The Unexpected Outcomes of Anti-Aging, Rejuvenation, and Life Extension Studies: An Origin of Modern Therapies

Abstract

The search for life-extending interventions has been often perceived as a purely academic pursuit, or as an unorthodox medical enterprise, with little or no practical outcome. Yet, in fact, these studies, explicitly aiming to prolong human life, often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery. At least several modern biomedical fields have directly originated from rejuvenation and life extension research: 1) Hormone Replacement Therapy was born in Charles-Edouard Brown-Séquard's rejuvenation experiments with animal gland extracts (1889). 2) Probiotic diets originated in Elie Metchnikoff's conception of radically prolonged "orthobiosis" (c. 1900). 3) The development of clinical endocrinology owed much to Eugen Steinach's "endocrine rejuvenation" operations (c. 1910s-1920s). 4) Tissue transplantations in humans (allografts and xenografts) were first widely performed in Serge Voronoff's "rejuvenation by grafting" experiments (c. 1910s-1920s). 5) Tissue engineering was pioneered during Alexis Carrel's work on cell and tissue immortalization (c. 1900-1920). 6) Cell therapy (and particularly human embryonic cell therapy) was first widely conducted by Paul Niehans for the purposes of rejuvenation as early as the 1930s. Thus, the pursuit of life extension and rejuvenation has constituted an inseparable and crucial element in the history of biomedicine. Notably, the common principle of these studies was the proactive maintenance of stable, long-term homeostasis of the entire organism.

Full text

The Unexpected Outcomes of Anti-Aging,
Rejuvenation, and Life Extension Studies:
An Origin of Modern Therapies
Ilia Stambler
Abstract
The search for life-extending interventions has been often perceived as a purely academic pursuit, or as an
unorthodox medical enterprise, with little or no practical outcome. Yet, in fact, these studies, explicitly aiming
to prolong human life, often constituted a formidable, though hardly ever acknowledged, motivation for
biomedical research and discovery. At least several modern biomedical fields have originated directly from
rejuvenation and life extension research: (1) Hormone replacement therapy was born in Charles-Edouard
Brown-Se
´quard’s rejuvenation experiments with animal gland extracts (1889). (2) Probiotic diets originated in
Elie Metchnikoff’s conception of radically prolonged ‘‘orthobiosis’’ (c. 1900). (3) The development of clinical
endocrinology owed much to Eugen Steinach’s ‘‘endocrine rejuvenation’’ operations (c. 1910s–1920s). (4)
Tissue transplantations in humans (allografts and xenografts) were first widely performed in Serge Voronoff’s
‘‘rejuvenation by grafting’’ experiments (c. 1910s–1920s). (5) Tissue engineering was pioneered during Alexis
Carrel’s work on cell and tissue immortalization (c. 1900–1920). (6) Cell therapy (and particularly human
embryonic cell therapy) was first widely conducted by Paul Niehans for the purposes of rejuvenation as early as
the 1930s. Thus, the pursuit of life extension and rejuvenation has constituted an inseparable and crucial
element in the history of biomedicine. Notably, the common principle of these studies was the proactive
maintenance of stable, long-term homeostasis of the entire organism.
Introduction
The search for life extension and rejuvenation has
been often considered a rather academic, theoretical, or
basic pursuit, with little or no practical returns, or else as an
unorthodox medical enterprise with little or no evidence-
based health benefits. Thus, famously the American geron-
tologist Leonard Hayflick claimed in 1994, regarding the
practical inutility of these studies:
1
Why then, have I spent my lifetime learning more about
aging and longevity if it is not my goal to manipulate the
processes? First, as a scientist, I am curious about how the
world works.
Thus it may seem that the chief purpose of research of
aging is to satisfy the researcher’s curiosity. On the other
hand, much earlier, in 1956, the British gerontologist Alex
Comfort countered
2
:
Insofar as biology is more than a branch of idle curiosity, its
assignment in the study of old age is to devise if possible
means of keeping human beings alive in active health for a
longer time than would normally be the case—in other
words, to prolong individual life.
Hayflick’s approach appears to be pessimistic, empha-
sizing the immense complexity of the aging process, hence
the immense difficulty of attempting to intervene and extend
the human life span without producing unwanted side ef-
fects. On the other hand, Comfort’s view is optimistic,
valorizing the inherent malleability of the aging process,
hence the possibility of its manipulation and restoration of
the structural and functional state of the elderly. Yet both
approaches are rather speculative and would require a pro-
longed period of testing to ascertain the results of some
putative interventions on the actual human life span. How-
ever, investors and policy makers often want immediate
returns and are not prepared to wait for extended periods
until a potential life-extending intervention proves its worth.
The only immediately perceptible effects can be in terms of
treatment of diseases and instant restoration of health (which
do not always correlate with a longer life span or better
Department of Science, Technology and Society, Bar Ilan University, Israel.
REJUVENATION RESEARCH
Volume 17, Number 3, 2014
ªMary Ann Liebert, Inc.
DOI: 10.1089/rej.2013.1527
297

health span in the long term). This may partly explain the
relative reluctance to invest great efforts and resources in
life extension research.
Yet, in fact, quite encouragingly, the life extension
studies have very often produced entirely tangible and
immediately perceptible therapies and even cures for
particular diseases and conditions, even without expecting
such results. Moreover, as an historical analysis will show,
these studies, explicitly aiming to prolong human life,
often provided powerful, yet seldom recognized impulses
for biomedical research and discovery. At least several
modern biomedical fields have directly originated from
rejuvenation and life extension research.
3
Several exam-
ples will be presented here, mainly from the early 20
th
century, a period valorizing the modern ideals of scientific
progress. (Unless otherwise specified, all of the excerpts
are in my translation.) The most common term then was
‘‘rejuvenation,’’ implying both the combat of the deterio-
ration of aging and the attempt to prolong life. Hence the
concepts of ‘‘rejuvenation,’’ ‘‘anti-aging,’’ ‘‘life exten-
sion,’’ or ‘‘life span extension’’ will be used here rather
interchangeably.
It is sometimes assumed that the ‘‘rejuvenation research’’
of the early 20
th
century was of a diminished quality and
status as compared to other branches of contemporary
medical research.
4
Moreover, it is often assumed that the
only surviving branch of that ‘‘rejuvenation research’’ is the
current ‘‘anti-aging medicine,’’ which has often also carried
negative connotations.
5
Indeed, the lack of efficacy of a large
number of so far proposed ‘‘rejuvenative’’ and ‘‘anti-aging’’
remedies can be hardly disputed. Yet arguably the historical
relation of ‘‘rejuvenation research’’ with the larger body of
contemporary medical science was more extensive and pos-
itive than commonly believed. In fact, early in the 20
th
cen-
tury, ‘‘rejuvenation’’ was a well-established scientific subject,
employing state of the art knowledge and techniques. Ac-
cording to Nathan Shock’s comprehensive Classified Biblio-
graphy of Gerontology and Geriatrics (1951, 1957, 1963),
there were hundreds of scientific publications (books and
articles) specifically on ‘‘rejuvenation,’’ reaching a peak in
the late 1920s, and declining in the early 1940s (presumably
due to a shift of emphasis during World War II).
6
The term ‘‘anti-aging,’’ which was first broadly used in
the 1920s in chemical engineering, seems to have become
noticeable in medical discourse only after the war, in the
late 1940s. Whatever failures may have been later associ-
ated with the term ‘‘anti-aging,’’ at its introduction the term
did not seem to carry any unscientific connotations. One of
the primary biomedical studies emphasizing this term was
published in 1948 by the American biologist Thomas
Samuel Gardner (1908–1963), in an article entitled ‘‘The
design of experiments for the cumulative effects of vitamins
as anti-aging factors,’’ one of the pioneering works in the
research of vitamins as ‘‘gerontotherapeutic’’ substances.
7
The study integrally related the concepts of ‘‘anti-aging,’’
‘‘gerontotherapeutics,’’ addressing ‘‘the aging problem,’’
‘‘longevity research,’’ and ‘‘rejuvenation research.’’ The
potential practical implications of such research appeared
evident:
It would not be an exaggeration to suggest that longevity
research work may be the most profitable field of human
well-being, as well as from the commercial returns, of all
of the present fields of medical investigations.
This conclusion seems to be valid also with regard to
Gardner’s own work on the therapeutic applications of vi-
tamins in the aged, as well as for other fields of ‘‘longevity
research’’ and ‘‘rejuvenation research,’’ some of whose
practical offshoots will be shown below. Clearly, some
‘‘rejuvenators’’ promised such immediate and radical results
that gave grounds to relegate them to the realm of quack-
ery.
8
Most of them, however, presented their methods as
the first experimental steps in research programs for the
future, which, they hoped, would be developed further on.
As will be shown below, quite often they were justified in
their hopes.
Hormone Replacement Therapy Was Born in Charles-
Edouard Brown-Se
´quard’s Rejuvenation Experiments
with Animal Gland Extracts (1889)
Arguably one of the most significant outcomes of reju-
venation research was hormone replacement therapy. The
histories of the two fields have been long linked. Precursors
of hormone replacement therapy can be traced far back to
extracts from animal tissues (sex glands in particular) that
were used for rejuvenation for at least two millennia. Such
means are mentioned in the ancient Chinese Mawangdui
manuscripts (c. 200 BCE)
9
and the ancient Indian medical
treatise Sushruta Samhita (c. 300 BCE).
10
They continued to
be used across the world, well into the 19
th
century, when
such treatments were better known under the name ‘‘opo-
therapy’’ from the Greek ‘‘opos,’’ juice. Yet, their first ex-
perimental application, tested and reported according to
the scientific method, and thus representing the birth of
scientific therapeutic endocrinology, is attributable to the
late 19
th
century rejuvenation experiments of the president
of the French Biological Society and Chair of Experimental
Medicine at the College de France (Claude Bernard’s Suc-
cesor), Dr. Charles-Edouard Brown-Se
´quard (1817–1894).
On June 1, 1889, Brown-Se
´quard announced the results of
his experiments on self-injection with extracts from testes of
guinea pigs and dogs, explicitly for the purpose of rejuve-
nation, and reported an improvement of work capacity and
vigor.
11
Brown-Se
´quard thus described the guiding motiva-
tion for his work. Without venturing any figures for a max-
imal attainable longevity, he postulated the fundamentally
proactive ideology of the anti-aging and life-extensionist
pursuit as the basis for his work
12
:
They show great ignorance who maintain that it is impos-
sible in old men to reverse their organic state so that they
resemble that of an earlier age, especially since the organic
changes resulting from better nutrition are possible at all
ages..If the degenerations, if the senile alterations are
diseases, a day will come when it will be possible to cure
them.
This rejuvenation attempt started modern hormone re-
placement therapy or therapeutic endocrinology at large,
introducing longevity and rejuvenation research as an inte-
gral part of scientific discourse. The effects of Brown-
Se
´quard’s intervention proved to be limited and short lasting
(he died 5 years after the injections). Yet, its influence on
the development of medicine was strong. A great many
298 STAMBLER

endocrinologists up to the 1930s admitted Brown-Se
´quard’s
priority.
13
The practical and economic impact of hormone
replacements can now hardly be doubted.
14
Pro-Biotic Diets Originated in Elie Metchnikoff’s
Conception of Radically Prolonged
‘‘Orthobiosis’’ (c. 1900)
About the same time as Brown-Se
´quard’s work, seminal
contributions to the development of medicine were made by
the Russian biologist Elie Metchnikoff (1845–1916), since
1887 working at the Pasteur Institute in Paris. Metchnikoff
was awarded the Nobel Prize in Physiology or Medicine in
1908 (together with Paul Ehrlich) in recognition of his
‘‘work on immunity,’’
15
specifically the introduction of the
cell theory of immunity, first suggested by him around 1882.
Yet, the later period of Metchnikoff’s work—since the end
of the 19
th
century (circa 1897) literally until his death in
1916—was dedicated almost exclusively to research to
postpone the deterioration of aging and prolong healthy life.
Metchnikoff coined both the terms ‘‘gerontology’’ and
‘‘thanatology’’ in his book devoted to those topics, entitled
Etudes on the Nature of Man (1903).
16
As Metchnikoff
defined the imperative for his work
17
:
We should, by all means, strive that people, ourselves in-
cluded, live their full life cycle in harmony of feeling and of
mind.The main misfortune on earth is that people do not
live to that limit and die prematurely. This statement is the
basis of all moral actions.
Several medical applications were derived directly from
this research. According to Metchnikoff, the deteriorative
aging process was largely due to cumulative self-intoxication
by putrefactive bacteria of the intestines, particularly the
large intestine. Inspired by this model, the British surgeon
William Arbuthnot Lane (1856–1943) suggested colectomy
as a means to remove the source of damage. Yet, according
to Metchnikoff, the most practical and readily available
means to fight the intoxication (and hence the deterioration
of aging) would be through an appropriate diet. In Metch-
nikoff’s theory, fermented/acidified dairy products (such as
yogurt), containing lactic acid bacteria, were able to sup-
press putrefactive microflora and detoxify the body.
Metchnikoff himself followed this dietary practice and at-
tributed to it his relatively high longevity (though coming
from a very short-lived family). Generally, Metchnikoff
advocated a simple and restricted diet. He believed luxuri-
ous cuisines favor toxigenicity, and therefore are detri-
mental to health and longevity, to the ‘‘correct course of
life’’ or ‘‘orthobiosis’’ which according to him should last
about 150 years on the average. This line of thought has
continued in the multitude of modern dietary practices
aimed at healthy life extension and life enhancement, in-
cluding bio-active, vitamin-rich, pro-biotic, anti-toxic, anti-
inflammatory, differential, and calorie-restricted diets.
18
In particular, Metchnikoff’s anti-aging theory was the
direct origin of probiotic diets. The life-prolonging proper-
ties of fermented milk products were suggested to Metch-
nikoff by the robust and long-lived Bulgarian peasants for
whom this was a traditional diet. Yet, after Metchnikoff’s
scientific analysis and endorsement, this nutritional regimen
for longevity spread from Europe to the United States and
Japan. The term ‘‘pro-biotics’’ was coined only in 1953 by
the German biologist Werner Kollath, yet the theory behind
their use is entirely due to Metchnikoff’s work on aging and
life extension. Metchnikoff’s priority in developing pro-
biotic diets has been generally acknowledged,
19
yet the or-
igin of this therapy in anti-aging and life-extending
experiments has been rarely emphasized. The health care
and economic value of this development is difficult to
overestimate.
20
An additional ramification from Metchnikoff’s anti-aging
and life extension research was the development of systemic
and adjuvant immunotherapy, stemming from his work on
cytotoxic sera. Metchnikoff and his assistant at the Pasteur
Institute and future Nobel laureate in physiology or medi-
cine Jules Bordet (1870–1961) believed that cytotoxic sera
can be used as a double-edged sword in the fight against
aging: In large doses, the sera can be used to eliminate or
inhibit undesirable tissues, but in small doses they can be
applied to stimulate these very same tissues if their prolif-
eration is desired.
21
This line of research was continued by
the Russian physician, director of the Moscow Institute for
Blood Transfusion (successor of the Institute’s founder, the
rejuvenator Alexander Bogdanov, 1873–1928) and later
director of the Kiev Institute of Clinical Physiology and
president of the Ukrainian Academy of Sciences, Alexander
Bogomolets (1881–1946). In the 1930s to the early 1940s,
Bogomolets developed and widely applied the ‘‘anti-
reticular cytotoxic serum’’ (ACS) for the stimulation of
connective tissues (rather than parenchymal tissues as in
Metchnikoff’s first experiments). Similarly to Metchnikoff,
the primary explicit purpose of the ACS was ‘‘treatment of
old age’’ and ‘‘prolongation of life.’’
22
Yet, insofar as Bo-
gomolets believed that age-related deterioration of the
connective tissue is a common ‘‘root’’ cause of a variety of
age-related pathologies, the serum was applied as a treat-
ment for a host of diseases—from chronic infectious and
neurological diseases through wound and fracture healing
to cancer. Self-admittedly owing to Metchnikoff’s initial
idea, this was the birth of systemic/adjuvant immunother-
apy, primarily originating from anti-aging and rejuvenation
research.
The Development of Clinical Endocrinology Owed
Much to Eugen Steinach’s ‘‘Endocrine Rejuvenation’’
Operations (c. 1910s–1920s)
Continuing Brown-Se
´quard’s line of research, in 1910,
the Austrian physiologist, Director of the Biological Institute
of the Viennese Academy of Sciences, Eugen Steinach
(1861–1944) suggested several techniques for endocrine
‘‘rejuvenation’’ (Verju
¨ngung) or ‘‘combating aging’’ (Alter-
sbeka
¨mpfung). For that purpose, Steinach proposed to use
either the ‘‘autoplastic’’ approach (strengthening or attenu-
ating particular parts within the patient’s own body) or
‘‘homoplastic/heteroplastic’’ approach (adding reserve mate-
rials from the outside, as in transplantation from humans or
animals) to bring the body into balance. In men, the vasoli-
gation of the seminal ducts (vas deferens)wastheprimary
‘‘autoplastic’’ procedure. The purpose of this technique was
to suppress sperm-producing activity and at its expense
stimulate sex hormone production and thereby increase
the blood flow and induce ‘‘rejuvenation.’’ Usually only one
seminal duct was ligated to avoid infertility. In men,
FROM LIFE EXTENSION STUDIES TO MODERN THERAPIES 299

transplantation of testicular tissue was the less favored ‘‘ho-
moplastic/heteroplastic’’ alternative. Women were ‘‘rejuve-
nated’’ by fallopian tube ligation or irradiation of the ovaries
(the ‘‘autoplastic approach’’) or transplantation of ovarian
tissue (the ‘‘homoplastic/heteroplastic approach’’). Steinach’s
conclusions after the initial 10 years of research (in 1920),
even though rather cautious, were nonetheless highly opti-
mistic and posited the combat of aging as the foremost mo-
tivation for this research: ‘‘Senescence, within certain limits,
can be influenced,’’ he asserted. In men ‘‘premature deterio-
ration can be fought against,’’ and in women ‘‘rejuvenating
effects’’ can be produced.
23
The practical outcomes of this intertwined research into
rejuvenation, prolongation of life, and improved sexual
function were significant. Steinach made pioneering con-
tributions for determining the general role of physiological
sex hormones in the human organism, particularly their role
for developing primary and secondary sex characteristics,
using sex gland transplantation or ‘‘reactivation’’ of sexual
function.
24
The techniques used in his rejuvenation experi-
ments (such as transplantation and duct ligation) became
reliable methods to establish the function of particular en-
docrine glands. For example, in the extraction of insulin in
1921 by the Canadian researchers Frederick Banting and
Charles Best for the treatment of (senile) diabetes, these
investigators applied on the pancreas ‘‘a surgical procedure
corresponding in principle to [Steinach’s] already well-
known vasoligature (or vasoligation).’’
25
Yet another implication was the foundation for later ‘‘sex
change’’ operations. The first male-to-female ‘‘sex re-
assignment surgery’’ was performed on Lili Elbe (b. Einar
Wegener, 1882–1931) in 1930 in Dresden, Germany, by
Magnus Hirschfeld and Kurt Warnekros, Steinach’s fol-
lowers.
26
But perhaps the most significant practical contri-
bution of Steinach’s work was for the wide spread of
surgical reproduction control—vasoligation and vasectomy
in men and fallopian tube ligation in women—after Steinach
and his followers performed thousands of such operations in
Europe and across the world, accompanied by wide and
often sensationalist publicity. By the beginning of the 21
st
century, over 50 million men and 200 million women had
undergone such procedures worldwide.
27
Following these experiments, Steinach was nominated for
a Nobel Prize in 1922 for the ‘‘work on transplantation of
reproductive glands and particularly on rejuvenation.’’ In
fact, Steinach was nominated for the Nobel Prize 11 times,
from 1921 to 1938, mainly for ‘‘work on the functions of the
reproductive glands,’’ but only in 1922 he was nominated
with specific reference to ‘‘rejuvenation.’’
28
Yet, ‘‘rejuve-
nation’’ was the root and main stem of Steinach’s studies, as
asserted in Steinach’s book concluding his life’s work: Sex
and Life; Forty Years of Biological and Medical Experi-
ments (1940). That book also defended Steinach’s priorities
in developing endocrinological techniques and determining
the roles of sex hormones.
As is common in the history of medicine, the question of
priorities was not unequivocal. Transplantations of sex
glands had already been performed in animals in the 18
th
century by the British surgeon John Hunter (1728–1794).
29
And vasoligation and vasoresection were apparently among
the first actively used for the sterilization of prisoners at the
Indiana Reformatory at Jeffersonville, in 1899 by Harry Clay
Sharp (1870–1940) to fight ‘‘sexual over-excitement’’ of the
inmates. Still, these earlier instances support the main argu-
ment of the present article, namely that practical biomedical
techniques and therapies have been born from rejuvenation
and life extension research. Thus, Hunter attentively consid-
ered age-related changes in vitality. And Sharp too, in his
procedure, had rejuvenation in mind, reporting an increase in
the inmates’ vitality, which was attributed to the retention of
the seminal fluid following the vasectomy. In fact, Sharp
explicitly quoted the studies on testicular extracts by earlier
rejuvenators—Drs. Brown-Se
´quard (1889, France), Poehl
(1890, Russia) and Zath (1896, United States)—as providing
direct theoretical support for the invigorating effects of his
operation.
30
Yet, Steinach’s rejuvenation studies, employing
vasoligation, strongly contributed to perfecting the techniques
of reproductive control and their global dissemination.
Tissue Transplantations in Humans (Allografts and
Xenografts) Were First Widely Performed in Serge
Voronoff’s ‘‘Rejuvenation by Grafting’’ Experiments
(c. 1910s–1920s)
A technique related to Steinach’s operation was advanced
by the Parisian physician Serge Voronoff (1866–1951). Like
Steinach, he chiefly operated on sex glands. Yet unlike
Steinach’s preferred ‘‘autoplastic’’ approach (rearranging
parts in the organism for its stimulation), Voronoff valorized
‘‘homoplastic/heteroplastic’’ methods that involved true
supplementation, or replenishment of deficits to maintain
body balance. His key method was the introduction into the
host of additional reserve materials via sex gland tissue
transplantation or, as Voronoff termed it, ‘‘rejuvenation by
grafting.’’ (Notably, Steinach also performed sex glad
transplantations, mainly in animals; in fact, he was one of
the pioneers of the technique. Yet Voronoff gave it a much
stronger boost and notoriety.)
After testing the technique in animal models for 7 years,
in 1920 Voronoff started male sex gland tissue transplan-
tations in humans for the explicit purpose of rejuvenation
and life prolongation. Between 1920 and 1923, 52 such
testicular grafting operations were performed: In one case
the graft was taken from man (a homograft), and in all the
other cases from apes (xenografts).
31
In 1930, Voronoff
reported 475 cases of testes transplantations from apes
(mainly chimpanzees).
32
Thus, Voronoff made one of the
first wide demonstrations of live tissue transplantation into
humans, and a first of its kind massive attempt at xeno-
transplantation from apes to humans.
Voronoff’s contribution may have been not so much in
terms of originality, as in terms of development and pro-
motion. Indeed, the idea of organ transplantation is old.
Transplantations are mentioned in the ancient Chinese leg-
ends of Bian Que,
33
the Indian epic of the Ramayana,
34
and
the Christian legends about Saints Cosmas and Damian.
35
Actual methods of skin transplantation to adhere severed
earlobes and restore mutilated noses are described in the
ancient Indian medical treatise Sushruta Samhita.
36
Since
then, transplantations of various organs and tissues had been
attempted up to Voronoff’s times (of particular note are
Alexis Carrel’s experiments on immortalization, see below).
The idea of transplanting sex glands in particular was not
new either. Voronoff himself listed over 30 researchers who
300 STAMBLER

performed such transplantations before or at the same time
as he did; almost all of them were rejuvenators employing
transplantation for the purposes of life extension. Voronoff
did not seem bothered by priority disputes and asserted that
science is a cumulative, collective enterprise and that ‘‘what
is new in the idea is its practical application.’’
37
And indeed,
in application, in terms of the numbers of operations per-
formed and publications spawned, Voronoff was an un-
doubted leader, making transplantation, and particularly
xenotransplantation, a familiar topic across the world. The
prominence of his work is demonstrated in Nathan Shock’s
Classified Bibliography of Gerontology and Geriatrics. The
bibliography lists about 300 works on ‘‘rejuvenation’’
published from 1900 to 1960, including about 150 specifi-
cally referring to ‘‘sex glands and hormones.’’ Nearly all of
these works refer to the studies by Steinach and Voronoff.
Also, in the bibliography, the overlap of authors listed in the
sections on ‘‘rejuvenation’’ (most often comprising avowed
followers of Steinach and Voronoff) and authors on the
‘‘endocrine system’’ is very considerable.
38
Clearly, Voronoff’s tissue replacement operations were
problematic, involving the high likelihood of tissue rejection,
the possibility of infection and overstimulation (short-term
invigoration followed by rapid exhaustion and deterioration),
as well as the possible influences of psychosomatic or au-
tosuggestion factors on the results. Voronoff, however, ac-
ted on the state-of-the-art knowledge of his time, according
to which people and chimpanzees appeared morphologically
and immunologically close enough to make transplantations
possible. No tissue rejection was expected, and, of course,
only apparently healthy specimens were selected for trans-
plantation. Furthermore, Voronoff took great pains to rule
out autosuggestion as well as the possibility of overstimu-
lation.
39
Thus, any drawbacks might be attributed to con-
temporary imperfections of knowledge and technique, rather
than to malice or lack of rigor. Despite the drawbacks,
these rejuvenation studies strongly contributed to introduc-
ing the idea of live tissue transplantation into wide clinical
practice.
Tissue Engineering Was Pioneered During Alexis
Carrel’s Work on Cell And Tissue Immortalization
(c. 1900–1920)
Both Steinach’s and Voronoff’s operations might (self-
admittedly) have been impossible without the developments
in blood vessel suturing (anastomosis) done by the French-
American physician Alexis Carrel (1873–1944) that enabled
the integral connection of body parts during surgery, in
particular during transplantation. Carrel’s initial success
earned him the Nobel Prize in Physiology or Medicine of
1912 ‘‘in recognition of his work on vascular suture and the
transplantation of blood vessels and organs.’’
40
(Concurrent
work on blood vessels suture was done by Mathieu Jaboulay
of Lyon and Emerich Ullmann of Vienna.) Using the per-
fected anastomosis techniques (including asepsis and trian-
gulated suture on all the layers of the vessels), from the early
1900s Carrel pioneered the transplantation of kidneys,
limbs, thyroid, ovaries, and heart in animals. These were
essential contributions for the development of transplanta-
tion surgery, including ‘‘rejuvenation by grafting.’’ The
underlying idea was that body parts could be replaced as
they wear out, just as the worn-out parts of a machine could
be replaced for its sustained maintenance.
In Carrel’s vision, tissues and organs for transplantation
could be artificially grown. For that purpose, around 1910,
he started a series of experiments on growing tissues, at-
tempting to find the culture medium conditions and stimu-
lants for their speedy regeneration and indefinite maintenance
and growth, thus pioneering the field of tissue engineering.
His famous experiment on culturing the chicken embryonic
heart tissue was started in 1912.
41
That tissue culture (in fact,
composed of fibroblast connective tissue, rather than muscle
tissue) was maintained in continuous growth by Carrel’s as-
sistant Albert Ebeling until 1946. Thus, the longevity of the
tissue seemed to exceed many times the life span of the
organism from which it was taken. The tissue culture ap-
peared to be potentially immortal, and hence seemingly ca-
pable of indefinite use for transplantation.
This tenet about the tissue ‘‘potential immortality’’ was
disputed in the 1960s, with the publication of ‘‘Hayflick’s
limit,’’ positing that normal somatic cells can only undergo
a limited number of divisions, and thus inescapably age and
die. Carrel’s findings of cells’ apparent immortality were
explained by Leonard Hayflick as due to the introduction of
fresh cells into the culture,
42
perhaps even intentionally, as
alleged by the historian of biology Jan Anthony Witkowski.
43
Still, the existence of ‘‘cellular immortality’’ of some cell
types and under certain conditions, e.g., malignancy, has been
well recognized (also by Hayflick). Regardless this debate,
the idea to culture and manipulate the growth of organs and
tissues was quite novel and can be considered one of the
foundations of modern tissue engineering, initiated during
the study of ‘‘immortalization.’’
Even though growing entire organs was not feasible at the
time, Carrel succeeded in maintaining existing organs out-
side of the body. He began this research in 1912 with sus-
taining a ‘‘visceral organism’’—a system of animal heart,
lungs, liver, stomach, intestines, and kidneys—in an artifi-
cial medium. But the highest success was achieved in the
1930s, thanks to the development of the ‘‘perfusion pump’’
(in collaboration with Charles Lindbergh) that was capable
of providing a flow of nutrients and oxygen to excised or-
gans. The perfusion apparatus (the ‘‘Lindbergh pump’’) was
perfected by 1935, applying a more ‘‘natural’’ pulsating
pressure to circulate the perfusion fluid, and having effec-
tively solved the problem of infection by using a sterile,
filtered system of air and nutrient medium supply to the
organs. A wide variety of organs were thus maintained—
heart, kidney, spleen, pancreas, fallopian tubes, thyroid, and
more.
44
This system was an essential step in a series of
developments that eventually led to the creation of ‘‘heart-
lung’’ and ‘‘dialysis’’ machines, making open-heart surgery
possible, and generally enabling the maintenance of organs
for transplantation.
But Carrel’s vision extended further, directly relating to
anti-aging research. In his foundational work on The Culture
of Organs of 1938, Carrel gives the following descriptions
of ‘‘the ultimate goal’’ of this research. Using out-of-body
organs, natural, non-rejectable bio-pharmaceuticals can be
manufactured. Furthermore, diseased organs can be removed
from the body, treated, and then re-implanted.
45
And perhaps
crucially, by examining extra-corporeally cultured organs, the
optimal nutrition requirements can be established for each
FROM LIFE EXTENSION STUDIES TO MODERN THERAPIES 301

organ, and these needs can be provided to achieve the organs’
optimal growth, regeneration, and organic equilibrium within
the body. Not only could worn-out parts of the body be re-
moved, treated, and replaced, but the aging process of each
and every organ could be understood and countered through
appropriate nutrition. Carrel announced
46
:
A new era has opened. Now anatomy is capable of appre-
hending bodily structures in the fullness of their reality, of
understanding how the organs form the organism, and how
the organism grows, ages, heals its wounds, resists disease,
and adapts itself with marvelous ease to changing envi-
ronment. The ultimate goal of the culture of organs is to
obtain this new knowledge and to pursue it through the
complexity of its unpredictable consequences.
An additional line of Carrel’s research concerned tissue
and organ preservation. The preservation of organs for
transplantation was vital, and Carrel was among the first to
achieve this by cold storage of blood vessels and entire
organs. In an article of 1908 regarding ‘‘transplantation of
vessels and organs,’’ he considered in detail both tissue
preservation by freezing (cold storage) and chemical pres-
ervation (desiccation and chemical arrest of metabolic ac-
tivity, e.g., using calcium chloride).
47
Carrel conducted a
series of experiments with long-term drying and reviving of
small animals, mostly rotifers. Speculations abounded, fos-
tered by Carrel himself, about a possible future induc-
tion of a similar ‘‘resting state’’ in humans, perhaps to
preserve them for centuries.
48
Concurrently, experiments on
the preservation of tissues and small animals were per-
formed by Carrel’s colleagues at the Rockefeller Institute
for Medical Research in New York, Jacques Loeb (1859–
1924) and Loeb’s doctoral student, the future Nobel Laureate
in chemistry John Howard Northrop (1891–1987).
49
Slightly earlier, such experiments were done by the Russian
biologist Porfiry Bakhmetiev (1860–1913) who was appar-
ently the first to achieve suspended animation (anabiosis)
in animals (bats) by freezing.
50
In all of those studies, the
prolongation of life was the explicit purpose. Thus, it can be
seen that the development of tissue preservation and cryo-
biology also received a strong impetus from life extension
research.
Notably, Carrel was quite skeptical of previous rejuve-
nation attempts as well as wary of the possible negative
social implications of extending longevity without a parallel
improvement in the quality of life. The skepticism and
caution, however, did not mean a disbelief in the possibility
of life prolongation or rejuvenation or readiness to abandon
longevity research. Far from it, ‘‘we can believe that a
partial reversal of physiological time will become realiz-
able’’ Carrel insisted. Some methods of rejuvenation could
include implanting ‘‘glands of a stillborn infant and the
blood of a young man’’ according to him. ‘‘With the aid of
the methods already existing, and of those which will be
discovered, we must pursue the search for the great se-
cret.’’
51
‘‘A better knowledge of the mechanisms of physi-
ological duration,’’ obtained through empirical studies of
heredity and environment, nutrition and lifestyle, ‘‘could
bring a solution of the problem of longevity.’’
52
Thus, in
Carrel’s writings, the subjects of combating aging, rejuve-
nation, longevity, life extension, and perhaps above all tis-
sue ‘‘immortalization’’ appear to be some of the chief
concerns and motivations for his work, out of which many
developments in cell, tissue, and organ culturing and ma-
nipulation were born.
Cell Therapy (and Particularly Human Embryonic
Cell Therapy) Was First Widely Conducted by Paul
Niehans for the Purposes of Rejuvenation As Early
As the 1930s
There has been a persistent integral connection between
transplantation of organs and tissues (replacing body parts)
and the studies of rejuvenation and life extension, from
Hunter to Carrel. Yet the forms and methods of tissue re-
placement have been perfected continuously. An additional
boost to the development of tissue replacement therapy was
given by the Swiss rejuvenator Paul Niehans (1882–1971).
Niehans became interested in endocrine rejuvenation
methods in the late 1920s, and in the early 1930s developed
his own method, the cell therapy (Zellular-therapie). In 20
Jahre Zellular-Therapie (Twenty Years of Cell Therapy,
1952), Niehans described the gist of his method
53
:
The new healing method, that today may still seem revolu-
tionary, employs specific embryonic or youthful fresh cells,
cell cultures, conserved cells or cell-rich liquids, to treat the
sufferings against which contemporary medical art had been
powerless.
In 1952, 3000 injections of about 10 cm
3
of cell suspen-
sion were reported, with no anaphylactic or other adverse
reactions. The mechanism of action was unclear, yet the
results appeared positive:
Whether the injected fresh cells travel to their targets or are
degraded on the spot by the organism to produce the
building blocks necessary for its healing, is a question that
must be answered by a physiologist and not by a physician.
One thing is clear: Cell Therapy promotes the regeneration
of damaged cells, until reaching a necessary quantitative
activity threshold. Beyond that physiological threshold,
there is no activity; therefore the introduced cells can cause
no damage.
For diagnosis, Niehans extensively used the method de-
veloped by the Swiss-born biochemist Emil Abderhalden
(the ‘‘Abderhalden reaction’’), determining the levels of
protein degradation in particular organs and tissues. After
the organ diagnosis, Niehans injected the patients with cell
suspensions from corresponding organs. Thus, cell therapy
was applied to regenerate the nervous system—the brain
cortex, the middle brain, thalamus, and hypothalamus, etc.
(Niehans noted that contrary to the dominant conviction that
nerve cells do not regenerate, his practice showed that they
can indeed undergo some degree of regeneration.) Success
was reported in the treatment of blindness, deafness, and
idiocy. Dysfunctions of endocrine glands—pituitary, thy-
roid, parathyroid, thymus, pancreas, adrenals, and sex
glands—were treated by cells from corresponding organs.
The same was done for the heart, liver, intestinal mucosa,
the reticulo-endothelial system, bones (using injections of
osteoblasts), bone marrow, kidneys, etc. Injections of pla-
cental tissue and ‘‘cell-rich’’ blood, particularly enriched
fractions of leukocytes, were among the favorite treatments.
Niehans believed that cell therapy could be applied
against virtually all chronic organic diseases, including
302 STAMBLER

cancer. But its major purpose was rejuvenation proper, the
‘‘mitigation of the deterioration of aging.’’ According to
Niehans, ‘‘premature senescence is a pathological problem,
which can be in a large degree solved through the revi-
talization of damaged organs, particularly the sex glands.’’
In Niehans’s view, ‘‘youthful cells serve the tired, the ill,
the old, and the weak. Here science bestows on us a new
capital of life. Many valuable people thus avoid a dis-
abled existence and enjoy life afresh, overcoming their
depressions.’’
54
As Niehans’s reports make us understand, the cells for
treatments were obtained from domestic animals, either
animal fetuses (whose cells were believed to be the least
rejectable or the least toxic) or young animals (in case par-
ticular organs were not sufficiently developed in the fetus).
Sheep were the donors of choice (as they were believed to
be the most resistant to diseases). Yet, Niehans let it surface
that in some cases human embryonic cells, most likely from
abortions, were used. Thus ‘‘cell cultures of the pancreas of
a human fetus’’ were injected to Herr F.A., born 1894,
suffering from diabetes mellitus.
55
(For Niehans, the use of
such tissues did not seem to raise any ethical concerns
whatsoever.) Thus, Niehans may be well considered as one of
the primary instigators of ‘‘regenerative cell therapy’’ in
general and ‘‘embryonic stem cell therapy’’ in particular.
Today these therapies are among the most hotly debated
fields of biomedical research, both in terms of their potential
efficacy and ethical implications. Some 70–80 years after
Niehans’s first attempts, the promise of these therapies is yet
to be validated, much ‘‘further research’’ being needed.
56,57
Yet another ramification from Niehans’s cell therapy may
have been ‘‘gene therapy.’’ Niehans preferred to use fresh
cells for his treatments, but lyophilized cells (dried by
freezing in vacuum) were prepared for shipments. However,
some of Niehans’s disciples in the 1960s, such as the
German Wolfgang Goetze-Claren and the British Peter
Stephan, in place of using entire cells, sought to extract their
active, rejuvenating ingredients. DNA and RNA seemed to
be likely candidates, so they were extracted and adminis-
tered, giving rise to ‘‘gene/genetic therapy.’’
58
Of course,
those methods of ‘‘gene therapy’’ were rather crude, using
direct ingestion or injection of DNA/RNA extracts, without
employing any sophisticated viral transmission vectors that
are tried today. Yet, they did carry the title of ‘‘gene ther-
apy.’’ As with ‘‘regenerative cell therapy,’’ ‘‘gene therapy’’
is still in research and development.
59
Also considering the ‘‘cell therapy’’ or ‘‘stem cell ther-
apy,’’ the question of priority is difficult to settle conclu-
sively. An early precursor of the stem cell concept was the
supposition of 1875 by the German researcher Julius Frie-
drich Cohnheim (1839–1884) about the origin of cancer
from residual embryonic cells.
60
The very concept of ‘‘stem
cells’’ was introduced by the Russian physician Alexander
Maximov (1874–1928) in 1909, during his work on blood
formation (hematopoiesis) at St. Petersburg Military Medi-
cal Academy.
61
Moreover, cell therapy by injection was
attempted by the surgeon Hermann Ku
¨ttner of Breslau
(Wroclaw, Poland) in 1912.
62
Nonetheless, the first wide
application and promotion of cell therapy can be undoubt-
edly attributed to Paul Niehans (in a large degree, thanks to
his well-organized industrial and commercial operation, and
advertisements gained from treatments of celebrities such as
Winston Churchill, Charles de Gaulle, and Pope Pius XII). It
is of course necessary to note that the efficacy of Niehans’s
treatments was far from being generally proven or ac-
knowledged, to say the least. The possibility of transplanted
cell lysis in a non-histocompatible host and placebo effects
were highly likely. Even Niehans’s own descriptions of the
results (such as ‘‘suffering disappears’’) were rather vague.
Nonetheless, Niehans’s contribution to the development and
spread of the fields now known as ‘‘cell therapy,’’ ‘‘em-
bryonic stem cell therapy,’’ and ‘‘regenerative medicine’’
generally—born of rejuvenation research—must be recognized.
Conclusions
As the examples above show, several practically signifi-
cant fields of medicine originated in rejuvenation and life
extension research. There might be several potential expla-
nations as to why the specific therapies emerged in such
seemingly unrelated and generalized studies. One explana-
tion may be simply the nature of goal setting. When setting
the goal of achieving healthy longevity, the researchers
strove to approximate that goal and by it measured their
successes and failures. Thus, while ‘‘aiming high,’’ they
may have been bound to achieve at least some results, even
though most often falling short of the original aspirations.
The situation may not have been dissimilar to that of al-
chemy, which, while seeking perfect control over matter and
life and not achieving it, was at least able to lay down the
foundations of modern chemistry and pharmacology.
63
Another explanation may have to do with the specific
mindset that may have been involved in rejuvenation and
life extension research. Because the purpose of such re-
search was to maintain the life of the organism in a youthful
functional state for as long as possible, then of necessity
more attention was paid to the workings of the organism as a
whole, to the interrelation of its components, rather than to
individual disconnected details and symptoms. The degen-
erative aging processes are evidently the root cause of
many chronic age-related diseases.
64
Therefore, by learning
to tend to the root, ways were found to tend to the entire
organism more effectively than by treating branches ex-
clusively. Also, more attention was paid to long-term
durability rather than to short-term improvements in per-
formance and momentary sense of well-being. The emphasis
on constancy, reliability, stability, balance, or sustainability
was pervasive in those studies. Indeed, ‘‘equilibrium’’ was
the key term in the writings of all the researchers discussed
so far, from Brown-Sequard to Niehans. (The term ‘‘ho-
meostasis’’ became entrenched later, following the work of
the Harvard physiologist, board member of the American
Life Extension Institute, Walter Cannon [1871–1945],
which was also strongly related to longevity research.
65
)
With such a mindset bent on sustainability and balance,
new therapies may have been likely to be born and devel-
oped. There are grounds to expect that additional novel
therapies will continue to be born and developed in the future
if the sustainability mindset and the pursuit of rejuvenation
and life extension are not depleted of encouragement.
Author Disclosure Statement
No competing financial interests exist.
FROM LIFE EXTENSION STUDIES TO MODERN THERAPIES 303

References
1. Hayflick L. How and Why We Age. Ballantine Books, New
York, 1994, p. 338.
2. Comfort A. The Biology of Senescence. Butler & Tanner,
London, 1956, p. 191.
3. Stambler I. ‘‘A History of Life-Extensionism in the Twentieth
Century.’’ PhD Dissertation. Bar-Ilan University, Ramat Gan,
Israel, 2012. Available at www.longevityhistory.com/
4. Hamilton D. The Monkey Gland Affair. Chatto and Windus,
London, 1986.
5. Hayflick L. ‘Anti-aging’ is an oxymoron. J Gerontol A Biol
Sci Med Sci 2004;59:B573–B578.
6. Shock NW, ed. A Classified Bibliography of Gerontology
and Geriatrics. Stanford University Press, Stanford, Cali-
fornia, 1951, 1957, 1963, reprinted in 1980.
7. Gardner TS. The design of experiments for the cumulative
effects of vitamins as anti-aging factors. J Tenn Acad Sci
1948;23:291–306.
8. Fishbein M. The Medical Follies. An Analysis of the Foi-
bles of Some Healing Cults, Including Osteopathy, Ho-
meopathy, Chiropractic, and the Electronic Reactions of
Abrams, with Essays on the Antivivisectionists, Health
Legislation, Physical Culture, Birth Control, and Re-
juvenation. Boni and Liveright, New York, 1925.
9. Unschuld PU. Huang Di Nei Jing Su Wen: Nature, Knowl-
edge and Imagery in an Ancient Chinese Medical Text.
University of California Press, Berkeley, CA, 2003, p. 286.
10. Bhishagratna KKL, ed. An English translation of the Sus-
hruta samhita, based on original Sanskrit text. Calcutta,
1907, 1911, 1916, Vol. 2, Chikitsasthanam (Therapeutics),
ch. 26, p. 512.
11. Brown-Se
´quard CE. Des effets produits chez l’homme par
des injections sous-cutane
´es d’un liquide retire
´des testi-
cules frais de cobaye et de chien (Effects in man of sub-
cutaneous injections of freshly prepared liquid from guinea
pig and dog testes). Comptes Rendus des Se
´ances de la
Socie
´te
´de Biologie 1889;Se
´rie 9,1:415–419. Reprinted and
translated in: Emerson GM, ed. Benchmark Papers in
Human Physiology, Vol. 11, Aging. Dowden, Hutchinson
and Ross, Stroudsburg, Pennsylvania, 1977, pp. 68–76.
12. Brown-Se
´quard CE. Du Role Physiologique et The
´rapeu-
tique d’un suc extrait de testicules d’animaux d’apre
`s
nombre de faits observes chez l’homme (The physiological
and therapeutic role of animal testicular extract based on
several experiments in man). Archives de Physiologie
Normale et Pathologique 1889;1:739–746. Reprinted and
translated in: Emerson GM, ed. Benchmark Papers in
Human Physiology, Vol. 11, Aging. Dowden, Hutchinson
and Ross, Stroudsburg, Pennsylvania, 1977, pp. 92–105.
13. Romeis B. Altern und Verju
¨ngung. Eine Kritische Darstellung
der Endokrinen ‘‘Verju
¨ngungsmethoden’’, Ihrer Theore-
tischen Grundlagen und der Bisher Erzielten Erfolge (Aging
and Rejuvenation. A Critical Presentation of Endocrine ‘‘Re-
juvenation Methods’’, Their Theoretical Foundations and Up-
to-Date Successes). Verlag von Curt Kabitzsch, Leipzig, 1931,
p. 1948.
14. Global Industry Analysts. The global market for hormone
replacement therapy (HRT) is forecast to reach US$3.04
billion by the year 2017. PRWEB, San Jose, California,
October 6, 2011.
15. The Nobel Prize in Physiology or Medicine 1908: Ilya
Mechnikov, Paul Ehrlich. www.nobelprize.org/nobel_
prizes/medicine/laureates/1908/
16. Metchnikoff E. Etudy o Prirode Cheloveka (Etudes On the
Nature of Man). Izdatelstvo Academii Nauk SSSR (The
USSR Academy of Sciences Press), Moscow, 1961 (first
published in 1903), ch. 12, Obshy obzor i vyvody (General
review and conclusions), p. 242.
17. Metchnikoff E. Sorok Let Iskania Razionalnogo Mir-
ovozzrenia (Forty Years in Search of a Rational World-
view), 1914. In: Vasezky GS, ed. I.I. Metchnikoff.
Academicheskoe Sobranie Sochineniy (Elie Metchnikoff.
Academic Collected Works). Academia Medizinskikh
Nauk SSSR (The USSR Academy of Medical Sciences),
Moscow, 1954, vol. 13, pp. 9–22.
18. Walford RL. Beyond the 120-Year Diet: How to Double
Your Vital Years. Four Walls Eight Windows, New York,
2000.
19. Baek YJ, Lee BH. Probiotics and prebiotics as bioactive
compounds in dairy products. In: Park YW, ed. Bioactive
Components in Milk and Dairy Products. Wiley-Blackwell,
Hoboken, New Jersey, 2009, pp. 287–310.
20. Transparency Market Research. Global Probiotics Market
is Expected to Reach USD 44.9 Billion in 2018. PRWEB,
Albany, New York, August 18, 2013.
21. Metchnikoff E. The Nature of Man: Studies in Optimistic
Philosophy, translated by P.C. Mitchell. Putnam, New
York, 1903, pp. 245–246.
22. Bogomolets A. The Prolongation of Life, translated by
Peter V. Karpovich and Sonia Bleeker. Essential Books,
Duel, Sloan and Pearce, New York, 1946, pp. 89–93.
23. Steinach E. Verju
¨ngung durch experimentelle Neubelebung
der alternden Puberta
¨tsdru
¨se (Rejuvenation by Experi-
mental Revitalization of the Aging Puberty Gland).
Springer, Berlin, 1920, pp. 60, 63.
24. Steinach E, Loebel J. Sex and Life; Forty Years of Biolo-
gical and Medical Experiments. Faber, London, 1940, pp.
61–72.
25. Steinach E, Loebel J. Sex and Life; Forty Years of Biological
and Medical Experiments. Faber, London, 1940, p. 56.
26. Herrn R. Schnittmuster des Geschlechts: Transvestitismus
und Transsexualita
¨t in der fru
¨hen Sexualwissenschaft
(Sex Patterns: Transvestism and transsexualism in the
early sexology). Psychosozial Verlag, Giessen, 2005, pp.
204–211.
27. United Nations Department of Economic and Social
Affairs. World Contraceptive Use 2005. New York, 2005.
Avaialble at www.un.org/esa/population/publications/
contraceptive2005/WCU2005.htm
28. The Official Web Site of the Nobel Prize. The Nomination
Database for the Nobel Prize in Physiology or Medicine,
1901–1953. Available at http://nobelprize.org/nobel_prizes/
medicine/nomination/database.html
29. Hamilton D. A History of Organ Transplantation: Ancient
Legends to Modern Practice. Pittsburgh University Press,
Pittsburgh, PA, 2012, pp. 31–48.
30. Sharp HC. Vasectomy as a means of preventing procreation
in defectives. J Am Med Assoc 1909;53:1897–1902.
31. Voronoff S. Rejuvenation by Grafting (Imianitoff FF,
translator). George Allen and Unwin Ltd, London, 1925,
p. 37.
32. Voronoff S, George Alexandrescu. La greffe testiculaire du
singe a
`l’homme (Testicular grafts from apes to men). Doin,
Paris, 1930.
33. Giles L. Taoist Teachings. Translated from the book of
Lieh-Tzu
¨with Introduction and Notes by Lionel Giles. J.
Murray, London, 1912, pp. 81–83.
304 STAMBLER

34. Griffith RTH (translator). Ramayan of Valmiki, Book 3,
Cantos 18–19. EJ Lazarus an Co., Benares, 1895, pp. 251–253.
35. Hayes H. An Anthology of Plastic Surgery. Aspen Pub-
lishers, New York, 1986, pp. 40–41.
36. Bhishagratna KKL, ed. An English translation of the Sus-
hruta samhita, based on original Sanskrit text. Calcutta,
1907, vol. 1, ch. 16, pp. 141–154.
37. Voronoff S. Rejuvenation by Grafting (Imianitoff FF, trans-
lator). George Allen and Unwin Ltd., London, 1925, p. 32–34.
38. Shock NW, ed. A Classified Bibliography of Gerontology
and Geriatrics. Stanford University Press, Stanford, CA,
1951, 1957, 1963, reprinted in 1980.
39. Voronoff S. Rejuvenation by Grafting (Imianitoff FF,
translator). George Allen and Unwin Ltd, London, 1925,
pp. 29, 36, 45–51.
40. The Nobel Prize in Physiology or Medicine 1912: Alexis
Carrel. Available at www.nobelprize.org/nobel_prizes/
medicine/laureates/1912/
41. Carrel A. On the permanent life of tissues outside of the
organism. J Exp Med 1912;15:516–528.
42. Hayflick L. The limited in vitro lifetime of human diploid
cell strains. Exp Cell Res 1965;37:614–636.
43. Witkowski JA. Dr. Carrel’s immortal cells. Med Hist
1980;24:129–142.
44. Carrel A, Lindbergh C. The Culture of Organs. Paul
B. Hoeber, New York, 1938, pp. 87–105.
45. Carrel A, Lindbergh C. The Culture of Organs. Paul
B. Hoeber, New York, 1938, pp. 219–221.
46. Carrel A, Lindbergh C. The Culture of Organs. Paul B.
Hoeber, New York, 1938, p. 221.
47. Carrel A. Further studies on transplantation of vessels and
organs. Proc Am Phil Soc 1908;47:677–696.
48. Venzmer G. Lang leben und jung bleiben! (Live long and
stay young!). Franckh’sche Verlagshandlung, Stuttgart,
1941, pp. 18–19.
49. Loeb J, Northrop JH. What determines the duration of life
in metazoan. Proc Natl Acad Sci USA 1917;3:382–386.
50. Bakhmetiev PI. Kak ya nashel anabioz u mlekopitayushikh
(How I discovered anabiosis in mammals). Priroda (Nature–
Moscow) 1912;1:606–622.
51. Carrel A. Man, The Unknown. Burns & Oates, London, 1961
(1935), pp. 147–148.
52. Carrel A. Man, The Unknown. Burns & Oates, London,
1961 (1935), pp. 144–145.
53. Niehans P. 20 Jahre Zellular-Therapie (Twenty Years of
Cell Therapy). Verlag Urban & Schwarzenberg, Berlin-
Mu
¨nchen-Wien, 1952, p. 1.
54. Niehans P. 20 Jahre Zellular-Therapie (Twenty Years of
Cell Therapy). Verlag Urban & Schwarzenberg, Berlin-
Mu
¨nchen-Wien, p. 15.
55. Niehans P. 20 Jahre Zellular-Therapie (Twenty Years of
Cell Therapy). Verlag Urban & Schwarzenberg, Berlin-
Mu
¨nchen-Wien, pp. 1, 8–9.
56. Atala A. Extending life using tissue and organ replacement.
Curr Aging Sci 2008;1:73–83.
57. Mason C, Brindley DA, Culme-Seymour EJ, Davie NL.
Cell therapy industry: Billion dollar global business with
unlimited potential. Regen Med 2011;6:265–272.
58. McGrady PM. The Youth Doctors. Coward-McCann, New
York, 1968, pp. 109–110.
59. Rattan SI, Singh R. Progress and prospects: Gene therapy in
aging. Gene Ther 2009;16:3–9.
60. Cohnheim J. Congenitales, quergestreiftes Muskelsarkom
der Niere (Congenital sarcoma of striated muscle of the
kidney). Virchows Archiv fu
¨r pathologische Anatomie und
Physiologie und fu
¨r klinische Medizin 1875;65:64–69.
61. Maximow A. Der Lymphozyt als gemeinsame Stammzelle
der verschiedenen Blutelemente in der embryonalen En-
twicklung und im postfetalen Leben der Sa
¨ugetiere (The
lymphocyte as a common stem cell for different blood
elements in embryological development and post-fetal
life of mammals) Folia Haematologica Leipzig 1909;8:
125–134.
62. Ku
¨ttner H. Die Verimpfung anstelle der Transplantation
hochwertiger Organe (Inoculation instead of transplantaiton
of highly valuable tissues). Zentralblatt fu
¨r Chirugie 1912;
1:390–397.
63. Gruman GJ. A History of Ideas about the Prolongation of
Life. The Evolution of Prolongevity Hypotheses to 1800.
Trans Am Phil Soc 1966;56:1–102.
64. Rae MJ, Butler RN, Campisi J, de Grey ADNJ, Finch CE,
Gough M, Martin GM, Vijg J, Perrott KM, Logan BJ. The
demographic and biomedical case for late-life interventions
in aging. Sci Transl Med 2010;2:40cm21.
65. Cannon WB. The Wisdom of the Body. Norton, New York,
1932, p. 302.
Address correspondence to:
Ilia Stambler
Department of Science, Technology, and Society
Bar Ilan University
Ramat Gan 52900
Israel
E-mail: ilia.stambler@gmail.com
Received: November 2, 2013
Accepted: February 13, 2014
FROM LIFE EXTENSION STUDIES TO MODERN THERAPIES 305