Senescence, Senotherapeutics and Mitochondria, Volume 136 offers updates on this unique topics, with chapters covering Cellular Senescence in Aging: Molecular Basis, Implications and Therapeutic Interventions, Mitochondria-associated Cellular Senescence Mechanisms: Biochemical and Pharmacological Perspectives, Mitochondria in cell senescence: Friend or Foe?, The role of mitochondria and mitophagy in cell senescence, Small molecules targeting mitochondrial dysfunction for potential senotheraputics, Senolytic and senomorphic interventions to defy senescence-associated mitochondrial dysfunction, Mitochondrial targeting peptides and probes, Mitochondria-derived peptides in healthy ageing and therapy of age-related diseases, and much more. Other sections cover Targeting of mitostasis-proteostasis axis by antioxidant polysaccharides in neurodegeneration, Phytotherapeutic targeting of the mitochondria in neurodegenerative disorders, Melatonin as mitochondria-targeted drugs, Coenzyme Q-related compounds to maintain healthy mitochondria during aging, Changing ROS, NAD and AMP: a path to longevity via mitochondrial therapeutics, and more. Updates on how mitochondria are closely related to the survival of senescent cells using either mitochondria-targeted senolytic or redox modulator senomorphic strategies Differentiates itself from other books with its multidisciplinary perspectives and multidimensional clinical approaches Offers a novel perspective on both the basic and clinical sciences for a wide group of well-established academicians, students and researchers in medicinal chemistry, gerontology, geriatrics, oncology, pharmacology, pathology, bioinformatics, sports science and nutritional sciences

This book offers comprehensive information on the new and rapidly evolving science of identifying and targeting senescent cells, and on the exciting prospect of new diagnostic and therapeutic opportunities for stopping, and even reversing, the progression of disease and the deterioration of the human body due to ageing. According to recent United Nations data, by 2050 one in six people worldwide will be older than age 65, with peaks rising to one in four people in Europe and North America. Remarkably, the number of persons aged 80 years or older is expected to triple, from 143 million in 2019 to 426 million in 2050. First documented in the 1960s, the concept of cellular senescence as an underlying cause of ageing has been established in the course of the last decade. Using genetically engineered mouse models, researchers have demonstrated that the selective elimination of senescent cells can block and even reverse a number of age-related dysfunctions and pathologies, promoting both better health and longer life in the elderly. These include cardiovascular diseases; neurological disorders; type 1 and type 2 diabetes; inflammatory diseases; fibrosis; geriatric syndromes; chronic diseases resulting in organ dysfunction; the integrity of the musculoskeletal system; and cancer. Some senolytic agents have already progressed into trials. These include UBX0101 for the treatment of osteoarthritis (now in phase II), a cocktail of dasatinib and quercetin for the management of idiopathic pulmonary fibrosis and chronic kidney disease, and ABT-263 in combination with senescence-inducing chemotherapies for the treatment of advanced solid tumours. In addition, the book discusses pathways to early phase clinical trials and translational approaches in medicine and ageing, highlighting new opportunities as well as current limitations, challenges and alternatives. Given its scope, it will benefit a broad audience of advanced educators, researchers, graduate students and practitioners.

This book aims to present the age-related alterations in redox signaling networks and their diagnostic biomarkers in aging cells using multidisciplinary approach. Establishing sensitive and specific biomarkers of dynamic redox homeostasis is crucially important in the development of effective antiaging and senolytic interventions. Recent years have seen tremendous advances in the understanding of redox signaling events which highlight the process of aging and age-related pathologies. A major challenge in biological aging research is developing reliable biomarkers to determine the consequences of disrupted redox signaling networks long before the clinical diagnosis of age-related diseases is made. Therefore, we have chosen to concentrate on aging-induced aberrant redox signaling networks, their biomarkers, and pathological consequences in this book. Although oxidation is a natural metabolic process, the imbalance in the level of oxidants and antioxidants causes oxidative stress and eventually leads to inflammatory conditions, diabetes, neurodegenerative diseases, and cancer. Novel redox-sensitive biomarkers for the evaluation of aging-induced proteinopathies such as amyloid ß and tau proteins in Alzheimer's disease, α-synuclein in Parkinson's disease, and islet amyloid polypeptides in type 2 diabetes mellitus recently drew the attention of researchers. Inside this textbook, readers will find comprehensive perspectives on the association between redox homeostasis and the aging process both at the molecular and clinical levels. Due to the inherent relationship between impaired metabolic activities and oxidative stress, the temporal interaction between intermediary metabolism and disturbed redox status can lead to greater susceptibility to aging-induced diseases and disorders, such as cardiovascular diseases, hypertension, and diabetes. This knowledge could be a key to continued research toward improving medication regimens such as in cancer and cardiovascular therapies, and procedural outcomes for patients. This book brings together current research evidence and knowledge on redox signaling and biomarkers in aging in chapters written by leading global experts in this rapidly evolving field. We hope that this textbook is of interest to a wide group of researchers, advanced students, scientifically curious non-specialist readers and clinicians alike.

This book describes current methods for the identification and characterization of the major hallmarks of senescent cells. Chapters focus on the high heterogeneity of the senescence phenotypes, and techniques to induce and identify specific senescence programs. Additional chapters describe cellular and mouse models in which is possible to study the complex cell and non-cell autonomous functions of senescent cells. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Cellular Senescence: Methods and Protocols aims to ensure successful results in the further study of this vital field.

Progression of chronic diseases in general and chronic kidney disease in particular has been traditionally viewed in the light of various contributors to development of glomerulosclerosis and tubulointerstitial scarring culminating in renal fibrosis. Indeed, this dogma prevailed for decades underscoring experimental attempts to halt fibrotic processes. Breakthrough investigations of the past few years on stem/progenitor cell involvement in organ regeneration caused a conceptual shift in tackling the mechanisms of nephrosclerosis. It has become clear that the rate of progression of chronic kidney disease is the net sum of the opposing trends: degenerative fibrotic processes and regenerative repair mechanisms. The latter part of this equation has been by and large ignored for years and only recently attracted investigative attention. This book revisits the problem of kidney disease by focusing on regenerative mechanisms in renal repair and on the ways these regenerative processes can become subverted by an intrinsic disease process eventuating in its progression. Cutting-edge investigations are summarized by the most experienced international team of experts. Presents a comprehensive, translational source for all aspects of renal stem cells, tissue regeneration, and stem cell therapies for renal diseases in one reference work. This will ultimately result in time savings for academic, medical and pharma researchers Experts in the renal stem cell system in kidney repair and regeneration take readers from the bench research to new therapeutic approaches, providing a common language for nephrology researchers, fellows and other stem cell researchers. This enables the discussion of development of stem cells and their use in the repair and regeneration of the kidney

In this eBook, we have grouped together 16 original contributions which have addressed the translational potential for therapeutics developed on the conceptual framework of the resolution of inflammation. The take home message of our effort, and the efforts of our colleagues who wrote these pieces, is that completely different drugs can be designed and modelled on the mediators and targets of resolution. By implementing this 180° shift in the way we plan the drug development programme (that is by focusing on agonists and/or promoting the actions of pro-resolution agonists) we can offer a fresh approach to the clinical management of chronic diseases that affect the modern society. With this series of articles we foresee the birth of Resolution Pharmacology. The 16 contributions presented herein confirm the broad relevance of pro-resolving physio-pharmacology with the description of pro-resolving mechanisms in distinct diseases, from atherosclerosis and heart infarct, to cystic fibrosis and diabetes. This testifies on one hand the fundamental role that inflammatory mechanisms play in virtually all pathological settings and, on the other hand, the great potential that a novel approach to anti-inflammatory therapy by exploiting resolution mediators and targets may have. Thus, while there is broad recognition that evidence-based interventions have transformed cardiovascular, inflammation and endocrine care, new therapies are still needed for growing numbers of patients with unmet needs. As an example, an estimated 17 million people world-wide die annually of cardiovascular diseases, particularly heart attacks and strokes. Cardiovascular diseases occur almost equally in men and women and are the leading cause of death and morbidity worldwide. It is estimated that only 1/1,000 compounds entering preclinical testing are then trialled in man and the actual cost of developing a new therapeutic into clinical practice has grown exponentially over the past two decades (estimated $1.2B). Over the last 20 years or more, scientists have appreciated the biology of the resolution of inflammation, which provides a new paradigm in our understanding of the inflammatory process with the appreciation of genetic, molecular and cellular mechanisms that are engaged to actively resolve inflammation. The ‘resolution of acute inflammation’ is enabled by counter-regulatory checkpoints to terminate the host reaction while at the same time promoting healing and repair. The potential of lipid mediators to enact pro-resolving effects in the context of cystic fibrosis is presented by Recchiuti et al., while Fredman reasons on the potential for these molecules in atherosclerosis. This resonates well with the contributions from Bäck and colleagues who have focused on pro-resolving receptors to offer vasculo-protection in intimal hyperplasia and more generally in cardiovascular disease. On the same vein is the scholar contribution of Leoni and Soehnlein who focus on heart disease, with Qin et al. presenting the latest findings on the effect of an Annexin A1-derived peptide in myocardial infarction. Hansen et al. and de Gaetano et al. bring in the complexity of diabetes and associated morbidity with a focus on specialised pro-resolving lipid mediators but also introducing the potential of dietary approaches. As the western diet favours disease, an omega-3 rich diet can lead to higher availability of lipid mediators to afford tissue protection if not reverting its pathological status. Docosahexaenoic acid and its bioactive derivatives are endowed with potent anti-nociceptive properties following bone fracture, as shown by Zhang et al. The broad relevance of the pharmacological approach reaches the skin with Resolvin D1 protecting against UV irradiation (Saito et al.). Reduced skin inflammation is also achieved with an Annexin A1 peptide that impacts on the outcome of heterologous transplantation (Lacerda et al.). Indeed, modulating the phenotype of immune cells can provide long lasting beneficial outcomes, as attained with CDK inhibitors (Cartwright et al.) and PI3K inhibitors in experimental gout (Galvao et al.). Such an effect is also achieved with a third group of pro-resolving therapeutics, the melanocortin receptor agonists, with important modulation of macrophage reactivity (Patruno et al.) with Spana et al., providing new pharmacology following selective activation of the MC1 receptor. Finally, Hopkin et al. discuss the potential for targeting immune cell trafficking as a way to control immune mediated diseases, bringing in not only pro-resolving mediator agonists, but also approaches to reduce chemo/cytokine gradients or modulating S1P and 11-beta hydroxysteroid dehydrogenase. Finally, we wish to highlight that this wealth of science has also bought to the forefront specific pro-resolving receptors (including FPR2/ALX, GPR32, ChemR23 and MC1), all G protein coupled receptors that are therefore amenable to pharmacological exploitation for drug discovery programmes. We see that not only agonists to the receptors can be developed, some of them modelled on the natural ligands (e.g. resolvins, lipoxins, Annexin A1-derived peptides or melanocortin peptides), but also that the creativity of this pharmacology can be attained through biased ligands and positive allosteric modulators. Deep knowledge of pro-resolving receptor biology and their cell-specific signalling can accelerate the generation of novel anti-inflammatory depicted on the resolution of inflammation. In conclusion, with this eBook, we propose time is ready to exploit the concepts of resolution and use its targets and mediators for the identification of better drugs to establish ‘Resolution Pharmacology’. We predict Resolution Pharmacology will represent an important innovation in the way common diseases will be treated in the next decades of this millennium.

"How long can humans live? Is immortality possible? Just what is the aging process? The aging and inevitable death of the human body have inspired more myths and outrageous quackery than anything else subject to scientific inquiry. . . . Now comes a most fascinating book, insightful and scholarly, to provide what answers have emerged so far." --San Francisco Chronicle Here, at last, preeminent cell biologist Leonard Hayflick presents the truth about human aging. Based on more than thirty years of pioneering research in the field, How and Why We Age explores not only how our major biological systems change as we grow older, but also examines the intangible alterations in our modes of thinking and feeling, our moods and sexual desires, our personality traits and our memories. With the immediacy of the latest scientific discoveries, Dr. Hayflick explains how aging affects every part of the body, and dispels many of the most persistent aging myths, to show that: * Hearts do not naturally get weaker with age. * Regular exercise and a low-fat diet won't slow aging. * Curing cancer would only add two years to the average sixty-five-year-old American life. Curing heart disease, however would add fourteen years. * Only five percent of people over the age of sixty-five are in nursing homes * No human has lived--or probably can live--past 120 years. Gracefully written, clearly organized, and packed with essential facts and statistics, How and Why We Age is a landmark study of the aging process for readers of all ages. "Written in clear, nontechnical language, it is an excellent introduction to the scientific and demographic literature on this multifacetedsubject." --Nature