor Klotho
191(1)
Inflammation, innate immunity, and TIF
192(1)
Senescence and TIF-physiology and pathology
193(2)
References
195(10)
Chapter 8 Kidney diseases: transplantation
205(22)
Anette Melk
Zulrahman Erlangga
Introduction
205(1)
Factors determining donor organ quality and their association with senescence
206(4)
Impact of cellular senescence on transplant-related injuries and transplant outcome
210(2)
Rejuvenating and protecting kidney transplants
212(2)
References
214(13)
Chapter 9 Vascular diseases: atherosclerosis and atherosclerotic cardiovascular diseases
227(42)
Goro Katsuumi
Tohru Minamino
Introduction-"a man is as old as his arteries"
227(1)
Features of cellular senescence in vascular cells
228(3)
Endothelial cells
228(2)
Vascular smooth muscle cells
230(1)
Immune cells
230(1)
Evidence of cellular senescence in atherosclerosis
231(4)
Evidence in human atherosclerosis
231(2)
Vascular senescence in mice models of atherosclerosis
233(2)
Factors involved in vascular senescence associated with the pathophysiology of atherosclerosis
235(8)
The renin-angiotensin-aldosterone system (RAAS)
235(1)
Sirtuins, NAD±, nicotinamide phosphoribosyltransferase (NAMPT)
236(2)
Hyperglycemia/diabetes and dyslipidemia (fatty acids, oxidized LDL)
238(1)
PI3K/Akt/mTOR, FOXO, AMPK, PPAR, PGC1a
239(2)
Noncoding RNAs (micro and long noncoding) in mediating vascular senescence
241(2)
Physical activity
243(1)
Therapeutics targeting cellular senescence for atherosclerosis
243(5)
Direct suppression of senescent signaling or modulating mediators driving cellular senescence
243(1)
Antisenescent effect of current therapies for atherosclerosis available in clinical settings
244(1)
Modulating metabolic signaling
245(1)
Modulating SASP
246(1)
Senolysis
246(2)
Other strategies
248(1)
Conclusions (limitations and perspectives)
248(1)
References
249(20)
Chapter 10 Diabetes: senescence in type 1 diabetes
269(20)
Peter J. Thompson
Anil Bhushan
Introduction
269(2)
The pathogenesis of type 1 diabetes
269(1)
Current clinical interventions for T1D and the role of beta cells
270(1)
Senescent beta cell accumulation as a novel pathogenic mechanism in T1D
271(7)
Molecular architecture of the beta cell senescence program in T1D
271(5)
Human beta cell senescence in T1D
276(1)
Roles of beta cell senescence in the pathogenesis of T1D
277(1)
Outstanding questions and future directions
278(3)
Mechanisms of senescent beta cell accumulation
278(1)
Senescence in other cell types in T1D
279(1)
Relationships between beta cell senescence and ER stress pathways
280(1)
Future clinical approaches to targeting beta cell senescence in T1D
280(1)
Conclusions and outlook
281(1)
References
282(7)
Chapter 11 Senescence in obesity: causes and consequences
289(20)
Allyson K. Palmer
Michael D. Jensen
Tamara Tchkonia
James L. Kirkland
Introduction
289(1)
Adipose tissue function in obesity
290(1)
Senescent cells accumulate in multiple tissues in obesity
291(2)
Adipose tissue
291(1)
Liver
291(1)
Pancreas
292(1)
Heart
292(1)
Brain
292(1)
Immune system
293(1)
Muscle
293(1)
Causes of cellular senescence in obesity
293(3)
Hyperglycemia
293(1)
Fatty acids
294(1)
Oxidative stress
294(1)
Telomere shortening
295(1)
Growth hormone axis
295(1)
mTOR activity
295(1)
Altered microbiome
295(1)
Threshold theory of senescent cell burden
296(1)
Implications of senescence in obesity: downstream effects
296(3)
Inflammation
296(1)
Inhibition of adipogenesis and ectopic lipid deposition
297(1)
NAD± depletion due to CD38± macrophage attraction
297(1)
Obesity-induced neurocognitive defects
297(1)
Paracrine effects on neighboring cells
298(1)
Promotion of cancer development
298(1)
Reduced regenerative potential
298(1)
Strategies to target obesity-related senescent cells
299(2)
Exercise and weight loss
299(1)
Senolytics
299(1)
SASP inhibitors or senomorphics
300(1)
Administration schedule of senescence-targeting therapies
300(1)
References
301(8)
Chapter 12 A framework for addressing senescent cell burden in the osteoarthritic knee: therapeutics, immune signaling, and the local-systemic interface
309(26)
Alexander F. Chin
Jin Han
Elise Gray-Gaillard
John Michel
Jennifer H. Elisseeff
Introduction
310(1)
Main
310(14)
Knee tissues degenerate in osteoarthritis
310(3)
Chronic presence of senescent cells in the knee accelerates osteoarthritic erosion
313(3)
Killing senescent cells in the knee can reduce OA-associated dysfunction
316(1)
Translating antisenescent therapies to the clinic for OA treatment
317(7)
Conclusion
324(1)
Competing interests
324(1)
Acknowledgments
325(1)
References
325(10)
Chapter 13 Osteoporosis and bone loss
335(28)
Sundeep Khosla
David G. Monroe
Joshua N. Farr
Osteoporosis as a public health problem
335(2)
The hallmarks of aging in bone
337(2)
The role of cellular senescence in mediating age-related bone loss
339(7)
Identification of senescent cells in the bone microenvironment
339(3)
Causal role for cellular senescence in mediating age-related bone loss
342(3)
Role of cellular senescence in mediating age-related frailty
345(1)
Estrogen deficiency and cellular senescence
346(2)
The role of cellular senescence in the effects of diabetes mellitus on bone
348(1)
Cellular senescence and radiation- and chemotherapy-induced bone loss
349(3)
Role of cellular senescence in the growth plate and regulation by parathyroid hormone-related peptide (PTHrP)
352(1)
Summary and conclusions
353(1)
Acknowledgments
353(1)
References
353(10)
Chapter 14 Cellular senescence in neurodegenerative diseases
363(20)
Peisu Zhang
Myong-Hee Sung
Cellular senescence: driving force or beneficial response in neurodegeneration7
364(2)
Postmitotic senescence in brain aging and neurodegenerative diseases
366(1)
Replicative senescence in brain aging and neurodegenerative diseases
367(1)
Demyelination, oligodendrocyte lineages, and Al plaque propagation in AD brains
368(3)
Senolytics as AD therapy
371(2)
Combination therapy for AD using senolytics and senomorphics
373(1)
Conclusions
374(1)
Acknowledgments
374(1)
References
375(6)
Further reading
381(2)
Chapter 15 Cell senescence is a cause of frailty
383(42)
Tengfei Wan
Satomi Miwa
Thomas von Zglinicki
What is frailty?
383(1)
How is frailty assessed in humans?
384(4)
How is frailty defined and assessed in experimental animals?
388(1)
What are the possible causes of frailty?
389(1)
What is cell senescence?
390(3)
Does cell senescence cause frailty? How good is the evidence for it?
393(13)
Correlative evidence: associations between cell senescence and frailty
393(3)
Direct tests: reducing senescent cell burden
396(9)
Direct tests: enhancing senescent cell burden
405(1)
Senostatics
406(1)
Conclusions
406(2)
References
408(17)
Part 3 Conclusions
Chapter 16 Senescence as a therapeutic target: current state and future challenges
425(18)
Kathleen Meyer
Jose Alberto Lopez-Dominguez
Mate Maus
Marta Kovatcheva
Manuel Serrano
Biological interpretations of cellular senescence
425(3)
Senescence as the end point of cellular aging
426(1)
Senescence as a tumor suppressive mechanism
426(1)
Senescence as a general cellular response to damage
426(1)
Senescence as a cellular program involved in tissue remodeling
427(1)
Tissue remodeling by senescence is a two-step process
428(1)
The two steps of senescence in cancer
428(1)
The two steps of senescence in disease
429(1)
SASP-induced tissue repair versus SASP-induced tissue dysfunction
429(1)
Molecular triggers of senescence
430(1)
Triggers of senescence in vivo
431(1)
The challenge of detecting cellular senescence in clinical settings
432(1)
Potential side effects of eliminating senescent cells
433(1)
Senolytics as an anti-aging strategy
434(1)
Declaration of interests
435(1)
References
435(8)
Index 443
Dr. Manuel Serrano did his PhD under the supervision of Margarita Salas (CBM-CSIC, Madrid) and a postdoctoral stay in David Beachs lab (Cold Spring Harbor Laboratory, NY, USA) from 1992 to 1996. During this time, he made one of his most important contributions, namely the discovery of the tumor suppressor p16.

The main contributions of Dr. Serranos lab during these years are related to the concept of oncogene-induced senescence and the anti-ageing activity of tumor suppressors. More recently, his group has reported on the relevance of tumor suppressors in metabolic syndrome, the existence of senescence during embryonic development, and the feasibility of embryonic reprogramming within living adult organisms (the latter was considered "Achievement of the Year 2013" in the stem cells field by Nature Medicine). Dr. Daniel Munoz-Espin is Senior Research Associate at the Department of Oncology of the University of Cambridge. His lab is part of the CRUK Cambridge Centre Early Detection Programme, working at interface between cellular senescence, plasticity and the fundamental processes and mechanisms that lie at the origin of cancer. We are also developing novel tools and nanodevices for cancer therapy and diagnosis.