Human Longevity: Omega-3 Fatty Acids, Bioenergetics, Molecular Biology, and Evolution

254 Pages·2014·13.17 MB·English

by  R C Valentine

Human
Longevity
Omega-3 Fatty Acids, Bioenergetics,
Molecular Biology, and Evolution

Human
Longevity
Omega-3 Fatty Acids, Bioenergetics,
Molecular Biology, and Evolution
Raymond C. valentine
David L. valentine

Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
Cover photo 2000 by Dave Valentine.
An elderly man walks through the mass graves that hold the remains of his comrades, lost to the siege of
Leningrad, 1942. Since that time his body has experienced the ravages of aging, which is considered in this
book as a bioenergetic disease that acts through mitochondria and their membranes.
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Version Date: 20140804
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Contents
Preface....................................................................................................................xiii
Acknowledgments ....................................................................................................xv
About the Authors ..................................................................................................xvii
Section i introduction to the Science of Human
Aging
Chapter 1 Mitochondrial Hypothesis of Aging Is Undergoing Revision ..............3
1.1 Historical Perspective ................................................................3
1.2 Conventional Mitochondrial Theory of Aging Is
Undergoing Revision .................................................................4
1.3 Changes Have Come to the Famous Oxidative Stress or
Free Radical Theory of Aging...................................................5
1.4 Membrane Polyunsaturation Theory Seems to Link
Mitochondrial- Oxidative Theories of Aging ............................6
1.5 Summary ...................................................................................8
References ............................................................................................9
Chapter 2 Oxidative Stress Defined as a Deadly Free Radical- Mediated
Chain Reaction: Case History of Paraquat.........................................11
2.1 Paraquat Generates Free Radicals That Target and
Destroy Chloroplasts along with the Plant’s Basic Energy
Supply ......................................................................................12
2.2 Nonlethal Doses of Paraquat and Related Chemicals Act
as Neurotoxins and Selectively Kill Parkinsonian Neurons ...15
2.3 Death and Murder by Paraquat................................................16
2.4 Summary .................................................................................17
References ..........................................................................................17
Chapter 3 Membranes of Deep- Sea Bacteria as Surrogates for
Mitochondrial Membranes of Humans .........................................19
3.1 Oxygen- Damaged Membrane Fatty Acids Score Positive
as Mutagens in the Ames Carcinogen Test .............................20

3.2 Lessons from DHA/ EPA- Producing Bacteria .........................21
v
vi Contents
3.3 Tripartite Membrane Fatty Acid Blending Code Can
Explain Bizarre Properties of an EPA Recombinant of
E. coli.......................................................................................24
3.4 The DHA Principle Has a Wide Range of Applications .........26
3.5 Tripartite Membrane Fatty Acid Blending Code Is Also
Likely Universal ......................................................................27
3.6 Applications to Mitochondria ..................................................29
3.7 Bacterial Recombinants and Mutants Deserve More
Attention as Models for Mitochondrial Membranes ...............31
3.8 Summary .................................................................................32
References ..........................................................................................32
Section ii Darwinian Selection of Membranes
enabling Longevity
Chapter 4 Protective Mechanisms for EPA Membranes in C. elegans and
Their Relationship to Life Span .........................................................37
4.1 Feeding an Excess of EPA Decreases Life Span of
C. elegans ................................................................................37
4.2 C. elegans Synthesizes One of the Most Highly
Unsaturated Membranes in Nature ..........................................39
4.3 EPA Benefits C. elegans by Enabling Extreme
Membrane Motion Important for Rapid Cycling of the
Synaptic Vesicles Essential for Fast Firing of Bending
Muscles ....................................................................................40
4.4 Sensory Perception in C. elegans Likely Depends
on EPA Enabling Extraordinary Membrane Motion ...............42
4.5 Sensory Systems That Protect against Membrane
Oxidation and Oxidative Stress ...............................................43
4.6 An Extremely Long- Lived Mutant Decreases EPA While
Increasing Levels of Monounsaturated Chains .......................45
4.7 C. elegans Targets EPA Away from Mitochondrial
Membranes Likely as a Protective Mechanism against
Oxidative Damage ...................................................................47
4.8 Growth of C. elegans Requires Methyl- Branched Fatty
Acids, Which Are Peroxidation Resistant ...............................48
4.9 Mutational Analysis of Nuclear Hormone Receptors
Provides an Alternative View of the Roles of Lipids in
Regulating Life Span ...............................................................48
4.10 Summary .................................................................................50
References ..........................................................................................51
Contents vii
Chapter 5 Remarkable Longevity of Queens of Social Insects Likely
Involves Dietary Manipulation to Minimize Levels of
Polyunsaturates and Decrease Membrane Peroxidation ....................53
5.1 Royalactin ................................................................................54
5.2 Royal Jelly ...............................................................................54
5.3 Hydroxy Fatty Acids Acting as Signaling Molecules
Might Be Linked to Longevity of Queens ...............................56
5.4 Polyunsaturated Fatty Acids Missing from Royal Jelly
May Be a Secret to Longevity of Queens ................................56
5.5 Dietary Manipulation of Protein Levels Also Has
Dramatic Effects on Longevity of Ants ..................................57
5.6 Lessons from Drosophila ........................................................59
5.7 dFOXO in Drosophila .............................................................60
5.8 Summary .................................................................................60
References ..........................................................................................61
Chapter 6 Membrane Peroxidation Hypothesis Helps Explain Longevity
in Birds, Rodents, and Whales ...........................................................63
6.1 Extreme Flight of Hummingbirds Is Dependent on
Highly Unsaturated Mitochondrial Membranes That
Might Dictate Their Short Life Span.......................................63
6.2 Similar Brain DHA Levels in Long- Lived Pigeons versus
Short- Lived Rats Seem to Defy Polyunsaturation Theory
of Aging ...................................................................................66
6.3 Naked Mole Rats Have One- Ninth the Level of DHA as
a Mouse and Live Nine Times Longer ....................................67
6.4 Membrane Polyunsaturation Model Predicts Whales as
the Longest- Lived Mammals ...................................................70
6.5 Summary .................................................................................73
References ..........................................................................................73
Chapter 7 Did Longevity Help Humans Become Super Humans? .....................75
7.1 Caspari’s Hypothesis of the Rise of Grandparents ..................75
7.2 Fossil Teeth Show Longevity Occurred Late in Human
Evolution ..................................................................................76
7.3 Ancient Artifacts Show Cultural Revolution and
Population Growth Coinciding with Longevity ......................77
7.4 Does Bioenergetics Help Explain the Evolution of
Grandparents? ..........................................................................77
7.5 Evolution of Human Longevity as a Genetic Event .................78
7.6 Convergent Evolution of Longevity .........................................79
7.7 Present- Day Risks of Human Longevity .................................80
viii Contents
7.8 Revised Holy Grail of Aging ...................................................81
7.9 Summary .................................................................................82
References ..........................................................................................82
Section iii R evised Mitochondrial Membrane
Hypothesis of Aging
Chapter 8 Mitochondrial Diseases and Aging Have Much in Common ............85
8.1 Leber’s Hereditary Optic Neuropathy (LHON) ......................85
8.2 Barth’s Syndrome ....................................................................88
8.3 Latent Mitochondrial Diseases Caused by Mutations
in the mtDNA- Replicating Machine (POLG) May Not
Display Symptoms for Up to Sixty Years ................................89
8.4 Friedreich’s Ataxia ..................................................................91
8.5 Summary .................................................................................93
References ..........................................................................................93
Chapter 9 Revised Mitochondrial Hypothesis of Aging Highlights Energy
Deficiency Caused by Errors of Replication (Mutations) of mtDNA ...95
9.1 MtDNA Encodes Seven Subunits of Complex 1 .....................95
9.2 Mutated POLG in Mice Accelerates Aging ............................97
9.3 Mutator Genes Accelerate Neurodegeneration
in Humans, Suggesting That the Brain Can Set the Pace
of Aging ...................................................................................98
9.4 Recent Data Confirm the Mutator Concept and Help
Explain How Mitochondrial Fusion Can Push Back
against Aging ...........................................................................99
9.5 Mixing of Components during Mitochondrial
Fusion Might Protect Membranes against Age-
Dependent Damage ...............................................................101
9.6 Summary ...............................................................................103
References ........................................................................................103
Chapter 10 Benefits of Polyunsaturated Mitochondrial Membranes ..................107
10.1 Conformational Dynamics Explain How Polyunsaturated
Chains Are Harnessed for Bioenergetic Gain .......................107
10.2 Overexpressing DHA/ EPA in Transgenic Mice Increases

Rates of Electron Transport ...................................................109
10.3 Mitochondrial Membrane Composition Reflects the Need
to Balance Energy Production and Energy Conservation .....109
Contents ix
10.4 Summary ...............................................................................113
References ........................................................................................113
Chapter 11 Mitochondrial Membranes as a Source of Reactive Oxygen
Species (ROS) ..................................................................................115
11.1 The Beneficial Role of ROS Production by Phagocytic
Cells Is to Kill Pathogens by Inflicting Catastrophic
Oxidative Damage, But There Are Side Effects ...................115
11.2 Mitochondria as a Major Source of ROS ..............................118
11.3 Mitochondrial Polyunsaturated Membranes as a Major
Source of ROS .......................................................................121
11.4 Summary ...............................................................................122
References ........................................................................................123
Chapter 12 Mitochondrial Membranes as Major Targets of Oxidation ..............125
12.1 Rhodopsin Membrane Disks Are Highly Enriched with
DHA and Age Rapidly ..........................................................125
12.2 Lessons from DHA- Enriched Tails of Sperm .......................129
12.3 Mitochondrial Membranes and Their Proteins as Targets
of Oxidative Damage .............................................................131
12.4 Summary ...............................................................................134
References ........................................................................................134
Section iV Many Mechanisms Have evolved
to Protect Human Mitochondrial
Membranes, enabling Longevity
Chapter 13 Apoptosis Caused by Oxidatively Truncated Phospholipids Can
Be Reversed by Several Mechanisms, Especially Enzymatic
Detoxification ...................................................................................139
13.1 Lipid Whiskers and Their General Properties ......................139
13.2 Lipid Whiskers Signal Phagocytic Cells to Converge on a
Damaged Membrane Site ......................................................141
13.3 Phagocytic Cells Hyperactivated by Lipid
Whiskers Can Increase Oxidative Damage Fostering
Inflammation .........................................................................142
13.4 Oxidatively Truncated Phospholipids as Triggers of

Apoptosis Mediated by Mitochondria ...................................143
13.5 Summary ...............................................................................144
References ........................................................................................145
x Contents
Chapter 14 Selective Targeting of HUFAs Away from Cardiolipin and
Beta- Oxidation Combine to Protect Mitochondrial Membranes
against Oxidative Damage ...............................................................147
14.1 Selective Fatty Acid Targeting Has Been Demonstrated
for DHA in Sperm and Other Cells .......................................148
14.2 Selective Targeting and Avoidance of Polyunsaturated
Chains in Cardiolipin as a Pro- Longevity Mechanism .........150
14.3 Beta- Oxidation Is Responsible for Degrading a Vast
Majority of DHA in the Body, Thus Minimizing DHA
Incorporation into Most Cellular Membranes .......................151
14.4 Comparative Biochemistry of DHA Detoxification ..............153
14.5 Summary ...............................................................................154
References ........................................................................................155
Chapter 15 Oxygen Limitation Protects Mitochondrial Phospholipids,
Especially Cardiolipin ......................................................................157
15.1 DHA Turnover in the Brain Is Surprisingly Slow,
Suggesting the Operation of Novel Protective Mechanisms ...157
15.2 O Avoidance by Mitochondria .............................................159
2
15.3 During O -Limited Conditions Cells Have the Option of
2
Rebalancing the Ratio of Respiration to Glycolysis: Case
History of Sperm ...................................................................161
15.4 Model for O Protection by Myelin Found in Root
2
Nodule Bacteria .....................................................................163
15.5 Summary ...............................................................................164
References ........................................................................................165
Chapter 16 Uncoupling Proteins (UCPs) of Mitochondria Purposely Waste
Energy to Prevent Membrane Damage ............................................167
16.1 Nature of Mitochondrial Energy UCPs and Their
Activation by PUFAs, HUFAs, and Fatty Acid
Peroxidation Products ............................................................167
16.2 A Molecular Model Linking Membrane Unsaturation
with Longevity .......................................................................171
16.3 Summary ...............................................................................172
References ........................................................................................173
Chapter 17 Mitochondrial Fission Protects against Oxidative Stress by
Minting a Continuous Supply of Cardiolipin and Other

Polyunsaturated Phospholipids ........................................................175
17.1 Discovery of MAMs ..............................................................175
17.2 Major Molecular Species of Mitochondrial Phospholipids
and Their Biosynthesis ..........................................................177