Rejuvenation and Longevity Introduction to Rejuvenology

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Khachik K. Muradian Vadim E. Fraifeld
Department of Biology of Aging and Life The Shraga Segal Department
Span Extension of Microbiology
State Institute of Gerontology Immunology and Genetics
Academy of Medical Sciences of Ukraine Center for Multidisciplinary Research on
Kiev, Ukraine Aging
Ben-Gurion University of the Negev
Beer-Sheva, Israel

ISSN 2199-9007 ISSN 2199-9015 (electronic)

Healthy Ageing and Longevity
ISBN 978-3-031-64994-3 ISBN 978-3-031-64995-0 (eBook)
https://doi.org/10.1007/978-3-031-64995-0

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Preface

“Since the beginning of time”, rejuvenation is a human aspiration. How many heroes
of fairy-tales and real folk explorers wandered in vain through forests and other inac-
cessible places in search for the elixir of youth? Their expected failure made rejuve-
nation a symbol of sorcerers, alchemists or up to charlatans. Like the discouraging
disputes on perpetuum mobile, rejuvenation was confined from serious scientific
discussion as an impossible abstraction. Even now, most scientists and laymen are
skeptical about reality of rejuvenation. Being largely expelled from the academic
milieu, the studies on rejuvenation acquired numerous limitations. Preparing a book
in these obstacles was a real challenge, and we are sorry for the objective and subjec-
tive shortcomings and mistakes that could hardly be avoided. Nevertheless, during
the last decade, rejuvenation has acquired a realistic shape and becomes a subject
of scientific analysis. It would not be an exaggeration to say that right now a new
science is emerging—Rejuvenology.
Various approaches and concepts have been proposed and tested up to date. Yet,
there are neither basic theories or hypotheses of rejuvenation nor recognized defini-
tions, hallmarks, etc. All this definitely requires a comprehensive critical analysis.
This book is the first of its kind, in which the accumulated data on rejuvenation is
systemized and analyzed, starting from the evolutionary aspects of the origin of life,
rejuvenation and immortality to the evidence indicating that biological time could
be reversible. Despite the obvious progress in the field, scientific and near-scientific
community is still divided into two “opposing camps”—for and against rejuvenation
and radical life span extension. The book can be interesting for both parties and could
hopefully be useful for the establishment of mutually beneficial compromises. Thus,
we hope that our work could serve as a basis for further creative discussion of the
problem and will stimulate research in the field.

v
vi Preface

We apologize to all the authors whose contributions we could not cite owing
to space limitations. We thank our colleagues and students for fruitful discussions
and their real contribution to the field. We are particularly grateful to Dr. Ekaterina
Rudnitsky for her assistance in preparing this book.

Kiev, Ukraine Khachik K. Muradian

Beer-Sheva, Israel Vadim E. Fraifeld
Contents

1 Introduction to Optimistic Gerontology . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1 Paradoxical Triangle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 RNA-World and FUCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.3 Concise Definition of Aging and Rejuvenation . . . . . . . . . . . . . . . . 2
1.4 Aging and Rejuvenation: Cooperation Instead
of Confrontation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.5 Transposons, Aging, and Rejuvenation . . . . . . . . . . . . . . . . . . . . . . 3
1.6 Is Immortality Possible? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.7 Other Sophisticated Issues and Still Unexplored
Possibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2 The Origin of Life, Immortality, and Aging . . . . . . . . . . . . . . . . . . . . . . 7
2.1 The Origin of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2 RNA Concept of the Life and Rejuvenation Origin . . . . . . . . . . . . 8
2.3 LUCA and FUCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.4 Senescence and Immortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.5 Symmetric and Asymmetric Partitioning . . . . . . . . . . . . . . . . . . . . . 10
2.5.1 Escherichia coli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.5.2 Schizosaccharomyces pombe . . . . . . . . . . . . . . . . . . . . . . . . 11
2.6 The Origin of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.7 Growth and Damage Dilution Are Primordial Mechanisms
of Longevity in Multicellulars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.8 Immortality of Bacterial, Stem and Cancer Cells Show
Similarity in Gene Expression Profiles . . . . . . . . . . . . . . . . . . . . . . 13
2.9 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

vii
viii Contents

3 Cellular Learning, Decision-Making, and Rejuvenation . . . . . . . . . . . 17

3.1 Cognitive Abilities in the World of Cells . . . . . . . . . . . . . . . . . . . . . 18
3.2 DNA and Proteins in Cellular Computing . . . . . . . . . . . . . . . . . . . . 19
3.3 Cellular Command-Analytical Hub . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.4 DNA Methylation and Epigenetic Aging Clock . . . . . . . . . . . . . . . 20
3.5 Cellular Pluripotency, Decision-Making, and Rejuvenation . . . . . 21
3.6 How a Cell Finds the Way Back to Pluripotency
and Rejuvenation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.7 Cellular Rejuvenation Center and Fountain of Youthfulness . . . . 22
3.8 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4 Sporulation, Meiosis, and Rejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.1 Sporulation and Spores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.2 Spores Can Exist in Dormancy for Years and More . . . . . . . . . . . . 28
4.3 Fermi Paradox, Panspermia, and Spores . . . . . . . . . . . . . . . . . . . . . 29
4.4 Are Dormant Spores Metabolically Active? . . . . . . . . . . . . . . . . . . 29
4.5 Sporulation and Meiosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.6 The Genome and Gene Expression in Meiotic Rejuvenation . . . . 30
4.7 Age and Meiotic Rejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.8 Spore Germination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.9 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
5 Longevity Secrets of the Three Marine Beauties—Sponges,
Corals, and Sea Anemones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.1 Basal Metazoans Are Flourishing Worldwide . . . . . . . . . . . . . . . . . 37
5.2 Sponges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.3 Corals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.4 Sea Anemones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
5.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
6 Metazoans Who Live Longer Than Jeanne Calment . . . . . . . . . . . . . . 45
6.1 Species Exceeding Human Longevity (SEHL) . . . . . . . . . . . . . . . . 46
6.2 Hypoxic-Hypercapnic Environment and Anabiosis
in SEHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.3 Ocean Quahog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
6.4 Greenland Shark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.5 Vestimentiferan Tubeworms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
6.6 Bowhead Whales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6.7 Sea Urchins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6.8 Rockfish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.9 Freshwater Pearl Shell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Contents ix

6.10 Geoduck Clams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

6.11 Giant Tortoise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.12 Sturgeon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.13 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
7 Transposable Elements and Rejuvenation of Genome . . . . . . . . . . . . . 61
7.1 In ‘Stormy Sea’ of Transposable Elements . . . . . . . . . . . . . . . . . . . 62
7.2 We Have So Much in Common … . . . . . . . . . . . . . . . . . . . . . . . . . . 63
7.3 Active and Dormant Transposable Elements . . . . . . . . . . . . . . . . . . 63
7.4 Transposable Elements in the First Meeting of Rejuvenation
and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
7.5 LINE1 and Other Retrotransposons in Early Embryonic
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7.6 Zygotic Genome Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7.7 The New/Old Integrations of Endogenous Retroviruses
and Mammalian Longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
7.8 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
8 Embryonic Stem Cells and the ‘Last-Minute’ Correction . . . . . . . . . . 71
8.1 Embryonic Stem Cells as a Gold Standard of Cellular
Pluripotency and Immortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
8.2 Hypoxic-Hypercapnic Environment (HHE) in Mammalian
Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8.3 ESC Growth Rate and Mammalian Longevity . . . . . . . . . . . . . . . . 73
8.4 One ICM Cell—One Type of a Differentiated Cell . . . . . . . . . . . . 74
8.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
9 Muse Cells and VSEL Stem Cells in Longevity
and Rejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
9.1 Pluripotent Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
9.2 The Five Giant PSCs for Tissue Recovery and Longevity . . . . . . . 79
9.3 Multilineage-Differentiating Stress-Enduring Stem Cells
(Muse Cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
9.4 Very Small Embryonic-Like (VSEL) Stem Cells . . . . . . . . . . . . . . 82
9.5 Conclusion Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
x Contents

10 The Paradox of the Adult Stem Cells: Relevance to Aging

and Rejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
10.1 Adult Stem Cells (ASCs): Brief Overview . . . . . . . . . . . . . . . . . . . 89
10.2 ASCs Quiescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
10.3 ASCs, Metabolism, and Mitochondria . . . . . . . . . . . . . . . . . . . . . . . 91
10.4 ASCs Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
10.5 Age-Related Changes in ASCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
10.6 Are ASCs Potentially Immortal? . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
10.7 Mitotic ‘Glider’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
10.8 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
11 Biological Age Can Be Moved in Both Directions . . . . . . . . . . . . . . . . . 97
11.1 The Plasticity of Biological Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
11.2 The Aging/Rejuvenation Ratio (rar ) . . . . . . . . . . . . . . . . . . . . . . . . . 98
11.3 Epigenetics and Biological Aging Clocks: Cytosine
Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
11.4 Epigenome and Decision-Making Structures . . . . . . . . . . . . . . . . . 105
11.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
12 Rejuvenation Is on Its Way . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
12.1 Rejuvenation and Blood Exchange Models in Mammals . . . . . . . 111
12.2 Cellular Washup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
12.3 Rejuvenation of Organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
12.4 The First and Second Laws of Rejuvenation . . . . . . . . . . . . . . . . . . 117
12.5 Rejuvenation Before and After the Birth . . . . . . . . . . . . . . . . . . . . . 118
12.6 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Chapter 1
Introduction to Optimistic Gerontology

Abstract Aging, rejuvenation and immortality are the apexes of a triangle full of
amazing paradoxes and gems of simple truths. Their discussion often provokes heated
confrontation and disputes warmed up by a wealth of fascinating and yet controversial
investigations.

Keywords RNA-world · FUCA · Definitions of aging · Rejuvenation ·

Immortality

Immortality is for the gods, but man’s search for its elusive secrets, perhaps as old
as man
himself, will continue.
—Wan Po

1.1 Paradoxical Triangle

Aging, rejuvenation and immortality are the apexes of a triangle full of amazing para-
doxes and gems of simple truths. Their discussion often provokes heated confronta-
tion and disputes warmed up by a wealth of fascinating and yet controversial inves-
tigations (Frolkis and Muradian 1991; Abramovich et al. 2008; Lewis and de Grey
2024; Yücel and Gladyshev 2024). Is aging obligatory for all biological objects? Can
rejuvenation counterbalance the negative effects of aging? Is immortality achiev-
able? Rapidly accumulating data allows for shedding some light on these and related
sophisticated issues. In fact, this book is a first attempt to systemically analyze what
rejuvenation is and its relationships with aging, longevity, origin of life, and the
existence of life as is. In this introductory chapter, we describe in brief the main
problems, hypotheses and questions that are discussed in the book.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 1

K. K. Muradian and V. E. Fraifeld, Rejuvenation and Longevity, Healthy Ageing and
Longevity 20, https://doi.org/10.1007/978-3-031-64995-0_1
2 1 Introduction to Optimistic Gerontology

1.2 RNA-World and FUCA

Conversion of chemical substances into a self-replicating living system is the most

fateful event and thrilling evolutionarily transformation. This event manifested the
transition from the ‘cold chemistry’ to the ‘warm biology’. According to the RNA-
world concept, biological life has been raised due to the unique universality of
RNA molecules, carrying simultaneously genetic, catalytic, structural, and regu-
latory functions. RNA can store and replicate genetic information as DNA and at
the time catalyze biochemical reactions critical for life as protein enzymes. More-
over, two RNA molecules can indefinitely long catalyze each other’s synthesis
in a self-sustained and exponentially amplifying manner in the absence of DNA,
proteins or other biomolecules. In the reaction, RNA vesicles can increase in size
due to the synthesis of new molecules, fragment apart into smaller ones and again
regrow into new larger vesicles. It is a simple and reliable model of the breathtaking
event—shifting of an inanimate matter into an immortal living matter.
The Last Universal Common Ancestor (LUCA) is a widely accepted though still
hypothesized concept. It is believed that LUCA gave rise to the three main domains
of life (Bacteria, Archaea, and Eukarya). Here, we propose to honor the first two
molecules of RNA, from which life has originated, by the abbreviation FUCA (the
First Universal Common Ancestor) (Chap. 2).
All in all, it seems plausible that life and rejuvenation originated simultaneously in
a self-replicating RNA, thus showing that life and rejuvenation are inseparable. Aging
appeared later as an adaptive mechanism for elimination of defective prokaryotes
from the population. Rejuvenation has evolved first and foremost and only afterwards
appeared aging.

1.3 Concise Definition of Aging and Rejuvenation

There are hundreds of definitions of aging. A concise ‘three-words’ definition argues

that aging is a permanent global catastrophe. In fatality, aging cannot be compared
to anything. No cataclysm, war or accident brings as much grief and loss as aging.
Millions of people, among them our friends, die yearly because of age-related
diseases. A vibrant adult man turns into a decrepit old patient during few decades
and passes away often in physical and psychological torments. Therefore, all means
are justified to ameliorate consequences of aging.
Rejuvenation is intuitively understood as an antipode of aging. However, there
is no strict mechanistic definition of rejuvenation. It is urgently needed. As a first
approximation, rejuvenation could be defined phenomenologically as a process that
opposes aging and can decrease the biological age. It could occur at any age, and may
enhance the functional capacity, resistance to stress, and reverse, fully or partially, the
development of age-related diseases. Although rejuvenation is primarily an organ-
ismal feature, it is also relevant to the tissue or cellular level, or even to single
1.5 Transposons, Aging, and Rejuvenation 3

biomolecules. It should be emphasized again that rejuvenation is a real natural

mechanism for ridding off the load of aging. The major rejuvenative events in multi-
cellular organisms are primarily associated with gametogenesis and early embryo
development (Kerepesi et al. 2021; Kerepesi and Gladyshev 2023) (Chaps. 4, 7, 8).

1.4 Aging and Rejuvenation: Cooperation Instead

of Confrontation

All hypotheses of aging claim that the avalanche of age-related changes is so destruc-
tive and pervasive that a cell will inevitably accumulate lethal damage and die.
Yet, the rate of damage could be slowed down close to zero as it occurred in self-
replicating RNAs and further in protocells and prokaryotes. Rejuvenation paradigm
posits claims that modern biological life originated due to intensively replicating
immortal protocells and prokaryotes. At a certain rate of a cell division, dilution of
damage can reach the level when a cell has ‘neither possibility, nor time for aging’.
The immortality program could be fixed in a cell genome and transferred to the next
generations, including cells of multicellular organisms. Since then, biological life
has been thriving for billions of years due to the efficient defense and rejuvenative
systems. Aging and rejuvenation are tightly interconnected and well-balanced. The
question is how to shift this balance towards rejuvenation and whether we have any
tools in hand for doing so.

1.5 Transposons, Aging, and Rejuvenation

Transposable elements (TEs) are relics of ancient viral invasions. With few excep-
tions, TEs are discovered in all sequenced species and tissues of metazoans, with the
highest level of expression in ESCs and reproductive organs. TEs could be symbiotic
in embryogenesis and fetal development, being significant for embryonic rejuvena-
tion, silent in adulthood and loosely controlled and harmful in aging. They could
be key players in the zygotic genome activation (ZGA). Indeed, ZGA starts from
the heterochromatin relaxation followed by the burst of transcription activity. The
mobility of endogenous retroviruses (ERVs) and their multiple positioning could
give them advantages in opening the relaxation sites.
It is hardly believable but around 70% of the human genome is derived from retro-
viruses. During the last 10 million years, integration of ERVs in hominoid genomes
decreased by several fold. Humans demonstrated especially strong protection against
new viral insertions. As we have shown, mammalian longevity correlates with the
ability to resist the integration of new EVRs (Chap. 7). Whatever the case, it would
be hardly possible to discuss human rejuvenation and longevity without considering
the putative role of TEs in embryogenesis and aging.
4 1 Introduction to Optimistic Gerontology

1.6 Is Immortality Possible?

Infinity is a philosophical or mathematical abstraction. In the real physical world, all

events have an arbitrarily large or small but finite probability of realization. Therefore,
immortality cannot exist in the real world. Limited life expectancy will remain even
if all age-related diseases become curable. Of note, in this case the mean human life
span could be around the biblical Methusael’s 800–1000 years.
Humans are the longest-lived terrestrial mammalian species. Nevertheless, from
ancient times humans strived for a longer life and even dreamed of being immortal.
As Wan Po elegantly noted, “Immortality is for the gods, but man’s search for its
elusive secrets, perhaps as old as man himself, will continue.” The existence of
animals exceeding human longevity by hundred and thousand times supports the
idea of ‘practical immortality’.
Maximal life span (MLS) of ocean sponges reaches 10–15 thousand years.
Another basic metazoan, corals, are the second longest-lived animal species (over
4200 years). Sponges and corals exhibit the highest regenerative capacity among
metazoans, which is largely associated with their stem cell systems. Even the moder-
ately long-lived species, such as ocean quahog (over 500 years), Greenland shark
(over 400 years), tubeworm (over 300 years) or bowhead whale (over 200 years) could
be robust samples of longevity, worth of meticulous examination and imitation (see
Chaps. 5 and 6).

1.7 Other Sophisticated Issues and Still Unexplored

Possibilities

The phenomenon of cellular reprogramming suggests a high plasticity of the cell

which ‘remembers’ the way to youthfulness and which rejuvenation program could
be activated by relatively simple means, including external signals (Muradian and
Fraifeld 2020; Knyazer et al. 2021; Yang et al. 2023) (Chap. 11). Another feasible
perspective for rejuvenation and radical health span extension could be attributed to
a proper maintenance and functionality of somatic pluripotent stem cells (e.g., Muse,
multilineage-differentiating stress-enduring stem cells) (Dezawa 2018) (Chap. 9).
Any rejuvenative interventions in an advanced age would be hardly possible
without strong repression of TEs/ERVs expression and mobility. With this in mind,
nucleoside reverse transcriptase inhibitors could be included in ‘rejuvenative cock-
tails’ as promising components (Brochard et al. 2023). Whatever, multiple targeting
seems to be more efficient (Lewis and de Grey 2024). Already successfully tested
blood plasma exchange (Mehdipour et al. 2020; Kim et al. 2022) and thus far only
suggested by us ‘wash-up’ technics for dilution and clearance of intra- and intercel-
lular garbage indicate that rejuvenative procedures could be relatively simple and,
anyway, much less sophisticated than their results ( ) (Chap. 11).
References 5

It is believed that there have been times when the Earth was inhabited mainly by
immortal prokaryotes, viruses and unicellular species. At the dawn of multicellularity,
symbiosis of these entities resulted in long-lived metazoans which have later been
replaced by the current aggressive and relatively short-lived multicellular species.
Evolution is a good tactician but not a strategist. Now a man has taken the initiative.
Let’s see what we can and will do.

Ethics All the materials and data described in the book have been approved by Ethical Committee
for Animal Experimentation or Helsinki Committee for Research on Humans of the organizations,
where corresponding investigations have been done.

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Chapter 2
The Origin of Life, Immortality,
and Aging

Abstract Biological life and immortality have originated due to the unique ability
of RNA molecules to catalyze each other’s synthesis in RNA-templated RNA-
polymerization reactions. Covered by lipid envelopes, RNA vesicles increase in
size through the synthesis of new molecules. The larger vesicles fall occasionally
apart into smaller ones and regrow into newer large vesicles. It is a simple and reli-
able model of self-replicating life origin. By analogy with LUCA (the last universal
common ancestor), we propose to honor the first two molecules of RNA from which
life originated by the abbreviation FUCA (the first universal common ancestor).
According to the well-known dogma, prokaryotes and some unicellular eukaryotes
in the permissive conditions generate genetically identical daughter cells without
any alterations that can be interpreted as aging. Moreover, they have decreased the
population doubling time up to few hours. At these rates of cell division, they have
‘neither time nor possibility for normal aging’. Aging has obviously emerged later
as a useful tool for quick removal of cellular damage. Altruistic ‘kamikaze’ cells
selectively accumulated cellular garbage, aged and were eliminated by asymmetric
partitioning. In the evolutionary odyssey of multicellular organisms, however, aging
has changed the role of the useful tool to the most destructive factor. Why has this
mysterious transformation occurred and what could be done to recover the reputation
of aging in multicellular organisms? In a human body, there are nearly equal numbers
of bacterial and multicellular cells. Modifications of immortal ‘personalized’ cells
(e.g., bacteria with the adult stem cells) could be promising. Remarkably, immortal
cells strongly increase expression of the old (bacterial) genes and decrease transcrip-
tion of the multicellular (new) genes. The main difference here is that bacterial cells
are immortal in the normal conditions and could age only in stressful environments,
whereas the cells of multicellular organisms undergo aging in the normal conditions
and could become immortal after ‘struggle’ with the differentiation factors. This is
a short scenario about the origin of life, immortality, and aging.

Keywords The origin of life · Rejuvenation origin · The origin of aging · RNA
concept of life · LUCA · FUCA · Senescence · Immortality ·
Symmetric partitioning · Asymmetric partitioning

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 7

K. K. Muradian and V. E. Fraifeld, Rejuvenation and Longevity, Healthy Ageing and
Longevity 20, https://doi.org/10.1007/978-3-031-64995-0_2