Sustained Energy for Enhanced Human Functions and Activity

Editor

Debasis Bagchi

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Preface

Section 1. Introduction

1. Information Theory and the Thermodynamic Efficiency of Biological Sorting Systems: Case Studies of the Kidney and of Mitochondrial ATP-Synthase

Introduction

A Summary of the Working of the Kidney

The Paradox of the Thermodynamic Efficiency of the Kidney

Maxwell's Demon, Its Exorcism, and the Entropic and Energetic Cost of Sorting

The Kidney as a Maxwell's Demon

Mitochondrial Adenosine 5′-Triphosphate (ATP)-Synthase as a Maxwell's Demon

Closing Remarks

2. Roles of AMP, ADP, ATP, and AMPK in Healthy Energy Boosting and Prolonged Life Span

Introduction

5′-Adenosine Monophosphate-Activated Protein Kinase

Mechanistic Target of Rapamycin/Mammalian Target of Rapamycin/FK506-Binding Protein 12-Rapamycin-Associated Protein 1

Acknowledgments

3. An Overview of Nitrite and Nitrate: New Paradigm of Nitric Oxide

Nitric Oxide Biochemistry and Physiology

Endothelial Dysfunction and Loss of NO Production

l-Arginine Supplementation

Nitrate–Nitrite–Nitric Oxide Pathway

Summary

4. An Overview on Nitric Oxide and Energy Metabolism

Introduction

Biochemistry of Nitric Oxide

Regulation of Mitochondrial Respiration

Nitric Oxide Regulates Energy Metabolism and Body Composition

Conclusion

5. Antioxidants and Mitochondrial Bioenergetics

Introduction

Experimental Studies

Therapeutic Potential of Antioxidants

Mosquito-Borne Diseases and Cancer

Clinical Significance of Charnoly Body Theranostics

Clinical Significance of Charnoly Body Formation in Zika Virus and Other Diseases

Personalized Nanotheranostics

Fetal Alcohol Syndrome and Zika Virus Disease

Autophagy Versus Charnolophagy

Phagolysosome Versus Charnolophagosome

Clinical Significance of Charnoly Body and Charnolophagy

Metallothioneins Provide Mitochondrial Neuroprotection

Therapeutic Potential of Antioxidants

Significance of Charnolopharmacotherapy

Conclusion

6. Protein, Carbohydrates, and Fats: Energy Metabolism

Introduction

Carbohydrates

Protein

Lipids

Diet-Induced Thermogenesis/Specific Dynamic Action

Energy Metabolism and Obesity

Conclusion

Abbreviations

Section 2. Botanicals and Herbal Indgredients and Marine Nutraceuticals

7. Role of Selected Medicinal Plants in Sports Nutrition and Energy Homeostasis

Introduction

Diverse Medicinal Plants

Conclusions

8. Withania somnifera: Ethnobotany, Pharmacology, and Therapeutic Functions

Introduction

Chemical Composition

Toxicologic Studies of Withania somnifera

Pharmacokinetic Profile of Withania somnifera

Neuroprotective Effects of Withania somnifera

Anti-Parkinson Effects of Withania somnifera

Anti-Alzheimer Effects of Withania somnifera

Antiischemic and Antihypoxic Effects of Withania somnifera

Cardioprotective Effects of Withania somnifera

Anticancer Effects of Withania somnifera

Antiinflammatory Effects of Withania somnifera

Antimicrobial Effects of Withania somnifera

Antiarthritic Effects of Withania somnifera

Antistress Effects of Withania somnifera

Antidiabetic Effects of Withania somnifera

Aphrodisiac Effects of Withania somnifera

Conclusion

9. An Overview on Tribulus terrestris in Sports Nutrition and Energy Regulation

Introduction

Aphrodisiac Activity

Supplementation in Sport

Contamination and/or Adulteration of Dietary Supplements

Recommendations for Sport Nutrition With Supplements

Risk of Violating Antidoping Rules

10. The Use of Maca (Lepidium meyenii) for Health Care: An Overview of Systematic Reviews

Introduction

Methods

Data Extraction

Results

Discussion

11. An Overview on Rhodiola rosea in Cardiovascular Health, Mood Alleviation, and Energy Metabolism

Introduction/Overview

Active Constituents

Rhodiola rosea and Exercise Performance

Rhodiola rosea Combined With Other Substances

Mechanisms of Action

How to Take

Side Effects

Conclusions and Gap Analysis

12. Energy and Health Benefits of Shilajit

Introduction

Chemistry

Safety Studies

Research Studies

Discussion and Summary

13. An Overview on Ginseng and Energy Metabolism

Review

Introduction of Ginseng

Active Chemical Constituents

Pharmacological Effects

Health Effects

Conclusions

14. Glycyrrhiza glabra (Licorice): Ethnobotany and Health Benefits

Effect on Respiratory System

Hepatoprotective Effect

Effect on Cardiovascular System

Immunity Regulation and Antiinflammation Effects

Antitumor Activities

Effect on Gastrointestinal Tract

Effect on Endocrine System

Side Effects and Cautions

Conclusion and Perspective

Abbreviations

15. An Overview of Yohimbine in Sports Medicine

Introduction

Mechanisms of Action

What Are the Needs for Sports Enhancement?

Theoretical Reflections

Metabolic Effects in Humans

Proven and Potential Toxicities

Would Yohimbine Be Unique in Its Activity for Sports?

Has Yohimbine Been Adequately Studied for Sports?

16. Black Ginger Extract Enhances Physical Fitness Performance and Muscular Endurance

Introduction

Mechanisms of Kaempferia parviflora Extract Underlying Increases in Physical Fitness by Kaempferia parviflora Extract

Effects of Kaempferia parviflora Extract on Physical Fitness and Muscular Endurance in Mice

Clinical Trials

Conclusion

17. Role of Marine Nutraceuticals in Cardiovascular Health

Introduction to Angiotensin-I–Converting Enzyme Inhibition

Marine-Derived Angiotensin-I–Converting Enzyme Inhibitors

Concluding Remarks

18. Royal Jelly in Medicinal to Functional Energy Drinks

Introduction

Royal Jelly

Energy-Enhancing Actions

Formulations

Marketing Challenges

Conclusion

19. Role of Caffeine in Sports Nutrition

Introduction

An Overview on Caffeine Metabolism

Effects of Caffeine on Endurance Performance

Effects of Caffeine on Strength Performance

Effects of Caffeine on Power Performance

Caffeine Ingestion: Source and Dosage

Mechanisms of Action of Caffeine

Side Effects, Health Risks, and Cautions

Summary

20. Beneficial Roles of Caffeine in Sports Nutrition and Beverage Formulations

Caffeine: History

Sources and Consumption

Mechanisms of Action

Effects on Performance

Caffeine Responders

Caffeine Habituation

Caffeine Abstinence Period

Timing of Caffeine Administration

Caffeine Dosage

Caffeine Effects and Training Status/Specificity of Training

Summary

Section 3. Amino Acids

21. Amino Acids and Energy Metabolism: An Overview

Introduction

Amino Acid Metabolism

Glucogenic Amino Acids and Ketogenic Amino Acids

Catabolism of Amino Acid Carbon Skeletons

Control of Body Temperature and Energy Metabolism

Conclusion

22. Branched Chain Amino Acids and Sports Nutrition and Energy Homeostasis

Biological Bases of Branched Chain Amino Acids

Branched Chain Amino Acids and Athletic Performance

Scientific Opinions and Guidelines of Governing Bodies and Institutions

Effects of Administration of Branched Chain Amino Acids in Different Sports

Practical Applications and Concluding Remarks

23. HMB Supplementation: Clinical and Performance-Related Effects and Mechanisms of Action

Introduction

Metabolism

Pharmacokinetics

Clinically Related Effects

Ergogenic-Related Effects

Mechanisms of Action

Conclusions

Section 4. Antioxidants and B-Vitamins

24. Antioxidants and Vitamins: Roles in Cellular Function and Metabolism

Antioxidants

Antioxidant Enzymes

Vitamins

Effects of Antioxidant and Vitamin Supplementation

Oxidative Stress

Consequences of Antioxidant and Vitamin Deficiency: Oxidative Stress in Cellular System

Antioxidant and Oxidative Stress Hypothesis of Aging

Conclusion

Section 5. Design a Novel Beverage Formulation

25. Salient Features for Designing a Functional Beverage Formulation to Boost Energy

Introduction

Designing a Functional Energy Beverage

Energy Beverage Formulations

Additives, Thickeners, Soluble Dietary Fiber, and Carbohydrates

Energy Formulations and Future Trends

Conclusion

Section 6. Safety and Toxicity

26. Caffeine-Containing Energy Drinks/Shots: Safety, Efficacy, and Controversy

Introduction

Caffeine's Prevalence in Society and the Emergence of CEDS

Pharmacology of Caffeine

Safety of CEDS

Efficacy of CEDS

Controversy

Conclusion

27. An Overview on the Constituents and Safety of Energy Beverages

Introduction

Epidemiology

Constituents

Extracardiac Effects

Cardiac Effects

Electrical Effects

Coronary Disease

Heart Muscle Disease

Effects in Specific Populations

Long-Term Effects

Conclusions

28. Interactions of Commonly Used Prescription Drugs With Food and Beverages

Introduction

Food–Drug Interactions

Drug–Beverage Interactions

Conclusion

Section 7. Commentary and Future Directions

Novel Energy Beverage Formulations: Efficacious, Healthy, and Safe

Energy: A High School Student's Perspective: Fossil Fuel to Renewables

Index

Copyright

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Notices

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Dedication

Dedicated to my respected and beloved Raj Bhaiya, Mr. Raj Kumar Kaushal, Chandigarh, India, who is always full of energy and inspiration.

List of Contributors

Muzamil Ahmad

Indian Institute of Integrative Medicine (CSIR), Srinagar, India

Academy of Scientific and Innovative Research, Indian Institute of Integrative Medicine (CSIR), Jammu, India

Asif Ali,     Aligarh Muslim University, Aligarh, India

Carlos E. Neves Amorim,     Federal University of Maranhão (UFMA), São Luís-MA, Brazil

Dawn E. Anderson,     Taylor University, Upland, IN, United States

Debasis Bagchi

University of Houston College of Pharmacy, Houston, TX, United States

Cepham Research Center, Piscataway, NJ, United States

Manashi Bagchi,     Dr. Herbs LLC, Concord, CA, United States

Karan Bhatti,     The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States

Nathan S. Bryan,     Baylor College of Medicine, Houston, TX, United States

Christian E.T. Cabido,     Federal University of Maranhão (UFMA), São Luís-MA, Brazil

Jason M. Cholewa,     Coastal Carolina University, Conway, SC, United States

Nevio Cimolai,     University of British Columbia, Vancouver, BC, Canada

Neil D. Clarke,     Coventry University, Coventry, United Kingdom

Nawab J. Dar

Indian Institute of Integrative Medicine (CSIR), Srinagar, India

Academy of Scientific and Innovative Research, Indian Institute of Integrative Medicine (CSIR), Jammu, India

Amitava Das,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Michael Duncan,     Coventry University, Coventry, United Kingdom

Elia Salinas García,     Nutriresponse, Madrid, Spain

Lucas Guimarães-Ferreira,     Federal University of Espirito Santo, Vitoria, Brazil

Bill J. Gurley,     University of Arkansas for Medical Sciences, Little Rock, AR, United States

Safia Habib,     Aligarh Muslim University, Aligarh, India

Zhang Han,     Tianjin University of Traditional Chinese Medicine, Tianjin, China

Kohsuke Hayamizu,     Yokohama University of Pharmacy, Yokohama, Japan

John P. Higgins

The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States

Memorial Hermann Ironman Sports Medicine Institute, Houston, TX, United States

Lyndon B. Johnson General Hospital, Houston, TX, United States

HEARTS (Houston Early Age Risk Testing & Screening Study), Houston, TX, United States

Daniel A. Jaffe,     United States Military Academy, West Point, NY, United States

Raj K. Keservani,     Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India

Rajesh K. Kesharwani,     NIMS University, Janupur, India

Se-Kwon Kim,     Pukyong National University, Busan, Republic of Korea

Tae-Hun Kim,     Kyung Hee University, Seoul, Republic of Korea

Rick Kingston,     University of Minnesota, Bloomington, MN, United States

Marijana Zovko Končić,     University of Zagreb, Zagreb, Croatia

Jarosław Krzywański,     National Centre for Sports Medicine, Warsaw, Poland

Temitope O. Lawal

University of Illinois at Chicago, Chicago, IL, United States

University of Ibadan, Ibadan, Nigeria

Hye Won Lee,     Korea Institute of Oriental Medicine, Daejeon, Republic of Korea

Myeong Soo Lee,     Korea Institute of Oriental Medicine, Daejeon, Republic of Korea

Fernanda Lima-Soares,     Federal University of Maranhão (UFMA), São Luís-MA, Brazil

Gail B. Mahady,     University of Illinois at Chicago, Chicago, IL, United States

Lou Massa,     City University of New York, New York, NY, United States

Chérif F. Matta

Mount Saint Vincent University, Halifax, NS, Canada

Dalhousie University, Halifax, NS, Canada

Saint Mary's University, Halifax, NS, Canada

Université Laval, Quebec, QC, Canada

Moinuddin,     Aligarh Muslim University, Aligarh, India

Barbara Morawin,     University of Zielona Gora, Zielona Gora, Poland

Hiroyoshi Moriyama,     The Japanese Institute for Health Food Standards, Tokyo, Japan

Arundathi Nair,     Laramie High School, Laramie, WY, United States

Aurora Norte,     Nursing Department, University of Alicante, Alicante, Spain

Kassiana Araújo Pessôa,     Federal University of Maranhão (UFMA), São Luís-MA, Brazil

Andrzej Pokrywka

University of Zielona Gora, Zielona Gora, Poland

National Centre for Sports Medicine, Warsaw, Poland

Yufeng Qin

National Engineering Technology Research Center of Glue of Traditional Medicine, Dong'e, China

Shandong Dong-E-E-Jiao Co., Ltd., Dong'e, China

Nishikant A. Raut

University of Illinois at Chicago, Chicago, IL, United States

Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India

Sashwati Roy,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Wenwen Ru

National Engineering Technology Research Center of Glue of Traditional Medicine, Dong'e, China

Shandong Dong-E-E-Jiao Co., Ltd., Dong'e, China

José Miguel Martínez Sanz,     Nursing Department, University of Alicante, Alicante, Spain

Chandan K. Sen,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Sushil Sharma,     Saint James School of Medicine, St. Vincent, West Indies

Hiroshi Shimoda,     Oryza Oil & Fat Chemical Co. Ltd., Ichinomiya, Japan

Kanhaiya Singh,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Prabhakar Singh,     Veer Bahadur Singh Purvanchal University, Jaunpur, India

Isabel Sospedra,     Nursing Department, University of Alicante, Alicante, Spain

Sidney J. Stohs,     Creighton University School of Pharmacy and Health Professions, Omaha, NE, United States

Anand Swaroop,     Cepham Research Center, Piscataway, NJ, United States

Sheila L. Thomas,     University of Arkansas for Medical Sciences Library, Little Rock, AR, United States

Kazuya Toda,     Oryza Oil & Fat Chemical Co. Ltd., Ichinomiya, Japan

Eric T. Trexler,     University of North Carolina, Chapel Hill, NC, United States

Yamini B. Tripathi,     Banaras Hindu University, Varanasi, India

Dongliang Wang

National Engineering Technology Research Center of Glue of Traditional Medicine, Dong'e, China

Shandong Dong-E-E-Jiao Co., Ltd., Dong'e, China

Sheila M. Wicks,     Rush University, Chicago, IL, United States

Isuru Wijesekara,     University of Sri Jayewardenepura, Nugegoda, Sri Lanka

Wang Xiaoying,     Tianjin University of Traditional Chinese Medicine, Tianjin, China

Durgavati Yadav,     Banaras Hindu University, Varanasi, India

Wang Yu,     Tianjin University of Traditional Chinese Medicine, Tianjin, China

Nelo E. Zanchi,     Federal University of Maranhão (UFMA), São Luís-MA, Brazil

Agnieszka Zembroń-Lacny,     University of Zielona Gora, Zielona Gora, Poland

Haojun Zhang,     Qilu University of Technology, Jinan, China

Xiangshan Zhou

National Engineering Technology Research Center of Glue of Traditional Medicine, Dong'e, China

Shandong Dong-E-E-Jiao Co., Ltd., Dong'e, China

Preface

The term energy represents the strength, vigor, enthusiasm, vitality, tenacity, power, or zest required for sustained physical or mental activity. Sustainable or sustained energy fulfills the needs of the present as well as future needs. Sustained energy has two major components: (1) renewable energy and (2) energy efficiency. Thus, the provision of continuous energy resources should be distributed in a way such that they meet the needs of the present requirements of the body without compromising the ability to meet the future needs of the body.

Human energy comes from the foods that we consume and the liquids/beverages that we drink. The three main nutrients used for energy are carbohydrates, proteins, and fats. The human body can also use protein and fats for energy once carbohydrates have been depleted. Once food is consumed, the human body breaks down nutrients into smaller components and absorbs them to use as energy or fuel. This process is known as metabolism. This book will discuss the physiological aspects of the human body and highlight how nutraceuticals/functional foods, botanicals and herbal supplements, structurally diverse antioxidants, B-vitamins, and diverse amino acids, including branched chain amino acids (BCAA), marine nutraceuticals, caffeine, and vital nutrients, can boost human energy safely and effectively for enhanced functions.

Regulating energy level is a fundamental process in every living organism. Adenosine triphosphate (ATP), a key, vital component of sustained energy, should be maintained at optimal levels in the cells in order to regulate the metabolic process. Maintaining a balance between energy supply and energy expenditure is very important for the whole body to function effectively. On the other hand, failing to regulate energy metabolism results in a huge increase in the prevalence of metabolic disorders. The human body needs to maintain an optimal level of ATP for routine energy production and physical performance. This supply of ATP is absolutely vital for the heart, lungs, and skeletal muscles to have all of the energy required for maximum strength and endurance output. The ATP level is also decreased during myocardial ischemia–reperfusion injury. Recent studies have demonstrated that proper nutrition, including antioxidants, vitamins, micronutrients, and selected amino acids, can enhance the energy level in the body and protect the heart as well as lungs from ischemia–reperfusion injury.

Selected nutraceuticals and functional foods, including standardized extracts of Withania somnifera, Tribulus terrestris, Lepidium meyenii (maca), Trigonella foenum-graecum, Glycyrrhiza glabra (liquorice), Kaempferia parviflora (black ginger), Camellia sinensis (black and green tea), Rhodiola rosea, Schisandra chinensis, shilajit, ginseng, green coffee bean, cocoa leaves, white willow, yohimbine, guarana, and cola nuts; caffeine in requisite amounts; amino acids, especially BCAA and including leucine, isoleucine, and valine; as well as phenylalanine, taurine and glutamine, chromium(III), magnesium, zinc, and copper supplements, are well demonstrated to promote sustained energy, reduce stress and exhaustion, improve endurance and immune function, decrease anxiety, and exhibit antiinflammatory, nerve-relaxant, and adaptogenic properties.

This book will address the basic mechanistic aspects of energy metabolism, the chemistry, biochemistry, and pharmacology of a variety of botanical or herbal supplements, micronutrients, antioxidants, structurally diverse amino acids, and other nutraceuticals, which have demonstrated a boost in and sustained functional energy. There are a number of chapters on caffeine so that readers may thoroughly understand the pros and cons. Also, a chapter highlighting the detrimental interactions of nutraceuticals and functional foods with commonly used prescriptions medications is included in this book. The Commentary and Future Directions section summarizes the earlier chapters, highlights paradigm shifts in the field, and envisions future directions. Finally, a talented high school student, Arundathi Nair, who received numerous state and national awards and recognitions, provided a section of her innovative thoughts on energy.

Today, it is very important to maintain good health and an optimal quality of life with effective energy. This new book will discuss the basic biochemistry and physiology of the human body and will demonstrate how exercise, proper nutrition, and selected ingredients can help humans to remain healthy, happy, and survive with sustained energy. A growing body of evidence demonstrates that nutraceutical and functional foods may naturally normalize this delicate balance. This book demonstrates how proper nutrient balance is useful to boost sustained energy.

Finally, I extend my sincere regards and gratitude to the esteemed authors for their valuable contributions to this book. I also wish to sincerely acknowledge Nancy Maragioglio, Megan R. Ball, Billie Jean-Fernandez, Namrata Bagchi, and Anirban Misra for their tremendous encouragement, helpful suggestions, criticisms, and technical support.

Debasis Bagchi, PhD, MACN, CNS, MAIChE

Section 1

Introduction

Outline

1. Information Theory and the Thermodynamic Efficiency of Biological Sorting Systems: Case Studies of the Kidney and of Mitochondrial ATP-Synthase

2. Roles of AMP, ADP, ATP, and AMPK in Healthy Energy Boosting and Prolonged Life Span

3. An Overview of Nitrite and Nitrate: New Paradigm of Nitric Oxide

4. An Overview on Nitric Oxide and Energy Metabolism

5. Antioxidants and Mitochondrial Bioenergetics

6. Protein, Carbohydrates, and Fats: Energy Metabolism

1

Information Theory and the Thermodynamic Efficiency of Biological Sorting Systems

Case Studies of the Kidney and of Mitochondrial ATP-Synthase

Chérif F. Matta¹,²,³,⁴, and Lou Massa⁵     ¹Mount Saint Vincent University, Halifax, NS, Canada     ²Dalhousie University, Halifax, NS, Canada     ³Saint Mary's University, Halifax, NS, Canada     ⁴Université Laval, Quebec, QC, Canada     ⁵City University of New York, New York, NY, United States

Abstract

It occurs that the kidney, an organ, and the mitochondrion, an organelle, are both physical realizations of a Maxwell demon. To understand how this occurs, a detailed analysis of the operation of the demon construct and of organ and organelle is given. The focus of attention in this chapter is upon the energetic cost of gathering information, as occurs in the biological function of both the kidney and mitochondrion. We give the mathematical definition of the cost of information. Horton A. Johnson and Knud D. Knudsen pioneered the use of this expression in calculating the efficiency of the kidney, solving a paradox long held, to the effect that the kidney efficiency was an order of magnitude less than that of comparable organs. By accounting for the cost of information gathered by the kidney in its biological function, its efficiency was shown to be of a magnitude similar to other such organs. Here we follow the reasoning of Johnson and Knudsen, but apply it to the biological function of the mitochondrion. In this way, we arrive at an efficiency for the mitochondrial oxidative phosphorylation that is approaching 90%, considerably higher than the corresponding textbook value of some 60%. This increase in the efficiency of the mitochondria parallels precisely the increase in the efficiency of the kidney achieved by Johnson, and for the same reason, viz., recognizing explicitly that there is an energy cost of information that must be paid for by whatever is the ultimate source of energy that is driving the process. Remarkably, information is not free but must be accounted for. The minimal energetic cost of one binary decision is kT ln2, irrespective of the precise mechanism at play. The parallel of the kidney and the mitochondrion, as two realizations of Maxwell's demon of substantially different size, is a biological illustration of an almost poetic observation of Feynman, to the effect that nature's patterns in the small are to be found repeated in the large, reminiscent as we might say of the repetitions characteristic of fractals.

Keywords

ATP; ATP-synthase; ATPase; Biological thermodynamics; Chemiosmotic theory; Information theory; Maxwell's demon; Regulatory organs; Thermodynamic efficiency

Physiologically, the work represented by the composition of the final urine is an almost negligible fraction of the work it is known the kidney must do. … [It] represents only about one per cent of the probable metabolism of the kidney as calculated from the oxygen consumption. This is not to say that the efficiency of the kidney is only one percent. … [T]he kidney's efficiency may be very high indeed—it is the thermodynamic approach that is only one per cent efficient.¹

Smith (1951)

Finally comes the universality of the gravitational law, and the fact that it extends over such enormous distances that Newton, in his mind, worrying about the solar system, was able to predict what would happen in an experiment of Cavendish, where Cavendish's little model of the solar system, two balls attracting, has to be expanded ten million million times to become the solar system, Then ten million million times larger again we find galaxies attracting each other by exactly the same law. Nature uses only the longest threads to weave her patterns, so each small piece of her fabric reveals the organization of the entire tapestry.¹

Feynman (1965)

Introduction

It happens that the kidney, which is an organ, and the mitochondrion, which is an organelle, are both physical realizations of Maxwell's demon. To understand how this occurs, an analysis of the operation of the demon construct is given as it applies to the kidney and the mitochondrion as information-gathering regulatory devices. Remarkably, information is not free, but costs a minimum of kT  ln  2 per bit irrespective of the mechanism at play. H.A. Johnson and K.D. Knudsen pioneered an accounting of the cost of information and resolved the long-held paradox that the kidney's thermodynamic efficiency appears to be significantly lower than that of comparable organs. Applying this approach to mitochondrial adenosine 5'-triphosphate (ATP)-synthase, the efficiency of oxidative phosphorylation is shown to approach 90% rather than the oft-quoted value of ∼60%. The parallel of the kidney and the mitochondrion as two realizations of Maxwell's demon of substantially different sizes is a biological illustration of an almost poetic observation of Feynman to the effect that nature's patterns in the small are found to be repeated in the large, and are reminiscent of repetitions characteristic of fractals.

A Summary of the Working of the Kidney

The kidney is the principal organ for osmoregulation in higher organisms. It regulates osmolarity by first filtering water and small solutes and then selectively reabsorbing what is needed, leaving out the rest as waste in the urine. The functional unit of the kidney is the nephron, which constitutes its repeating building block (Fig. 1.1); there are on the order of 10⁶ nephrons in a kidney. Arterial blood flowing into the nephron's glomerulus (via the afferent arteriole) gets partly filtrated in Bowman's capsule pushed through the pores by arterial blood pressure. The filtrate containing ions and small molecules is then channeled to the proximal convoluted tubule. The remainder of the blood is channeled away through the efferent arteriole (Fig. 1.1).

Many of the ions (e.g., Na+) and small molecules (e.g., glucose, amino acids) in the lumen of the proximal convoluted tubule are important for the organism and need to be reabsorbed. Reabsorption to the nearby blood capillaries occurs through the tubule cells (forming the wall of the tubule) against a concentration gradient (that is, going from low to high concentration), and hence is done actively with consumption of energy in the form of adenosine 5′-triphosphate (ATP). The manner by which this is achieved is described next.

A cell lining the lumen of the tubule, a tubule cell, has a side facing the tubule lumen called the luminal surface and a side facing the interstitial medium away from the tubule called the basal surface. Na+ ions penetrate a given tubule cell through its luminal surface in the direction of the concentration gradient via cotransporters that drag along with it other crucial solutes such as glucose and amino acids into the cell.

Once inside a tubule cell, the Na+ ions need to cross the opposite (far) side (that is, the basal surface) to reach the interstitial fluid. The movement of Na+ ions crossing the basal cell toward the interstitial fluid is in a direction opposite to the concentration gradient, and hence necessitates the expenditure of energy (active transport). That active transport is catalyzed by the basal surface's membrane-bound Na+-K+ pump (Na+-K+-ATPase) that uses one ATP to pump three Na+ ions out of the cell, each Na+ being cotransported with one K+ and two Cl− ions (Na+/2Cl−/K+ cotransport system) (Greger and Schlatter, 1983). This pumping maintains low intracellular Na+ concentration encouraging more to be reabsorbed from the filtrate residing in the lumen of the tubule. Glucose, amino acids, and other small crucial molecules have their concentration build up inside the cell (they are cotransported with Na+ from the lumen across the luminal surface) and diffuse passively on the other (basal) side down their concentration gradients.

Figure 1.1  Simplified diagram of a nephron showing its location within the tissue of a human kidney. www.bioweb.uncc.edu; http://player.slideplayer.com/38/10766277/#.

The filtrate then enters the loop of Henle, first into the descending limb and then into the ascending limb of this loop. The ascending limb is primarily permeable to small ions such as Na+, K+, and Cl−, which are actively transported, again using ATP, into the renal medulla to maintain its hypertonicity. Although permeable to salts, the ascending limb of the loop of Henle is impermeable to water in contrast to the descending limb which is permeable to water but not to salts.

Because the medullary interstitium is hypertonic, water leaks from the filtrate in the descending limb of the loop of Henle into the medulla by passive transport under osmotic pressure created by the ascending limb. This is the mechanism nature has fine-tuned to regain a large portion of the water (99%) that has been filtered in Bowman's capsule, because ATP-coupled transporters are optimized to operate on ions rather than water. The fluid contained in the upper segments of the loop of Henle (whether the descending or ascending limbs) near the outer border of the medulla have a concentration on the order of 0.1−0.3  ×  10³ osmol/L. The fluid in the bottom segment, the farthest from the outer surface of the medulla, has a significantly higher osmolarity to the tune of 1.2  ×  10³ osmol/L.

The fluid then passes to the distal convoluted tubule, where further and final reabsorption of ions, small molecules, and water occurs before fluid from different nephrons is eventually pooled into collecting ducts that pass through the medulla again. The collecting ducts have an adjustable permeability to water that is modulated by the action of antidiuretic hormone (ADH), also called vasopressin, and secreted by the posterior pituitary gland.

ADH is secreted in the bloodstream when osmoreceptors located in the hypothalamus sense a rise in the tonicity of the blood's plasma, e.g., after a salty meal, in which case the organism must retain water to regain the osmotic balance for its optimal vital functions. When the levels of ADH are high, permeability of the collecting ducts to water increases, allowing its passive diffusion into the medulla in view of its hypertonicity. This reabsorption in the medullary interstitium has the effect of concentrating the fluid (urine) before it is collected into the urinary bladder for eventual excretion.

The Paradox of the Thermodynamic Efficiency of the Kidney

The thermodynamic efficiency of an organ or of an organelle can be defined as the ratio of the work output w ), that is:

(1.1)

) by the amount of ATP used to produce wis about −50  kJ/mol (Garrett and Grisham, 2013; Guérin, 2004).

For a reversible heat engine (only for a heat engine and not just any type of engine), efficiency is governed by the second law which, according to Kelvin's equation, cannot exceed:

(1.2)

where the second term is the ratio of the absolute temperatures (in K) of the cold and hot reservoirs. Because most if not all known biochemical processes occur under approximately isothermal conditions, (Pereira and Cuesta, 2016).

, that is:

(1.3)

then:

(1.4)

) (Pereira and Cuesta, 2016; Nelson et al., 2011).

The partial osmotic work w exerted by the kidney owing to one given solute (in the mixture of solutes constituting urine) can be estimated by an equation derived in 1905 by von Rhorer, (1905) [or by its improved form for ions (Eggleton et al., 1940)]:

(1.5)

where n is the total number of moles of this solute extracted from blood to urine when the blood plasma concentration is cplasma and the concentration of this solute in urine is curine. Using this equation and after several simplifications and assumptions [described in detail in Eggleton et al. (1940), examples of which are the use of electrical conductivity to estimate the total electrolyte concentration or the use of vapor pressure measurements to estimate the total molar concentration], the estimated work is slightly underestimated, but by no more than  ∼5%–15% (Eggleton et al., 1940). In a nutshell, this is how the energy output is evaluated experimentally.

To evaluate efficiency, we now need the energy input. The chemical energy use in isolated dog kidney preparations was estimated by Eggleton et al. (1940) by measuring oxygen consumption. This is accomplished by measuring the oxygen tension in the arterial blood in both the afferent and efferent arterioles, with the drop in O2 tension being the measure of its use by the kidney (Eggleton et al., 1940). The energetic conversion factor is taken to be an energy of 5  kcal for every liter of consumed O2 [5  kcal/L(O2)].

With the osmotic work output estimated as described earlier and with an energy input obtained from measuring the change in O2 tension, the kidney's thermodynamic efficiency was found to be on the order of 1% (Eggleton et al., 1940), a value that corroborates earlier estimates such as that of Borsook and Winegarden (1931). These efficiency evaluations of isolated dog kidney are also in close agreement with estimates performed on anaesthetized human subjects (Clark and Barker, 1951).

An energy transduction efficiency of 1% is extremely low compared with, say, muscles with a transduction efficiency of the order of 45%–66% (taking into account both the heat emitted and the mechanical work produced versus ATP consumed by the muscle) (Wilkie, 1975). Commenting on their calculated efficiency of human kidneys, Clark and Baker (1951) list among their principal conclusions that:

These data suggest that the bulk of oxygen consumed by the kidney is used for purposes not measured by external work.

In making this statement, the authors were possibly referring to their previous observation that a large expenditure of energy is spent to maintain steady-state conditions in the kidney (Clark and Barker, 1951). Their remark however, does not preclude other contributions to this disproportionate energy expenditure compared with the osmotic work output of the kidney. This is exactly what Johnson and Knudsen (JK) argued in their 1965 article in Nature (Johnson and Knudsen, 1965), and (Johnson) in two following publications (Johnson, 1970, 1987). It all hinges on how thermodynamic efficiency is defined.

JK cite Wiener's observation that an electronic valve is energetically inefficient because it produces no mechanical or chemical work; its function is mainly to allow an oscillating current to pass in only one direction (Wiener, 1961). Most of the energy consumed by the valve is wasted in heating the filament to emit electrons that are channeled in only one direction. The electronic valve has not been designed to perform mechanical or chemical work but rather it constitutes an open control loop device: that is, a cybernetic rather than a mechanical or electrochemical machine.

Control devices can have substantial energetic expenditures in sorting actions such as unidirectional allowance or forbiddance of the passage of a given ion through a channel, the selection of a particular solute from a solution with multiple components, etc. To perform this type of sorting, the device first has to acquire information about the target that allows the control device to distinguish the right target from the wrong one. In this aspect, such a control device can be regarded as a realization of Maxwell’s demon, and hence must experience an increase in entropy that needs to be dissipated to recover the demon's initial state for a subsequent measuring act.

Maxwell's Demon, Its Exorcism, and the Entropic and Energetic Cost of Sorting

Maxwell discovered that the individual molecular speeds (v) at any given temperature T differ greatly from one molecule to another. The probability distribution of molecular speeds at a certain temperature is known as the Maxwell–Boltzmann distribution, which, in modern standard notation, is written:

(1.6)

where k is the Boltzmann constant and m is the molecular mass of the ideal gas.

Figure 1.2  Maxwell–Boltzmann distribution of molecular speeds of O 2 molecules (molecular weight   =   32   g/mol) at two different temperatures.

Fig. 1.2 displays this distribution for O2 molecules at two different temperatures. Enshrined within this distribution is the second law of thermodynamics itself because if we bring a hot and cold body into contact, molecular collisions at their interface (solid) or in the bulk (fluid mixture) will cause those of the hotter body to decelerate and those of the colder body to move faster on average. That is, heat flows spontaneously from the hotter to the colder body as required by the second law.

The distribution can be split at the median speed so that 50% of the molecules will be slower (colder) and 50% faster (hotter) than this speed. If we could somehow have a pair of ultrafine tweezers to pick and separate these molecules into a colder group and a hotter group, we would have introduced order, reduced entropy of the system, and created a system capable of performing useful work for nothing. This is the gist of what became known as Maxwell's demon's apparent violation of the second law of thermodynamics.

In a section entitled Limitation of the Second Law of Thermodynamics, Maxwell (1872) writes in his classic 1872 monograph Theory of Heat:

One of the best established facts in thermodynamics is that it is impossible in a system enclosed in an envelope which permits neither change of volume nor passage of heat, and in which both the temperature and the pressure are everywhere the same, to produce any inequality of temperature or of pressure without the expenditure of work. This is the second law of thermodynamics, and it is undoubtedly true as long as we can deal with bodies only in mass, and have no power of perceiving or handling the separate molecules of which they are made up. But if we conceive a being whose faculties are so sharpened that he can follow every molecule in its course, such a being, whose attributes are still as essentially finite as our own, would be able to do what is at present impossible to us. For we have seen that the molecules in a vessel full of air at uniform temperature are moving with velocities by no means uniform, though the mean velocity of any great number of them, arbitrarily selected, is almost exactly uniform. Now let us suppose that such a vessel is divided into two portions, A and B, by a division in which there is a small hole, and that a being, who can see the individual molecules, opens and closes this hole, so as to allow only the swifter molecules to pass from A to B, and only the slower ones to pass from B to A. He will thus, without expenditure of work, raise the temperature of B and lower that of A, in contradiction to the second law of thermodynamics.

The entire thought experiment described by Maxwell hinges on the act of "seeing, i.e., observing the molecules' paths as they approach the supernatural being. The being, later called by William Thomson (Lord Kelvin) Maxwell's demon, needs to determine the speed (momentum) of the incoming molecules to determine if they are cold or hot and also continuously measure their positions to open the shutter to allow them to the correct" portion, A or B, respectively.

With today's core knowledge that includes quantum mechanics, one has to consider Heisenberg's indeterminacy principle in such acts of observation of gas molecules because according to quantum mechanics position x and velocity (momentum p  =  mv:

(1.7)

Although this principle is a fundamental limitation on the precision of any observation irrespective of any experimental setup, it is insignificant in most cases of relevance to Maxwell's thought experiment. Heisenberg's indeterminacy principle can be more important in the case of light atoms and high pressures but not for heavier atoms, the low pressures typically found in biology, or molecules with masses that are several thousands of times larger than the mass of an electron. [See the discussion of this point on page 163 of Brillouin (2004) and the references cited therein.] Thus, ignoring any role of quantum indeterminacy, we depict Maxwell's thought experiment in the diagram of Fig. 1.3, which is self-explanatory.

Maxwell's apparent contradiction of the second law was addressed by several workers for over 60  years (Brillouin, 2004; Szilard, 1929; Leff and Rex, 1990, 2003; Bennett, 1987) until it was resolved by L. Szilard in his important publication in 1929. Szilard (1929) realized that the demon's act of seeing or observing these molecules, a first indispensable step to enable it to sort them, will result in the rapid increase in the entropy of the demon, and that as a result the entropy of the entire closed system (container  plus  demon) will increase as required by the second law. To use Brillouin's words, the demon has been exorcised (Brillouin, 2004). Let us now briefly retrace Brillouin's argumentation, exorcism, and derivation of the principal result (Brillouin, 2004).

Figure 1.3  A representation of Maxwell's demon. The demon observes the molecules in the two compartments and allows fast (hot) molecules ( red circles ) to go only from the right partition to the left partition and the slow (cold) molecules ( blue squares ) only from left to right. After some time, all hot molecules will be found at the left and all cold molecules at the right. By observing the particles and sorting them based on speed using a frictionless door the demon appears to have violated the second law creating order out of disorder.

Consider an isolated thermodynamic system (a system that does not exchange matter or energy with its surroundings) that consists of a gas at constant temperature T0 in a partitioned container and a demon operating a shutter at the hole in the partition, as displayed in Fig. 1.3. Included in the system is also an electric bulb (with a battery as its power supply) that the demon will use to illuminate the incoming molecules to see them.

To produce light, the filament is heated by the current flowing from the battery and is brought to a temperature T1  >  T0. The light produced in this manner will have a frequency such that it is visible against the blackbody radiation thermal background (kT0), the condition being:

(1.8)

As it produces current, the battery itself produces energy E but no change in the entropy of the system, although the filament loses entropy to the gas by radiating E:

(1.9)

The energy radiated by the filament is absorbed by the gas at the lower temperature T0, and hence the entropy of the gas increases by:

(1.10)

In the absence of any action by the demon, the overall change in the entropy of this isolated system must be positive, i.e.,

(1.11)

The demon must detect (absorb, by whatever mechanism) at least one scattered photon from the molecule. Hence, given the condition expressed by inequality Eq. (1.8), the demon's entropy will increase by:

(1.12)

Before any of these operations, the initial entropy of system S0 can be expressed in terms of the total number of indistinguishable microstates P0 according to Boltzmann's formula:

(1.13)

Once the demon has gained information about the system, that information can be used to decrease the entropy of the gas by more completely specifying its microscopic configuration or microstate (which is termed, in older parlance, complexion). Stated differently, the information gained by the demon decreases the number of possible microstates, say by p. Hence, the reduced number of microstates is now:

(1.14)

and the resulting change in the entropy of the system owing to the gain of information is:

(1.15a)

(1.15b)

Remembering the Taylor series expansion:

(1.16)

and because p  <<  P0 we can ignore all but the lead term in the Taylor expansion of the right-hand side of Eq. (1.15b) to obtain:

(1.17)

Using Eqs. (1.12) and (1.17), the total change of entropy in the isolated system owing to the gain of information by the demon is then:

(1.18)

because b  >  1 (Eq. 1.8) and p/P0  <  1, as required to satisfy the second law. This remarkable result is a generalization of Carnot's second law of thermodynamics, which can now be stated in a more suggestive notation as:

(1.19)

because information entropy has the reverse sign of thermodynamic entropy.

Acquiring information by the demon while reducing the entropy of the gas by sorting hot and cold molecules produces more entropy within the demon so that the overall change complies with the second law.

Because entropy and energy are closely related, the production of entropy in the demon is tantamount to absorption of heat. This is made clear by writing the definition of the change in entropy:

(1.20)

symbol.

Every binary decision the demon undertakes (allowing a cold molecule to the right or a hot one to the left) halves the total number of possible microstates, and Eq. (1.13) is modified to (Johnson, 1987):

(1.21)

so that the entropy change in the gas per binary decision is:

(1.22)

Brillouin (2004) [and before him, (Szilard, 1929)] proceed to show that there exists a minimum principle that is a law of nature (analogous to the Heisenberg indeterminacy principle) irrespective of the particular mechanism by which the sorting or information gathering is accomplished. In Brillouin's words:

every physical measurement requires a corresponding entropy increase, and there is a lower limit, below which the measurement becomes impossible. This limit corresponds to a change in entropy of the order of k, Boltzmann's constant. A more accurate discussion will prove later that the exact limit is k ln 2, or approximately 0.7 k for 1  bit of information obtained. As Gabor states it: [D. Gabor, M. I. T. Lectures, 1951] "We cannot get anything for nothing, not even an observation."²

To be able to continue functioning, the demon must dissipate his gained entropy outside the system, perhaps in the form of heat to the surroundings, which is possible only if the system is no longer isolated. Overall, if the system is to continue operating, it must dissipate the energy from the demon.

The amount of information necessary to achieve one binary sorting decision is 1  bit (e.g., the amount of information upon receiving a message that has a binary message such as yes/no, 1/0, heads/tails, etc.). Gaining 1 bit of information is accompanied by a minimal increase in the entropy given by:

(1.23)

in J/K (SI units), or equivalently, a gain of

(1.24)

of heat [in joules per bit (SI units)], which cannot be converted to any useful work and must be dissipated by the system to regain its initial state (Brillouin, 2004; Szilard, 1929).

We term the energy spent in recognition the sorting work output (SWO) because SWO must be taken into account in any efficiency calculation of a regulatory apparatus, organ, or organelle.

Thus a Maxwell’s demon is essentially a device converting negative entropy [or negentropy, a word coined by Schrödinger in What Is Life? (Schrödinger, 1944)], into information. The negative entropy the demon converts is by radiating light to shine on the molecules. The demon then converts this negentropy into information, reducing the entropy of the system by reducing its configurational Boltzmann entropy [Eqs. (1.13) and (1.14)]. The demon uses the information to reduce the gas' entropy but inevitably increasing its own entropy, completing Brillouin's cycle (Brillouin, 2004):

(1.25)

In an important article that appeared in 1961, to erase 1  bit of information from a computer's memory requires the expenditure of at least the same minimum amount of energy as in Eq. (1.24) (Landauer, 1961; Smith, 2008). This limit is again completely independent of the mechanism of information erasure and is also a fundamental principal of nature.

In Table 1.1 we provide the energetic cost of 1  bit of information (kT ln2) at various temperatures (some extreme temperatures as well as temperatures of typical relevance to biochemistry). The Landauer principle places a limit on the speed of any future supercomputer owing to excessive heat production even though today's computers are still far from reaching the Landauer limit.

There may be another limit on computer speed, reflecting quantum uncertainty. Because 1  bit of information is associated with a minimum energy below which it cannot be read or erased (listed in Table 1.1 for a few selected temperatures), that energy minimum dictates the lifetime of the interaction between the observed physical system and the observing demon.

Table 1.1

Temperature Dependence of the Energy Equivalent of the Bit (εmin) and of the Uncertainty in the Characteristic Time to Discern 1 Bit of Information (Δt)

The timescale for reading or erasing 1  bit of information can be found by applying Heisenberg's time–energy indeterminacy relation:

(1.26)

as a measure of the order of magnitude of the uncertainty in energy, we get:

(1.27)

with representative values illustrated in Table 1.1. The values listed in this table show that at biological temperature (25−37oC) the temporal uncertainty in the acquisition of 1  bit is of the order of 10−¹⁴  s (∼10  fs), which is consistent with a fast chemical reaction, as expected in the combination of two reactants in the process of molecular recognition.

From Table 1.1 it is clear that the cost of 1  bit of information is small (less than 0.5 kcal/mol at biologically relevant temperatures such as the human body temperature of 37°C).

bits):

(1.28)

kg/bit (at T  =  293K).

The Kidney as a Maxwell's Demon

Johnson and Knudsen (1965), and Johnson (1970, 1987), demonstrated that the low thermodynamic efficiency of the kidney, alluded to earlier, hinges on how its efficiency is defined. If one defines the efficiency of the kidney strictly on the basis of osmotic work, it would appear to be inefficient with an efficiency to the tune of only 1% which is out of step with most remaining organs in the body.

In its broader sense, efficiency is defined as:

(1.29)

where the work output includes all useful work that the device performs averaged over a long time. However, the kidney is not just an osmotic pump; it is also, and primarily, a physical realization of Maxwell's demon, i.e., an ion sorting machine.

As a control organ, the sorting activity of the kidney is of prime importance, and by including the energetic penalty of sorting into its Wout, JK demonstrated that the kidney has an efficiency commensurate with other body organs such as muscles only when the cost of sorting is accounted for.

Essentially, the calculation of efficiency concerns energy bookkeeping. In that bookkeeping the energetic cost of sorting by a control device cannot be ignored. This is especially true because the cost of sorting, which accompanies dissipation of free energy to restore the demon to its initial state, is the most useful form of work a control device can perform.

The pioneering work of JK that resolved the paradox of the kidney's thermodynamic inefficiency is now recapped briefly from the three main publications (Johnson and Knudsen, 1965; Johnson, 1970, 1987). To concentrate all attention on JK's main arguments of thermodynamics, citations referring to experimental quantities are omitted in the remainder of this section as they can be found in JK's articles (Johnson and Knudsen, 1965; Johnson, 1970, 1987). The bookkeeping distilled from JK's articles can be summarized, ignoring osmotic work (introducing an error of only  ∼1%), as:

• From  =  0.019  eV.

ions/min:

(1.30)

• The known input power of the kidney is ∼100  cal/min.

• Assuming a noiseless environment in which the sorting is performed by the demon, the efficiency is:

(1.31)

• However the environment in the kidney is noisy, given the background thermal bath in which the operation of sorting takes place. To make a binary decision in a noisy environment with 95% reliability, the signal-to-noise ratio must be at least 3 (Brillouin, 2004). In the kidney, the background environmental noise is ∼kT  eV.

• The realistic minimum energy to sort ions per minute in the kidney is thus:

(1.32)

• Thus in a noisy environment, the efficiency of the sorting work is revised to:

(1.33)

The kidney is the second highest consumer of power per unit tissue mass after the heart muscle. Its apparent inefficiency is an aberration that puzzled physiologists for decades. The puzzle is resolved if we enlarge the definition of efficiency to include the energetic penalty of measuring and sorting. The 30% efficiency obtained when this is done aligns the kidney's efficiency as a control organ with that of the heart muscle as a mechanical pump and that of a contemporary gasoline engine as a heat engine.

Mitochondrial Adenosine 5′-Triphosphate (ATP)-Synthase as a Maxwell's Demon

The mitochondrion is a cell organelle of utmost importance in sustaining life. There could be anywhere from a few hundreds to a few thousands mitochondria in any given eukaryotic cell. The mitochondrion is the location of central metabolism of all higher forms of life: that is, the Krebs [tricarboxylic acid (TCA)] cycle and oxidative phosphorylation. These two interconnected networks of reactions use respiratory O2 to burn the common end products of the metabolism of nutrients (carbohydrates, proteins, and lipids) into CO2 and metabolic water. The ΔG released from this gradual oxidation is eventually captured in adenosine 5'-triphosphate (ATP), the universal energy currency of living matter, the exergonic hydrolysis of which to adenosine 5′-diphosphate (ADP) and inorganic phosphate pulls thousands of