Inflammation, Advancing Age and Nutrition

Research and Clinical Interventions

Irfan Rahman, Debasis Bagchi

• Publisher: Academic Press
• Year: 2013
• ISBN:
  9780123978073
• Topic: Technology & Engineering
• Subtopic: Food Science
• Index: Technology & Engineering

The book provides a comprehensive overview to understanding the integrated impact of the concepts of cellular and molecular aspects, models, environmental factors, and lifestyle involved in premature aging. Additionally, it examines how functional food, dietary nutraceuticals or pharmacological compounds can reverse inflammation and premature aging based on personalized medicine. This book is a valuable resource for health professionals, scientists and researchers, nutritionists, health practitioners, students and for all those who wish to broaden their knowledge in the allied field.

• Includes models of aging, including worm, mouse and human
• Explores the relationship of inflammation with diseases, including ocular health, Alzheimer's and Parkinson's disease, and muscle health
• Encompasses a variety of lifestyle impacts, including diet, exercise and nutrition
• Includes suggested nutritional interventions

Chapter 1

Biomarkers and Inflammatory Network in Aging

Targets for Therapies

Carmela Rita Balistreri, Giulia Acccardi, Calogero Caruso and Giuseppina Candore, Section of General Pathology, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory, Palermo, Italy

Abstract

Humans are characterized by a large heterogeneity in lifespans. The aging rate, measured as a decline of functional capacity and stress resistance, is different in every individual. Several attempts have been made to define the so-called biological age, but without achieving real success. Biomarkers of aging, which are represented by biological indicators selected using appropriate criteria, should help to characterize the biological age. Since age is a major risk factor in many degenerative diseases, such biomarkers could subsequently be used to identify individuals at a high risk of developing age-associated diseases or disabilities. In this chapter, some inflammatory biomarkers will be discussed to provide a better understanding of the concept of biological aging, which will assist in the development of a working hypothesis on the potential targets of new therapeutic strategies and improve, as a consequence, the quality of life of the elderly population.

Keywords

aging process; biological age; inflammatory biomarkers; inflammatory network; NF-κB signaling

Introduction

Aging is recognized as a complex process, induced by intricate interactions between genetic, epigenetic, stochastic, and environmental factors. These factors contribute to a loss of molecular fidelity that results from the random accumulation of damage (particularly to nuclear and mitochondrial DNA) at the cellular, tissue, and organ levels and/or to the whole body, compatible with the “disposable soma” theory of aging [1]. This theory states that both the architecture and functioning of physiological processes and regulatory (immune and endocrine) systems are modified during aging, which leads to a deterioration of homeostatic capacity. In elderly people, induced homeostatic processes show increased amplitudes and take longer to return to baseline. Accordingly, elderly people are more vulnerable to internal and external stressors, frailty, disability, and disease. In addition, the decline in DNA integrity, one of the main types of random damage that reduces cellular fidelity and induces cellular senescence, is caused by altered or lack of expression of stress resistance and survival genes that are involved in the cellular and organismal defense to environmental stresses, and which maintain homeostasis [2]. However, wide variations have been observed in the occurrence, complications, speed, and age- and gender-specific manifestation of the aging process occurring at the cellular, tissue, and organ levels, and/or in the whole body both within and between individuals of the same species or of different species. In humans, there are individuals aged ≥ 90 years who are still in good mental and physical condition, and others who show cognitive difficulties and/or the onset of chronic inflammatory diseases, such as Alzheimer disease (AD), cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and cancer at age ≥ 60 years [3].

The large heterogeneity in the aging rate in humans has been ascribed to genetic and different environmental factors. However, the overall impression is that environmental factors are the major determinants of both aging and age-related diseases [3,4].No genetic program has emerged to explain the aging process [4]. This conclusion is based on studies on the heritability of age-related diseases and aging. In particular, they suggest that the heritability of age-related disease is similar to current estimates of the heritability of life expectancy [5,6]. Population-based and twin studies on late-onset disorders such as AD, cancer, CVD, and T2DM indicate that heritability is less than 40% [6]. Lifespan studies in worms and mice suggest heritability to be 10–35% [5]. Most literature reviews on human life expectancy are based on Scandinavian twin studies that estimate heritability at about 25–33% [7,8]. However, this relatively small genetic contribution does not imply that genes are irrelevant. On the contrary, modern genetic techniques identified mutations in familial forms of AD that have helped to unravel the molecular mechanisms of disease, such as the toxicity of amyloid beta peptide and potential therapeutic targets in more common sporadic late-onset AD [9]. Thus, genetic contributions to aging and diseases of later life are probably complex and the effects of individual genes are probably weak [4]. Furthermore, there is a distinction between the genetics of aging and exceptional longevity. Human genome-wide genetic analyses have revealed only a few age-related loci and polymorphic longevity genes [10–12]. Among these, current promising candidates are sirtuins and forkhead box O proteins (FOXOs), and the field of epigenetics. Functional genomics has revealed a group of genes that are differentially expressed in aging, such as immune/inflammatory genes [13].

Another critical point emerging from the above observations is that in humans biological age rather than chronological age is a better determinant of both the aging rate and onset of the common diseases of later life [14]. This concept opened an important area of research focused on addressing the complex question of whether aging should be considered the “cause or effect of disease,” and, consequently, eliminating the confusing influence of disease from research into aging. With the aim of resolving this dilemma, over the last few decades gerontologists have focused their efforts on measuring biological aging by identifying potential molecular targets as biomarkers of human aging [15]. On the one hand, this might finally cast light on the paradigm “aging: a cause or effect of disease” and, on the other hand, it could identify potential treatment strategies. The hypothetical treatment of aging could retard or prevent age-associated diseases, resulting in widespread health and social and economic benefits. Such treatments could include genetic engineering, such as gene therapy or endogenous gene repair, pharmacological therapies, or changes in lifestyle.

Many of these aspects are summarized in this chapter. Particular emphasis is given to describing the cellular and serum biomarkers of inflammation. In particular, the data discussed in this chapter are based on expert opinion derived from the author’s findings derived from studies on age-related diseases and inflammation.

Aging Biomarkers: Definition and Selection Criteria

To date, when one talks about a biomarker, one refers, as established officially by the National Institutes of Health, to a “feature objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [16].

In the case of the aging process, this definition might concern measures related to physical changes, such as gray hair, reduced skin elasticity, wrinkles, reduced muscle strength, or changes affecting near vision, which are thought to result from molecular mechanisms occurring in old age [17]. However, these changes reflect chronological age rather than biological age. Biological age represents the most important indicator of health and potential lifespan [14]. Consequently, in considering these changes as aging biomarkers, the problem of measuring the real age of an individual remains. A biomarker of real aging should preferably reflect a process associated with aging, be easily reproducible in cross-species comparisons, and be easily obtainable. In addition, more than one biomarker of aging should be considered, since aging is assumed to be the consequence of deterioration of more than one system or process. This assumption leads to the decision to preferentially use “panels” of biomarkers associated with conditions, alterations, or changes to a set of critical systems to assess the biological age of any organism [15,17].

Gerontologists began to face this problem in the early 1980s, with the development of a large number of aging biomarkers [15,17]. Despite numerous efforts and the support of this research by the National Institute of Aging, to date most biomarkers, including inflammatory markers, hormones, markers of oxidative stress, and telomere shortening are still under discussion [15,17]. In addition, most (perhaps all) markers have not been supported by longitudinal studies in humans. Moreover, they have been developed for a variety of purposes, which are not sufficiently defined. Most investigators have used biomarkers as tools for comparing rates of aging between different populations or between subgroups of a single population. In contrast, others have sought biomarkers for identifying individual predisposition to aging. The latter is much more challenging, principally because aging, as a biological process, is not well defined at the individual level. Furthermore, searching for comparative or predictive biomarkers has resulted in the attempted use of panels of measures associated with survival, healthy old age, frailty, and age-related (multi)morbidity and mortality [15,17]. Classic examples of these panels are indicators of physical function, body mass and composition, inflammation, endocrine function, and micronutrient status.

Besides, none of the identified biomarkers is a “true” biomarker of aging: most biomarkers are related not only to aging but also to diseases. Several biomarkers have indeed been developed and tested for conditions for which biological age is the single biggest risk factor, such as peripheral blood cellular telomere length, which is an indicator of immunosenescence and does not correlate with disease-specific diagnoses. In addition, biomarkers of age-related diseases and aging have been documented only in young-old populations (typically aged 60–85), and not in the oldest old (aged 85 and above) [15,17]. For example, it has been demonstrated that blood pressure, indicators of metabolic syndrome, and telomere length do not associate significantly with age-related morbidity or mortality in population-based studies of the oldest old [18–20]. Thus, in general, the utility of biomarkers of aging and age-related diseases for understanding the health trajectories of the oldest old is unexplored territory. It is important that this gap is filled, given the rapid growth in the number of very old people in many contemporary populations.

In order to clarify, it is important to know not only how such a biomarker is defined, but also the criteria for its selection. Accordingly, the American Federation for Aging Research has proposed detailed criteria, which have been recently reviewed by Johnson [17] and Sprott [15] (see Table 1.1). Based on these criteria, a true biomarker of aging, in order to be both accurate and useful, should predict a person’s physiological, cognitive, and physical function in an age-related way. At the same time, it should be easily testable and not harmful to test individuals. For example, it could be a blood test or an imaging technique that can be performed accurately and reproducibly without the need for specialized equipment or techniques. Preliminary testing should be done in laboratory animals, such as mice, and then in humans. Thus, a biomarker needs to be simple and inexpensive to use. It should cause little or no pain or stress [15,17].

TABLE 1.1

Selection Criteria for an Aging Biomarker

1	It must predict the rate of aging. Operationally, it must be a better predictor of lifespan than chronological age alone.
2	It must monitor a basic process that underlies the aging process, not the effects of diseases.
3	It must be able to be tested repeatedly without harming the person; for example, a blood test or an imaging technique.
4	It must be something that works in both humans and laboratory animals. So, it must be tested in laboratory animals before being validated in humans.

Furthermore, current clinical and basic research into aging biomarkers is designed to exchange knowledge and resolve differences between these fields by making comparisons between clinical and basic research data. On the other hand, biomarkers represent a hot topic and have the ability to change our lives, if real predictions about individuals are made ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Biography
• Preface
• Contributors
• Chapter 1. Biomarkers and Inflammatory Network in Aging: Targets for Therapies
• Chapter 2. The Biological Significance of Zinc in Inflammation and Aging
• Chapter 3. Immunity, Inflammation, and Aging
• Chapter 4. Oxidative Stress, Inflammaging, and Immunosenescence
• Chapter 5. Stress Response, Inflammaging, and Cancer
• Chapter 6. Aging, Immunosenescence, and Cancer
• Chapter 7. Telomere Biology in Senescence and Aging: Focus on Cardiovascular Traits
• Chapter 8. Epigenetics, Inflammation, and Aging
• Chapter 9. Nutrition as an Epigenetic Modifier in Aging and Autoimmunity
• Chapter 10. Connecting Phytochemicals, Epigenetics, and Healthy Aging: Is Metabolism the Missing Link?
• Chapter 11. Diet/Nutrition, Inflammation, Cellular Senescence, Stem Cells, Diseases of Aging, and Aging
• Chapter 12. Circadian Clock Mechanisms Link Aging and Inflammation
• Chapter 13. Obesity, Insulin Resistance, and Inflammaging
• Chapter 14. Organelle Stress and mTOR in Aging-Associated Inflammation
• Chapter 15. SIRT1 and Inflammaging in Chronic Obstructive Pulmonary Disease
• Chapter 16. Stress-Induced Premature Senescence: Another Mechanism Involved in the Process of Accelerated Aging in Chronic Obstructive Pulmonary Disease
• Chapter 17. Cellular Senescence and Premature Aging in Lung Diseases
• Chapter 18. Rheumatoid Arthritis: Disease Pathophysiology
• Chapter 19. Aging and Anti-Aging in Hair and Hair Loss
• Chapter 20. Muscle Wasting, Dysfunction, and Inflammaging
• Chapter 21. Matrix Metalloproteinases and Skin Inflammaging
• Chapter 22. Ocular Health, Vision, and a Healthy Diet
• Chapter 23. The Role of Physical Activity in Healthy Living: Its Anti-Inflammatory Effects
• Chapter 24. Erectile Dysfunction in Inflammaging
• Chapter 25. Role of Saturated and Polyunsaturated Fat in Obesity-Related Inflammation
• Chapter 26. Cellular Stress Response, Hormesis, and Vitagens in Aging and Longevity: Role of mitochondrial “Chi”
• Chapter 27. Inflammaging Signaling in Health Span and Life Span Regulation: Next Generation Targets for Longevity
• Chapter 28. Trophokines: Novel Therapy for Senescence-Related Fibrosis
• Chapter 29. Frailty: A Basic and Clinical Challenge for the Future
• Index