Volume 2

The overarching purpose of this book is to promote a deeper understanding of metabolism from the integrated perspectives of the laws of physics and biological chemistry in states of health and disease. The book’s first volume has provided a lens from multiple disciplines of modern physics to acquaint the beauty and organizational perfection of living systems. Volume two now seeks to connect these insights to the causes of this perfection going awry, in the context of unhealthy human life style and behaviors as well as gradual degradation due to natural processes of aging. While the relevance is not intended to provide cookbook algorithms, the hope is to buttress the reader’s scientific creativity and outline the links between art and science that strengthen problem solving in patient care.

Moreover, we propose and describe a powerful model for the future of Medicine, the Physiological Fitness Landscape. This mathematical model represents a practical implementation of a precision personalized scale of Medicine. It offers the potential to provide the optimal intervention, which is both patient-specific and disease-specific, and changes over time as a result of both the aging processes and pharmacological or lifestyle interventions.

Despite the scientific scale of complexity and a large swath of scientific territory covered in this book, there is conceptual simplicity in all of the book’s messages. One such message is the loss over time of free will, the freedom to act as we please; this becomes the case when voluntary behaviors develop unhealthy patterns. These behaviors elicit biological responses that become feedforward and bidirectional inputs into a matrix of inextricably intertwined self-exacerbating behavioral and organic driven parameters of disease. It becomes unavoidably frustrating when initially voluntary behaviors in an otherwise mentally competent person become patho- biologically rooted and progressively involuntary. The overshoot and example in the two paragraphs below may be viewed from the different perspectives of each of the chapters presented in this second volume.

For example, a pattern of dietary excess is classically recognized to be an extrinsic contributor to chronic disease. However, other unhealthy behaviors, whether they are initiating or not, also become inescapable components in a pathogenic web. In particular, these include poor quality or timing of diet, other abnormal circadian patterns such as sleep, rest and activity, and prolonged exaggerated stress responses. Further, an altered compositional pattern and reduced diversity of the microbiota is a central nexus to the intrinsic control parameters of disease, particularly redox and inflammatory stress, mitochondrial dysfunction and insulin resistance (in metabolic tissues responsive to insulin signaling for glucose and lipid energy homeostasis).

The following mechanistic overshoot is illustrative of one way to describe how human behaviors (extrinsic control parameters of disease) promote biological responses (intrinsic control parameters of disease), which in turn ingrain a wider range of unhealthy behaviors, thus amplifying biological factors. Consequently, there evolves a feedforward potentiation of one another’s pathogenic contributions within a matrix of metabolic and chronic disease. Take for instance dietary excess, which exceeds mitochondrial bioenergetic capacity. This leads to superoxide formation and a proinflammatory response, which may become systemic. Inflammatory cytokinemia may also result from disturbing effects of the diet on microbiota health. Moreover, proinflammatory cytokines consequently affect the limbic system in the brain that reduces the threshold for the perception of a threatening stress response. This stress response disturbs the quality of the diet, virtually always. It also disturbs the timing of the diet, as well as of the sleep wake cycle and other circadian behaviors. Additionally, the chronically activated HPA axis and autonomic branches of the stress response together cause immune suppression that contributes to further disruption of the microbiota, greater severity of the systemic inflammatory milieu, cell redox stress, mitochondrial dysfunction and insulin resistance.

This second volume of the book will provide numerous examples of relevance to the main theme of the book, namely that metabolism is not only a key functional difference between living and non-living matter but also that metabolism is positioned at the center between health and disease. Its organizational perfection leading to organism-wide synchronization of biological processes can be disturbed by various voluntary and involuntary mechanisms causing pathological transformations. Key to our understanding of these transformations and their inherent risks is the concept of stress response. A fundamental insight into the quantitative and qualitative description of stress response can be gained by the introduction of the Physiological Fitness Landscape whereby control parameter changes elicit not always proportional changes of the physiological fitness level. These changes can restore homeostasis, lead to allostasis or drive the system to allostatic overload. It is my belief that proper incorporation of the mathematical models such as the Physiological Fitness Landscape will transform the practice of Medicine bringing it much closer to a data driven branch of science than we have ever imagined. I invite your mind to new exciting ideas and embark on this journey into the future of Medicine with me.

Volume 2


The Metabolic Landscape of Health and Disease

Chapter 1. Introduction to Metabolism – A New Model for Medicine

1.1    Brief History of Metabolism and the Complex Personalities of the Scientists Who Shaped It

1.2    Opening Remarks

1.3    Metabolism Fuels Biological Motors and Engines

1.4    Metabolic Pathways and Cellular Respiration

1.4.1 Metabolic Modes of Energy Production

1.4.2 Metabolic Cycles and Metabolic Rate

1.4.3 Metabolic Rate, Metabolic Efficiency, and Cellular Respiration in  Medicine

1.5    Biological Entropy Production Rate and Aging

1.5.1  Biological Entropy Production Rate and Pharmacological Implications

1.6      Key Bioenergetics Concepts

1.7      Dysfunction in Electron Transport System, Mitochondrial Function and its Importance in Chronic Disease

1.7.1    Biochemistry of the Electron Transport System

1.7.2    Biochemical Characteristics of Electron Transport Chain Dysfunction

1.7.3    Clinical Perspective of Electron Transport System Dysfunction

1.7.4    Influence of Glucose and Lipid Metabolism on the Function of the Electron Transport System

1.7.5    Redox Potential and its Importance in Biochemical Reactions

1.7.6    Clinical Application and Examples of Redox Application to Insulin Resistance and Type 2 Diabetes

1.7.7    Contributions of Macronutrients to Redox Potential, Proton Motive Force, and Oxidative Stress

1.7.8    Elevated Fatty Acid Metabolism and its Relevance in Aging and Chronic Diseases

1.7.9    Targeting the Electron Transport System for the Treatments of Metabolic Disease Improving Mitochondrial Metabolism Manipulation of Mitochondrial Redox System for Therapeutic Implications: Pharmacologic Intervention

1.7.10 Conclusion

1.8       Ketone Bodies in Metabolism in Health and Disease

1.8.1    Ketone Bodies are “Super Fuels” and Electron Scavengers

1.8.2    Role of Ketone Bodies in Starvation

1.8.3    Benefits and Dangers of Ketosis in Diabetes

1.8.4    Potential Benefits of Ketosis in Non-Diabetic Diseases

1.8.5    Yin-Yang Perspectives on Ketone Body Metabolism

1.8.6    Conclusions

1.9       Energy Sensors and Fuel Gauges

1.9.1    Energy Sensors, Circadian Biology and Metabolic Homeostasis

1.9.2    Parameters of Diet and an ETC Mechanistic Model of Human Metabolic Health and Disease

1.10     The Genesis of Accelerated Aging and Chronic Diseases of Aging

1.10.1 Insulin Resistance, Diet, Peripheral Clocks and Metabolism

1.10.2 Insulin Resistance and Hyperinsulinemia: The Chicken or the Egg?

1.10.3 The Protective Role of Visceral Adiposity

1.10.4  Loss of or Lipolysis of VAT and Autonomic Dysfunction: An Unrecognized Parameter of Premature Chronic Disease and Mortality

1.10.5  An Anecdote for Current Times: Obesity and SARS-CoV-2 in Pulmonary Fibrosis

1.10.6 Endotoxicosis and Insulin Resistance

1.10.7 Visceral Adiposity at the Intersection of an Inflammatory Diet and Insulin Resistance

1.11    Models of Chronic Diseases in Medicine as Metabolic Disorders

1.11.1 The Warburg Effect: A Modern Perspective of an Old Hypothesis

1.11.2 An Extension of Brownlee’s Unifying Hypothesis

1.11.3 The Warburg Effect and the Extension of the Unifying Hypothesis: A Broader Unifying Pathobiology

1.12    Concluding Remarks


Chapter 2. The Stress Response: From Health to Disease

Chapter Overview

2.1       What is Stress?

2.1.1    The Interdisciplinary Nature of Stress

2.2       The Stress Response

2.2.1    Homeostasis, Allostatic Load & Allostatic Overload

2.2.2    The Stress Paradox The Impact of Social Networks on the Stress Paradox A Clinical Example of the Stress Paradox

2.2.3    Stress through the Physiological Fitness Landscape

2.2.4    The Effects of Stress on Synchronized Physiology and Metabolism

2.3       A Modern-Day Stress Response

2.3.1    The Metabolic Demand of Stress

2.3.2    The Uncertainty Reduction Model

2.4       The Neural Circuitry of Stress

2.4.1    Interconnections

2.4.2    Neuroendocrine Response to Stress and Insulin Resistance

2.4.3    Stress and Norepinephrine

2.4.4    The Neural Circuitry of Uncertainty

2.4.5    Uncertainty and Chronic Anxiety

2.4.6    The Neural Circuitry of Energy Expenditure under Stress

2.5       Motivation and Reward

2.5.1    The Neural Circuitry of Reward

2.5.2    The Reward Circuitry, Stress and the Uncertainty Model

2.5.3    Gender Differences in Response to Stress

2.5.4    Possible Interventions for Addictions

2.6       Synaptic Plasticity

2.6.1    Long-Term Potentiation

2.6.2    Long-Term Depression

2.6.3    Synaptic Plasticity, Will Power and Consciousness

2.6.4    Quantum Consciousness through the Lens of the Prefrontal Cortex

2.7       Toward Integration of Physical Concepts into Medical Practice

2.7.1    Stress and the Control Parameters The Entanglement of the Stress Response and Biology of Time The Importance of Circadian Behavior Synchronization The Impact of Stress on Circadian Functions Downstream effects of Uncoordinated Stress and Circadian Systems The Influence of Stress on the Microbiota

2.7.2    The Physiological Fitness Landscape as a Clinically Useful Model

2.7.3    Improving Clinical Practice by Integrating Physical and Chemical Concepts with Biology

2.7.4    Mediators of the Shift from Health to Disease

2.7.5    Implementation of the Physiological Fitness Landscape Model in Clinical Practice

2.8       Chapter Take-Home Messages


Chapter 3. Nuclear Hormone Receptors: Mediators of Dynamic (Patho)physiological Responses

Chapter Overview

3.1          Historical Context

3.2          Introduction

3.2.1    Nuclear hormone receptor structure

3.2.2    Nuclear hormone receptor classifications

3.3          NHR Sense and Modulate Use of Energy

3.3.1    Nuclear hormone receptors in lipid homeostasis

3.3.2    NHRs in glucose metabolism

3.3.3    NHRs and Redox Homeostasis

3.3.4    NHRs in the Response to Exercise

3.4          Nuclear Hormone Receptors Integrate Environmental Signals in a Timely Manner

3.5          Nuclear Hormone Receptors are Important Pharmacological Targets with Clinical Applications

3.6          Summary

3.7          Bile Acid Metabolism – A Pivotal Crossroad for Nutrient Signaling and Circadian Networking


Chapter 4. The Biology of Time: How Molecular Clocks Make Living Cells Tick

Chapter Overview

4.1          Historical Context

4.2          Introduction

4.3          Physical Time, Biological Time and Physiological Aging

4.1.1    Physical Time Applied to Biology

4.1.2    Biological Time

4.1.3    Measuring Time

4.4          Biological Clocks, Metabolism, and ATP

4.5          Molecular Clocks Keep Biological Time

4.6          Cellular and Organ System Clock Organization

4.6.1    The Suprachiasmatic Nucleus (SCN)

4.6.2    Clock Synchronization – External Cues Light (SCN) Food: Feeding/Fasting Cycles (Liver, Pancreas, Adipose Tissue, Skeletal Muscle)

4.6.3    Exercise, Stress, and Hypoxia Exercise Stress Hypoxia

4.6.4    Phase Shifts

4.7          Hormones Display Circadian Rhythmicity

4.8          Chronobiology and Nuclear Receptors

4.8.1    Steroid Receptors Glucocorticoid Receptor (GR)

4.8.2    Retinoid X Receptor (RXR) Heterodimeric Receptors Thyroid Hormone Receptor (TR) Farnesoid X Receptor (FXR) Constitutive Androstane Receptor (CAR)- Xenobiotic Metabolism

4.8.3    Lipid Sensors Retinoid-related Orphan Receptor (RORs) Peroxisome Proliferator-Activated Receptors (PPARs) Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α) Rev-erbs- A Family of Nuclear Hormone Receptors

4.8.4    Nuclear hormone receptors in metabolism and as exercise memetics

4.9       Synchrony and Desynchrony of Environmental and Internal Timing: Clocks and Disease States

4.9.1    Metabolism Explained by Scales of Time and Space

4.9.2    Common Causes of Circadian Disruption

4.9.3    Sleep

4.9.4    Circadian Interactions with Nutrient Balance in Health and Disease

4.9.5    Glucose, Insulin, and Metabolic Disease

4.9.6    Cyclical Insulin Resistance and the Role of Forkhead Box O (FOXO) Transcription Factors

4.9.7    Circadian Misalignment of Endogenous Oscillating Cycles Contribute to Metabolic Disease and Chronic Disease of Aging

4.9.8    Nocturnal Eating and Insulin Resistance

4.9.9    Redox Status and Circadian Rhythms

4.9.10 Adrenal Insufficiency

4.9.11 Cortisol, Cushing’s, and Obesity

4.10        Therapeutic Interventions- Fitness Landscape Model

4.11        Future Advances in Circadian Biology and Circadian Medicine

4.12        Chapter Take-Home Messages


Chapter 5. Calorie Restriction, Intermittent Fasting, and Time-Restricted Feeding

Chapter Overview

5.1          Philosophical and Mechanistic Perspectives

5.1.1    Physical and Biological Systems

5.1.2    Longevity, Aging, and Chronic Disease

5.2          Stress Responses to Calorie Restriction

5.2.1    Hormesis, Vitalizing Stress, and Devitalizing Stress

5.2.2    Cell Stress Leading to Allostatic Overload

5.2.3    Metabolic Rate and Take-Over Threshold

5.3          Energy Signals and Metabolic Responses

5.3.1    Energy Sensing Functions of AMPK and SIRT1    The Role of AMPK in Mitochondrial Biogenesis    AMPK, Mitochondrial Function, and Fitness    The Role of PGC1α in the Activation of Downstream Transcription Factors    The Role of FOXO and Stress Resilience Programs    FOXO Transcription Factors and Autophagy Autophagy and Nutrient Scarcity Autophagy and Insulin Signaling Autophagy and Antioxidant Systems    FOXO Regulation of Cellular Metabolism    The Importance of Circadian Fluctuations in Insulin Signaling and FOXO Activation

5.4       Mechanistic Insights of Insulin Resistance at the Cellular Level

5.4.1    Nodes of Insulin Signaling

5.4.2    The Role of GSK3 in Cell Resistance

5.4.3    The Role of mTOR in Cell Resistance

5.5       Circadian Insulin Signaling

5.5.1    Hormesis and Circadian Insulin Signaling

5.5.2    Circadian Insulin Resistance and Cell Redox Stress Resistance Programs

5.5.3    Transition from Circadian to Chronic Non-Cyclical Insulin Resistance Energy Sensor Responses to Non-Cyclical Insulin Resistance Nocturnal Eating, Overconsumption and the Development of Metabolic Disease

5.6       Ketone Body Metabolism

5.6.1    Evolutionary Insights to Ketone Body Metabolism Fasting, Ketogenesis and Cognition

5.6.2    Ketosis – A Danger or a Health Signal?

5.6.3    Approaches to Achieve Ketosis Beta-Hydroxybutyrate Esters as a Metabolic Performance Enhancer for Military Use Beta-Hydroxybutyrate Esters as a Metabolic Performance Enhancer in Athletes

5.6.4    How Long Can Human Health and Survival Endure Fasting?

5.7       Chronic Overnutrition

5.7.1    The Role of Metabolic Flexibility in Insulin Sensitivity

5.7.2    Ectopic Lipid Deposition During Chronic Overnutrition

5.8       Chapter Take-Home Messages


Chapter 6. The Microbiota, in Symbiotic Entanglement with HumanMetabolism

Chapter Overview      

6.1       The Microbiota and Human Liaison: Better Together

6.1.1    Overview and Importance of the Gut Microbiota

6.1.2    The Relationship of the Gut Microbiota and the Human Host

6.1.3    The Microbial Flora: Impacts and Implications of an Altered Microbiota Composition

6.1.4    Genetics

6.1.5    Epigenetic Systems

6.1.6    The Ecology of the Microbiota and the Supraorganism

6.2          The Supraorganism

6.2.1    Co-development: From Birth, Through Life

6.2.2    The Gastrointestinal Tract: Where Microbiota Meets Host

6.2.3    The Microbiota and the Immune System: More than Just Flagging Good vs. Bad

6.2.4    The Nervous System: Two Brains

6.2.5    The Hypothalamic-Pituitary-Adrenal (HPA) Axis: A Lifeline in Times of Need

6.2.6    Impacts on Host Metabolism

6.2.7    Co-evolution: Commensalism and Beyond

6.3       Control and Order Parameters

6.3.1    Extrinsic Control Parameters

6.3.2    Intrinsic Order Parameters

6.3.3    The Microbiota as an Extrinsic Control Parameter and Intrinsic Order Parameter

6.3.4    Extrinsic Control Parameters and Targeted Interventions

6.3.5    Intrinsic Order Parameters Through the Lens of the Innate Immune System

6.3.6    Integration of Bottom-Up and Top-Down Order and Control Parameters

6.3.7    New Prospects


Chapter 7. The Role of Insulin Resistance in Metabolic Disease

Chapter Overview

7.1      Physiological Role of Insulin in Classical Insulin Targeted Tissues

7.2       Insulin Resistance Under Healthy and Pathologic Conditions

7.3       Historical Context of Insulin Resistance

7.3.1    History of Syndrome X

7.3.2    Insulin Resistance Has Many Effects on the Body

7.3.3    Spotlight on C Ronald Kahn and Critical Nodes in the Insulin Signaling Pathway

7.3.4    Spotlight on Gerald Shulman

7.3.5    Spotlight on Phillipp Scherer’s Work on Ceramides and Inflammation

7.3.6    Ceramides, Ectopic Fat and ROS

7.3.7    Chronic Diseases of Aging as Manifestations of Insulin Resistance

7.4       Foundations of Insulin Resistance

7.4.1    Insulin Resistance and Metabolic Flexibility Clinical Tools: The Respiratory Quotient Dyssynchronous Insulin Signaling and the Loss of Metabolic Flexibility The Development of Pathogenic Hyperinsulinemia and Insulin Resistance Ectopic Lipid Accumulation and Insulin Resistance

7.4.5    The Role of Free Radicals and Oxidative Stress in Insulin Resistance

7.4.6    Implications of Insulin Resistance Across Different Tissues of the Body

7.4.7    The Relationship Between Mitochondrial Dysfunction and Insulin Resistance

7.4.8    Control Parameters of Insulin Signaling Insulin Resistance and Alzheimer’s Disease Insulin Resistance and Cardiovascular Disease

7.4.9    The Role of Insulin Signaling Dysregulation in Cancer

7.5       Bioenergeticsand the Basis for the Development of Insulin Resistance

7.5.1    Cellular Bioenergetics Under Normal Physiological Conditions

7.5.2    The Role of Mitochondria in Cellular Bioenergetics

7.5.3.   Mitochondrial Function and Insulin Resistance

7.5.4    Pyruvate Dehydrogenase Enzyme Complex May be the Key to Fighting Insulin Resistance Role of PDH in Energy Production and Insulin Resistance Yin and Yang of Glyceroneogenesis in Patients with Insulin Resistance

7.6       Insulin Signaling and the Link to Cancer

7.6.1    The Role of Insulin Resistance and Mitochondrial Dysfunction in the Pathogenesis of Cancer

7.6.2    Insulin Signaling, Cancer and Bioinformatics: Defining Simple Rules

7.7      Accelerated Cognitive Decline, Alzheimer’s Disease, and Insulin Resistance

7.7.1    Effects of Insulin Resistance on Microtubule Dynamics

7.7.2    Impaired Insulin Signaling, Neurofibrillary Tangles, and Amyloid Plaques

7.7.3    Brain Glucose Metabolism and Alzheimer’s Disease

7.7.4    Therapeutic Strategies for Treatment

7.7.5    Bioenergetics, PDK and Alzheimer’s Disease

7.8       Integrated Systems Biology Approach to Human Health and Disease

7.8.1    Osteocalcin and Insulin Signaling

7.8.2    Adiponectin, Leptin and Insulin Signaling Leptin and Circadian Insulin Signaling

7.9       Symmetry, Neuroendocrinology and Insulin Resistance

7.9.1    Order and Control Parameters in Insulin Resistance

7.9.2    Insulin Resistance as a Chronic Control Parameter

7.9.3    Stress as an Allostatic Response: Corticotropin Releasing Hormone and Growth Hormone as Antagonizers of Insulin Action

7.9.4    Prolonged Stress Response Resulting in Allostatic Load

7.9.5    Targeting Upstream Control Parameters to Treat Disease

7.10     Chapter Take-Home Messages


Chapter 8. Mitochondrial Function and Dysfunction and Insulin Resistance

Chapter Overview

8.1       Mitochondrial Dysfunction and Aging

8.1.1    Air Hunger as a Sign of Mitochondrial Dysfunction

8.1.2    Supplements for Mitochondrial Health L-Carnitine Transfers Fuel into the Mitochondria B Vitamins Are Essential for Energy Production Alpha-Lipoic Acid and Dihydrolipoate Recharge Other Antioxidants Coenzyme Q10 May Counter Myalgias Vitamin D Promotes Mitochondrial Function Mediated by Both Anti-inflammatory and Insulin Sensitizing Effects Benefits and Dangers of Peroxisome Proliferator Activated Receptor ɣ Supplementation Dimethyl Fumarate Stimulates Antioxidant Genes Vitamin K Maintains Calcium Homeostasis and Improves Insulin Sensitivity Minerals and Trace Elements

8.2       Linchpin Concepts Connecting Mitochondrial Dysfunction to Chronic Diseases of Aging

8.2.1    Mitochondria: The Bioenergetic Powerhouse of the Cell

8.2.2    Mitochondria: Structure, Function, and Pathophysiology Mitochondrial Function Influence of Nutrient/Diet on Mitochondrial Function

8.2.3    Intertwined Relationship Between Mitochondrial Dysfunction and Insulin Resistance The Evolution of Insulin Resistance in Insulin Responsive Metabolic Tissues Development of Insulin Resistance in Skeletal Muscle Development of Insulin Resistance in Liver and Visceral Adipose Tissue Overconsumption, Mitochondrial Dysfunction, and Insulin Resistance Circadian Disturbances, Insulin Resistance, and Mitochondrial Dysfunction

8.2.4 Metabolism of Macronutrient Substrates and Insulin Resistance Cellular Lipid Deposition, Mitochondrial Dysfunction and Insulin Resistance Role of Intracellular Fatty Acid Metabolites in Insulin Resistance Fatty Acid Metabolism, Mitochondrial Function and Insulin Resistance Influence of Timing and Fuel Selection on Metabolic Flexibility and Mitochondrial Function Is Mitochondrial Dysfunction a Cause or Consequence of Insulin Resistance?

8.2.5    Future Perspectives

8.3      Chapter Take-Home Messages


Chapter 9. Chronic Diseases of Aging as Metabolic Disorders

Chapter Overview

9.1    The Role of Metabolism in the Chronic Diseases of Aging

9.1.1 Relationship of Mitochondria and Insulin Signaling in Metabolic and Chronic Diseases of Aging The Interdependent  Relationship of Obesity, Inflammation, and Insulin Signaling in Cancer Quest for the Truth

9.2        Cancer as a Metabolic Disease

9.2.1    Obesity and Cancer

9.2.2    Insulin Signaling and the Warburg Effect

9.2.3    Oncogenic Signaling and the Warburg Effect

9.2.4    Anaplerosis: Connecting the Warburg Effect and Mitochondrial Function in Proliferating Cells

9.2.5    Targeting Carbohydrate Metabolism for Cancer Therapy

9.2.6    Targeting Amino Acid Metabolism in Tumorigenesis

9.2.7    Targeting Lipid Metabolism in Tumors

  1. Targeting Cholesterol Metabolism
  2. Targeting Fatty Acid Metabolism

9.2.8    Targeting Whole Body Metabolism (Systemic) for Cancer Management

  1. Fasting
  2. Ketogenic Diets
  3. Caloric Restriction

9.2.9    Repurposing Metabolism-Related Drugs to Fight Cancer

  1. Metformin
  2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

9.2.10 Conclusion and Future Perspectives

9.3      Alzheimer’s Disease: Another Chronic Metabolic Disease

9.3.1    Amyloid Beta and Synaptic Dysfunction

9.3.2    The Shared Pathogenesis of Insulin Resistance and Alzheimer’s Disease Dyslipidemia

9.3.3    The Role of Amylin in Amyloid Beta Accumulation

9.3.4    Alzheimer’s Disease and the Reverse Warburg Effect

9.3.5    Insulin Resistance, Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

9.3.6    The Brain’s High Energy Requirements Make it Susceptible to Mitochondrial Dysfunction

9.3.7    Insulin Resistance and Cognitive Decline

9.3.8    Molecular and Genetic Contributors to Alzheimer’s Disease Pathology The GSK3 Hypothesis of Alzheimer’s Disease

9.3.9    Pharmacologic Therapies for Alzheimer’s Disease

9.4       Metabolic Cardiomyopathy

9.4.1    An Overview

9.4.2    Physiological Cardiac Hypertrophy

9.4.3    Pathological Cardiac Hypertrophy Diabetic and Metabolic Cardiomyopathy

9.4.4    Non-ischemic Dilated Cardiomyopathy

9.4.5    Ischemic Dilated Cardiomyopathy

9.4.6    Vascular Atherosclerosis Lipoproteins, Cholesterol and Vascular Atherosclerosis Current Therapies and Algorithmic Indications of Cholesterol Reduction Therapy Prospective New Therapies

9.4.7    Metabolic Pharmacotherapy of Heart Disease Metformin Fibrates, TZDs, and Vitamin D Trimetazidine

9.5       The Physiological Fitness Landscape – A New Model of                   Personalized Precision Medicine

9.6       Summary

9.7       Chapter Take-Home Messages


Biological Time, Fitness Landscapes, Control Parameters of Aging, and their Effects on Health and Disease

Brian J. Fertig

Department of Diabetes & Endocrinology, JFK Medical Center, Piscataway, NJ 08854

Synchronized energy production in the human body is described by quantum metabolism involving coherent endogenous clock-controlled gene outputs. This is linked to aging and disease by integration with the concepts of time/cycles, stress response and diet/microbiota as control parameters that mediate disease. They crucially initiate pathology via molecular mechanisms that drive inflammation and oxidative modifications. Each control parameter perturbs the others in a vicious cycle of cause-effect amplification. Importantly, disturbances in these 3 parameters accelerate the pace of aging as a function of impaired metabolic rate and efficiency, and the inextricably entangled compromise of redox and free energy homeostasis. Prolonged stress response alters circadian timing, dieet, and microbiota and is nonlinearly compounded to the detriment of health. The neuroendocrine and autonomic nervous systems mediate allostasis but if prolonged, cause allostatic overload that disturbs homeostasis. For simplicity, we propose the concept of fitness landscape where control parameters are represented as horizontal axes and the vertical axis maps the fitness function measured in response to them. Valleys in the stress response plots correspond to stability regions but peaks and ridges delineate boundaries. These areas refer to optimal health, a pre-diabetic state, and advanced disease. Almost all chronic diseases of aging share the same control parameters, hence a common framework should be developed instead of a fragmented approach. Three critical aspects on the periphery of modern medical interventions: chronophysiology, microbiota and prolonged stress, are entering the mainstream of medical research thanks to advances in understanding how they affect our health. Their inclusion within the fitness landscape methodology consistent with special relativity offers a practical approach to optimal solutions for healthy aging and precision-medicine therapies for age-related diseases.


Chapter Overviews

CHAPTER 2 The Stress Response: From Health to Disease

Colloquially speaking, stress is often used to describe an unpleasant situation (e.g., an overbearing boss), the reaction to the situation (i.e., headache, chest pain, heartburn) or the cumulative response to these reactions (i.e., an ulcer or a heart attack). Historically, stress was often perceived as negative and synonymous with distress – a physical, mental, or emotional strain. However, stress has both positive (health-promoting) and negative (health-damaging) functions. Stress is any challenge to the normal balance of biological systems of the body. Stressors may include work or school stress, social conflict and isolation, financial stress, adjustment stress, bereavement stress, competition stress and health stress. The type, amount, and effect of stress on the body can be quite subjective depending on physical, psychological and social makeup. However, resilience to stress is required for a healthy state just as debilitating stress is required for a diseased state.

Stress, in the context of this volume, is defined as any disruption or a threat of disruption to homeostasis, the body’s dynamic equilibrium. Homeostasis is the maintenance of morphological, physiological and behavioral daily routines of the life cycle through allostasis. Allostasis is the healthy, adaptive response to maintaining/restoring homeostasis through the hormonal, autonomic and immune systems. Allostatic load is the cumulative result of an allostatic state and a subthreshold critical point whereby homeostasis of vital organ systems is maintained. Beyond this threshold is allostatic overload, which is tantamount to the onset of chronic disease. This is represented when allostasis can no longer maintain homeostasis of vital organ systems. Disharmony in this exquisite, organizationally complex system can drive the body from health to disease.

When the brain senses a stressful situation, it activates the autonomic nervous system or the body’s “fight or flight” response, triggering a metabolically-demanding cascade of stress hormones that produce well-orchestrated physiological changes. The brain, particularly the hypothalamus, signals the adrenal glands on the kidneys to release stress hormones such as adrenaline, cortisol and norepinephrine. As these hormones travel through the bloodstream, they increase heart rate, increase blood pressure and dilate the air passageways of the lungs to bring in more oxygen with each breath. Extra oxygen delivered to the brain increases alertness and heightens the body’s senses, priming the body for instant action. Following this fast-acting surge of hormones, the secondary stress response system activates what is known as the hypothalamic pituitary adrenal axis, continuing to release hormones into the bloodstream if the brain continues to perceive a threat. Acute and short-lived stress promotes enhanced cognition and emotion regulation whereas prolonged and chronic stress deteriorates learning and memory, and accelerates the trajectory to mental illness and biological diseases of aging.

There is an amazingly complex network of molecular pathways and receptors dedicated to the handling of stress at the cellular level. This chapter will provide the reader with an up-to-date overview of these networks and the key players at a molecular, cellular and organ levels. Stress may be understood in terms of the binding of cortisol to glucocorticoids and mineralocorticoid receptor neuron cells of particular structures in the brain where objective cognitions occur. Some of the major brain regions involved in the stress response are the amygdala, the emotional seat of salient information in the brain, the hippocampus, where contextual memory consolidation and retrieval mainly occur and, the prefrontal cortex, where stress regulation and higher order cognitive functioning take place such as decision-making. This should be thought of as shorthand and not an indication of brain regions with completely separate functions in the stress response.

Anxiety is often related to psychogenic stress. The root cause of anxiety (accumulated prolonged and excessive levels of stress) resides in the failure to achieve a solution to a problem, which leads to a state of uncertainty. When this occurs often and surpasses a critical threshold, a chronic state of anxiety sets in leading to allostatic overload whose consequences can be detrimental to an individual’s state of health. Prolonged stress may result in exaggerated stress responses, chronic anxiety, pathophysiology, and psychopathology. Conversely, one way to reduce anxiety is to lower expectations of the goal state. An adaptive stress response is required of an individual to build resilience to be able to cope with stress and maintain allostasis. Allostasis is mediated by hormonal (endocrine), catecholamine (nervous) and cytokine (immune) system responses. Mediators of allostasis can be both protective, in the case of allostasis (stability through change), and harmful, in the case of allostatic overload. This is known as the stress paradox whereby acute stress can be vitalizing (health-promoting and lead to resilience) but chronic levels of stress can be devitalizing (health-damaging and lead to psychophysiological ramifications).

Psychogenic stress manifests not only as anxiety but also as depression, anger, and aggression, all fundamentally rooted in the fear of the inability to control, and the consequences of, challenges/stressors. The aggressive behavior of an individual with alcohol use disorder, which is often attributed to the drinking itself, the “alcohol makes him/her aggressive or violent”, is rather due to the fear of not being able to control the resistance not to drink, and the fear of its consequences. These are very important concepts discussed in this chapter that need to be emphasized here.

The most fundamental concepts of this current chapter are homeostatic-allostatic balance, the stress-driven progression from healthy to diseased states and, the implementation of a stress-centric predictive model to improve clinical practice known as the physiological fitness landscape model (Figure 2.S1). The physiological fitness landscape model is a quantitative measure of an individual’s state of health or disease represented by a multi-dimensional topography.  Each axis in this model consists of control and order parameters. A control parameter represents a potential stress factor that can be applied to the organism. For example, a control parameter can be nutritional intake, physical exertion or even the disturbances in circadian rhythmicity (See Chapter 4 for more on biological clocks). Equally important, an order parameter is a variable that the living system changes in response to the control parameters and whose value is a measure of health or disease. A classic example would be the maximum heart rate that correlates with the VO2 max (maximal oxygen uptake) in response to vigorous exercise, the latter being measured by speed of running or the maximum velocity attained on a stationary bike.

Figure 2.S1. Stress response summary. Prolonged or chronic stress leads to a variety of downstream physiological outcomes including increased inflammation, immune system dysfunction, emotional and cognitive disturbances, anxiety, depression, disturbed microbial composition, and sleep disruption.

Importantly, the perception of stress underscores its effect on the body. Overall, people who report experiencing high levels of stress increase their risk of death by 43%. However, people who report experiencing high levels of stress but do not perceive the stress as harmful to their health have a considerably low mortality rate, comparable to those who report low levels of stress. So, can the body’s perception of stress alter life expectancy? New research on the effects of stress on the body, presented in Chapter 2, suggests that this may be possible. For example, when the brain senses a stressful situation, it signals increases in heart rate, blood pressure and oxygen intake. These physiological changes are often interpreted as signs of anxiety or the body’s incapability of coping with stress. However, if individuals perceive these physiological changes as the body’s preparation to successfully meet the challenge it is facing, psychological and physiological effects of stress are dampened, and the body is able to return to homeostasis.

The intention of Chapter 2 is to give the stress response the recognition it deserves. This chapter hopes to shed light on how the stress response provides a unifying explanation for virtually all chronic diseases of aging, which is often the most underappreciated element in medicine and public health. The perception of stress can alter life expectancy, which is the single greatest challenge to the profession of medicine – predicting death and intervening appropriately to delay it. The notion of stress can be extremely useful in clinical medicine as a model for testing susceptibility states of disease that cannot be assessed reliably in the baseline state, e.g., using a cardiac stress test to assess adrenal sufficiency. Monitoring responses to stressors and adaptability once the stressors are removed on a patient-by-patient basis can provide more valuable insights into disease prediction and progression as well as recommendations for optimal therapeutic interventions.

CHAPTER 3 Nuclear Hormone Receptors: Mediators of Dynamic (Patho)physiological Responses

In humans, the regulation of growth, metabolic homeostasis, and development processes involve extensive intercellular communication. This is achieved by various endocrine signals that often communicate with intracellular receptors that regulate gene expression. In this latter process, transcription factors, specifically nuclear hormone receptors (NHRs), participate in the up- or down-regulation of gene expression. Nuclear hormone receptors are ligand-inducible transcription factors that mediate changes to whole-body metabolic pathways (Figure 3.S1).

Figure 3.S1. Nuclear Hormone Receptor summary. NHRs are involved in numerous physiological processes including metabolism, reproduction, cell growth and differentiation, immune function, and CNS functions. Adapted from Yang X. (2010). A wheel of time: the circadian clock, nuclear receptors, and physiology. Genes & development, 24(8), 741–747.

Nuclear receptors include steroid ligand nuclear receptors such as: androgen receptors (AR), estrogen receptors (ER), progesterone receptors (PR), glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). These classical hormone nuclear receptors bind to DNA as homodimers inducing transcription. They have evolved to regulate carbohydrate and lipid metabolism, development, reproduction, and electrolyte balance.

The regulation of ligands that bind to these hormone receptors takes place via the classical hypothalamic-pituitary axis negative feedback mechanisms. The extended family of steroid nuclear hormone receptors such as GR and peroxisome proliferator- activated receptors (PPARs) utilize energy and are involved in sensing. For example, the hormone glucocorticoid binds to the GR, as it regulates hepatic and systemic glucose metabolism. PPARs regulate whole-body glucose and lipid metabolism. Thus, under normal physiological conditions, GR and PPARs maintain systemic energy homeostasis.

Additionally, recent studies have suggested that NHRs are tractable targets for cardiovascular disease and diabetes therapy, especially Farnesoid X receptors (FXRs) and liver X receptors (LXRs), which regulate multiple metabolic pathways. As metabolic regulators, FXR and LXR play a major role in glucose and lipid metabolism. Upon activation by bile acids, FXR regulates various aspects of lipid and glucose metabolism. LXRs play a crucial role in regulating the reverse cholesterol transport pathway in lipogenesis and in the maintenance of whole-body glucose homeostasis.

Current studies have indicated that both LXR and FXR are associated with the development of metabolic diseases. Therefore, FXR and LXR might have therapeutic implications for the treatment of metabolic diseases such as type 2 diabetes and cardiovascular disease. In addition to this, ~25% of the adipose tissue genes are regulated by the circadian clock to maintain lipid energy metabolism. Thus, the nuclear receptor family plays a pivotal role in mediating communication between circadian rhythms and metabolic functions to maintain whole-body energy homeostasis.

CHAPTER 4 The Biology of Time: How Molecular Clocks Make Living Cells Tick

Time is a concept that we are all acutely aware of, especially of its passing, but would have great difficulty defining in precise terms. It’s a relational quantity. We measure it in terms of some controllable processes using devices such as clocks, or in relation to the cycles of the Sun, the Moon, or galaxies in the night sky. Einstein demonstrated that time is relative and there is no universal frame of reference for time or space for this matter. The most fundamental cycle in biology is the metabolic cycle that sets the clock rate, or number of cycles per unit of time, for the whole body.

All living systems age and die and the average length of time between birth and death is called life expectancy, but it differs significantly between men and women as well as different populations analyzed by country, ethnicity, and even profession. In this chapter, we delve into the all-important topic of the biology of time, a topic that has now produced astonishing insights into the existence of molecular clocks. This is intimately related to two major physical issues involved, namely cyclicity of biochemical reactions and its gradual degradation due to the increased entropy production as our bodies age and lose their synchronized perfection.

Biological cycles are categorized as circadian (24 hours), infradian (longer than 24 hours) and ultradian (shorter than 24 hours) systems, which together are intricately interactive and interconnected. The aging process is a manifestation of the desynchronization away from the exquisitely orchestrated beauty of biological perfection of cyclical processes at all levels of organization that operate as a singular whole in youthful states of optimal health.

The overarching message of this chapter is the notion of a biological cycle. We also underline the strong connection between biological cycles and the superfamily of thyroid and steroid nuclear hormone receptors. These receptors act as transcriptional regulators of hormone- and lipid-derived ligands to maintain the acid-base, redox and energy branches of metabolic homeostasis organism-wide.

Time is an essential variable in biological systems, measured in terms of cycles. The constant influx of energy in a living system maintains it in a far from equilibrium state. Time is measured externally with mechanical clocks composed of physical oscillators. Biological processes are measured and conducted by internal endogenous clocks, molecular machinery present in all cells that have DNA. These molecular clocks are the astonishing evolutionary incarnate of the earth’s rotation around its own axis.

The cell’s endogenous timepieces include central (SCN) and peripheral (non-SCN) circadian oscillators that link metabolic pathways of physiology and behavior to 50% of the human genome. This temporal organizing strategy is essential for maintaining energy and redox homeostasis, and hence life itself. The SCN receives primary sensory cues in the form of visible light and thus synchronizes to the diurnal light-dark cycle of the external environment. The circadian pattern of neurotransmission originating from the master pacemaker reaches many other regions of the brain such as the hypothalamus and the pineal gland. Central circadian regulation of these areas of the brain from the SCN in turn provides neural and hormonal cues to different tissues and organ systems throughout the body, thus temporally coordinating many aspects of physiology. These cues include autonomic fibers, hypothalamic-pituitary-adrenal gland axis (HPA axis) and melatonin. Accordingly, while the autonomic nervous system and HPA axis mediate the body’s stress response, and melatonin promotes sleep induction and slow wave sleep, these are also central conductors of systems biology within and between tissues of the body. This allows the time organizational coherence of physiology to function as a system whole.

It follows that diurnal external light cues coming in through the retina of the eyes ultimately entrain the cell-autonomous circadian peripheral clocks that drive the timing of organ system physiology. Entrainment is the stable synchronization of external cycling events of the environment to the internal cycling pathways that conduct physiology. Teleologically, this orchestration between the central and peripheral clocks allows the anticipation and accordingly the adaptation to environmental changes, promoting maximum metabolic efficiency and homeostasis. There are many inputs received by the body that can entrain physiology, with the two strongest cues being light (for the master clock) and food for peripheral clocks.

Coordination with the major cycling external cues of light and food includes but is not limited to behavioral cycles of fasting/feeding, sleep/wake, and rest/activity. Additionally, aligned to external cues and to behavioral cycles are physiological cycles of core body temperature, neuroendocrine function and autonomic function (Figure 4.S1).

Figure 4.S1. Light serves as the primary visual cue which transmits information about the environment to the master clock, the suprachiasmatic nucleus (SCN). The SCN in turn signals to numerous brain regions and tissues that regulate hormone systems, the autonomic nervous system, and behavior.

The master metabolic regulator, AMP activated protein kinase (AMPK), and sirtuin 1 (SIRT1) are energy sensors with a complex and strong bidirectional interplay between themselves and with clock function in several tissues, most notably in the hypothalamus and the liver. AMPK and SIRT1 are intricately coupled to the steroid and thyroid superfamily of nuclear hormone receptors (NHR’s) and other transcriptional regulators that govern the circadian cycles of the energy and redox programs of metabolic homeostasis. Accordingly, these programs in states of excellent physiological health, align with circadian behaviors of the sleep-wake and fasting-feeding cycles. During nocturnal fasting energy consuming pathways are inhibited while energy (ATP) producing pathways are stimulated. Thus, for example, NHR peroxisome proliferator activated- receptor gamma (PPARgamma), which promotes anabolic pathways of adipogenesis and in parallel adipocyte filling lipogenesis, is upregulated during the daytime feeding phase of the circadian cycle (Figure 4.S2). Conversely, NHR PPARalpha, which promotes fatty acid oxidation, is diurnally activated during the nocturnal and fasting phase.

Figure 4.S2. Metabolic/physiological fitness landscape of changing bodyweight. a) Metabolically healthy obese – persistent dietary in the context of a pear-shape body type, or pharmacologic drug prescription with a PPAR???? agonist, promotes weight gain in the absence of developing pathogenic metabolic parameters. In these individuals there is greater adaptive storage capacity for excess lipids that correlates with the predominance of subcutaneous adipose tissue. Accordingly, there is resilience to the evolution of insulin resistance features (such as dysglycemia, hypertension and dyslipidemia), and correspondingly to a decline in the amplitude of the metaphorical physiological fitness landscape stable state. b) Metabolically unhealthy obese – persistent dietary overconsumption in the context of an apple-shape body type has less adipose tissue storage capacity. Consequently, there is less resilience to the loss of metabolic fitness, represented in a decline in the altitude of the metaphorical stable state within the topological terrain of the fitness landscape.

The timing of eating plays a key role in the timing, coordination and efficiency of metabolic pathways. It appears evident that 12 hours, and even up to 18 hours of consistent fasting on a daily basis of time restricted eating (TRE), particularly during the night, is a powerful if not crucial method for achieving optimal physiological body weight and health. This is rooted in the circadian rhythm of the synchronized symbiotic intestinal microbiota with human host metabolism. When we eat at a time that our body anticipates it, as is the case of TRE, the feeding cue reinforces and amplifies the circadian rhythms. However, when we eat at irregular times, when our body is not prepared for it, it provides conflicting cues to the circadian pathways that guide physiology and behavior.

Nocturnal eating induces impaired fasting glucose, fasting hyperlipidemia, insulin resistance and weight gain through a number of mechanisms. These include carbohydrate and fat consumption superimposed on a malalignment of nocturnal processes of hepatic glucose output and adipose tissue release of fatty acids respectively. These events may lead to glucose toxicity and lipotoxicity which induce inflammatory and redox stress, and insulin resistance that disrupt metabolic homeostasis. An additional contribution is the diurnal releasing pattern of melatonin at night. Melatonin inhibits pancreatic release of insulin and thus accordingly, this is another exacerbatory factor that potentiates not only hyperglycemia with nocturnal eating, but other manifestations of insulin resistance.

Eating patterns at times that conflict with other cues to the circadian clocks, and hence at a time when the body is not prepared, compromise metabolic function. Summarily, in addition to diet and other circadian behaviors, control parameters of biological time in the form of cycles include the stress response and the microbiome. Spatial-temporal desynchronization of metabolic pathways is consequent to a conflict in behavioral and physiological circadian cues. What ensues is a feedforward self-amplifying matrix of reverberating cascades whereby the control parameters and the primary markers of disease itself, i.e. redox, energy and inflammatory stress, cannot be extricated. Taken together, human disease may be defined from the perspective of a breakdown in the temporal organization of physiological processes and control parameters.

CHAPTER 5 Calorie Restriction, Intermittent Fasting, and Time-Restricted Feeding

The goal or physiological purpose of any living system is the survival of the organism, and species as a whole. Survival requires meeting the continually changing metabolic bioenergetic demands of the body. This demand is met by acquiring nutrients from the environment in order to provide the body with the energy required to perform biological function and maintain homeostasis. Like most things in life, there is an optimal level of nutrient consumption and both too little or too much can precipitate chronic diseases of aging.

Chapter 5 of this book focuses on Calorie Restriction, Intermittent Fasting, and Time- Restricted Feeding with biological and clinical discussions including: 1) how the energy sensors and the fuel gauges of the body (AMPK and SIRT1) promote survival and slow the pace of aging in a way that increases longevity; 2) the notion of hormesis with regard to optimal metabolic balance between and among systems; 3) the importance of endogenous circadian biology (both synchronized and dyssynchronous) on insulin signaling and underlying molecular cascades; 4) the interwoven relationship between nutrient intake, energy sensing, insulin resistance, mitochondrial dysfunction, and chronic diseases of aging; 5) and finally, the effects of chronic overnutrition on metabolic signaling and accelerated aging.

Survival early in life is more metabolically demanding and requires a higher energy input. It is during these years that higher levels of physical fitness, aerobic capacity, and endurance are supported. During post-reproductive years, longevity is the main goal. It has been demonstrated that calorie restriction is beneficial in promoting longevity, and preventing age-related chronic disease. Not only are there changes in optimal energy consumption based on the stage of life, but there are different genes that promote survival early or later in life. The most favorable of these lifestyle parameters are fundamentally connected to the optimal activation of the energy sensors AMPK and SIRT1 to promote survival and slow the pace of aging, thereby increasing longevity. These energy-sensing fuel gauges are coupled to gene programs of stress resistance, including DNA and cellular repair, antioxidant systems, autophagy, cell differentiation, and apoptosis. AMPK activity is upregulated during circumstances of calorie restriction, fasting, and exercise associated with accelerated ATP consumption. It is thought that the health benefits of calorie restriction are induced by AMPK-dependent inhibition of mTOR, acting to improve insulin resistance, promote mitochondrial biogenesis, prevent obesity and metabolic disease, and increase overall lifespan (Figure 5.S1).

Figure 5.S1. Calorie restriction summary. Excess nutrient consumption increases insulin levels and leads to desynchronization of biological clocks resulting in negative outcomes of cell growth, mitogenesis, mitochondrial dysfunction and suppression of longevity genes. Alternately, calorie restriction maintains low insulin levels that preserve synchronized clock function and result in beneficial effects such as induction of longevity gene transcription, activation of stress resistance programs, and mitochondrial biogenesis.

Optimal insulin sensitivity is known to coincide with calorie restriction, while excess nutrient intake has been associated with the development of insulin resistance. One characteristic of insulin resistance that makes it pathological is the loss of the circadian cyclicity of insulin secretory and sensitivity patterns in metabolic tissues. A common pathogenic behavior is chronic dietary overconsumption, not just in terms of total daily caloric intake, but the quantity of intake relative to the time of the day. Nuclear hormone receptors lie at the intersection between the endogenous clocks and metabolism, coupling metabolic processes to cyclical circadian output. In a negative feedback loop/bidirectional relationship, poor sleep results in insulin resistance due to increased stress response and disruption of endogenous clock synchronicity, while insulin resistance promotes poor quality sleep by inducing obstructive sleep apnea.

Chronic overnutrition can be defined as long-term nutrient intake that exceeds energy expenditure demands, which can then exceed the capacity for mitochondrial production of ATP, resulting in mitochondrial dysfunction. When there is mitochondrial dysfunction or overload, oxidation of nutrients is prevented and is instead diverted to storage within the cell. Lipid accumulation that exceeds the storage capacity of the hepatocyte eventually leads to insulin resistance and ultimately accelerated aging.

One underlying message of this chapter is the notion of hormesis, the perfect balance of stress. It is thought that stress at a lower level can be vitalizing, while stress at higher levels can be harmful or lethal. This balance is individual and depends on the stage of the life cycle, and can change dynamically over the course of a lifetime. This concept of hormesis can be used for physical exercise. The beneficial effects of activity and diet, both intensity and quantity, should be considered relative to the stage in the life cycle. Hormesis, importantly, can also be applied to caloric intake. There is a level that is optimal; based on energy expenditure as well as stage in the life cycle. Intake that is too low or too high can lead to oxidative stress and inflammation as well as insulin resistance and/or hyperinsulinemia. Many of the signaling pathways mentioned previously depend on a balance between nutrient depletion and nutrient overabundance. Allostatic load is “the wear and tear on the body;” chronic stress over time can lead to increased susceptibility to chronic disease.

CHAPTER 6 The Microbiota, a Symbiotic Entanglement of Human Metabolism

A greatly underappreciated aspect of human health is the crucial role played by the microbes with whom we share our bodies and upon whom we are unequivocally dependent. While the collection of microbes, or microbiota, is composed of bacteria, archaebacteria, eukaryotic microbes (including fungi), and viruses, this book focuses on the impacts of the bacterial members, the most thoroughly studied and understood. Roughly 95% of the resident bacteria—who outnumber us cell per cell—live in cooperative guilds (functional ecosystems) on the surface of the colon (the large intestine). It is here that we have some of our most critical interactions with the outside world and offer a hospitable, responsive environment for the microbiota.

Astoundingly, while bacteria populated the earth roughly 4.2 billion years and the first Homo sapiens emerged nearly 4 billion years later, we speak the same language, using shared signaling molecules and receptors, supporting one another in our mutual quests for life. Humans have had no choice but to co-evolve with the bacteria, making our more complex human capabilities totally dependent on their presence. Indeed, the bacteria are not parasites or even visitors; they are inextricable components of the “supraorganism” that functions coherently and in an enhanced manner due to our synergistic mutualism, as was so aptly realized by Nobel laureate Joshua Lederberg. Indeed, the components of the healthy supraorganism sing to the tune of the same circadian rhythms, share the same diet (though humans generally get the first pickings), and experience the same physical and psychogenic stresses.

While Hippocrates (460-370 B.C.) was convinced that “all diseases begin in the gut” and Antonie van Leewenhoek (in the 1680s) noted striking differences in microbes between oral and fecal samples as well as between healthy and diseased individuals, the importance of the gut microbiota regarding health was outweighed by the attention shifted toward getting rid of infectious agents (recognized as being microorganisms in the 20th century), knowing they could cause illness and even death. It has been a mere 10-20 years during which we are finally coming to appreciate that human health is critically dependent upon the health of our microbiota—for better and worse.

A major chapter in Volume 2 is devoted to this topic. Among the marvels of the microbiota that will be addressed therein are: (1) its necessity in activating and training our innate and adaptive immune systems (some 70% of which resides in our gut), enabling them to differentiate between symbiotic bacteria vs. pathogenic bacteria and healthy human cells vs. cancer cells; (2) its role as a so-called “second brain” associated with its own enteric nervous system that communicates back and forth with the same signaling molecules and neurotransmitters of the human brain; (3) its ability to elicit far-reaching transcriptional and epigenetic activity throughout the body; (4) its ability to turn dietary fibers indigestible to humans into indispensable vitamins, regulatory molecules, and other essential products; and (5) its balance of “healthy” versus “unhealthy” strains that has profound impacts on our health, mediating such modern—indeed, epidemic—ailments as obesity, type 2 diabetes, cardiovascular disease, a host of autoimmune diseases, a range of mental illnesses (e.g., depression, anxiety, ADD, ADHD, autism, and schizophrenia), Alzheimer’s and Parkinson’s diseases, irritable bowel syndrome, compromised liver and kidney function, and a variety of cancers. Like an endocrine organ, the impacts of the microbiota extend throughout the body and are unquestionably fundamental to our health (Fig. 5.29).

For the modern-day medical practitioner, the time has come to embrace the potential of the microbiota to address health in new ways. With urbanized lifestyle-driven shifts in our microbiota leading to reductions in the diversity and fraction of healthy bacterial strains in the gut, the onus is upon our medical practitioners to examine the spectrum of bacteria and bacterial metabolites that might be foundational to the panoply of related illnesses and consider restoring the gut with critically missing microbes from a repository of such microbes. Patient-specific restorations could be more effective than the standard use of medicines that often address symptoms rather than causes, or hurt the body’s immune system, for example. Metabolic or Physiological Fitness Landscapes could be employed to great effect to identify appropriate precision restoration treatments that have the potential to reverse a wide range of the modern westernized metabolic- and inflammatory-related health epidemics. We refer the reader to a dedicated chapter in Volume 2 which presents a comprehensive discussion of the role of microbiota in maintaining good health.

Figure 6.S1: An illustrative microbiota summary. An interwoven, bidirectional and self-amplifying web of parameters that affect microbial health.

CHAPTER 7 The Role of Insulin Resistance in Metabolic Disease

Insulin resistance is a cardinal underlying mechanism in the pathogenesis of chronic disease states. In many cases, insulin resistance results from adaptive responses in efforts to promote survival under circumstances of scarce energy availability. Insulin signaling pathways typically induce mechanisms of cell survival and growth in the presence of required bioenergetic machinery such as healthy mitochondria. Although it is linked to metabolic disease, insulin resistance also plays a role in healthy physiology under conditions of periodic cyclicity such as the fasting/feeding circadian cycles seen in humans. Insulin resistance additionally results as an adaptation to cope with excess energy stores. Under these conditions it serves as a protective mechanism for metabolic tissue and prevents these tissues from being exposed to the threat of increased energy influx. There are currently two predominant theories of the exact etiology of insulin resistance that debate whether it precedes or follows a state of hyperinsulinemia. Another less widely discussed theory involves the notion of subclinical endotoxicosis promoting inflammation, which ultimately leads to hyperinsulinemia and secondarily to insulin resistance. Each of these arguments is discussed in great detail in the Insulin Resistance Chapter.

Insulin secretion and signaling are each under circadian regulation. Moreover, insulin signaling governs the timing of biological clock activity. This bidirectional relationship hi- lights the significance of food as the strongest external cue for peripheral clocks. The loss of circadian rhythm of daytime insulin sensitivity and secretion alternating with nocturnal insulin resistance is a primary driver and component in the pace of aging and in the pathogenicity of chronic diseases of aging. Furthermore, non-circadian insulin resistance is integrally linked to mitochondrial dysfunction. Consequently, there is a matrix of feed forward self-amplifying loops of redox and inflammatory stress that are intrinsic to the most basic elements of metabolic disease, that also include imbalances of energy and acid-base. The relationship of redox, energy and acid-base parameters of metabolic homeostasis is highlighted by a strikingly tandem correlation between the Nernst (redox), Gibbs free energy and Henderson-Hasselbalch (acid-base) equations.

The energy sensors AMPK and SIRT1 are primary metabolic regulators with a strong circadian influence. They connect energy consuming and producing pathways (in the case of AMPK) and redox stress resistance programs (in the case of SIRT1) in an inextricably coupled fashion to biological clocks for the maintenance of metabolic homeostasis.

Fundamental to the development of metabolic disease is the decoupling between the cytosolic glycolysis pathway that converts glucose to pyruvate and mitochondrial oxidative combustion (oxidative phosphorylation). This is especially important in tissues (such as skeletal and cardiac muscle, adipose tissue and brain) where glucose metabolism is dependent on insulin signaling. This is specific to GLUT4-mediated translocation of glucose into the cell and the enzyme complex pyruvate dehydrogenase complex (PDC) catalyzed decarboxylation of pyruvate to acetyl-CoA in mitochondria prior to feeding into the TCA cycle.

The term metabolic flexibility is classically reserved for the circadian “metabolic switch” that occurs in skeletal muscle at the transition of the fasting-feeding (nocturnal-daytime) cycle. Accordingly, fatty acid oxidation occurs during the nocturnal hours while glucose oxidation occurs during the day. The loss of circadian rhythm is therefore tantamount to the conversion from cyclical (healthy) to noncyclical chronic (unhealthy) insulin resistance.

Metabolic flexibility is lost in the setting of mitochondrial dysfunction. Thus, there is a decoupling of mitochondria from cytosolic glucose bioenergetic metabolism. Accordingly, glucose combustion cannot be completed by the process of oxidative phosphorylation in the cells of any tissue where mitochondria are not functional. Thus, cells are inflexible in the sense of adaptability to changes in energy substrate availability, and the presence of ectopic lipid deposits ensures that fatty acid oxidation (FAO) outcompetes glucose oxidation. The significance of this inflexibility is rooted in the greater oxidative stress generated by FAO versus glucose oxidation. The exact mechanisms of this decoupling of these pathways are detailed in the Insulin Resistance Chapter.

The perspective of mitochondrial function in the clinical approach to diabetes has been a crucial missing piece. There are currently a few drugs that may be used to help restore mitochondrial function in the treatment of diabetes and other metabolic disorders. One newly approved drug, 6j, targets the enzyme complex PDC and thus helps repair the coupling of glucose metabolism in the cytosolic glycolysis pathway to pyruvate with mitochondrial oxidative metabolism. Another drug, Imeglimin, targets nuclear hormone receptor (NRH) coactivator PGC1a to promote mitochondrial biogenesis. It is also relevant in the connection of insulin signaling and secretion to circadian biology and NHR biology. Chapters 3 and 4 are dedicated to NHR metabolic regulation and the Biology of Time, thus these drugs are highly relevant to the focus of these discussions.

Chapter 7 is dedicated to these topics of insulin signaling and resistance. Insulin signaling is discussed from a genomics and molecular perspective to unveil relevant pathways critical to the pathogenesis of insulin resistance. On a more translational and clinical basis, insulin resistance is examined here in the contexts of cancer, type 2 diabetes, cardiovascular disease, obesity, neuroendocrinology, and Alzheimer’s disease (Figure 7.S1).

Figure 7.S1. Insulin resistance and hyperinsulinemia lead to the pathogenesis of chronic diseases such as obesity, cardiovascular disease, type 2 diabetes, Alzheimer’s disease, cancer, and accelerated cognitive decline.

CHAPTER 8 Mitochondrial Function and Dysfunction and Insulin Resistance

This Chapter is where we connect all the dots regarding the bioenergetics of metabolism. We detail the crucial function of mitochondria in health and discuss how the inextricable and bidirectional link  between dysfunction of mitochondria and resistance to insulin contributes to chronic diseases of aging. We consider underlying and intertwined factors such as the stress response, circadian rhythms, gut microbiota, immune system response, and bioenergetics.

The central ideas covered in this book are metabolic health, metabolic disease, the initiation of metabolic health and disease, and therapeutics aimed at slowing down, stopping, or even reversing metabolic dysfunction. Metabolic health is directly linked to the energy producing organelles, mitochondria. Dysfunction of mitochondria is associated with insulin resistance and changes in VO2 max and VO2 submax. Skeletal muscle biopsy with cell mitochondrial stress testing can assessVO2 max and VO2 submax using rotenone and other electron transport chain inhibitors.

In the sense that mitochondrial function and insulin signaling are inseparably intertwined, mitochondrial dysfunction is interwoven in the fabric of insulin resistance. Whether the presence of insulin resistance and mitochondrial dysfunction overlaps completely remains unclear. Comparable to “the chicken or the egg,” the question of which of these parameters came first in the pathogenic process is posed. We would argue that this bidirectional, feed-forward relationship may be initiated by either mitochondrial dysfunction or insulin resistance, depending on patient-specific circumstances and genetic susceptibilities. On the one hand, it may be that all patients either develop insulin resistance as a cause, and subsequently an effect, of mitochondrial dysfunction, or it may be initially caused by mitochondrial dysfunction. In either case, if one accepts the premise that all chronic diseases of aging are rooted in mitochondrial bioenergetic compromise, then all individuals who eventually develop a chronic disease would also in parallel manifest underlying pathologies of insulin resistance and mitochondrial dysfunction. For counterarguments exploring the other sides of insulin resistance and dysfunctional mitochondria, see Sidebar 12.

CHAPTER 9 Chronic Diseases of Aging as Metabolic Disorders

This book’s primary aim has been to provide a fresh new perspective on biological systems and human physiology, especially related to metabolism and metabolic diseases, drawing largely on modern concepts in physics and information sciences.

The final Chapter is dedicated to the discussion of how the interwoven nature of mitochondrial dysfunction and insulin resistance (see Chapter 8) contribute to the progression of chronic diseases of aging such as cancer, Alzheimer’s disease, and cardiovascular disease. Taking into consideration other parameters such as the stress response, gut microbiota, circadian rhythms, immune responses and bioenergetics, these diseases are discussed and presented as metabolic disorders. Finally, we propose a new model for personalized precision medicine utilizing The Physiological Fitness Landscape (PFL).

Cancer is approached as a metabolic disease and discussed in the context of insulin resistance, bioenergetics and metabolic flexibility. Therapeutic approaches such as dietary alterations including calorie restriction, fasting, and ketogenic diets as well as the use of pharmaceuticals like metformin and NSAIDs are also detailed within this Chapter. Alzheimer’s can likewise be seen as a metabolic disorder due to the high energy demands of the brain and its resultant sensitivity to mitochondrial dysfunction. We outline how disruption in mitochondrial efficiency promotes insulin resistance and affects nerve cells leading to such neurodegenerative disorders and associated cognitive impairments. Cardiovascular disease and cardiomyopathy are also associated with insulin resistance, obesity and metabolic inflexibility and are examined as metabolic disorders here.

This Chapter concludes with an explanation of the proposal of a new model of medicine that is The Physiological Fitness Landscape. The significance of control and order parameters and the function of the PFL in creating a map to the restoration of health are discussed in detail. We emphasize the most important factors in maintaining a healthy life: vitalizing stress, diverse microbiota, proper chronophysiology, acid-base balance, redox homeostasis and a healthy regimen of exercise and diet that keeps inflammation at bay. Altogether, we show how physical science can inform medicine.